JP6483701B2 - Tnf活性のモジュレーターとしてのベンゾトリアゾール誘導体 - Google Patents
Tnf活性のモジュレーターとしてのベンゾトリアゾール誘導体 Download PDFInfo
- Publication number
- JP6483701B2 JP6483701B2 JP2016537530A JP2016537530A JP6483701B2 JP 6483701 B2 JP6483701 B2 JP 6483701B2 JP 2016537530 A JP2016537530 A JP 2016537530A JP 2016537530 A JP2016537530 A JP 2016537530A JP 6483701 B2 JP6483701 B2 JP 6483701B2
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- Prior art keywords
- alkyl
- pyrimidinyl
- methyl
- disorders
- optionally substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 230000000694 effects Effects 0.000 title description 7
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 title description 5
- 125000003354 benzotriazolyl group Chemical class N1N=NC2=C1C=CC=C2* 0.000 title 1
- -1 ethoxycarbonylethyl Chemical group 0.000 claims description 1262
- 125000000217 alkyl group Chemical group 0.000 claims description 278
- 150000001875 compounds Chemical class 0.000 claims description 197
- 125000001424 substituent group Chemical group 0.000 claims description 122
- 239000001257 hydrogen Substances 0.000 claims description 93
- 229910052739 hydrogen Inorganic materials 0.000 claims description 93
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 62
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 59
- 229910052736 halogen Inorganic materials 0.000 claims description 57
- 150000002367 halogens Chemical class 0.000 claims description 57
- 238000011282 treatment Methods 0.000 claims description 51
- 150000002431 hydrogen Chemical class 0.000 claims description 49
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 43
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 42
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 41
- 150000003839 salts Chemical class 0.000 claims description 35
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 34
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 34
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 30
- 125000001153 fluoro group Chemical group F* 0.000 claims description 30
- 125000004043 oxo group Chemical group O=* 0.000 claims description 30
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 208000035475 disorder Diseases 0.000 claims description 25
- 239000012453 solvate Substances 0.000 claims description 23
- PIGFYZPCRLYGLF-UHFFFAOYSA-N Aluminum nitride Chemical compound [Al]#N PIGFYZPCRLYGLF-UHFFFAOYSA-N 0.000 claims description 21
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 19
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 18
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 17
- 208000023275 Autoimmune disease Diseases 0.000 claims description 15
- 150000001204 N-oxides Chemical class 0.000 claims description 14
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 208000027866 inflammatory disease Diseases 0.000 claims description 10
- 230000002757 inflammatory effect Effects 0.000 claims description 10
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 9
- 208000012902 Nervous system disease Diseases 0.000 claims description 9
- 208000025966 Neurological disease Diseases 0.000 claims description 9
- 208000030159 metabolic disease Diseases 0.000 claims description 9
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 9
- 230000000926 neurological effect Effects 0.000 claims description 9
- 230000000771 oncological effect Effects 0.000 claims description 9
- 238000011321 prophylaxis Methods 0.000 claims description 9
- 208000022873 Ocular disease Diseases 0.000 claims description 8
- 208000002193 Pain Diseases 0.000 claims description 8
- 230000003040 nociceptive effect Effects 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- USCRMGNGGKEZAL-UHFFFAOYSA-N 1-[5-[3-[[2-(difluoromethoxy)phenyl]methyl]benzotriazol-5-yl]pyrimidin-2-yl]piperidine-4-carboxylic acid Chemical compound FC(OC1=C(C=CC=C1)CN1N=NC2=C1C=C(C=C2)C=1C=NC(=NC=1)N1CCC(CC1)C(=O)O)F USCRMGNGGKEZAL-UHFFFAOYSA-N 0.000 claims description 2
- FAQDMWBGQDNYKX-UHFFFAOYSA-N 1-[[2-(difluoromethoxy)phenyl]methyl]-6-(2-piperazin-1-ylpyrimidin-5-yl)benzotriazole Chemical compound FC(OC1=C(C=CC=C1)CN1N=NC2=C1C=C(C=C2)C=1C=NC(=NC=1)N1CCNCC1)F FAQDMWBGQDNYKX-UHFFFAOYSA-N 0.000 claims description 2
- NGNNQZSTSMPKES-UHFFFAOYSA-N 1-[[2-(difluoromethoxy)phenyl]methyl]-6-[2-(4-methylsulfonylpiperazin-1-yl)pyrimidin-5-yl]benzotriazole Chemical compound FC(OC1=C(C=CC=C1)CN1N=NC2=C1C=C(C=C2)C=1C=NC(=NC=1)N1CCN(CC1)S(=O)(=O)C)F NGNNQZSTSMPKES-UHFFFAOYSA-N 0.000 claims description 2
- ONFJKYOHMDUEIJ-UHFFFAOYSA-N 4-[5-[3-[[2-(difluoromethoxy)phenyl]methyl]benzotriazol-5-yl]pyrimidin-2-yl]piperazin-2-one Chemical compound FC(OC1=C(C=CC=C1)CN1N=NC2=C1C=C(C=C2)C=1C=NC(=NC=1)N1CC(NCC1)=O)F ONFJKYOHMDUEIJ-UHFFFAOYSA-N 0.000 claims description 2
- 241000255925 Diptera Species 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- CYALFPAIQGCMPZ-UHFFFAOYSA-N 4-[5-[3-[[2-(difluoromethoxy)phenyl]methyl]benzotriazol-5-yl]pyrimidin-2-yl]morpholine Chemical compound FC(F)OC1=CC=CC=C1CN1C2=CC(C=3C=NC(=NC=3)N3CCOCC3)=CC=C2N=N1 CYALFPAIQGCMPZ-UHFFFAOYSA-N 0.000 claims 1
- 125000006588 heterocycloalkylene group Chemical group 0.000 claims 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 77
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 67
- 125000003118 aryl group Chemical group 0.000 description 45
- 125000001072 heteroaryl group Chemical group 0.000 description 45
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 43
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 35
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 description 34
- 238000006243 chemical reaction Methods 0.000 description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 29
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 28
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 27
- 238000000034 method Methods 0.000 description 27
- 125000003282 alkyl amino group Chemical group 0.000 description 26
- 125000000714 pyrimidinyl group Chemical group 0.000 description 26
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 24
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 23
- 239000000543 intermediate Substances 0.000 description 23
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 22
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 22
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 20
- 239000002585 base Substances 0.000 description 20
- 239000000203 mixture Substances 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000013078 crystal Substances 0.000 description 18
- 125000000753 cycloalkyl group Chemical group 0.000 description 18
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 18
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 18
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 17
- 125000004076 pyridyl group Chemical group 0.000 description 17
- 125000005213 alkyl heteroaryl group Chemical group 0.000 description 16
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 16
- 125000002757 morpholinyl group Chemical group 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 125000003831 tetrazolyl group Chemical group 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 239000000651 prodrug Substances 0.000 description 14
- 229940002612 prodrug Drugs 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 13
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 description 12
- 125000002947 alkylene group Chemical group 0.000 description 12
- 125000001246 bromo group Chemical group Br* 0.000 description 12
- 125000000392 cycloalkenyl group Chemical group 0.000 description 12
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 12
- 125000005843 halogen group Chemical group 0.000 description 12
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 12
- 229910052717 sulfur Inorganic materials 0.000 description 12
- 125000001544 thienyl group Chemical group 0.000 description 12
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 11
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 239000003054 catalyst Substances 0.000 description 11
- 229930182480 glucuronide Natural products 0.000 description 11
- 150000008134 glucuronides Chemical class 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 10
- 150000001602 bicycloalkyls Chemical group 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 10
- 150000007529 inorganic bases Chemical class 0.000 description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- 125000000335 thiazolyl group Chemical group 0.000 description 10
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 125000004193 piperazinyl group Chemical group 0.000 description 9
- 125000003386 piperidinyl group Chemical group 0.000 description 9
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 9
- 125000003107 substituted aryl group Chemical group 0.000 description 9
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 9
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 125000002877 alkyl aryl group Chemical group 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- 125000005215 cycloalkylheteroaryl group Chemical group 0.000 description 8
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 8
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 150000007530 organic bases Chemical class 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 125000003373 pyrazinyl group Chemical group 0.000 description 8
- 125000003226 pyrazolyl group Chemical group 0.000 description 8
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 7
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 7
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 7
- 125000006310 cycloalkyl amino group Chemical group 0.000 description 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 7
- 125000001041 indolyl group Chemical group 0.000 description 7
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 7
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000011593 sulfur Chemical group 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- 229910052723 transition metal Inorganic materials 0.000 description 7
- 150000003624 transition metals Chemical class 0.000 description 7
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 6
- 230000001363 autoimmune Effects 0.000 description 6
- 125000000068 chlorophenyl group Chemical group 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 description 6
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 6
- 125000006263 dimethyl aminosulfonyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])S(*)(=O)=O 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 238000002875 fluorescence polarization Methods 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 125000002883 imidazolyl group Chemical group 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 6
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 125000004414 alkyl thio group Chemical group 0.000 description 5
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 5
- 125000000000 cycloalkoxy group Chemical group 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 5
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- 238000002953 preparative HPLC Methods 0.000 description 5
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- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 5
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- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
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- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
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- 208000032839 leukemia Diseases 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 125000002098 pyridazinyl group Chemical group 0.000 description 4
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 4
- 238000003571 reporter gene assay Methods 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
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- 229940068638 simponi Drugs 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229940023144 sodium glycolate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 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 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000004300 thiazolidin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])SC1([H])* 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4192—1,2,3-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D249/18—Benzotriazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Description
(式中、
Eは、共有結合を表し、或いはEは、−S(O)2−又は−N(R5)−を表し、或いはEは、場合によって置換された直鎖状又は分枝状C1〜4アルキレン鎖を表し、
Yは、C3〜7シクロアルキル、アリール、C3〜7ヘテロシクロアルキル又はヘテロアリールを表し、それらの基のいずれも1つ又は複数の置換基により場合によって置換されていてもよく、
R1、R2、R3及びR4は、水素、ハロゲン、シアノ、ニトロ、ヒドロキシ、トリフルオロメチル、トリフルオロメトキシ、−ORa、−SRa、−SORa、−SO2Ra、−SF5、−NRbRc、−NRcCORd、−NRcCO2Rd、−NHCONRbRc、−NRcSO2Re、−N(SO2Re)2、−NHSO2NRbRc、−CORd、−CO2Rd、−CONRbRc、−CON(ORa)Rb、−SO2NRbRc又は−SO(NRb)Rd;又はC1〜6アルキル、C2〜6アルケニル、C2〜6アルキニル、C3〜7シクロアルキル、C4〜7シクロアルケニル、C3〜7シクロアルキル(C1〜6)アルキル、アリール、アリール(C1〜6)−アルキル、C3〜7ヘテロシクロアルキル、C3〜7ヘテロシクロアルキル(C1〜6)アルキル、C3〜7ヘテロシクロアルケニル、C4〜9ヘテロビシクロアルキル、ヘテロアリール、ヘテロアリール(C1〜6)アルキル、(C3〜7)ヘテロシクロアルキル(C1〜6)アルキル−アリール−、ヘテロアリール(C3〜7)ヘテロシクロアルキル−、(C3〜7)シクロアルキル−ヘテロアリール−、(C3〜7)シクロアルキル−(C1〜6)アルキル−ヘテロアリール−、(C4〜7)シクロアルケニル−ヘテロアリール−、(C4〜9)ビシクロアルキル−ヘテロアリール−、(C3〜7)ヘテロシクロアルキル−ヘテロアリール−、(C3〜7)ヘテロシクロアルキル(C1〜6)アルキル−ヘテロアリール−、(C3〜7)ヘテロシクロアルケニル−ヘテロアリール−、(C4〜9)ヘテロビシクロアルキル−ヘテロアリール−又は(C4〜9)スピロヘテロシクロアルキル−ヘテロアリール−を独立に表し、それらの基のいずれも1つ又は複数の置換基により場合によって置換されていてもよく、
R5は、水素又はC1〜6アルキルを表し、
Raは、C1〜6アルキル、アリール、アリール(C1〜6)アルキル、ヘテロアリール又はヘテロアリール(C1〜6)アルキルを表し、それらの基のいずれも1つ又は複数の置換基により場合によって置換されていてもよく、
Rb及びRcは、水素若しくはトリフルオロメチル、又はC1〜6アルキル、C3〜7シクロアルキル、C3〜7シクロアルキル(C1〜6)アルキル、アリール、アリール(C1〜6)アルキル、C3〜7ヘテロシクロアルキル、C3〜7ヘテロシクロアルキル(C1〜6)アルキル、ヘテロアリール若しくはヘテロアリール(C1〜6)アルキルを独立に表し、それらの基のいずれも1つ又は複数の置換基により場合によって置換されていてもよく、或いは
Rb及びRcは、それらの両方が結合している窒素原子と一緒になったとき、アゼチジン−1−イル、ピロリジン−1−イル、オキサゾリジン−3−イル、イソオキサゾリジン−2−イル、チアゾリジン−3−イル、イソチアゾリジン−2−イル、ピペリジン−1−イル、モルホリン−4−イル、チオモルホリン−4−イル、ピペラジン−1−イル、ホモピペリジン−1−イル、ホモモルホリン−4−イル又はホモピペラジン−1−イルを表し、それらの基のいずれも1つ又は複数の置換基により場合によって置換されていてもよく、
Rdは、水素、又はC1〜6アルキル、C3〜7シクロアルキル、アリール、C3〜7ヘテロシクロアルキル若しくはヘテロアリールを表し、それらの基のいずれも1つ又は複数の置換基により場合によって置換されていてもよく、
Reは、C1〜6アルキル、アリール又はヘテロアリールを表し、それらの基のいずれも1つ又は複数の置換基により場合によって置換されていてもよい。)
R1は、ハロゲン若しくはシアノ、又はC1〜6アルキル、C2〜6アルケニル、C2〜6アルキニル、C3〜7シクロアルキル、C4〜7シクロアルケニル、C3〜7シクロアルキル(C1〜6)アルキル、アリール、アリール(C1〜6)アルキル、C3〜7ヘテロシクロアルキル、C3〜7ヘテロシクロアルキル(C1〜6)アルキル、C3〜7ヘテロシクロアルケニル、C4〜9ヘテロビシクロアルキル、ヘテロアリール、ヘテロアリール(C1〜6)アルキル、(C3〜7)ヘテロシクロアルキル(C1〜6)アルキル−アリール−、ヘテロアリール(C3〜7)ヘテロシクロアルキル−、(C3〜7)シクロアルキル−ヘテロアリール−、(C3〜7)シクロアルキル−(C1〜6)アルキル−ヘテロアリール−、(C4〜7)シクロアルケニル−ヘテロアリール−、(C4〜9)ビシクロアルキル−ヘテロアリール−、(C3〜7)ヘテロシクロアルキル−ヘテロアリール−、(C3〜7)ヘテロシクロアルキル(C1〜6)アルキル−ヘテロアリール−、(C3〜7)ヘテロシクロアルケニル−ヘテロアリール−、(C4〜9)ヘテロビシクロアルキル−ヘテロアリール−又は(C4〜9)スピロヘテロシクロアルキル−ヘテロアリール−を表し、それらの基のいずれも1つ又は複数の置換基により場合によって置換されていてもよく、
E、Y、R2、R3及びR4は、上で定義した通りである。
(式中、
アスタリスク(*)は、分子の残りの部分への結合部位を表し、
nは、ゼロ、1又は2であり、
Xは、酸素又は硫黄を表し、
Rfは、水素、C1〜6アルキル又は−CH2CH(OH)CH2OHであり、
Rgは、C1〜6アルキル、トリフルオロメチル、−CH2CH2F、−CH2CHF2、−CH2CF3又は−CF2CF3を表し、
Rhは、水素、シアノ又は−CO2Rdを表し、Rdは、上で定義した通りであり、
Rjは、水素又はハロゲンを表す。)
.4]ヘプタニルピリミジニル、カルボキシ−2−アザスピロ[3.3]ヘプタニル−ピリミジニル、2−オキサ−6−アザスピロ[3.3]ヘプタニルピリミジニル、2−オキサ−6−アザスピロ[3.4]オクタニル−ピリミジニル、2−オキサ−6−アザスピロ[3.5]ノナニルピリミジニル、2−オキサ−7−アザスピロ[3.5]ノナニル−ピリミジニル及び(ジオキソ)(メチル)−2,4,8−トリアザスピロ[4.5]デカニルピリミジニルを含む。
(式中、
R11は、ハロゲン又はシアノを表し、或いはR11は、C1〜6アルキル、C2〜6アルキニル、アリール、C3〜7ヘテロシクロアルキル、C3〜7ヘテロシクロアルケニル、ヘテロアリール、(C3〜7)ヘテロシクロアルキル−(C1〜6)アルキル−アリール−、ヘテロアリール(C3〜7)ヘテロシクロアルキル−、(C3〜7)シクロアルキル−ヘテロアリール−、(C3〜7)シクロアルキル(C1〜6)アルキル−ヘテロアリール−、(C4〜7)シクロアルケニル−ヘテロアリール−、(C4〜9)ビシクロアルキル−ヘテロアリール−、(C3〜7)ヘテロシクロアルキル−ヘテロアリール−、(C3〜7)ヘテロシクロアルキル(C1〜6)アルキル−ヘテロアリール−、(C3〜7)ヘテロシクロアルケニル−ヘテロアリール−、(C4〜9)ヘテロビシクロアルキル−ヘテロアリール−又は(C4〜9)スピロヘテロシクロアルキル−ヘテロアリール−を表し、それらの基のいずれも1つ又は複数の置換基により場合によって置換されていてもよく、
R12は、水素、ハロゲン、トリフルオロメチル又は場合によって置換されたC1〜6アルキルを表し、
R15及びR16は、水素、ハロゲン、シアノ、ニトロ、C1〜6アルキル、トリフルオロメチル、ヒドロキシ、C1〜6アルコキシ、ジフルオロメトキシ、トリフルオロメトキシ、C1〜6アルキルチオ、C1〜6アルキルスルフィニル、C1〜6アルキルスルホニル、アミノ、C1〜6アルキルアミノ、ジ(C1〜6)アルキルアミノ、アリールアミノ、C2〜6アルキルカルボニルアミノ、C1〜6アルキルスルホニルアミノ、ホルミル、C2〜6アルキルカルボニル、C3〜6シクロアルキルカルボニル、C3〜6ヘテロシクロアルキルカルボニル、カルボキシ、C2〜6アルコキシカルボニル、アミノカルボニル、C1〜6アルキルアミノカルボニル、ジ(C1〜6)アルキルアミノカルボニル、アミノスルホニル、C1〜6アルキルアミノスルホニル又はジ(C1〜6)アルキルアミノスルホニルを独立に表し、
Eは、上で定義した通りである。)
リミジニル、カルボキシ−2−アザスピロ[3.3]ヘプタニルピリミジニル、2−オキサ−6−アザスピロ[3.3]ヘプタニル−ピリミジニル、2−オキサ−6−アザスピロ[3.4]オクタニルピリミジニル、2−オキサ−6−アザスピロ[3.5]ノナニル−ピリミジニル、2−オキサ−7−アザスピロ[3.5]ノナニルピリミジニル及び(ジオキソ)(メチル)−2,4,8−トリアザスピロ[4.5]デカニルピリミジニルを含む。
(式中、
Vは、C−R22又はNを表し、
R21は、水素、ハロゲン、ハロ(C1〜6)アルキル、シアノ、C1〜6アルキル、トリフルオロ−メチル、C2〜6アルケニル、C2〜6アルキニル、ヒドロキシ、ヒドロキシ(C1〜6)アルキル、C1〜6アルコキシ、(C1〜6)アルコキシ−(C1〜6)アルキル、ジフルオロメトキシ、トリフルオロメトキシ、トリフルオロエトキシ、カルボキシ(C3〜7)シクロアルキル−オキシ、C1〜6アルキルチオ、C1〜6アルキルスルホニル、(C1〜6)アルキルスルホニル(C1〜6)アルキル、アミノ、アミノ−(C1〜6)アルキル、C1〜6アルキルアミノ、ジ(C1〜6)アルキルアミノ、(C1〜6)アルコキシ(C1〜6)アルキルアミノ、N−[(C1〜6)−アルキル]−N−[ヒドロキシ(C1〜6)アルキル]アミノ、C2〜6アルキルカルボニルアミノ、(C2〜6)アルキルカルボニルアミノ−(C1〜6)アルキル、C2〜6アルコキシカルボニルアミノ、N−[(C1〜6)アルキル]−N−[カルボキシ(C1〜6)アルキル]アミノ、カルボキシ(C3〜7)シクロアルキルアミノ、カルボキシ(C3〜7)シクロアルキル(C1〜6)アルキルアミノ、C1〜6アルキル−スルホニルアミノ、C1〜6アルキルスルホニルアミノ(C1〜6)アルキル、ホルミル、C2〜6アルキルカルボニル、(C2〜6)アルキルカルボニルオキシ(C1〜6)アルキル、カルボキシ、カルボキシ(C1〜6)アルキル、C2〜6アルコキシカルボニル、モルホリニル(C1〜6)アルコキシカルボニル、C2〜6アルコキシカルボニル(C1〜6)アルキル、C2〜6アルコキシカルボニル−メチリデニル、アミノカルボニル、C1〜6アルキルアミノカルボニル、ジ(C1〜6)アルキルアミノカルボニル、アミノスルホニル、C1〜6アルキルアミノスルホニル、ジ(C1〜6)アルキルアミノスルホニル、(C1〜6)アルキル−スルホキシミニル又は[(C1〜6)アルキル][N−(C1〜6)アルキル]スルホキシミニルを表し、或いはR21は、(C3〜7)シクロアルキル、(C3〜7)シクロアルキル(C1〜6)アルキル、(C4〜7)シクロアルケニル、(C4〜9)ビシクロアルキル、(C3〜7)ヘテロシクロアルキル、(C3〜7)ヘテロシクロアルケニル、(C4〜9)ヘテロビシクロアルキル又は(C4〜9)スピロヘテロシクロアルキルを表し、それらの基のいずれも1つ又は複数の置換基により場合によって置換されていてもよく、
R22は、水素、ハロゲン又はC1〜6アルキルを表し、
R23は、水素、C1〜6アルキル、トリフルオロメチル又はC1〜6アルコキシを表し、
E、R12、R15及びR16は、上で定義した通りである。)
(式中、
Tは、−CH2−又は−CH2CH2−を表し、
Uは、C(O)又はS(O)2を表し、
Wは、O、S、S(O)、S(O)2、S(O)(NR5)、N(R31)又はC(R32)(R33)を表し、
−M−は、−CH2−又は−CH2CH2−を表し、
R31は、水素、シアノ(C1〜6)アルキル、C1〜6アルキル、トリフルオロメチル、トリフルオロ−エチル、C1〜6アルキルスルホニル、(C1〜6)アルキルスルホニル(C1〜6)アルキル、ホルミル、C2〜6アルキルカルボニル、カルボキシ、カルボキシ(C1〜6)アルキル、C2〜6アルコキシカルボニル、C2〜6アルコキシカルボニル(C1〜6)アルキル、カルボン酸等配電子体若しくはプロドラッグ部分Ω、−(C1〜6)アルキル−Ω、アミノカルボニル、C1〜6アルキルアミノカルボニル、ジ(C1〜6)アルキルアミノカルボニル、アミノスルホニル又はジ(C1〜6)アルキルアミノ−スルホニルを表し、
R32は、水素、ハロゲン、シアノ、ヒドロキシ、ヒドロキシ(C1〜6)アルキル、C1〜6アルキルスルホニル、ホルミル、C2〜6アルキルカルボニル、カルボキシ、カルボキシ(C1〜6)アルキル、C2〜6アルコキシカルボニル、C2〜6アルコキシカルボニル(C1〜6)アルキル、アミノスルホニル、(C1〜6)アルキル−スルホキシミニル、[(C1〜6)アルキル][N−(C1〜6)アルキル]スルホキシミニル、カルボン酸等配電子体若しくはプロドラッグ部分Ω、又は−(C1〜6)アルキル−Ωを表し、
R33は、水素、ハロゲン、C1〜6アルキル、トリフルオロメチル、ヒドロキシ、ヒドロキシ−(C1〜6)アルキル、C1〜6アルコキシ、アミノ又はカルボキシを表し、
R34は、水素、ハロゲン、ハロ(C1〜6)アルキル、ヒドロキシ、C1〜6アルコキシ、C1〜6アルキルチオ、C1〜6アルキルスルフィニル、C1〜6アルキルスルホニル、アミノ、C1〜6アルキルアミノ、ジ(C1〜6)アルキル−アミノ、(C2〜6)アルキルカルボニルアミノ、(C2〜6)アルキルカルボニルアミノ(C1〜6)アルキル、(C1〜6)アルキル−スルホニルアミノ又は(C1〜6)アルキルスルホニルアミノ(C1〜6)アルキルを表し、
V、E、R5、R12、R15、R16、R23及びΩは、上で定義した通りである。)
(式中、
E、W、R12、R15、R16及びR21は、上で定義した通りである。)
(式中、E、Y、R1、R2、R3及びR4は、上で定義した通りである。)の化合物を亜硝酸塩、例えば、亜硝酸ナトリウムなどのアルカリ金属亜硝酸塩と反応させることを含む方法により調製することができる。
(式中、Y、R1、R2、R3及びR4は、上で定義した通りであり、E1は、共有結合又は場合によって置換された直鎖状若しくは分枝状C1〜4アルキレン鎖を表し、L1は、適切な脱離基を表す。)の化合物と反応させることを含む方法により調製することができる。
(式中、R1、R2、R3及びR4は、上で定義した通りである。)の化合物を亜硝酸塩と、式(III)の化合物及び亜硝酸塩の間の反応について上述した条件と同様の条件下で反応させることにより調製することができる。
(式中、E1、Y、R1、R2、R3、R4及びL1は、上で定義した通りである。)の化合物と、化合物(IV)及び式L1−E1−Yの化合物の間の反応について上述した条件と同様の条件下で反応させることにより調製することができる。
(式中、E1、Y、R1、R2、R3及びR4は、上で定義した通りである。)の化合物と反応させることにより調製することができる。
化合物(A)の調製
下文で「化合物(A)」と呼ぶ1−(2,5−ジメチルベンジル)−6−[4−(ピペラジン−1−イルメチル)フェニル]−2−(ピリジン−4−イル−メチル)−1H−ベンゾイミダゾールは、国際公開第2013/186229号(2013年12月19日公開)の例499に記載されている手順又はそれと同様の手順により調製することができる。
化合物(A)(27.02mg、0.0538mmol)をDMSO(2mL)に溶解した。5(−6)カルボキシ−フルオレセインスクシンイミルエステル(24.16mg、0.0510mmol)(Invitrogenカタログ番号:C1311)をDMSO(1mL)に溶解して、鮮黄色の溶液を得た。2つの溶液を室温で混合したところ、混合物が赤色になった。混合物を室温で撹拌した。混合直後に20μLのアリコートを除去し、1200RR−6140 LC−MSシステムによるLC−MS分析のためにAcOH:H2Oの80:20混合物で希釈した。クロマトグラムは、両方が5−及び6−置換カルボキシフルオレセイン基を有する、形成された2つの生成物に対応する、質量(M+H)+=860.8amuを有する、1.42及び1.50分の保持時間の2つの近接して溶出したピークを示した。2.21分の保持時間のさらなるピークは、化合物(A)に対応する、(M+H)+=502.8amuの質量を有していた。未反応の5(−6)カルボキシフルオレセインスクシンイミルエステルについてはピークは観察されなかった。ピーク面積は、3つのシグナルについて22.0%、39.6%及び31.4%であり、その時点における所望の蛍光コンジュゲートの2つの異性体への変換が61.6%であったことがわかる。さらなる20μLのアリコートを数時間後に、次いで一夜撹拌した後に抜き出し、前のように希釈し、LC−MS分析にかけた。変換百分率は、これらの時点にそれぞれ79.8%及び88.6%と測定された。混合物は、UV指向性分取HPLCシステムにより精製した。プールした精製画分を凍結乾燥して、過剰の溶媒を除去した。凍結乾燥後、0.027mmolの蛍光コンジュゲートに相当し、反応及び分取HPLC精製の53%の総収率に対応する、橙色固体(23.3mg)が回収された。
化合物は、蛍光コンジュゲートの添加及び室温での20時間のさらなるインキュベーションの前に、20mM トリス、150mM NaCl、0.05% Tween 20中で室温で60分間TNFαとともにプレインキュベートすることにより、25μMから始まる5%DMSOの最終アッセイ濃度での10種の濃度で試験した。TNFα及び蛍光コンジュゲートの最終濃度は、25μLの総アッセイ容積でそれぞれ10nM及び10nMであった。プレートは、蛍光偏光を検出することができるプレートリーダー(例えば、Analyst HTプレートリーダー又はEnvisionプレートリーダー)で読み取った。IC50値は、ActivityBaseでXLfit(商標)(4パラメーターロジスティックモデル)を用いて計算した。
TNFα誘導性NF−κB活性化の阻害
TNFαによるHEK−293細胞の刺激は、NF−κB経路の活性化をもたらす。TNFα活性を測定するために用いたレポーター細胞系は、InvivoGenから購入した。HEK−Blue(商標)CD40Lは、5つのNF−κB結合部位に融合させたIFNβ最小プロモーターの制御下でSEAP(分泌胚アルカリホスファターゼ)を発現する安定なHEK−293トランスフェクト細胞系である。これらの細胞によるSEAPの分泌は、TNFαにより用量依存的に刺激され、ヒトTNFαのEC50は、0.5ng/mLである。化合物を10mM DMSO保存液から希釈して(最終アッセイ濃度0.3%DMSO)、10ポイント3倍連続希釈曲線(例えば、30000nM〜2nM最終濃度)を得た。希釈化合物は、384ウエルマイクロタイタープレートに加え、18時間インキュベートする前に、TNFαとともに60分間プレインキュベートした。アッセイプレートにおける最終TNFα濃度は、0.5ng/mLであった。SEAP活性は、比色基質、例えば、QUANTI−Blue(商標)又はHEK−Blue(商標)検出媒体(InvivoGen)を用いて上清において測定した。化合物希釈物の阻害百分率は、DMSO対照と最大阻害(過剰の対照化合物による)とから計算し、IC50値は、ActivityBaseでXLfit(商標)(4パラメーターロジスティックモデル)を用いて計算した。
DCM:ジクロロメタン
EtOAc:酢酸エチル
MeOH:メタノール
DMSO:ジメチルスルホキシド
EtOH:エタノール
Et2O:ジエチルエーテル
DMF:N,N−ジメチルホルムアミド
AcOH:酢酸
Pd(dppf)Cl2:[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)
h:時間
M:質量
HPLC:高速液体クロマトグラフィー
LCMS:液体クロマトグラフィー質量分析
ES+:エレクトロスプレー陽イオン化
RT:保持時間
ACD/Name Batch(Network)バージョン11.01及び/又はAccelrys Draw 4.0を用いて化合物を命名した。
分析HPLC
カラム:Waters、X Bridge、20×2.1mm、2.5μm
移動相A:水中10mMギ酸アンモニウム+0.1%アンモニア
移動相B:アセトニトリル+5%溶媒A+0.1%アンモニア
注入容量:5.0μL
流速:1.00mL/分
勾配プログラム:4分間で5%Bから95%B;5.00分まで保持;5.10分の時点でB濃度は6.5分まで5%である
[2−(3−オキソピペラジン−1−イル)ピリミジン−5−イル]ボロン酸
2−クロロピリミジン−5−イルボロン酸(1.0g、6.32mmol)及びピペラジン−2−オン(1.6g、16.0mmol)を1,4−ジオキサン(10mL)中に懸濁させ、混合物をマイクロ波照射下100℃で45分間加熱した。懸濁液から上澄み液をデカントし、残渣をMeOH及びEt2Oとすり混ぜた。得られた固体を濾別し、真空下で乾燥させて、表題化合物(706mg、30%)を淡桃色固体として得た。LCMS: MH+ 223.
1−(5−ボロノピリミジン−2−イル)ピペリジン−4−カルボン酸
2−クロロピリミジン−5−イルボロン酸(2.00g、12.6mmol)及びイソニペコチン酸(1.63g、12.6mmol)をEtOH(25mL)中に懸濁させた。トリエチルアミン(1.78mL、12.65mmol)を添加し、混合物を80℃で16時間加熱した。反応混合物を室温に冷却し、真空中で濃縮乾固した。水(30mL)を添加し、反応混合物を、生成物が完全に溶解するまでかき混ぜた。静置すると、結晶化が起こった。混合物を氷浴中で30分間冷却し、次いで濾過した。得られた固体を水で控えめに洗浄し、吸引下で乾燥させ、次いで凍結乾燥して、表題化合物(1.90g、60%)を白色固体として得た。δH (400 MHz DMSO-d6) 8.60 (s, 2H), 8.06 (br s, 2H), 4.60-4.52 (m, 2H), 3.14-3.02 (m, 2H), 2.60-2.54 (m, 1H), 1.90-1.80 (m, 2H), 1.55-1.39 (m, 2H). LCMS (ES+) 252 (M+H)+.
5−ブロモ−2−ニトロアニリン
密封管内で0℃に維持したMeOH(5mL)中の4−ブロモ−2−フルオロ−1−ニトロベンゼン(5g、22.7mmol)の溶液に、メタノール性アンモニア(15mL)を添加した。反応混合物を室温で12時間撹拌し、次いで濃縮した。粗残渣をペンタン及びEt2Oとすり混ぜて、表題化合物(4.5g、91%)を得、これをさらに精製することなく次のステップに使用した。δH (400 MHz, CD3OD) 7.93 (d, J 9.1 Hz, 1H), 7.18 (d, J 2.1 Hz, 1H), 6.74 (dd, J 9.2, 2.1 Hz, 1H).
5−ブロモ−N−{[2−(ジフルオロメトキシ)フェニル]メチル}−2−ニトロアニリン
0℃に維持したDMF(10mL)中の中間体3(4.5g、20.73mmol)の溶液に、NaH(0.82g、20.73mmol)を添加した。反応混合物を0℃で30分間撹拌した。反応混合物に、1−(ブロモメチル)−2−(ジフルオロメトキシ)−ベンゼン(3.58g、20.73mmol)を添加した。反応混合物を室温で2時間撹拌し、次いでH2Oを用いてクエンチした。水性層をEtOAcで抽出した。次いで、有機層をH2Oで洗浄し、Na2SO4で脱水し、真空中で蒸発により濃縮した。粗残渣をEt2O中ですり混ぜて、表題化合物(5.12g、66%)を固体として得、これをさらに精製することなく使用した。δH (400 MHz, CD3OD) 8.66-8.45 (m, 1H), 8.04 (d, J 9.1 Hz, 1H), 7.49-7.27 (m, 2H), 7.21 (m, 2H), 7.08-7.04 (m, 1H), 6.81 (dd, J 9.2, 2.0 Hz, 1H), 4.79 (s, 2H).
4−ブロモ−N2−{[2−(ジフルオロメトキシ)フェニル]メチル}ベンゼン−1,2−ジアミン
0℃のMeOH(10mL)中の中間体4(5.12g、0.01372mol)の溶液に、Zn粉末(5.38g、0.08235mol)、続いてギ酸アンモニウム(5.18g、0.08235mol)を添加した。反応混合物を室温で5時間撹拌し、次いで真空中で蒸発により濃縮した。粗残渣を酢酸エチルで希釈し、セライトに通して濾過した。有機層をH2Oで洗浄し、Na2SO4で脱水し、真空中で蒸発により濃縮した。粗残渣をカラムクロマトグラフィー(シリカ 100〜200メッシュ、ヘキサン中20%EtOAc)により精製して、表題化合物(4g、85%)を得た。LCMS (ES+) (M+H)+ 343.
6−ブロモ−1−{[2−(ジフルオロメトキシ)フェニル]メチル}ベンゾトリアゾール
0℃に維持したAcOH(10mL)中の中間体5(2g、5.8mmol)の溶液に、H2O(3mL)中のNaNO2(1.18g、17.49mmol)を30分間かけて添加した。反応混合物を0℃で1時間撹拌し、次いでNaHCO3の飽和水溶液に注ぎ入れ、EtOAcで抽出した。有機層をH2O及びブラインで洗浄し、次いで真空中で蒸発により濃縮した。粗残渣をカラムクロマトグラフィー(シリカ 100〜200メッシュ、ヘキサン中25%EtOAc)により精製して、表題化合物(1.5g、72%)を得た。δH (400 MHz, CD3OD) 8.00-7.83 (m, 2H), 7.53 (dd, J 8.9, 1.7 Hz, 1H), 7.41 (ddd, J 8.7, 7.1, 1.8 Hz, 2H), 7.29 (dd, J 7.6, 1.8 Hz, 1H), 7.26-7.19 (m, 1H), 6.90 (t, J 73.6 Hz, 1H), 5.94 (s, 2H). LCMS (ES+) (M+H)+356.1.
4−[5−(1−{[2−(ジフルオロメトキシ)フェニル]メチル}ベンゾトリアゾール−6−イル)ピリミジン−2−イル]−モルホリン
1,4−ジオキサン(3mL)及びH2O(1mL)中の中間体6(0.200g、0.565mmol)、Na2CO3(0.179g、1.69mmol)及び[2−(モルホリン−4−イル)ピリミジン−5−イル]ボロン酸(0.164mg、0.5645mmol)の脱気溶液に、Pd(dppf)Cl2(0.046g、0.05649mol)を添加した。反応混合物をマイクロ波照射下125℃で2時間加熱し、次いでEtOAcで希釈し、セライトに通して濾過した。有機層を無水Na2SO4で脱水し、次いで真空中で蒸発により濃縮した。粗残渣を分取HPLCにより精製して、表題化合物(60mg、24%)を得た。δH (400 MHz, DMSO-d6) 8.82 (s, 2H), 8.11 (dd, J 5.2, 3.4 Hz, 2H), 7.72 (dd, J 8.8, 1.5 Hz, 1H), 7.52-7.36 (m, 2H), 7.25 (ddd, J 14.9, 9.8, 6.8 Hz, 3H), 6.00 (s, 2H), 3.78 (t, J 4.8 Hz, 4H), 3.69 (t, J 4.8 Hz, 4H). LCMS (ES+) 439.3 (M+H)+, RT 2.48分.
1−[5−(1−{[2−(ジフルオロメトキシ)フェニル]メチル}ベンゾトリアゾール−6−イル)ピリミジン−2−イル]−ピペリジン−4−カルボン酸
方法Aによる中間体6及び中間体2の反応により、表題化合物(収率18%)を得た。δH (400 MHz, CD3OD) 8.65 (s, 2H), 8.04 (d, J 9.1 Hz, 1H), 7.85 (s, 1H), 7.65 (d, J 9.1 Hz, 1H), 7.48-7.24 (m, 4H), 6.90 (t, J 73.6 Hz, 1H), 6.00 (s, 2H), 4.62 (d, 2H), 3.15 (t, 2H), 2.65 (m, 1H), 2.00 (m, 2H), 1.65 (m, 2H). LCMS (ES+) 481.3 (M+H)+, RT 1.70分.
4−[5−(1−{[2−(ジフルオロメトキシ)フェニル]メチル}ベンゾトリアゾール−6−イル)ピリミジン−2−イル]−ピペラジン−2−オン
方法Aによる中間体6及び中間体1の反応により、表題化合物(収率8%)を得た。δH (400 MHz, CD3OD) 8.78 (s, 2H), 8.04 (d, J 9.1 Hz, 1H), 7.90 (s, 1H), 7.65 (d, J 9.1 Hz, 1H), 7.48-7.24 (m, 4H), 6.90 (t, J 73.6 Hz, 1H), 6.00 (s, 2H), 4.40 (s, 2H), 4.15 (m, 2H), 3.25 (m, 2H). LCMS (ES+) 452.3 (M+H)+, RT 2.01分.
1−{[2−(ジフルオロメトキシ)フェニル]メチル}−6−[2−(ピペラジン−1−イル)ピリミジン−5−イル]−ベンゾトリアゾール
方法Aによる中間体6及び[2−(ピペラジン−1−イル)ピリミジン−5−イル]ボロン酸の反応により、表題化合物(収率85%)を得た。δH (400 MHz, DMSO-d6) 8.84 (s, 2H), 8.12 (dd, J 5.2, 3.4 Hz, 2H), 7.73 (dd, J 8.9, 1.5 Hz, 1H), 7.62-6.99 (m, 5H), 6.00 (s, 2H), 3.94 (t, J 5.0 Hz, 4H), 3.22 (t, J 5.1 Hz, 4H).
1−{[2−(ジフルオロメトキシ)フェニル]メチル}−6−{2−[4−(メチルスルホニル)ピペラジン−1−イル]−ピリミジン−5−イル}ベンゾトリアゾール
0℃に維持したDCM(3mL)中の例4(210mg、0.48mmol)の溶液に、トリエチルアミン(145mg、1.44mmol)、続いてメタンスルホニルクロリド(37mg、0.480mmol)を添加した。反応混合物を室温で3時間撹拌し、次いで濃縮し、EtOAcで希釈した。有機層をH2Oで洗浄し、Na2SO4で脱水し、真空中で蒸発により濃縮した。粗残渣を分取HPLCにより精製して、表題化合物(100mg、40%)を得た。δH (400 MHz, DMSO-d6) 8.84 (s, 2H), 8.12 (dd, J 5.2, 3.4 Hz, 2H), 7.73 (dd, J 8.9, 1.5 Hz, 1H), 7.62-6.99 (m, 5H), 6.00 (s, 2H), 3.94 (t, J 5.0 Hz, 4H), 3.22 (t, J 5.1 Hz, 4H), 2.90 (s, 3H). LCMS (ES+) 516.3 (M+H)+, RT 2.41分.
4−(1−{[2−(ジフルオロメトキシ)フェニル]メチル}ベンゾトリアゾール−6−イル)ベンゼンスルホンアミド
方法Aによる中間体6及び(4−スルファモイルフェニル)ボロン酸の反応により、表題化合物(収率53%)を得た。δH (400 MHz, DMSO-d6) 8.27-8.20 (m, 1H), 8.17 (d, J 8.7 Hz, 1H), 7.95 (d, J 1.3 Hz, 4H), 7.79 (dd, J 8.7, 1.7 Hz, 1H), 7.51-7.38 (m, 4H), 7.34-7.18 (m, 3H), 6.04 (s, 2H). LCMS (ES+) 431.2 (M+H)+, RT 2.14分.
Claims (11)
- 以下の式(IIB)により表される化合物若しくはそのN−オキシド、又はその薬学的に許容される塩若しくは溶媒和物
(式中、
Eは−CH 2 −を表し、
Vは、C−R22又はNを表し、
R 12 は、水素、フルオロ、クロロ、トリフルオロメチル、メチル、又はエトキシカルボニルエチルを表し、
R 15 は、ジフルオロメトキシを表し、
R 16 は、水素、ハロゲン、シアノ、C 1〜6 アルキル、トリフルオロメチル、ジフルオロメトキシ、又はアミノを表し、
R21 は、ヒドロキシ(C1〜6)アルキルを表し;或いはR21 は、(C3〜7)ヘテロシクロアルキルを表し、その基はC 1〜6 アルキルスルホニル、オキソ及びカルボキシから独立に選択される1つ、2つ又は3つの置換基により場合によって置換されていてもよく、
R22は、水素、ハロゲン又はC1〜6アルキルを表し、及び
R23は、水素、C1〜6アルキル、トリフルオロメチル又はC1〜6アルコキシを表す)。 - 4−[5−(1−{[2−(ジフルオロメトキシ)フェニル]メチル}ベンゾトリアゾール−6−イル)ピリミジン−2−イル]−モルホリン;
1−[5−(1−{[2−(ジフルオロメトキシ)フェニル]メチル}ベンゾトリアゾール−6−イル)ピリミジン−2−イル]−ピペリジン−4−カルボン酸;
4−[5−(1−{[2−(ジフルオロメトキシ)フェニル]メチル}ベンゾトリアゾール−6−イル)ピリミジン−2−イル]−ピペラジン−2−オン;
1−{[2−(ジフルオロメトキシ)フェニル]メチル}−6−[2−(ピペラジン−1−イル)ピリミジン−5−イル]−ベンゾトリアゾール;及び
1−{[2−(ジフルオロメトキシ)フェニル]メチル}−6−{2−[4−(メチルスルホニル)ピペラジン−1−イル]−ピリミジン−5−イル}ベンゾトリアゾール
から選択される請求項1に記載の化合物。 - TNFα機能のモジュレーターの投与の適応となる障害の処置及び/又は予防における使用のための請求項1に記載の式(IIB)の化合物若しくはそのN−オキシド、又はその薬学的に許容される塩若しくは溶媒和物を含むTNFα機能のモジュレーター。
- 炎症性若しくは自己免疫性障害、神経若しくは神経変性障害、疼痛若しくは侵害受容性障害、心血管障害、代謝障害、眼障害、又は腫瘍学的障害の処置及び/又は予防における使用のための請求項1に記載の式(IIB)の化合物若しくはそのN−オキシド、又はその薬学的に許容される塩若しくは溶媒和物を含むTNFα機能のモジュレーター。
- 請求項1に記載の式(IIB)の化合物若しくはそのN−オキシド、又はその薬学的に許容される塩若しくは溶媒和物を薬学的に許容される担体とともに含む医薬組成物。
- さらなる薬学的に活性な成分をさらに含む、請求項6に記載の医薬組成物。
- TNFα機能のモジュレーターの投与の適応となる障害の処置及び/又は予防のための請求項6又は7に記載の医薬組成物。
- 炎症性若しくは自己免疫性障害、神経若しくは神経変性障害、疼痛若しくは侵害受容性障害、心血管障害、代謝障害、眼障害、又は腫瘍学的障害の処置及び/又は予防のための請求項6又は7に記載の医薬組成物。
- TNFα機能のモジュレーターの投与の適応となる障害の処置及び/又は予防用の医薬品の製造のための請求項1に記載の式(IIB)の化合物若しくはそのN−オキシド、又はその薬学的に許容される塩若しくは溶媒和物の使用。
- 炎症性若しくは自己免疫性障害、神経若しくは神経変性障害、疼痛若しくは侵害受容性障害、心血管障害、代謝障害、眼障害、又は腫瘍学的障害の処置及び/又は予防用の医薬品の製造のための請求項1に記載の式(IIB)の化合物若しくはそのN−オキシド、又はその薬学的に許容される塩若しくは溶媒和物の使用。
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