JP2014525445A - キヌレニン−3−モノオキシゲナーゼインヒビターおよびその医薬組成物ならびにこれらの使用方法 - Google Patents
キヌレニン−3−モノオキシゲナーゼインヒビターおよびその医薬組成物ならびにこれらの使用方法 Download PDFInfo
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- JP2014525445A JP2014525445A JP2014528519A JP2014528519A JP2014525445A JP 2014525445 A JP2014525445 A JP 2014525445A JP 2014528519 A JP2014528519 A JP 2014528519A JP 2014528519 A JP2014528519 A JP 2014528519A JP 2014525445 A JP2014525445 A JP 2014525445A
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- JP
- Japan
- Prior art keywords
- chloro
- phenyl
- pyrimidine
- carboxylic acid
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 238000000034 method Methods 0.000 title claims abstract description 82
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 48
- 239000003112 inhibitor Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 177
- 239000000126 substance Substances 0.000 claims abstract description 85
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 49
- 230000000694 effects Effects 0.000 claims abstract description 45
- 238000011282 treatment Methods 0.000 claims abstract description 34
- 208000023105 Huntington disease Diseases 0.000 claims abstract description 9
- 102100037652 Kynurenine 3-monooxygenase Human genes 0.000 claims abstract description 9
- -1 2,3-dihydrobenzofuran-5-yl Chemical group 0.000 claims description 341
- 239000000203 mixture Substances 0.000 claims description 121
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 79
- 229910052739 hydrogen Inorganic materials 0.000 claims description 56
- 125000000217 alkyl group Chemical group 0.000 claims description 54
- 239000001257 hydrogen Substances 0.000 claims description 53
- 150000005829 chemical entities Chemical class 0.000 claims description 48
- 229910052757 nitrogen Inorganic materials 0.000 claims description 45
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 38
- 125000001072 heteroaryl group Chemical group 0.000 claims description 37
- 125000003118 aryl group Chemical group 0.000 claims description 28
- 125000005843 halogen group Chemical group 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 21
- 239000000651 prodrug Substances 0.000 claims description 20
- 229940002612 prodrug Drugs 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 125000003107 substituted aryl group Chemical group 0.000 claims description 15
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 15
- 125000004429 atom Chemical group 0.000 claims description 12
- 230000001404 mediated effect Effects 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 10
- DXXHGTWWVTYUIY-UHFFFAOYSA-N 6-(2,3-dihydro-1,4-benzodioxin-6-yl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C3OCCOC3=CC=2)=N1 DXXHGTWWVTYUIY-UHFFFAOYSA-N 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000004550 quinolin-6-yl group Chemical group N1=CC=CC2=CC(=CC=C12)* 0.000 claims description 8
- 108010033242 Kynurenine 3-monooxygenase Proteins 0.000 claims description 7
- KAPFCJYSHMMHHG-UHFFFAOYSA-N 6-(4-chloro-3-methoxyphenyl)pyrimidine-4-carboxylic acid Chemical compound C1=C(Cl)C(OC)=CC(C=2N=CN=C(C=2)C(O)=O)=C1 KAPFCJYSHMMHHG-UHFFFAOYSA-N 0.000 claims description 6
- HCMSVNWFFJPWJC-UHFFFAOYSA-N 6-quinolin-6-ylpyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C3C=CC=NC3=CC=2)=N1 HCMSVNWFFJPWJC-UHFFFAOYSA-N 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- YPOXGDJGKBXRFP-UHFFFAOYSA-N pyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=N1 YPOXGDJGKBXRFP-UHFFFAOYSA-N 0.000 claims description 6
- KLVJYJQPFYHIPX-UHFFFAOYSA-N 6-[3-chloro-4-[cyclopropyl(hydroxy)methyl]phenyl]pyrimidine-4-carboxylic acid Chemical compound C=1C=C(C=2N=CN=C(C=2)C(O)=O)C=C(Cl)C=1C(O)C1CC1 KLVJYJQPFYHIPX-UHFFFAOYSA-N 0.000 claims description 5
- 125000004533 benzofuran-5-yl group Chemical group O1C=CC2=C1C=CC(=C2)* 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 5
- 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 claims description 4
- LQBCVDIPSNMKDD-UHFFFAOYSA-N 6-(1,3-benzodioxol-5-yl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C3OCOC3=CC=2)=N1 LQBCVDIPSNMKDD-UHFFFAOYSA-N 0.000 claims description 4
- VIDDOIYIHXKWEQ-UHFFFAOYSA-N 6-(2,2-difluoro-1,3-benzodioxol-5-yl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C3OC(F)(F)OC3=CC=2)=N1 VIDDOIYIHXKWEQ-UHFFFAOYSA-N 0.000 claims description 4
- UPKQDTLLVVTZQT-UHFFFAOYSA-N 6-(3-chloro-4-cyclopropyloxyphenyl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C(Cl)C(OC3CC3)=CC=2)=N1 UPKQDTLLVVTZQT-UHFFFAOYSA-N 0.000 claims description 4
- AZGINHVEMXJOGL-UHFFFAOYSA-N 6-(3-chloro-4-cyclopropylphenyl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C(Cl)C(C3CC3)=CC=2)=N1 AZGINHVEMXJOGL-UHFFFAOYSA-N 0.000 claims description 4
- KYPSKXAYQTYOFI-UHFFFAOYSA-N 6-(3-chloro-4-pyrrolidin-1-ylphenyl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C(Cl)C(N3CCCC3)=CC=2)=N1 KYPSKXAYQTYOFI-UHFFFAOYSA-N 0.000 claims description 4
- QFQHJZKECPZGLZ-UHFFFAOYSA-N 6-(3-chloro-4-pyrrolidin-2-ylphenyl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C(Cl)C(C3NCCC3)=CC=2)=N1 QFQHJZKECPZGLZ-UHFFFAOYSA-N 0.000 claims description 4
- ANCVBRFECVCVKS-UHFFFAOYSA-N 6-(4-chloro-1,3-benzoxazol-6-yl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C3OC=NC3=C(Cl)C=2)=N1 ANCVBRFECVCVKS-UHFFFAOYSA-N 0.000 claims description 4
- SIYCDJHEVASOGW-UHFFFAOYSA-N 6-(4-chloro-3-cyclopropyloxyphenyl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C(OC3CC3)C(Cl)=CC=2)=N1 SIYCDJHEVASOGW-UHFFFAOYSA-N 0.000 claims description 4
- HAKPEXMHSQJZGE-UHFFFAOYSA-N 6-(4-chloro-3-propan-2-yloxyphenyl)pyrimidine-4-carboxylic acid Chemical compound C1=C(Cl)C(OC(C)C)=CC(C=2N=CN=C(C=2)C(O)=O)=C1 HAKPEXMHSQJZGE-UHFFFAOYSA-N 0.000 claims description 4
- SFEFRQOLESCMSD-UHFFFAOYSA-N 6-(4-tert-butyl-3-chlorophenyl)pyrimidine-4-carboxylic acid Chemical compound C1=C(Cl)C(C(C)(C)C)=CC=C1C1=CC(C(O)=O)=NC=N1 SFEFRQOLESCMSD-UHFFFAOYSA-N 0.000 claims description 4
- DTUYEUHTIOVJOT-UHFFFAOYSA-N 6-(5-chloroquinazolin-7-yl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C3N=CN=CC3=C(Cl)C=2)=N1 DTUYEUHTIOVJOT-UHFFFAOYSA-N 0.000 claims description 4
- WRYMFUKRHGTHBN-UHFFFAOYSA-N 6-(7-chloro-1-benzothiophen-5-yl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C3C=CSC3=C(Cl)C=2)=N1 WRYMFUKRHGTHBN-UHFFFAOYSA-N 0.000 claims description 4
- UREIJDJVIJFGEI-UHFFFAOYSA-N 6-(7-chloro-1-methyl-3a,7a-dihydroindazol-5-yl)pyrimidine-4-carboxylic acid Chemical compound C1=C(Cl)C2N(C)N=CC2C=C1C1=CC(C(O)=O)=NC=N1 UREIJDJVIJFGEI-UHFFFAOYSA-N 0.000 claims description 4
- KKQXSKUYVOCSAJ-UHFFFAOYSA-N 6-(7-chloro-2-cyclopropyl-1,3-benzoxazol-5-yl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C3N=C(OC3=C(Cl)C=2)C2CC2)=N1 KKQXSKUYVOCSAJ-UHFFFAOYSA-N 0.000 claims description 4
- UJWQTZGUQWSJQV-UHFFFAOYSA-N 6-(7-chloro-2-cyclopropyl-1,3-dihydroisoindol-5-yl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C(Cl)C=3CN(CC=3C=2)C2CC2)=N1 UJWQTZGUQWSJQV-UHFFFAOYSA-N 0.000 claims description 4
- ISEPNBNCKBSVBY-UHFFFAOYSA-N 6-(7-chloro-2-methyl-1,3-benzoxazol-5-yl)pyrimidine-4-carboxylic acid Chemical compound C=1C(Cl)=C2OC(C)=NC2=CC=1C1=CC(C(O)=O)=NC=N1 ISEPNBNCKBSVBY-UHFFFAOYSA-N 0.000 claims description 4
- JWGVHCNBKLKNLK-UHFFFAOYSA-N 6-(7-chloro-2-oxo-3h-1,3-benzoxazol-5-yl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C3NC(=O)OC3=C(Cl)C=2)=N1 JWGVHCNBKLKNLK-UHFFFAOYSA-N 0.000 claims description 4
- NEHRDWRJUKTTGJ-UHFFFAOYSA-N 6-(7-chloro-3-methyl-2-oxo-1,3-benzoxazol-5-yl)pyrimidine-4-carboxylic acid Chemical compound C=1C(Cl)=C2OC(=O)N(C)C2=CC=1C1=CC(C(O)=O)=NC=N1 NEHRDWRJUKTTGJ-UHFFFAOYSA-N 0.000 claims description 4
- OQJCQSNSJYSKQM-UHFFFAOYSA-N 6-(7-chloro-3a,7a-dihydro-1h-indol-5-yl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C(Cl)C3NC=CC3C=2)=N1 OQJCQSNSJYSKQM-UHFFFAOYSA-N 0.000 claims description 4
- YVEQACWEFQPLKG-UHFFFAOYSA-N 6-(7-chloro-3h-benzimidazol-5-yl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C3NC=NC3=C(Cl)C=2)=N1 YVEQACWEFQPLKG-UHFFFAOYSA-N 0.000 claims description 4
- FNHKPPQGEUDHRF-UHFFFAOYSA-N 6-(8-chloroimidazo[1,2-a]pyridin-6-yl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C2=CN3C=CN=C3C(Cl)=C2)=N1 FNHKPPQGEUDHRF-UHFFFAOYSA-N 0.000 claims description 4
- ZWOQQKKPRINPGY-UHFFFAOYSA-N 6-(8-chloroquinazolin-6-yl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C3C=NC=NC3=C(Cl)C=2)=N1 ZWOQQKKPRINPGY-UHFFFAOYSA-N 0.000 claims description 4
- NGFZWJQXSNGURC-UHFFFAOYSA-N 6-[3-chloro-4-(1-cyclopropyloxyethyl)phenyl]pyrimidine-4-carboxylic acid Chemical compound C=1C=C(C=2N=CN=C(C=2)C(O)=O)C=C(Cl)C=1C(C)OC1CC1 NGFZWJQXSNGURC-UHFFFAOYSA-N 0.000 claims description 4
- IPEAOABYMIDHCR-UHFFFAOYSA-N 6-[3-chloro-4-(1-methoxycyclopropyl)phenyl]pyrimidine-4-carboxylic acid Chemical compound C=1C=C(C=2N=CN=C(C=2)C(O)=O)C=C(Cl)C=1C1(OC)CC1 IPEAOABYMIDHCR-UHFFFAOYSA-N 0.000 claims description 4
- AITQWQMFPSGQKC-UHFFFAOYSA-N 6-[3-chloro-4-(1-methylcyclopropyl)phenyl]pyrimidine-4-carboxylic acid Chemical compound C=1C=C(C=2N=CN=C(C=2)C(O)=O)C=C(Cl)C=1C1(C)CC1 AITQWQMFPSGQKC-UHFFFAOYSA-N 0.000 claims description 4
- SNFLLZQLPWPDHF-UHFFFAOYSA-N 6-[3-chloro-4-(1h-imidazol-2-yl)phenyl]pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C(Cl)C(C=3NC=CN=3)=CC=2)=N1 SNFLLZQLPWPDHF-UHFFFAOYSA-N 0.000 claims description 4
- QLHXNWGOOJWHRP-UHFFFAOYSA-N 6-[3-chloro-4-(1h-pyrrol-2-yl)phenyl]pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C(Cl)C(C=3NC=CC=3)=CC=2)=N1 QLHXNWGOOJWHRP-UHFFFAOYSA-N 0.000 claims description 4
- IQXRYVHXDWKILP-UHFFFAOYSA-N 6-[3-chloro-4-(3-methyloxetan-3-yl)phenyl]pyrimidine-4-carboxylic acid Chemical compound C=1C=C(C=2N=CN=C(C=2)C(O)=O)C=C(Cl)C=1C1(C)COC1 IQXRYVHXDWKILP-UHFFFAOYSA-N 0.000 claims description 4
- ARJDUBLNQNMTBU-UHFFFAOYSA-N 6-[3-chloro-4-(cyclopropanecarbonyl)phenyl]pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C(Cl)C(C(=O)C3CC3)=CC=2)=N1 ARJDUBLNQNMTBU-UHFFFAOYSA-N 0.000 claims description 4
- UALYFQRKTBVXFI-UHFFFAOYSA-N 6-[3-chloro-4-(cyclopropylmethyl)phenyl]pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C(Cl)C(CC3CC3)=CC=2)=N1 UALYFQRKTBVXFI-UHFFFAOYSA-N 0.000 claims description 4
- YBGVQOWGBBFAAT-UHFFFAOYSA-N 6-[3-chloro-4-(cyclopropyloxymethyl)phenyl]pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C(Cl)C(COC3CC3)=CC=2)=N1 YBGVQOWGBBFAAT-UHFFFAOYSA-N 0.000 claims description 4
- XBUMWMDNAUQRRD-UHFFFAOYSA-N 6-[3-chloro-4-(furan-2-yl)phenyl]pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C(Cl)C(C=3OC=CC=3)=CC=2)=N1 XBUMWMDNAUQRRD-UHFFFAOYSA-N 0.000 claims description 4
- HSGCDKCENGBLPX-UHFFFAOYSA-N 6-[3-chloro-4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C(Cl)C(OC(F)(F)F)=CC=2)=N1 HSGCDKCENGBLPX-UHFFFAOYSA-N 0.000 claims description 4
- KTSNAFGBKMJBOA-UHFFFAOYSA-N 6-[3-chloro-4-[(cyclopropylamino)methyl]phenyl]pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C(Cl)C(CNC3CC3)=CC=2)=N1 KTSNAFGBKMJBOA-UHFFFAOYSA-N 0.000 claims description 4
- ZVMSGRHDUPQQGV-UHFFFAOYSA-N 6-[3-chloro-4-[1-(trifluoromethyl)cyclopropyl]phenyl]pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C(Cl)C(=CC=2)C2(CC2)C(F)(F)F)=N1 ZVMSGRHDUPQQGV-UHFFFAOYSA-N 0.000 claims description 4
- ADTHFFYDPUFSGE-UHFFFAOYSA-N 6-[3-chloro-4-[[cyclopropyl(methyl)amino]methyl]phenyl]pyrimidine-4-carboxylic acid Chemical compound C1CC1N(C)CC(C(=C1)Cl)=CC=C1C1=CC(C(O)=O)=NC=N1 ADTHFFYDPUFSGE-UHFFFAOYSA-N 0.000 claims description 4
- ZXDKEXDBLUBBCU-UHFFFAOYSA-N 6-[3-chloro-4-[cyclopropyl(methyl)amino]phenyl]pyrimidine-4-carboxylic acid Chemical compound C=1C=C(C=2N=CN=C(C=2)C(O)=O)C=C(Cl)C=1N(C)C1CC1 ZXDKEXDBLUBBCU-UHFFFAOYSA-N 0.000 claims description 4
- OMVLEVUANYVBNZ-UHFFFAOYSA-N 6-[4-(aziridin-1-ylmethyl)-3-chlorophenyl]pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C(Cl)C(CN3CC3)=CC=2)=N1 OMVLEVUANYVBNZ-UHFFFAOYSA-N 0.000 claims description 4
- URMVKRXVAAYVCB-UHFFFAOYSA-N 6-[4-chloro-3-(1,1,1-trifluoropropan-2-yloxy)phenyl]pyrimidine-4-carboxylic acid Chemical compound C1=C(Cl)C(OC(C)C(F)(F)F)=CC(C=2N=CN=C(C=2)C(O)=O)=C1 URMVKRXVAAYVCB-UHFFFAOYSA-N 0.000 claims description 4
- JRPORKJOVJJRHR-UHFFFAOYSA-N 6-[4-chloro-3-(2-methylpropoxy)phenyl]pyrimidine-4-carboxylic acid Chemical compound C1=C(Cl)C(OCC(C)C)=CC(C=2N=CN=C(C=2)C(O)=O)=C1 JRPORKJOVJJRHR-UHFFFAOYSA-N 0.000 claims description 4
- VKUIPVSZEKJXEM-UHFFFAOYSA-N 6-[4-chloro-3-(trifluoromethoxy)phenyl]pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C(OC(F)(F)F)C(Cl)=CC=2)=N1 VKUIPVSZEKJXEM-UHFFFAOYSA-N 0.000 claims description 4
- DAWCOJFZNHWQJJ-UHFFFAOYSA-N 6-pyrazolo[1,5-a]pyridin-5-ylpyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C2=CC3=CC=NN3C=C2)=N1 DAWCOJFZNHWQJJ-UHFFFAOYSA-N 0.000 claims description 4
- BXJIWHPLUHUMNN-UHFFFAOYSA-N 7-chloro-8-cyclopropyloxy-5h-chromeno[4,3-d]pyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=NC=NC(C2=CC=3)=C1COC2=C(Cl)C=3OC1CC1 BXJIWHPLUHUMNN-UHFFFAOYSA-N 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- 125000004539 5-benzimidazolyl group Chemical group N1=CNC2=C1C=CC(=C2)* 0.000 claims description 3
- PWFZXYHXMKUNLH-UHFFFAOYSA-N 6-(3-chloro-4-methoxyphenyl)pyrimidine-4-carboxylic acid Chemical compound C1=C(Cl)C(OC)=CC=C1C1=CC(C(O)=O)=NC=N1 PWFZXYHXMKUNLH-UHFFFAOYSA-N 0.000 claims description 3
- DFJNJNRBWMZOFO-UHFFFAOYSA-N 6-(3-chloro-4-methylphenyl)pyrimidine-4-carboxylic acid Chemical compound C1=C(Cl)C(C)=CC=C1C1=CC(C(O)=O)=NC=N1 DFJNJNRBWMZOFO-UHFFFAOYSA-N 0.000 claims description 3
- QNLAPYWAQTUSMO-UHFFFAOYSA-N 6-(7-chloro-1,3-benzothiazol-5-yl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C3N=CSC3=C(Cl)C=2)=N1 QNLAPYWAQTUSMO-UHFFFAOYSA-N 0.000 claims description 3
- JEKVAHBUQDMJET-UHFFFAOYSA-N 6-(7-chloro-1,3-benzoxazol-5-yl)pyrimidine-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC(C=2C=C3N=COC3=C(Cl)C=2)=N1 JEKVAHBUQDMJET-UHFFFAOYSA-N 0.000 claims description 3
- NOEXYBWFAOICAQ-UHFFFAOYSA-N 6-[3-chloro-4-(1-morpholin-4-ylpropan-2-yloxy)phenyl]pyrimidine-4-carboxylic acid Chemical compound C=1C=C(C=2N=CN=C(C=2)C(O)=O)C=C(Cl)C=1OC(C)CN1CCOCC1 NOEXYBWFAOICAQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000005605 benzo group Chemical group 0.000 claims description 3
- 125000004540 benzothiazol-5-yl group Chemical group S1C=NC2=C1C=CC(=C2)* 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000002619 bicyclic group Chemical group 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 claims description 3
- VRJCJIVIECVPBI-UHFFFAOYSA-N methyl 6-(3-chloro-4-methoxyphenyl)pyrimidine-4-carboxylate Chemical compound C1=NC(C(=O)OC)=CC(C=2C=C(Cl)C(OC)=CC=2)=N1 VRJCJIVIECVPBI-UHFFFAOYSA-N 0.000 claims description 3
- VILJUHIEKNITDI-UHFFFAOYSA-N methyl 6-(3-chloro-4-methylphenyl)pyrimidine-4-carboxylate Chemical compound C1=NC(C(=O)OC)=CC(C=2C=C(Cl)C(C)=CC=2)=N1 VILJUHIEKNITDI-UHFFFAOYSA-N 0.000 claims description 3
- 230000000626 neurodegenerative effect Effects 0.000 claims description 3
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 3
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- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
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- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000003936 working memory Effects 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
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- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Abstract
Description
XおよびYは、独立して−N−および−CH−から選択されるが、ただし、XとYのうち少なくとも一方は−N−であるものとし;
R1は、アリールまたは単環式ヘテロアリールであり、該アリールまたは単環式ヘテロアリールの各々は、
式−Z−R6の第1の基、および
第2の基
で置換されており、ここで、
Zは、−O−、−S−、−S(O)−、−S(O)2−、−CR11R12−、−OCR11R12−、−NR13−、−NR13CR11R12−、−CR11R12NR13−、および−C(O)−(式中、R11、R12およびR13は独立して、水素、低級アルキル、ヒドロキシルおよび低級アルコキシから選択される)から選択され、
R6は、水素、任意選択的に置換されているC1〜C6アルキル、任意選択的に置換されているシクロアルキル、任意選択的に置換されているアリール、任意選択的に置換されているヘテロアリール、および任意選択的に置換されているヘテロシクロアルキルから選択されるが、ただし、Zが−O−である場合、R6は、任意選択的に置換されているベンジルでも任意選択的に置換されているピリジルメチルでもないものとするか、または
R6とR13が、これらが結合している窒素と一体となって、任意選択的に置換されている5〜7員のヘテロシクロアルキル環を形成しており、
該第2の基は、ハロおよびハロで任意選択的に置換されている低級アルキルから選択されるか、あるいは
R1は、2,3−ジヒドロベンゾフラン−5−イル、クロマン−6−イル、1,3−ベンゾジオキソール−5−イル、2,3−ジヒドロ−1,4−ベンゾジオキシン−6−イル、1,3−ベンゾオキサゾール−5−イル、ベンゾイミダゾール−5−イル、1,3−ベンゾオキサゾール−6−イル、2−オキソ−2,3−ジヒドロ−1,3−ベンゾオキサゾール−5−イル、ベンゾチオフェン−5−イル、ベンゾチアゾール−5−イル、ベンゾフラン−5−イル、1H−インドール−5−イル、1H−インダゾール−5−イル、イソインドリン−5−イル、ベンゾ[c][1,2,5]オキサジアゾール−5−イル、1,2,3,4−テトラヒドロキノリン−6−イル、イミダゾ[1,2−a]ピリジン−6−イル、ピラゾロ[1,5−a]ピリジン−5−イル、キノリン−6−イル、キナゾリン−6−イル、キナゾリン−7−イルおよびキノキサリン−6−イル(これらの各々は、任意選択的に置換されている)から選択されるか、あるいは
R1とR3が、介在原子と一体となって、式
の二環式環を形成しており;
R2は、水素および任意選択的に置換されている低級アルキルから選択され;
R3は、水素、ハロ、任意選択的に置換されている低級アルキル、ヒドロキシル、任意選択的に置換されている低級アルコキシ、および任意選択的に置換されているアミノから選択され;
Lは、−C(O)−、−C(O)O−、−C(O)N(R4)−、−C(O)N(OR7)−、−N(R4)S(O)2−、−S(O)2N(R4)−、および−C(O)N(R4)−S(O)2−から選択され;
R4は、水素および低級アルキルから選択され;
R5は、水素、任意選択的に置換されている低級アルキル、任意選択的に置換されているアリール、任意選択的に置換されているヘテロアリール、任意選択的に置換されているシクロアルキル、および任意選択的に置換されているヘテロシクロアルキルから選択されるが、ただし、Lが−N(R4)S(O)2−である場合、R5は水素でないものとするか、あるいは
R4とR5が、これらが結合している窒素と一体となって、任意選択的に置換されている4〜7員のヘテロシクロアルキル環を形成しており、該環は、任意選択的に置換されているシクロアルキル、任意選択的に置換されているヘテロシクロアルキル、任意選択的に置換されているアリールまたは任意選択的に置換されているヘテロアリール環と任意選択的に縮合しているか、あるいは
R3とR5が、介在原子と一体となって、任意選択的に置換されている5〜7員の環を形成しており;
R7は、水素および低級アルキルから選択される)
の化合物ならびにその薬学的に許容され得る塩およびプロドラッグから選択される少なくとも1種類の化学物質であるが、
ただし、式Iの化合物は
6−(3−クロロ−4−メチル−フェニル)−ピリミジン−4−カルボン酸メチルエステル;
6−(3−クロロ−4−メチル−フェニル)−ピリミジン−4−カルボン酸;
6−(3−クロロ−4−メトキシ−フェニル)−ピリミジン−4−カルボン酸メチルエステル;および
6−(3−クロロ−4−メトキシ−フェニル)−ピリミジン−4−カルボン酸
から選択されるものではない、化学物質を提供する。
5員および6員の炭素環式芳香環、例えば、ベンゼン;
少なくとも1つの環が炭素環式芳香族である二環式環系、例えば、ナフタレン、インダン、およびテトラリン;ならびに
少なくとも1つの環が炭素環式芳香族である三環式環系、例えば、フルオレン
を包含する。
1個もしくは複数、例えば1〜4個、または一部の実施形態では1〜3個のN、OおよびSから選択されるヘテロ原子を含み、残りの環内原子が炭素である5〜7員の単環式の芳香環;ならびに
1個もしくは複数、例えば1〜4個、または一部の実施形態では1〜3個のN、OおよびSから選択されるヘテロ原子を含み、残りの環内原子が炭素であり、少なくとも1個のヘテロ原子が芳香環内に存在している二環式のヘテロシクロアルキル環
を包含する。例えば、ヘテロアリールとしては、5〜7員のヘテロシクロアルキル、5〜7員のシクロアルキル環と縮合している芳香環が挙げられる。また、例えば、ヘテロアリールとしては、5員または6員のヘテロシクロアルキル、5〜7員のアリール環と縮合している芳香環も挙げられる。環の一方のみが1個もしくは複数のヘテロ原子を含むかかる縮合二環式ヘテロアリール環系では、結合点はヘテロ芳香環またはシクロアルキル環に存在し得る。ヘテロアリール基内のS原子とO原子の総数が1を超える場合、該ヘテロ原子は互いに隣接していない。一部の実施形態では、ヘテロアリール基内のS原子とO原子の総数は2以下である。一部の実施形態では、芳香族複素環内のS原子とO原子の総数は1以下である。ヘテロアリール基の例としては、限定されないが、(1位と指定した結合位置から番号付けした場合)、2−ピリジル、3−ピリジル、4−ピリジル、2,3−ピラジニル、3,4−ピラジニル、2,4−ピリミジニル、3,5−ピリミジニル、2,3−ピラゾリニル、2,4−イミダゾリニル、イソオキサゾリル、イソオキサゾリニル、オキサゾリル、オキサゾリニル、オキサジアゾリル、チアゾリニル、チアジアゾリニル、テトラゾリル、チエニル、ベンゾチオフェニル、フラニル、ベンゾフラニル、ベンゾイミダゾリニル、ベンゾオキサゾリル、インドリニル、ピリジジニル、トリアゾリル、キノリニル、ピラゾリル、および5,6,7,8−テトラヒドロイソキノリンが挙げられる。名称が「−イル」で終わる一価のヘテロアリール原子団から、遊離原子価を有する炭素原子から1個の水素原子を除去することによって誘導される二価の原子団は、対応する一価の原子団の名称に「−イデン」を付けることによって呼称され、例えば、2つの結合点を有するピリジル基はピリジリデンと呼称される。ヘテロアリールは、上で定義したアリールを包含もせず、重複もしない。
−Ra、−ORb、−O(C1〜C2アルキル)O−(例えば、メチレンジオキシ−)、−SRb、グアニジン、グアニジン水素の1個もしくは複数が低級アルキル基で置き換えられているグアニジン、−NRbRc、ハロ、シアノ、オキソ(ヘテロシクロアルキルの置換基として)、ニトロ、−CORb、−CO2Rb、−CONRbRc、−OCORb、−OCO2Ra、−OCONRbRc、−NRcCORb、−NRcCO2Ra、−NRcCONRbRc、−SORa、−SO2Ra、−SO2NRbRc、および−NRcSO2Raから独立して選択される置換基によって置き換えられているアルキル、シクロアルキル、アリール、ヘテロシクロアルキル、およびヘテロアリールをそれぞれいい、
ここで、Raは、任意選択的に置換されているC1〜C6アルキル、任意選択的に置換されているシクロアルキル、任意選択的に置換されているアリール、任意選択的に置換されているヘテロシクロアルキル、および任意選択的に置換されているヘテロアリールから選択され;
Rbは、H、任意選択的に置換されているC1〜C6アルキル、任意選択的に置換されているシクロアルキル、任意選択的に置換されているアリール、任意選択的に置換されているヘテロシクロアルキル、および任意選択的に置換されているヘテロアリールから選択され;
Rcは、水素、および任意選択的に置換されているC1〜C4アルキルから選択されるか;あるいは
RbとRcおよびこれらが結合している窒素が、任意選択的に置換されているヘテロシクロアルキル基を形成しており;
ここで、任意選択的に置換されている基は、各々、非置換であるか、または独立して、C1〜C4アルキル、シクロアルキル、アリール、ヘテロシクロアルキル、ヘテロアリール、アリール−C1〜C4アルキル−、ヘテロアリール−C1〜C4アルキル−、C1〜C4ハロアルキル−、−OC1〜C4アルキル、−OC1〜C4アルキルフェニル、−C1〜C4アルキル−OH、−C1〜C4アルキル−O−C1〜C4アルキル、−OC1〜C4ハロアルキル、ハロ、−OH、−NH2、−C1〜C4アルキル−NH2、−N(C1〜C4アルキル)(C1〜C4アルキル)、−NH(C1〜C4アルキル)、−N(C1〜C4アルキル)(C1〜C4アルキルフェニル)、−NH(C1〜C4アルキルフェニル)、シアノ、ニトロ、オキソ(ヘテロアリールの置換基として)、−CO2H、−C(O)OC1〜C4アルキル、−CON(C1〜C4アルキル)(C1〜C4アルキル)、−CONH(C1〜C4アルキル)、−CONH2、−NHC(O)(C1〜C4アルキル)、−NHC(O)(フェニル)、−N(C1〜C4アルキル)C(O)(C1〜C4アルキル)、−N(C1〜C4アルキル)C(O)(フェニル)、−C(O)C1〜C4アルキル、−C(O)C1〜C4フェニル、−C(O)C1〜C4ハロアルキル、−OC(O)C1〜C4アルキル、−SO2(C1〜C4アルキル)、−SO2(フェニル)、−SO2(C1〜C4ハロアルキル)、−SO2NH2、−SO2NH(C1〜C4アルキル)、−SO2NH(フェニル)、−NHSO2(C1〜C4アルキル)、−NHSO2(フェニル)、および−NHSO2(C1〜C4ハロアルキル)から独立して選択される1つもしくは複数(例えば、1つ、2つまたは3つ)の置換基で置換されている。
Pharmaceutical Association and Pergamon
Press,1987,ならびにDesign of Prodrugs,H.Bundgaard編,Elsevier,1985に示されている。
Geometry in Organic Crystals”,Accounts of Chemical Research,17,pp.320−326(1984))。
a)疾患の予防、すなわち、疾患の臨床症状を発現させなくすること;
b)疾患進行の抑止;
c)臨床症状の発現の遅滞もしくは停止;および/または
d)疾患の軽減、すなわち、臨床症状の後退を引き起こすこと
が含まれる。
XおよびYは、独立して−N−および−CH−から選択されるが、ただし、XとYのうち少なくとも一方は−N−であるものとし;
R1は、アリールまたは単環式ヘテロアリールであり、該アリールまたは単環式ヘテロアリールの各々は、
式−Z−R6の第1の基、および
第2の基
で置換されており、ここで、
Zは、−O−、−S−、−S(O)−、−S(O)2−、−CR11R12−、−OCR11R12−、−NR13−、−NR13CR11R12−、−CR11R12NR13−、および−C(O)−(式中、R11、R12およびR13は独立して、水素、低級アルキル、ヒドロキシルおよび低級アルコキシから選択される)から選択され、
R6は、水素、任意選択的に置換されているC1〜C6アルキル、任意選択的に置換されているシクロアルキル、任意選択的に置換されているアリール、任意選択的に置換されているヘテロアリール、および任意選択的に置換されているヘテロシクロアルキルから選択されるが、ただし、Zが−O−である場合、R6は、任意選択的に置換されているベンジルでも任意選択的に置換されているピリジルメチルでもないものとするか、または
R6とR13が、これらが結合している窒素と一体となって、任意選択的に置換されている5〜7員のヘテロシクロアルキル環を形成しており、
該第2の基は、ハロおよびハロで任意選択的に置換されている低級アルキルから選択されるか、あるいは
R1は、2,3−ジヒドロベンゾフラン−5−イル、クロマン−6−イル、1,3−ベンゾジオキソール−5−イル、2,3−ジヒドロ−1,4−ベンゾジオキシン−6−イル、1,3−ベンゾオキサゾール−5−イル、1,3−ベンゾオキサゾール−6−イル、2−オキソ−2,3−ジヒドロ−1,3−ベンゾオキサゾール−5−イル、ベンゾチオフェン−5−イル、ベンゾチアゾール−5−イル、ベンゾイミダゾール−5−イル、ベンゾフラン−5−イル、1H−インドール−5−イル、1H−インダゾール−5−イル、イソインドリン−5−イル、ベンゾ[c][1,2,5]オキサジアゾール−5−イル、1,2,3,4−テトラヒドロキノリン−6−イル、イミダゾ[1,2−a]ピリジン−6−イル、ピラゾロ[1,5−a]ピリジン−5−イル、キノリン−6−イル、キナゾリン−6−イル、キナゾリン−7−イルおよびキノキサリン−6−イル(これらの各々は、任意選択的に置換されている)から選択されるか、
あるいは
R1とR3が、介在原子と一体となって、式
の二環式環を形成しており;
R2は、水素および任意選択的に置換されている低級アルキルから選択され;
R3は、水素、ハロ、任意選択的に置換されている低級アルキル、ヒドロキシル、任意選択的に置換されている低級アルコキシ、および任意選択的に置換されているアミノから選択され;
Lは、−C(O)−、−C(O)O−、−C(O)N(R4)−、−C(O)N(OR7)−、−N(R4)S(O)2−、−S(O)2N(R4)−、および−C(O)N(R4)−S(O)2−から選択され;
R4は、水素および低級アルキルから選択され;
R5は、水素、任意選択的に置換されている低級アルキル、任意選択的に置換されているアリール、任意選択的に置換されているヘテロアリール、任意選択的に置換されているシクロアルキル、および任意選択的に置換されているヘテロシクロアルキルから選択されるが、ただし、Lが−N(R4)S(O)2−である場合、R5は水素でないものとするか、あるいは
R4とR5が、これらが結合している窒素と一体となって、任意選択的に置換されている4〜7員のヘテロシクロアルキル環を形成しており、該環は、任意選択的に置換されているシクロアルキル、任意選択的に置換されているヘテロシクロアルキル、任意選択的に置換されているアリールまたは任意選択的に置換されているヘテロアリール環と任意選択的に縮合しているか、あるいは
R3とR5が、介在原子と一体となって、任意選択的に置換されている5〜7員の環を形成しており;
R7は、水素および低級アルキルから選択される)
の化合物ならびにその薬学的に許容され得る塩およびプロドラッグから選択される少なくとも1種類の化学物質であるが、
ただし、式Iの化合物は
6−(3−クロロ−4−メチル−フェニル)−ピリミジン−4−カルボン酸メチルエステル;
6−(3−クロロ−4−メチル−フェニル)−ピリミジン−4−カルボン酸;
6−(3−クロロ−4−メトキシ−フェニル)−ピリミジン−4−カルボン酸メチルエステル;および
6−(3−クロロ−4−メトキシ−フェニル)−ピリミジン−4−カルボン酸
から選択されるものではない、化学物質を提供する。
式−Z−R6の第1の基(式中、Zは、−O−、−S−、−S(O)−、−S(O)2−、および−CR11R12−から選択され;R6は、水素、任意選択的に置換されているC1〜C6アルキル、任意選択的に置換されているシクロアルキル、および任意選択的に置換されているヘテロシクロアルキルから選択される)、ならびに
ハロおよびハロで任意選択的に置換されている低級アルキルから選択される第2の基
で置換されているフェニルである。
式−Z−R6の第1の基(式中、Zは、−O−、−S−、−S(O)−、−S(O)2−、および−CR11R12−から選択され;R6は、水素、任意選択的に置換されているC1〜C6アルキル、任意選択的に置換されているシクロアルキル、および任意選択的に置換されているヘテロシクロアルキルから選択される)、ならびに
ハロおよびハロで任意選択的に置換されている低級アルキルから選択される第2の基
で置換されているピリジニルである。
の化合物ならびにその薬学的に許容され得る塩およびプロドラッグから選択される少なくとも1種類の化学物質を提供する。
6−(4−クロロ−3−メトキシ−フェニル)−ピリミジン−4−カルボン酸、
6−(3−アミノ−4−クロロ−フェニル)−ピリミジン−4−カルボン酸、
6−[4−クロロ−3−(テトラヒドロ−フラン−3−イルオキシ)−フェニル]−ピリミジン−4−カルボン酸、
6−[4−クロロ−3−(テトラヒドロ−フラン−3−イルオキシ)−フェニル]−ピリミジン−4−カルボン酸ピリジン−3−イルアミド、
6−[4−クロロ−3−(2−モルホリン−4−イル−エトキシ)−フェニル]−ピリミジン−4−カルボン酸ピリジン−3−イル−アミド、
6−(3−クロロ−4−イソプロピル−フェニル)−ピリミジン−4−カルボン酸、
6−(3−フルオロ−4−メチル−フェニル)−ピリミジン−4−カルボン酸、
6−(3−クロロ−4−イソプロポキシ−フェニル)−ピリミジン−4−カルボン酸、
6−(3−クロロ−4−イソプロポキシ−フェニル)−2−メチル−ピリミジン−4−カルボン酸、
6−(3−フルオロ−4−メチル−フェニル)−2−メチル−ピリミジン−4−カルボン酸、
6−(3−クロロ−4−シクロペンチルオキシ−フェニル)−ピリミジン−4−カルボン酸、
6−(3−クロロ−4−トリフルオロメトキシ−フェニル)−ピリミジン−4−カルボン酸、
6−(3−フルオロ−4−イソプロピル−フェニル)−ピリミジン−4−カルボン酸、
6−(4−(R)−sec−ブトキシ−3−クロロ−フェニル)−ピリミジン−4−カルボン酸、
6−(4−(S)−sec−ブトキシ−3−クロロ−フェニル)−ピリミジン−4−カルボン酸、
6−(3−クロロ−4−シクロプロポキシ−フェニル)−ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(2,2,2−トリフルオロ−1−メチル−エトキシ)−フェニル]−ピリミジン−4−カルボン酸、
4−(3−クロロ−4−シクロプロポキシ−フェニル)−ピリジン−2−カルボン酸、
6−(4−(R)−sec−ブトキシ−3−クロロ−フェニル)−ピリジン−4−カルボン酸、
6−(4−(S)−sec−ブトキシ−3−クロロ−フェニル)−ピリジン−4−カルボン酸、
4−(3−クロロ−4−イソプロポキシ−フェニル)−ピリジン−2−カルボン酸、
4−(3−クロロ−4−トリフルオロメトキシ−フェニル)−ピリジン−2−カルボン酸、
6−(3−クロロ−4−シクロブトキシ−フェニル)−ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(2−ピペリジン−1−イル−エトキシ)−フェニル]−ピリミジン−4−カルボン酸、
6−キノリン−6−イル−ピリミジン−4−カルボン酸、
6−(8−クロロ−クロマン−6−イル)−ピリミジン−4−カルボン酸、
6−(7−クロロ−ベンゾフラン−5−イル)−ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(ピロリジン−3−イルオキシ)−フェニル]−ピリミジン−4−カルボン酸、
6−(8−クロロ−1−メチル−1,2,3,4−テトラヒドロキノリン−6−イル)ピリミジン−4−カルボン酸、
6−(8−クロロキノリン−6−イル)ピリミジン−4−カルボキシレート、
N−[6−(3−クロロ−4−シクロプロポキシフェニル)ピリミジン−4−イル]ベンゼンスルホンアミド、
N−[6−(3−クロロ−4−シクロプロポキシフェニル)ピリミジン−4−イル]−4−フルオロベンゼン−1−スルホンアミド、
N−[6−(3−クロロ−4−シクロプロポキシフェニル)ピリミジン−4−イル]−4−(トリフルオロメトキシ)ベンゼン−1−スルホンアミド、
N−[6−(3−クロロ−4−シクロプロポキシフェニル)ピリミジン−4−イル]−3−(トリフルオロメトキシ)ベンゼン−1−スルホンアミド、
N−[6−(3−クロロ−4−シクロプロポキシフェニル)ピリミジン−4−イル]−2−フルオロベンゼン−1−スルホンアミド、
N−[6−(3−クロロ−4−シクロプロポキシフェニル)ピリミジン−4−イル]シクロプロパンスルホンアミド、
6−(8−クロロ−1,2,3,4−テトラヒドロキノリン−6−イル)ピリミジン−4−カルボキシレート、
6−(3−クロロ−4−シクロプロポキシフェニル)−5−メチルピリミジン−4−カルボキシレート、
6−{3−クロロ−4−[2−(モルホリン−4−イル)エトキシ]フェニル}ピリミジン−4−カルボキシレート、
6−[3−クロロ−4−(シクロプロピルメトキシ)フェニル]ピリミジン−4−カルボキシレート、
6−[3−クロロ−4−(オキセタン−3−イルオキシ)フェニル]ピリミジン−4−カルボキシレート、
4−(3−クロロ−4−シクロプロポキシフェニル)−5H,7H−フロ[3,4−d]ピリミジン−7−オン、
6−(3−クロロ−4−シクロプロポキシフェニル)−5−(ヒドロキシメチル)ピリミジン−4−カルボン酸、
4−(3−クロロ−4−シクロプロポキシフェニル)−5H,6H,8H−ピラノ[3,4−d]ピリミジン−8−オン、
6−(3−クロロ−4−シクロプロポキシフェニル)ピリミジン−4−カルボン酸[(2R,3S,4S,5R)−3,4,5,6−テトラヒドロキシオキサン−2−イル]メチル、
6−(3−クロロ−4−{[1−(モルホリン−4−イル)プロパン−2−イル]オキシ}フェニル)ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(シクロプロポキシメチル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(シクロプロピルメチル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(シクロプロピルスルファニル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(シクロプロパンスルフィニル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(シクロプロパンスルホニル)フェニル]ピリミジン−4−カルボン酸、
6−{3−クロロ−4−[シクロプロピル(ヒドロキシ)メチル]フェニル}ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(1−シクロプロポキシエチル)フェニル]ピリミジン−4−カルボン酸、
6−(3−クロロ−4−シクロプロパンカルボニルフェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−シクロプロピルフェニル)ピリミジン−4−カルボン酸、
6−[4−(アジリジン−1−イルメチル)−3−クロロフェニル]ピリミジン−4−カルボン酸、
6−{3−クロロ−4−[(ジメチルアミノ)メチル]フェニル}ピリミジン−4−カルボン酸
6−[3−クロロ−4−(シクロプロピルアミノ)フェニル]ピリミジン−4−カルボン酸、
6−{3−クロロ−4−[シクロプロピル(メチル)アミノ]フェニル}ピリミジン−4−カルボン酸、
6−{3−クロロ−4−[(シクロプロピルアミノ)メチル]フェニル}ピリミジン−4−カルボン酸、
6−(3−クロロ−4−{[シクロプロピル(メチル)アミノ]メチル}フェニル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2−シクロプロピル−2,3−ジヒドロ−1H−イソインドール−5−イル)ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(フラン−2−イル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(1−メトキシシクロプロピル)フェニル]ピリミジン−4−カルボン酸、
6−(2,3−ジヒドロ−1,4−ベンゾジオキシン−6−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2−メチル−1,3−ベンゾオキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2−オキソ−2,3−ジヒドロ−1,3−ベンゾオキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−3−メチル−2−オキソ−2,3−ジヒドロ−1,3−ベンゾオキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2−シクロプロピル−1,3−ベンゾオキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−{8−クロロイミダゾ[1,2−a]ピリジン−6−イル}ピリミジン−4−カルボン酸、
6−(4−クロロ−1,3−ベンゾオキサゾール−6−イル)ピリミジン−4−カルボン酸、
6−(キノリン−6−イル)ピリミジン−4−カルボン酸、
6−{ピラゾロ[1,5−a]ピリジン−5−イル}ピリミジン−4−カルボン酸、
6−(4−クロロ−3−シクロプロポキシフェニル)ピリミジン−4−カルボン酸、
6−(4−クロロ−3−メトキシフェニル)ピリミジン−4−カルボン酸、
6−[4−クロロ−3−(プロパン−2−イルオキシ)フェニル]ピリミジン−4−カルボン酸、
6−[4−クロロ−3−(2−メチルプロポキシ)フェニル]ピリミジン−4−カルボン酸、
6−[4−クロロ−3−(トリフルオロメトキシ)フェニル]ピリミジン−4−カルボン酸、
6−{4−クロロ−3−[(1,1,1−トリフルオロプロパン−2−イル)オキシ]フェニル}ピリミジン−4−カルボン酸、
6−(ベンゾ[d][1,3]ジオキソール−5−イル)ピリミジン−4−カルボン酸、
6−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)ピリミジン−4−カルボン酸、
6−(2,3−ジヒドロベンゾ[b][1,4]ジオキシン−6−イル)ピリミジン−4−カルボン酸、
6−(7−クロロベンゾ[b]チオフェン−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロベンゾ[d]チアゾール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロベンゾ[d]オキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロベンゾ[c][1,2,5]オキサジアゾール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2,3,3a,7a−テトラヒドロベンゾフラン−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−3a,7a−ジヒドロ−1H−インドール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−1−メチル−3a,7a−ジヒドロ−1H−インダゾール−5−イル)ピリミジン−4−カルボン酸、
6−(8−クロロキナゾリン−6−イル)ピリミジン−4−カルボン酸、
6−(5−クロロキナゾリン−7−イル)ピリミジン−4−カルボン酸、
6−(8−クロロキノキサリン−6−イル)ピリミジン−4−カルボン酸、
6−(8−クロロ−1,2,3,4−テトラヒドロキノリン−6−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−1H−ベンゾ[d]イミダゾール−5−イル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(1−メチルシクロプロピル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(1−(トリフルオロメチル)シクロプロピル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(3−メチルオキセタン−3−イル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(ピロリジン−1−イル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(ピロリジン−3−イル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(ピロリジン−2−イル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(1H−イミダゾール−2−イル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(1H−ピロール−2−イル)フェニル)ピリミジン−4−カルボン酸、
6−(4−tert−ブチル−3−クロロフェニル)ピリミジン−4−カルボン酸、および
7−クロロ−8−シクロプロポキシ−5H−クロメノ[4,3−d]ピリミジン−4−カルボン酸
から選択される化合物またはその薬学的に許容され得る塩もしくはプロドラッグを提供する。
6−[3−クロロ−4−(メチルスルファニル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(メチルスルフィニル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(メチルスルホニル)フェニル]ピリミジン−4−カルボン酸、
6−{3−クロロ−4−[シクロプロピル(ヒドロキシ)メチル]フェニル}ピリミジン−4−カルボン酸、
6−(3−クロロ−4−シクロプロパンカルボニルフェニル)ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(メトキシメチル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(1−メトキシエチル)フェニル]ピリミジン−4−カルボン酸、
6−{3−クロロ−4−[(ジメチルアミノ)メチル]フェニル}ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(シクロプロピルアミノ)フェニル]ピリミジン−4−カルボン酸、
6−{3−クロロ−4−[シクロプロピル(メチル)アミノ]フェニル}ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(ピロリジン−1−イル)フェニル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2−メチル−1,3−ベンゾオキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−(8−クロロキノキサリン−6−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2,3−ジヒドロ−1−ベンゾフラン−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2−シクロプロピル−1,3−ベンゾオキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−(4−クロロ−2−メチル−1,3−ベンゾオキサゾール−6−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−3−メチル−2−オキソ−2,3−ジヒドロ−1,3−ベンゾオキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−(2H−1,3−ベンゾジオキソール−5−イル)ピリミジン−4−カルボン酸、
4−(3,4−ジクロロフェニル)−5−メチルピリジン−2−カルボン酸、
6−(3−クロロ−4−{[1−(モルホリン−4−イル)プロパン−2−イル]オキシ}フェニル)ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(シクロプロポキシメチル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(シクロプロピルメチル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(1−シクロプロポキシエチル)フェニル]ピリミジン−4−カルボン酸、
6−(3−クロロ−4−シクロプロピルフェニル)ピリミジン−4−カルボン酸、
6−[4−(アジリジン−1−イルメチル)−3−クロロフェニル]ピリミジン−4−カルボン酸、
6−{3−クロロ−4−[(シクロプロピルアミノ)メチル]フェニル}ピリミジン−4−カルボン酸、
6−(3−クロロ−4−{[シクロプロピル(メチル)アミノ]メチル}フェニル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2−シクロプロピル−2,3−ジヒドロ−1H−イソインドール−5−イル)ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(フラン−2−イル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(1−メトキシシクロプロピル)フェニル]ピリミジン−4−カルボン酸、
6−(2,3−ジヒドロ−1,4−ベンゾジオキシン−6−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2−オキソ−2,3−ジヒドロ−1,3−ベンゾオキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−{8−クロロイミダゾ[1,2−a]ピリジン−6−イル}ピリミジン−4−カルボン酸、
6−(4−クロロ−1,3−ベンゾオキサゾール−6−イル)ピリミジン−4−カルボン酸、
6−(キノリン−6−イル)ピリミジン−4−カルボン酸、
6−{ピラゾロ[1,5−a]ピリジン−5−イル}ピリミジン−4−カルボン酸、
6−(4−クロロ−3−シクロプロポキシフェニル)ピリミジン−4−カルボン酸、
6−(4−クロロ−3−メトキシフェニル)ピリミジン−4−カルボン酸、
6−[4−クロロ−3−(プロパン−2−イルオキシ)フェニル]ピリミジン−4−カルボン酸、
6−[4−クロロ−3−(2−メチルプロポキシ)フェニル]ピリミジン−4−カルボン酸、
6−[4−クロロ−3−(トリフルオロメトキシ)フェニル]ピリミジン−4−カルボン酸、
6−{4−クロロ−3−[(1,1,1−トリフルオロプロパン−2−イル)オキシ]フェニル}ピリミジン−4−カルボン酸、
6−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)ピリミジン−4−カルボン酸、
6−(2,3−ジヒドロベンゾ[b][1,4]ジオキシン−6−イル)ピリミジン−4−カルボン酸、
6−(7−クロロベンゾ[b]チオフェン−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロベンゾ[d]チアゾール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロベンゾ[d]オキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロベンゾ[c][1,2,5]オキサジアゾール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−3a,7a−ジヒドロ−1H−インドール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−1−メチル−3a,7a−ジヒドロ−1H−インダゾール−5−イル)ピリミジン−4−カルボン酸、
6−(8−クロロキナゾリン−6−イル)ピリミジン−4−カルボン酸、
6−(5−クロロキナゾリン−7−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−1H−ベンゾ[d]イミダゾール−5−イル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(1−メチルシクロプロピル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(1−(トリフルオロメチル)シクロプロピル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(3−メチルオキセタン−3−イル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(ピロリジン−2−イル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(1H−イミダゾール−2−イル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(1H−ピロール−2−イル)フェニル)ピリミジン−4−カルボン酸、
6−(4−tert−ブチル−3−クロロフェニル)ピリミジン−4−カルボン酸、および
7−クロロ−8−シクロプロポキシ−5H−クロメノ[4,3−d]ピリミジン−4−カルボン酸、
から選択される化合物またはその薬学的に許容され得る塩もしくはプロドラッグを提供する。
本明細書に記載の化学物質、組成物および方法を、以下の非限定的な実施例によってさらに例示する。
DCM=ジクロロメタン
DME=ジメチルエーテル
DMEM=ダルベッコ改変イーグル培地
DMF=N,N−ジメチルホルムアミド
DMSO=ジメチルスルホキシド
EDC・HCl=1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩
EtOH=エタノール
Et2O=ジエチルエーテル
EtOAc=酢酸エチル
g=グラム
hr=時間
hrs=時間(複数)
HOBt=1−ヒドロキシベンゾトリアゾール
LiHMDS=リチウムヘキサメチル−ジシラジド
LC/MS=液体クロマトグラフィー/質量分析
mg=ミリグラム
min=分
mL=ミリリットル
mmol=ミリモル
mM=ミリモル濃度
ng=ナノグラム
nm=ナノメートル
nM=ナノモル濃度
PBS=リン酸緩衝生理食塩水
rt=室温
TBME=t−ブチルメチルエーテル
THF=テトラヒドロフラン
TMOF=オルトギ酸トリメチル
μL=マイクロリットル
μM=マイクロモル濃度
1g/1ml=1体積。
市販の試薬および溶媒(HPLC等級)は、さらに精製することなく使用した。
反応スキーム1
フェニルシクロプロパンカルボキシレートの粗製の4:1:1の混合物(2.77g)をトルエン(30mL)に溶解させた。TsOH一水和物(2.54g,13.4mmol)を添加し、反応液を115℃で16時間撹拌した。反応物を室温まで冷却し、濃縮し、褐色油状物を得た。残渣をEtOAc(100mL)に再度溶解させた。この溶液を飽和水性重炭酸ナトリウム(3×100mL)、水(3×100mL)、ブライン(50mL)で洗浄し、乾燥させた(MgSO4)。濾過および濃縮により褐色油状物を得た。カラムクロマトグラフィーにより(溶出:0から10%までのEtOAc−ヘプタン)、所望の化合物(1.18g,42%)をオレンジ色の結晶性固形物として得た。δH(500 MHz,DMSO)7.85(d,J=1.73 Hz,1 H)7.68(d,J=1.58 Hz,1 H)2.27 − 2.40(m,1 H)1.08 − 1.38(m,4 H);Tr(3分)=2.38分 m/z(ES+)(M+H)+ 272,274。
L−キヌレニン(KYN)のヒドロキシル化による生成物3−ヒドロキシ−キヌレニン(3OH−KYN)の形成をLC/MSによってモニタリングするための一般化手順を以下に記載する。生成物は、MSを用いた多重反応モニタリングによって定量する。
化合物:ストック濃度:100%DMSO中10mM。
細胞株:CHO GST HIS KMO細胞株,1E4細胞/ウェル/100μl(96ウェル細胞プレート内)。
基質:L−キヌレニン(Sigma:カタログ番号K3750,ストック濃度:100mMリン酸カリウムバッファー(pH7.4)中10mM)。
アッセイ条件:
培地:OptiMem(Reduced Serum Medium 1×,+L−グルタミン+HEPES−フェノールレッド;GIBCO:カタログ番号11058)。
アッセイ体積:200μl。
プレート形式:96ウェルプレート,透明(Corning)。
読み出し:生成物特異的MRMを用いた生成物(3OH−KYN)の定量。
読取り装置:LC/MS/MS。
アッセイプロトコル:
・100%DMSO中で化合物の連続希釈物(係数3)を調製する(最高濃度=6.67mM,100%DMSO)
[8点:6.67mM;2.22mM;0.74mM;0.247mM;0.082mM;0.027mM;0.009mM;0.003mM]。
・OptiMem培地中で各化合物濃度の300倍濃縮溶液(最高濃度22.22μM,0.3%DMSO)を調製する
[22.2μM;7.41μM;2.47μM;0.82μM;0.27μM;0.09μM;0.03μM;0.01μM]。
・基質(10mM)を培地中1.1mMの濃度に調製する。
・細胞プレート内の培地を廃棄する。
・細胞をOptiMem(100μl/ウェル)で洗浄し、再度培地を廃棄する。
・アッセイミックス:90μlのOptiMem/ウェル+90μlの化合物/ウェル(各濃度)
[最終化合物の最高濃度:10μM;0.15%DMSO]
[最終化合物の最低濃度:0.004μM;0.15%DMSO]。
・プレインキュベーション:37℃で30分間。
・20μl/ウェルの1.1mM基質溶液を添加する(最終アッセイ濃度:100μM)。
・陽性対照:200μlのOptiMem。
・陰性対照:180μlのOptiMem+20μlの1.1mM基質。
・37℃で約24時間インキュベートする。
・各ウェル内の100μlを透明な96ウェルプレート(Corning)に移す。
・100μl/ウェルの10%トリクロロ酢酸(TCA)含有水を添加する。
・プレートを4000rpmで3分間遠心分離する。
・生成物をLC/MSによって検出する(50μl/ウェルをインジェクション;20μl容の試料ループの2.5倍過剰を充填)。
データ解析:IC50を、自動フィッティングアルゴリズム(A+ Analysis)を用いて計算する。
L−キヌレニン(KYN)のヒドロキシル化による生成物3−ヒドロキシ−キヌレニン(3OH−KYN)の形成をLC/MSによってモニタリングする方法を以下に記載する。生成物は、多重反応モニタリングによって定量する。
化合物:ストック濃度:100%DMSO中10mM。
酵素:EvotecにおいてCHO−GST HIS KMO細胞からのミトコンドリアの単離によって調製されたKMO酵素。
基質:L−キヌレニン(Sigma:カタログ番号K3750)
[ストック濃度:100mMリン酸カリウムバッファー(pH7.4)中10mM]。
アッセイ条件:
バッファー:100mMリン酸カリウム,pH7.4,200μM NADPH,0.4U/ml G6P−DH(グルコース6−リン酸デヒドロゲナーゼ),3mM G6P(D−グルコース6−リン酸)。
アッセイ体積:40μl。
プレート形式:384ウェルプレート,透明(Matrix)。
読み出し:生成物特異的MRMを用いた生成物(3OH−KYN)の定量。
読取り装置:LC/MS/MS。
アッセイプロトコル:
・100%DMSO中で化合物の連続希釈物(係数3)を調製する(最高濃度=10mM,100%DMSO)
[8点:10mM;3.33mM;1.11mM;0.37mM;0.12mM;0.04mM;0.0137mM;0.0045mM,0.0015mM]。
・アッセイバッファー中で各化合物濃度の3.33倍濃縮溶液を調製する(最高濃度300μM,3%DMSO)
[濃度:300μM;100μM;33.3μM;11.1μM;3.70μM;1.23μM;0.41μM;0.137μM]。
・基質(10mM)をアッセイバッファー中1mMの濃度に調製する。
・アッセイミックス:4μlの化合物/ウェル(各濃度)+24μlのアッセイバッファー/ウェル+8μlのKMOヒト酵素+4μlの1mM基質(終濃度=100μM)
[最終化合物の最高濃度:30μM;0.3%DMSO]
[最終化合物の最低濃度:0.0137μM;0.3%DMSO]。
・陽性対照:4μlの50μM FCE28833(アッセイバッファー[0.5%DMSO]中)(最終アッセイ濃度=5μM)+24μlのアッセイバッファー/ウェル+8μlのKMOヒト酵素+4μlの1mM基質(終濃度=100μM)。
・陰性対照:28μlのアッセイバッファー/ウェル+8μlのKMOヒト酵素+4μlの1mM基質(終濃度=100μM)。
・室温で400分間インキュベートする。
・40μl/ウェルの10%トリクロロ酢酸含有水を添加してアッセイを終了させ、タンパク質を沈殿させる。
・プレートを4000rpmで3分間遠心分離する。
・LC/MSによって生成物を検出する(50μl/ウェルをインジェクション;20μl容の試料ループの2.5倍過剰を充填)。
データ解析:IC50を、自動フィッティングアルゴリズム(A+ Analysis)を用いて計算する。
L−キヌレニン(KYN)のヒドロキシル化による3−ヒドロキシ−キヌレニン(3OH−KYN)の形成をLC/MSによってモニタリングする方法を記載する。生成物は、多重反応モニタリング(MRM法)によって定量する。
化合物:ストック濃度:100%DMSO中10mM。
酵素:Evotecにおいてマウス肝臓(4〜6週齢)からミトコンドリア単離によって文献に記載のようにして調製されたKMO酵素。
基質:L−キヌレニン(Sigma:カタログ番号K3750,ストック濃度:100mMリン酸カリウムバッファー(pH7.4)中10mM)。
アッセイ条件:
バッファー:100mMリン酸カリウム,pH7.4,200μM NADPH,0.4U/ml G6P−DH(グルコース6−リン酸デヒドロゲナーゼ),3mM G6P(D−グルコース6−リン酸)。
アッセイ体積:40μl。
プレート形式:384ウェルプレート,透明(Matrix)。
読み出し:生成物特異的MRMを用いた生成物(3OH−KYN)の定量。
読取り装置:LC/MS/MS。
アッセイプロトコル:
・100%DMSO中で化合物の連続希釈物(係数3)を調製する(最高濃度=10mM,100%DMSO)
[8点:10mM;3.33mM;1.11mM;0.37mM;0.12mM;0.04mM;0.0137mM;0.0045mM,0.0015mM]。
・アッセイバッファー中で各化合物濃度の3.33倍濃縮溶液を調製する(最高濃度300μM,3%DMSO)
[濃度:300μM;100μM;33.3μM;11.1μM;3.70μM;1.23μM;0.41μM;0.137μM]。
・基質(10mM)をアッセイバッファー中1mMの濃度に調製する。
・アッセイミックス:4μlの化合物/ウェル(各濃度)+24μlのアッセイバッファー/ウェル+8μlのKMOマウス酵素+4μlの1mM基質(終濃度=100μM)
[最終化合物の最高濃度:30μM;0.3%DMSO]
[最終化合物の最低濃度:0.0137μM;0.3%DMSO]。
・陽性対照:4μlの50μM FCE28833(アッセイバッファー(0.5%DMSO)中)[最終アッセイ濃度=5μM]+24μlのアッセイバッファー/ウェル+8μlのKMOマウス酵素+4μlの1mM基質[終濃度=100μM]。
・陰性対照:28μlのアッセイバッファー/ウェル+8μlのKMOマウス酵素+4μlの1mM基質[終濃度=100μM]。
・室温で40分間インキュベートする。
・40μl/ウェルの10%トリクロロ酢酸含有水を添加してアッセイを終了させ、タンパク質を沈殿させる。
・プレートを4000rpmで3分間遠心分離する。
・LC/MSによって生成物を検出する(20μl/ウェルをインジェクション,10μlの試料ループの2倍過剰を充填)。
データ解析:IC50を、自動フィッティングアルゴリズム(A+ Analysis)を用いて計算する。
本明細書に記載のものと同様の手順を使用し、以下の化合物を活性についてアッセイした。
方法A.アミドカップリング.DMF中のカルボン酸(1当量)の溶液に、EDC.HCl(1当量)とHOBt(1〜1.2当量)またはHATU(1〜1.2当量)を添加した。反応混合物を周囲温度で30分間撹拌し、その後、適切なアミン(1当量)を添加した。反応を終了までLCMSによってモニタリングし、終了したら反応混合物を水に注入した。得られた析出物を濾過し、水(2回)、ヘプタン(2回)で洗浄し、真空乾燥させ、目的化合物を得た。析出物が形成されなかった場合は、反応混合物をEtOAc(3回)で抽出し、合わせた有機層を水(2回)、飽和水性NaCl(2回)で洗浄し、乾燥させ(Na2SO4またはMgSO4)溶媒を真空除去し、粗生成物を得た。精製を、フラッシュカラムクロマトグラフィー、分取用HPLCまたは両方の組合せによって行った。
Claims (39)
- 式I
XおよびYは、独立して−N−および−CH−から選択されるが、ただし、XとYのうち少なくとも一方は−N−であるものとし;
R1は、アリールまたは単環式ヘテロアリールであり、該アリールまたは単環式ヘテロアリールの各々は、
式−Z−R6の第1の基、および
第2の基
で置換されており、ここで、
Zは、−O−、−S−、−S(O)−、−S(O)2−、−CR11R12−、−OCR11R12−、−NR13−、−NR13CR11R12−、−CR11R12NR13−、および−C(O)−(式中、R11、R12およびR13は独立して、水素、低級アルキル、ヒドロキシルおよび低級アルコキシから選択される)から選択され、
R6は、水素、任意選択的に置換されているC1〜C6アルキル、任意選択的に置換されているシクロアルキル、任意選択的に置換されているアリール、任意選択的に置換されているヘテロアリール、および任意選択的に置換されているヘテロシクロアルキルから選択されるが、ただし、Zが−O−である場合、R6は、任意選択的に置換されているベンジルでも任意選択的に置換されているピリジルメチルでもないものとするか、または
R6とR13が、これらが結合している窒素と一体となって、任意選択的に置換されている5〜7員のヘテロシクロアルキル環を形成しており、
該第2の基は、ハロおよびハロで任意選択的に置換されている低級アルキルから選択されるか、あるいは
R1は、2,3−ジヒドロベンゾフラン−5−イル、クロマン−6−イル、1,3−ベンゾジオキソール−5−イル、2,3−ジヒドロ−1,4−ベンゾジオキシン−6−イル、1,3−ベンゾオキサゾール−5−イル、1,3−ベンゾオキサゾール−6−イル、2−オキソ−2,3−ジヒドロ−1,3−ベンゾオキサゾール−5−イル、ベンゾチオフェン−5−イル、ベンゾチアゾール−5−イル、ベンゾイミダゾール−5−イル、ベンゾフラン−5−イル、1H−インドール−5−イル、1H−インダゾール−5−イル、イソインドリン−5−イル、ベンゾ[c][1,2,5]オキサジアゾール−5−イル、1,2,3,4−テトラヒドロキノリン−6−イル、イミダゾ[1,2−a]ピリジン−6−イル、ピラゾロ[1,5−a]ピリジン−5−イル、キノリン−6−イル、キナゾリン−6−イル、キナゾリン−7−イルおよびキノキサリン−6−イル(これらの各々は、任意選択的に置換されている)から選択されるか、あるいは
R1とR3が、介在原子と一体となって、式
の二環式環を形成しており;
R2は、水素および任意選択的に置換されている低級アルキルから選択され;
R3は、水素、ハロ、任意選択的に置換されている低級アルキル、ヒドロキシル、任意選択的に置換されている低級アルコキシ、および任意選択的に置換されているアミノから選択され;
Lは、−C(O)−、−C(O)O−、−C(O)N(R4)−、−C(O)N(OR7)−、−N(R4)S(O)2−、−S(O)2N(R4)−、および−C(O)N(R4)−S(O)2−から選択され;
R4は、水素および低級アルキルから選択され;
R5は、水素、任意選択的に置換されている低級アルキル、任意選択的に置換されているアリール、任意選択的に置換されているヘテロアリール、任意選択的に置換されているシクロアルキル、および任意選択的に置換されているヘテロシクロアルキルから選択されるが、ただし、Lが−N(R4)S(O)2−である場合、R5は水素でないものとするか、あるいは
R4とR5が、これらが結合している窒素と一体となって、任意選択的に置換されている4〜7員のヘテロシクロアルキル環を形成しており、該環は、任意選択的に置換されているシクロアルキル、任意選択的に置換されているヘテロシクロアルキル、任意選択的に置換されているアリールまたは任意選択的に置換されているヘテロアリール環と任意選択的に縮合しているか、あるいは
R3とR5が、介在原子と一体となって、任意選択的に置換されている5〜7員の環を形成しており;
R7は、水素および低級アルキルから選択される)
の化合物ならびにその薬学的に許容され得る塩およびプロドラッグから選択される少なくとも1種類の化学物質であるが、
ただし、式Iの化合物は
6−(3−クロロ−4−メチル−フェニル)−ピリミジン−4−カルボン酸メチルエステル;
6−(3−クロロ−4−メチル−フェニル)−ピリミジン−4−カルボン酸;
6−(3−クロロ−4−メトキシ−フェニル)−ピリミジン−4−カルボン酸メチルエステル;および
6−(3−クロロ−4−メトキシ−フェニル)−ピリミジン−4−カルボン酸
から選択されるものではない、
化学物質。 - R1が、
式−Z−R6の第1の基(式中、Zは、−O−、−S−、−S(O)−、−S(O)2−、および−CR11R12−から選択され;R6は、水素、任意選択的に置換されているC1〜C6アルキル、任意選択的に置換されているシクロアルキル、および任意選択的に置換されているヘテロシクロアルキルから選択される)、ならびに
ハロおよびハロで任意選択的に置換されている低級アルキルから選択される第2の基
で置換されているフェニルである、請求項1に記載の少なくとも1種類の化学物質。 - Zが−O−である、請求項1または2に記載の少なくとも1種類の化学物質。
- Zが−S−である、請求項1または2に記載の少なくとも1種類の化学物質。
- Zが−S(O)2−である、請求項1または2に記載の少なくとも1種類の化学物質。
- Zが−CR11R12−である、請求項1または2に記載の少なくとも1種類の化学物質。
- R6が、水素、メチル、ジフルオロメチル、トリフルオロメチル、エチル、2,2,2−トリフルオロ−1−メチル−エチル、イソプロピル、(S)−sec−ブチル、(R)−sec−ブチル、シクロプロピル、シクロブチル、シクロペンチル、2−モルホリン−4−イル−エチル、2−ピペリジン−1−イル−エチル、ピロリジン−3−イル、およびテトラヒドロ−フラン−3−イルから選択される、請求項1〜6のいずれか1項に記載の少なくとも1種類の化学物質。
- R1が、3−クロロ−4−シクロブトキシ−フェニル、3−クロロ−4−シクロペンチルオキシ−フェニル、3−クロロ−4−シクロプロポキシ−フェニル、3−クロロ−4−イソプロポキシ−フェニル、3−クロロ−4−メトキシ−フェニル、[4−クロロ−3−(2−モルホリン−4−イル−エトキシ)−フェニル、3−クロロ−4−(2−ピペリジン−1−イル−エトキシ)−フェニル、3−クロロ−4−(ピロリジン−3−イルオキシ)−フェニル、4−(S)−sec−ブトキシ−3−クロロ−フェニル、4−(R)−sec−ブトキシ−3−クロロ−フェニル、4−クロロ−3−(テトラヒドロ−フラン−3−イルオキシ)−フェニル、3−クロロ−4−トリフルオロメトキシ−フェニル、3−クロロ−4−(2,2,2−トリフルオロ−1−メチル−エトキシ、3−メトキシ−フェニル、4−メトキシ−フェニル、3,4−ジメトキシフェニル、3−クロロ−4−イソプロピルフェニル、3−フルオロ−4−メチルフェニル、および3−フルオロ−4−イソプロピルフェニル、3,4−ビス(メチルスルファニル)フェニル、3,4−ビス(メチルスルホニル)フェニル、3,4−ビス(トリフルオロメトキシ)フェニル、3−クロロ−4−(ジフルオロメトキシ)フェニル、3−クロロ−4−(メチルスルファニル)フェニル、3−クロロ−4−(メチルスルホニル)フェニル、3−クロロ−4−(トリフルオロメトキシ)フェニル、3−クロロ−4−(シクロプロポキシメチル)フェニル、3−クロロ−4−(シクロプロピルメチル)フェニル、3−クロロ−4−(シクロプロパンスルフィニル)フェニル、3−クロロ−4−(シクロプロパンスルホニル)フェニル、3−クロロ−4−[シクロプロピル(ヒドロキシ)メチル]フェニル、3−クロロ−4−(1−シクロプロポキシエチル)フェニル、3−クロロ−4−シクロプロパンカルボニルフェニル、3−クロロ−4−シクロプロピルフェニル、4−(アジリジン−1−イルメチル)−3−クロロフェニル、3−クロロ−4−[(ジメチルアミノ)メチル]フェニル、3−クロロ−4−(シクロプロピルアミノ)フェニル、3−クロロ−4−[シクロプロピル(メチル)アミノ]フェニル、3−クロロ−4−[(シクロプロピルアミノ)メチル]フェニル、3−クロロ−4−{[シクロプロピル(メチル)アミノ]メチル}フェニル、3−クロロ−4−(1−メトキシシクロプロピル)フェニル、4−クロロ−3−[(1,1,1−トリフルオロプロパン−2−イル)オキシ]フェニル、4−クロロ−3−(トリフルオロメトキシ)フェニル、4−クロロ−3−(2−メチルプロポキシ)フェニル、4−クロロ−3−(プロパン−2−イルオキシ)フェニル、4−クロロ−3−(プロパン−2−イルオキシ)フェニル、4−クロロ−3−メトキシフェニル、4−クロロ−3−シクロプロポキシフェニル、および3−クロロ−4−{[1−(モルホリン−4−イル)プロパン−2−イル]オキシ}フェニルから選択される、請求項1に記載の少なくとも1種類の化学物質。
- R1が、3−クロロ−4−メトキシ−フェニル、3−クロロ−4−(トリフルオロメトキシ)フェニル、3−クロロ−4−シクロブトキシ−フェニル、3−クロロ−4−シクロプロポキシ−フェニル、3−クロロ−4−イソプロポキシ−フェニル、3−クロロ−4−メトキシ−フェニル、3−クロロ−4−(ピロリジン−3−イルオキシ)−フェニル、4−(S)−sec−ブトキシ−3−クロロ−フェニル、4−(R)−sec−ブトキシ−3−クロロ−フェニル、4−クロロ−3−(テトラヒドロ−フラン−3−イルオキシ)−フェニル、3−クロロ−4−トリフルオロメトキシ−フェニル、3−クロロ−4−(2,2,2−トリフルオロ−1−メチル−エトキシ、3−メトキシ−フェニル、4−メトキシ−フェニル、3,4−ジメトキシフェニル、3−クロロ−4−イソプロピルフェニル、3−フルオロ−4−メチルフェニル、および3−フルオロ−4−イソプロピルフェニル、3,4−ビス(トリフルオロメトキシ)フェニル、3−クロロ−4−(ジフルオロメトキシ)フェニル、3−クロロ−4−(トリフルオロメトキシ)フェニル、3−クロロ−4−(シクロプロポキシメチル)フェニル、3−クロロ−4−(シクロプロピルメチル)フェニル、3−クロロ−4−(シクロプロパンスルフィニル)フェニル、3−クロロ−4−(シクロプロパンスルホニル)フェニル、3−クロロ−4−[シクロプロピル(ヒドロキシ)メチル]フェニル、3−クロロ−4−(1−シクロプロポキシエチル)フェニル、3−クロロ−4−シクロプロパンカルボニルフェニル、3−クロロ−4−シクロプロピルフェニル、4−(アジリジン−1−イルメチル)−3−クロロフェニル、3−クロロ−4−[(ジメチルアミノ)メチル]フェニル、3−クロロ−4−(シクロプロピルアミノ)フェニル、3−クロロ−4−[シクロプロピル(メチル)アミノ]フェニル、3−クロロ−4−[(シクロプロピルアミノ)メチル]フェニル、3−クロロ−4−{[シクロプロピル(メチル)アミノ]メチル}フェニル、3−クロロ−4−(1−メトキシシクロプロピル)フェニル、4−クロロ−3−[(1,1,1−トリフルオロプロパン−2−イル)オキシ]フェニル、4−クロロ−3−(トリフルオロメトキシ)フェニル、4−クロロ−3−(2−メチルプロポキシ)フェニル、4−クロロ−3−(プロパン−2−イルオキシ)フェニル、4−クロロ−3−(プロパン−2−イルオキシ)フェニル、4−クロロ−3−メトキシフェニル、および4−クロロ−3−シクロプロポキシフェニルから選択される、請求項8に記載の少なくとも1種類の化学物質。
- R1が、1,3−ベンゾジオキソール−5−イル、クロマン−6−イル、2,3−ジヒドロベンゾフラン−5−イル、ベンゾフラン−5−イル、2,3−ジヒドロ−1H−イソインドール−5−イル、1,3−ベンゾオキサゾール−5−イル、2−オキソ−2,3−ジヒドロ−1,3−ベンゾオキサゾール−5−イル、1,3−ベンゾオキサゾール−5−イル、イミダゾ[1,2−a]ピリジン−6−イル、1,3−ベンゾオキサゾール−6−イル、キノリン−6−イル、およびピラゾロ[1,5−a]ピリジン−5−イル(これらの各々は、ハロ、ハロで任意選択的に置換されている低級アルキル、シクロアルキル、およびハロで任意選択的に置換されている低級アルコキシから選択される1つまたは2つの基で任意選択的に置換されている)から選択される、請求項1に記載の少なくとも1種類の化学物質。
- R1が、1,3−ベンゾジオキソール−5−イル、2,2−ジフルオロ−1,3−ベンゾジオキソール−5−イル、8−クロロ−クロマン−6−イル、7−クロロ−ベンゾフラン−5−イル、7−クロロ−2−シクロプロピル−2,3−ジヒドロ−1H−イソインドール−5−イル、7−クロロ−2−メチル−1,3−ベンゾオキサゾール−5−イル、7−クロロ−2−オキソ−2,3−ジヒドロ−1,3−ベンゾオキサゾール−5−イル、7−クロロ−3−メチル−2−オキソ−2,3−ジヒドロ−1,3−ベンゾオキサゾール−5−イル、7−クロロ−2−シクロプロピル−1,3−ベンゾオキサゾール−5−イル、8−クロロイミダゾ[1,2−a]ピリジン−6−イル、4−クロロ−1,3−ベンゾオキサゾール−6−イル、キノリン−6−イル、およびピラゾロ[1,5−a]ピリジン−5−イルから選択される、請求項10に記載の少なくとも1種類の化学物質。
- R1が、1,3−ベンゾジオキソール−5−イル、2,2−ジフルオロ−1,3−ベンゾジオキソール−5−イル、8−クロロ−クロマン−6−イル、7−クロロ−ベンゾフラン−5−イル、7−クロロ−2−メチル−1,3−ベンゾオキサゾール−5−イル、7−クロロ−2−シクロプロピル−1,3−ベンゾオキサゾール−5−イル、8−クロロイミダゾ[1,2−a]ピリジン−6−イル、4−クロロ−1,3−ベンゾオキサゾール−6−イル、キノリン−6−イル、およびピラゾロ[1,5−a]ピリジン−5−イルから選択される、請求項11に記載の少なくとも1種類の化学物質。
- R2が水素である、請求項1〜12のいずれか1項に記載の少なくとも1種類の化学物質。
- R2が低級アルキルである、請求項1〜12のいずれか1項に記載の少なくとも1種類の化学物質。
- R2がメチルまたはエチルである、請求項14に記載の少なくとも1種類の化学物質。
- R2がメチルである、請求項15に記載の少なくとも1種類の化学物質。
- R3が水素である、請求項1〜16のいずれか1項に記載の少なくとも1種類の化学物質。
- R3がフルオロまたはクロロである、請求項1〜16のいずれか1項に記載の少なくとも1種類の化学物質。
- R3がメチルである、請求項1〜16のいずれか1項に記載の少なくとも1種類の化学物質。
- R3が−CH2OHである、請求項1〜16のいずれか1項に記載の少なくとも1種類の化学物質。
- Xが−N−である、請求項1〜20のいずれか1項に記載の少なくとも1種類の化学物質。
- Yが−N−である、請求項1〜20のいずれか1項に記載の少なくとも1種類の化学物質。
- XとYが−N−である、請求項1〜20のいずれか1項に記載の少なくとも1種類の化学物質。
- Lが−C(O)O−である、請求項1〜23のいずれか1項に記載の少なくとも1種類の化学物質。
- Lが−C(O)N(R4)−である、請求項1〜23のいずれか1項に記載の少なくとも1種類の化学物質。
- Lが−N(R4)S(O)2−である、請求項1〜23のいずれか1項に記載の少なくとも1種類の化学物質。
- R4が水素である、請求項25または26に記載の少なくとも1種類の化学物質。
- R5が低級アルキルである、請求項1〜27のいずれか1項に記載の少なくとも1種類の化学物質。
- R5が水素である、請求項1〜27のいずれか1項に記載の少なくとも1種類の化学物質。
- nが1である、請求項30に記載の少なくとも1種類の化学物質。
- nが2である、請求項30に記載の少なくとも1種類の化学物質。
- 式Iの化合物が、
6−(4−クロロ−3−メトキシ−フェニル)−ピリミジン−4−カルボン酸、
6−(3−アミノ−4−クロロ−フェニル)−ピリミジン−4−カルボン酸、
6−[4−クロロ−3−(テトラヒドロ−フラン−3−イルオキシ)−フェニル]−ピリミジン−4−カルボン酸、
6−[4−クロロ−3−(テトラヒドロ−フラン−3−イルオキシ)−フェニル]−ピリミジン−4−カルボン酸ピリジン−3−イルアミド、
6−[4−クロロ−3−(2−モルホリン−4−イル−エトキシ)−フェニル]−ピリミジン−4−カルボン酸ピリジン−3−イル−アミド、
6−(3−クロロ−4−イソプロピル−フェニル)−ピリミジン−4−カルボン酸、
6−(3−フルオロ−4−メチル−フェニル)−ピリミジン−4−カルボン酸、
6−(3−クロロ−4−イソプロポキシ−フェニル)−ピリミジン−4−カルボン酸、
6−(3−クロロ−4−イソプロポキシ−フェニル)−2−メチル−ピリミジン−4−カルボン酸、
6−(3−フルオロ−4−メチル−フェニル)−2−メチル−ピリミジン−4−カルボン酸、
6−(3−クロロ−4−シクロペンチルオキシ−フェニル)−ピリミジン−4−カルボン酸、
6−(3−クロロ−4−トリフルオロメトキシ−フェニル)−ピリミジン−4−カルボン酸、
6−(3−フルオロ−4−イソプロピル−フェニル)−ピリミジン−4−カルボン酸、
6−(4−(R)−sec−ブトキシ−3−クロロ−フェニル)−ピリミジン−4−カルボン酸、
6−(4−(S)−sec−ブトキシ−3−クロロ−フェニル)−ピリミジン−4−カルボン酸、
6−(3−クロロ−4−シクロプロポキシ−フェニル)−ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(2,2,2−トリフルオロ−1−メチル−エトキシ)−フェニル]−ピリミジン−4−カルボン酸、
4−(3−クロロ−4−シクロプロポキシ−フェニル)−ピリジン−2−カルボン酸、
6−(4−(R)−sec−ブトキシ−3−クロロ−フェニル)−ピリジン−4−カルボン酸、
6−(4−(S)−sec−ブトキシ−3−クロロ−フェニル)−ピリジン−4−カルボン酸、
4−(3−クロロ−4−イソプロポキシ−フェニル)−ピリジン−2−カルボン酸、
4−(3−クロロ−4−トリフルオロメトキシ−フェニル)−ピリジン−2−カルボン酸、
6−(3−クロロ−4−シクロブトキシ−フェニル)−ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(2−ピペリジン−1−イル−エトキシ)−フェニル]−ピリミジン−4−カルボン酸、
6−キノリン−6−イル−ピリミジン−4−カルボン酸、
6−(8−クロロ−クロマン−6−イル)−ピリミジン−4−カルボン酸、
6−(7−クロロ−ベンゾフラン−5−イル)−ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(ピロリジン−3−イルオキシ)−フェニル]−ピリミジン−4−カルボン酸、
6−(8−クロロ−1−メチル−1,2,3,4−テトラヒドロキノリン−6−イル)ピリミジン−4−カルボン酸、
6−(8−クロロキノリン−6−イル)ピリミジン−4−カルボキシレート、
N−[6−(3−クロロ−4−シクロプロポキシフェニル)ピリミジン−4−イル]ベンゼンスルホンアミド、
N−[6−(3−クロロ−4−シクロプロポキシフェニル)ピリミジン−4−イル]−4−フルオロベンゼン−1−スルホンアミド、
N−[6−(3−クロロ−4−シクロプロポキシフェニル)ピリミジン−4−イル]−4−(トリフルオロメトキシ)ベンゼン−1−スルホンアミド、
N−[6−(3−クロロ−4−シクロプロポキシフェニル)ピリミジン−4−イル]−3−(トリフルオロメトキシ)ベンゼン−1−スルホンアミド、
N−[6−(3−クロロ−4−シクロプロポキシフェニル)ピリミジン−4−イル]−2−フルオロベンゼン−1−スルホンアミド、
N−[6−(3−クロロ−4−シクロプロポキシフェニル)ピリミジン−4−イル]シクロプロパンスルホンアミド、
6−(8−クロロ−1,2,3,4−テトラヒドロキノリン−6−イル)ピリミジン−4−カルボキシレート、
6−(3−クロロ−4−シクロプロポキシフェニル)−5−メチルピリミジン−4−カルボキシレート、
6−{3−クロロ−4−[2−(モルホリン−4−イル)エトキシ]フェニル}ピリミジン−4−カルボキシレート、
6−[3−クロロ−4−(シクロプロピルメトキシ)フェニル]ピリミジン−4−カルボキシレート、
6−[3−クロロ−4−(オキセタン−3−イルオキシ)フェニル]ピリミジン−4−カルボキシレート、
4−(3−クロロ−4−シクロプロポキシフェニル)−5H,7H−フロ[3,4−d]ピリミジン−7−オン、
6−(3−クロロ−4−シクロプロポキシフェニル)−5−(ヒドロキシメチル)ピリミジン−4−カルボン酸、
4−(3−クロロ−4−シクロプロポキシフェニル)−5H,6H,8H−ピラノ[3,4−d]ピリミジン−8−オン、
6−(3−クロロ−4−シクロプロポキシフェニル)ピリミジン−4−カルボン酸[(2R,3S,4S,5R)−3,4,5,6−テトラヒドロキシオキサン−2−イル]メチル、
6−(3−クロロ−4−{[1−(モルホリン−4−イル)プロパン−2−イル]オキシ}フェニル)ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(シクロプロポキシメチル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(シクロプロピルメチル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(シクロプロピルスルファニル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(シクロプロパンスルフィニル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(シクロプロパンスルホニル)フェニル]ピリミジン−4−カルボン酸、
6−{3−クロロ−4−[シクロプロピル(ヒドロキシ)メチル]フェニル}ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(1−シクロプロポキシエチル)フェニル]ピリミジン−4−カルボン酸、
6−(3−クロロ−4−シクロプロパンカルボニルフェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−シクロプロピルフェニル)ピリミジン−4−カルボン酸、
6−[4−(アジリジン−1−イルメチル)−3−クロロフェニル]ピリミジン−4−カルボン酸、
6−{3−クロロ−4−[(ジメチルアミノ)メチル]フェニル}ピリミジン−4−カルボン酸
6−[3−クロロ−4−(シクロプロピルアミノ)フェニル]ピリミジン−4−カルボン酸、
6−{3−クロロ−4−[シクロプロピル(メチル)アミノ]フェニル}ピリミジン−4−カルボン酸、
6−{3−クロロ−4−[(シクロプロピルアミノ)メチル]フェニル}ピリミジン−4−カルボン酸、
6−(3−クロロ−4−{[シクロプロピル(メチル)アミノ]メチル}フェニル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2−シクロプロピル−2,3−ジヒドロ−1H−イソインドール−5−イル)ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(フラン−2−イル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(1−メトキシシクロプロピル)フェニル]ピリミジン−4−カルボン酸、
6−(2,3−ジヒドロ−1,4−ベンゾジオキシン−6−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2−メチル−1,3−ベンゾオキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2−オキソ−2,3−ジヒドロ−1,3−ベンゾオキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−3−メチル−2−オキソ−2,3−ジヒドロ−1,3−ベンゾオキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2−シクロプロピル−1,3−ベンゾオキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−{8−クロロイミダゾ[1,2−a]ピリジン−6−イル}ピリミジン−4−カルボン酸、
6−(4−クロロ−1,3−ベンゾオキサゾール−6−イル)ピリミジン−4−カルボン酸、
6−(キノリン−6−イル)ピリミジン−4−カルボン酸、
6−{ピラゾロ[1,5−a]ピリジン−5−イル}ピリミジン−4−カルボン酸、
6−(4−クロロ−3−シクロプロポキシフェニル)ピリミジン−4−カルボン酸、
6−(4−クロロ−3−メトキシフェニル)ピリミジン−4−カルボン酸、
6−[4−クロロ−3−(プロパン−2−イルオキシ)フェニル]ピリミジン−4−カルボン酸、
6−[4−クロロ−3−(2−メチルプロポキシ)フェニル]ピリミジン−4−カルボン酸、
6−[4−クロロ−3−(トリフルオロメトキシ)フェニル]ピリミジン−4−カルボン酸、
6−{4−クロロ−3−[(1,1,1−トリフルオロプロパン−2−イル)オキシ]フェニル}ピリミジン−4−カルボン酸、
6−(ベンゾ[d][1,3]ジオキソール−5−イル)ピリミジン−4−カルボン酸、
6−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)ピリミジン−4−カルボン酸、
6−(2,3−ジヒドロベンゾ[b][1,4]ジオキシン−6−イル)ピリミジン−4−カルボン酸、
6−(7−クロロベンゾ[b]チオフェン−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロベンゾ[d]チアゾール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロベンゾ[d]オキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロベンゾ[c][1,2,5]オキサジアゾール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2,3,3a,7a−テトラヒドロベンゾフラン−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−3a,7a−ジヒドロ−1H−インドール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−1−メチル−3a,7a−ジヒドロ−1H−インダゾール−5−イル)ピリミジン−4−カルボン酸、
6−(8−クロロキナゾリン−6−イル)ピリミジン−4−カルボン酸、
6−(5−クロロキナゾリン−7−イル)ピリミジン−4−カルボン酸、
6−(8−クロロキノキサリン−6−イル)ピリミジン−4−カルボン酸、
6−(8−クロロ−1,2,3,4−テトラヒドロキノリン−6−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−1H−ベンゾ[d]イミダゾール−5−イル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(1−メチルシクロプロピル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(1−(トリフルオロメチル)シクロプロピル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(3−メチルオキセタン−3−イル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(ピロリジン−1−イル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(ピロリジン−3−イル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(ピロリジン−2−イル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(1H−イミダゾール−2−イル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(1H−ピロール−2−イル)フェニル)ピリミジン−4−カルボン酸、
6−(4−tert−ブチル−3−クロロフェニル)ピリミジン−4−カルボン酸、および
7−クロロ−8−シクロプロポキシ−5H−クロメノ[4,3−d]ピリミジン−4−カルボン酸
から選択される、請求項1に記載の少なくとも1種類の化学物質。 - 式Iの化合物が、
6−[3−クロロ−4−(メチルスルファニル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(メチルスルフィニル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(メチルスルホニル)フェニル]ピリミジン−4−カルボン酸、
6−{3−クロロ−4−[シクロプロピル(ヒドロキシ)メチル]フェニル}ピリミジン−4−カルボン酸、
6−(3−クロロ−4−シクロプロパンカルボニルフェニル)ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(メトキシメチル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(1−メトキシエチル)フェニル]ピリミジン−4−カルボン酸、
6−{3−クロロ−4−[(ジメチルアミノ)メチル]フェニル}ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(シクロプロピルアミノ)フェニル]ピリミジン−4−カルボン酸、
6−{3−クロロ−4−[シクロプロピル(メチル)アミノ]フェニル}ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(ピロリジン−1−イル)フェニル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2−メチル−1,3−ベンゾオキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−(8−クロロキノキサリン−6−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2,3−ジヒドロ−1−ベンゾフラン−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2−シクロプロピル−1,3−ベンゾオキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−(4−クロロ−2−メチル−1,3−ベンゾオキサゾール−6−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−3−メチル−2−オキソ−2,3−ジヒドロ−1,3−ベンゾオキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−(2H−1,3−ベンゾジオキソール−5−イル)ピリミジン−4−カルボン酸、
4−(3,4−ジクロロフェニル)−5−メチルピリジン−2−カルボン酸、
6−(3−クロロ−4−{[1−(モルホリン−4−イル)プロパン−2−イル]オキシ}フェニル)ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(シクロプロポキシメチル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(シクロプロピルメチル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(1−シクロプロポキシエチル)フェニル]ピリミジン−4−カルボン酸、
6−(3−クロロ−4−シクロプロピルフェニル)ピリミジン−4−カルボン酸、
6−[4−(アジリジン−1−イルメチル)−3−クロロフェニル]ピリミジン−4−カルボン酸、
6−{3−クロロ−4−[(シクロプロピルアミノ)メチル]フェニル}ピリミジン−4−カルボン酸、
6−(3−クロロ−4−{[シクロプロピル(メチル)アミノ]メチル}フェニル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2−シクロプロピル−2,3−ジヒドロ−1H−イソインドール−5−イル)ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(フラン−2−イル)フェニル]ピリミジン−4−カルボン酸、
6−[3−クロロ−4−(1−メトキシシクロプロピル)フェニル]ピリミジン−4−カルボン酸、
6−(2,3−ジヒドロ−1,4−ベンゾジオキシン−6−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−2−オキソ−2,3−ジヒドロ−1,3−ベンゾオキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−{8−クロロイミダゾ[1,2−a]ピリジン−6−イル}ピリミジン−4−カルボン酸、
6−(4−クロロ−1,3−ベンゾオキサゾール−6−イル)ピリミジン−4−カルボン酸、
6−(キノリン−6−イル)ピリミジン−4−カルボン酸、
6−{ピラゾロ[1,5−a]ピリジン−5−イル}ピリミジン−4−カルボン酸、
6−(4−クロロ−3−シクロプロポキシフェニル)ピリミジン−4−カルボン酸、
6−(4−クロロ−3−メトキシフェニル)ピリミジン−4−カルボン酸、
6−[4−クロロ−3−(プロパン−2−イルオキシ)フェニル]ピリミジン−4−カルボン酸、
6−[4−クロロ−3−(2−メチルプロポキシ)フェニル]ピリミジン−4−カルボン酸、
6−[4−クロロ−3−(トリフルオロメトキシ)フェニル]ピリミジン−4−カルボン酸、
6−{4−クロロ−3−[(1,1,1−トリフルオロプロパン−2−イル)オキシ]フェニル}ピリミジン−4−カルボン酸、
6−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)ピリミジン−4−カルボン酸、
6−(2,3−ジヒドロベンゾ[b][1,4]ジオキシン−6−イル)ピリミジン−4−カルボン酸、
6−(7−クロロベンゾ[b]チオフェン−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロベンゾ[d]チアゾール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロベンゾ[d]オキサゾール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロベンゾ[c][1,2,5]オキサジアゾール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−3a,7a−ジヒドロ−1H−インドール−5−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−1−メチル−3a,7a−ジヒドロ−1H−インダゾール−5−イル)ピリミジン−4−カルボン酸、
6−(8−クロロキナゾリン−6−イル)ピリミジン−4−カルボン酸、
6−(5−クロロキナゾリン−7−イル)ピリミジン−4−カルボン酸、
6−(7−クロロ−1H−ベンゾ[d]イミダゾール−5−イル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(1−メチルシクロプロピル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(1−(トリフルオロメチル)シクロプロピル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(3−メチルオキセタン−3−イル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(ピロリジン−2−イル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(1H−イミダゾール−2−イル)フェニル)ピリミジン−4−カルボン酸、
6−(3−クロロ−4−(1H−ピロール−2−イル)フェニル)ピリミジン−4−カルボン酸、
6−(4−tert−ブチル−3−クロロフェニル)ピリミジン−4−カルボン酸、および
7−クロロ−8−シクロプロポキシ−5H−クロメノ[4,3−d]ピリミジン−4−カルボン酸
から選択される、請求項1に記載の少なくとも1種類の化学物質。 - 請求項1〜34のいずれか1項に記載の少なくとも1種類の化学物質および少なくとも1種類の薬学的に許容され得る賦形剤を含む医薬組成物。
- キヌレニン3−モノ−オキシゲナーゼ活性によって媒介される状態または障害の処置を、かかる処置を必要とする被験体において行う方法であって、該被験体に治療有効量の請求項1〜34のいずれか1項に記載の少なくとも1種類の化学物質を投与する工程を含む方法。
- 前記状態または障害が神経変性病態を伴うものである、請求項36に記載の方法。
- 請求項35に記載の少なくとも1種類の医薬組成物、およびキヌレニン3−モノ−オキシゲナーゼ活性によって媒介される状態または障害に苦しんでいる被験体を処置するために該組成物を使用するための使用説明書を含む、パッケージ化医薬組成物。
- 前記状態または障害がハンティングトン病である、請求項38に記載のパッケージ化医薬組成物。
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