DE60222671T2 - Thienopyrimidinedione und deren verwendung in der behandlung von autoimmunerkrankungen - Google Patents

Info

Publication number

DE60222671T2

DE60222671T2 DE60222671T DE60222671T DE60222671T2 DE 60222671 T2 DE60222671 T2 DE 60222671T2 DE 60222671 T DE60222671 T DE 60222671T DE 60222671 T DE60222671 T DE 60222671T DE 60222671 T2 DE60222671 T2 DE 60222671T2

Authority

DE

Germany

Prior art keywords

methyl

pyrimidine

dione

thieno

ylcarbonyl

Prior art date

2001-07-28

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.)

Expired - Lifetime

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• 238000011282 treatment Methods 0.000 title description 10
• 208000023275 Autoimmune disease Diseases 0.000 title description 6
• QAFVXBQPQCSSLI-UHFFFAOYSA-N 1h-thieno[3,2-d]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)NC2=C1SC=C2 QAFVXBQPQCSSLI-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 364
• -1 isoxazolidin-2-ylcarbonyl Chemical group 0.000 claims description 281
• 238000000034 method Methods 0.000 claims description 189
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 121
• 229910052757 nitrogen Inorganic materials 0.000 claims description 100
• 125000000217 alkyl group Chemical group 0.000 claims description 91
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 81
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 49
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 48
• 150000003839 salts Chemical class 0.000 claims description 46
• 238000006243 chemical reaction Methods 0.000 claims description 38
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 36
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 35
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 34
• 125000001424 substituent group Chemical group 0.000 claims description 30
• 125000003118 aryl group Chemical group 0.000 claims description 27
• 125000000623 heterocyclic group Chemical group 0.000 claims description 27
• 125000004043 oxo group Chemical group O=* 0.000 claims description 27
• 125000005842 heteroatom Chemical group 0.000 claims description 24
• JGOOQALRLGHKIY-UHFFFAOYSA-N 1h-thieno[2,3-d]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)NC2=C1C=CS2 JGOOQALRLGHKIY-UHFFFAOYSA-N 0.000 claims description 23
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 23
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
• 239000001301 oxygen Substances 0.000 claims description 23
• 229910052760 oxygen Inorganic materials 0.000 claims description 23
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 17
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
• 229910052736 halogen Inorganic materials 0.000 claims description 16
• 150000002367 halogens Chemical class 0.000 claims description 16
• 229910052717 sulfur Chemical group 0.000 claims description 16
• 125000004385 trihaloalkyl group Chemical group 0.000 claims description 16
• 125000004122 cyclic group Chemical group 0.000 claims description 15
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 14
• 125000003545 alkoxy group Chemical group 0.000 claims description 14
• 239000011593 sulfur Chemical group 0.000 claims description 14
• 125000000464 thioxo group Chemical group S=* 0.000 claims description 14
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
• 125000004982 dihaloalkyl group Chemical group 0.000 claims description 13
• 125000001188 haloalkyl group Chemical group 0.000 claims description 13
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 12
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 10
• 125000002883 imidazolyl group Chemical group 0.000 claims description 10
• 229940002612 prodrug Drugs 0.000 claims description 10
• 239000000651 prodrug Substances 0.000 claims description 10
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 10
• 125000006413 ring segment Chemical group 0.000 claims description 10
• 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 9
• 230000015572 biosynthetic process Effects 0.000 claims description 9
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 9
• 150000002148 esters Chemical class 0.000 claims description 9
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 9
• 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
• 125000005493 quinolyl group Chemical group 0.000 claims description 9
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
• 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 8
• ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 8
• 125000003342 alkenyl group Chemical group 0.000 claims description 8
• 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 8
• 125000001041 indolyl group Chemical group 0.000 claims description 8
• 238000002360 preparation method Methods 0.000 claims description 8
• 230000035755 proliferation Effects 0.000 claims description 8
• 125000005843 halogen group Chemical group 0.000 claims description 7
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
• 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 6
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
• 210000001744 T-lymphocyte Anatomy 0.000 claims description 6
• 125000005946 imidazo[1,2-a]pyridyl group Chemical group 0.000 claims description 6
• 239000008194 pharmaceutical composition Substances 0.000 claims description 6
• 230000008569 process Effects 0.000 claims description 6
• 238000003786 synthesis reaction Methods 0.000 claims description 6
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
• RJQMDTLQTXDQAV-ZDUSSCGKSA-N 6-[[2-(hydroxymethyl)benzimidazol-1-yl]methyl]-5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-propan-2-ylthieno[2,3-d]pyrimidine-2,4-dione Chemical compound C1=2C(=O)N(C)C(=O)N(C(C)C)C=2SC(CN2C3=CC=CC=C3N=C2CO)=C1C(=O)N1C[C@H](O)CO1 RJQMDTLQTXDQAV-ZDUSSCGKSA-N 0.000 claims description 5
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 5
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
• 239000012453 solvate Substances 0.000 claims description 5
• 238000002560 therapeutic procedure Methods 0.000 claims description 5
• NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 4
• CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 claims description 4
• WDSFWGBGFCBBHF-HNNXBMFYSA-N 1-[[1-ethyl-5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]methyl]indole-5-carbonitrile Chemical compound C1=2C(=O)N(C)C(=O)N(CC)C=2SC(CN2C3=CC=C(C=C3C=C2)C#N)=C1C(=O)N1C[C@H](O)CO1 WDSFWGBGFCBBHF-HNNXBMFYSA-N 0.000 claims description 4
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 4
• 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 4
• KKZUMAMOMRDVKA-UHFFFAOYSA-N 2-chloropropane Chemical group [CH2]C(C)Cl KKZUMAMOMRDVKA-UHFFFAOYSA-N 0.000 claims description 4
• FOUGTHXAKKBTGL-INIZCTEOSA-N 5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-(2-methylpropyl)-6-(quinolin-4-ylmethyl)thieno[2,3-d]pyrimidine-2,4-dione Chemical compound C1=2C(=O)N(C)C(=O)N(CC(C)C)C=2SC(CC=2C3=CC=CC=C3N=CC=2)=C1C(=O)N1C[C@H](O)CO1 FOUGTHXAKKBTGL-INIZCTEOSA-N 0.000 claims description 4
• SYABSTPXYAKTOJ-AWEZNQCLSA-N 5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-(2-methylpropyl)-6-[(1,3,5-trimethylpyrazol-4-yl)methyl]thieno[2,3-d]pyrimidine-2,4-dione Chemical compound C([C@@H](O)C1)ON1C(=O)C=1C=2C(=O)N(C)C(=O)N(CC(C)C)C=2SC=1CC=1C(C)=NN(C)C=1C SYABSTPXYAKTOJ-AWEZNQCLSA-N 0.000 claims description 4
• VFHHJCWOWISPED-KRWDZBQOSA-N 5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methylquinolin-4-yl)methyl]thieno[2,3-d]pyrimidine-2,4-dione Chemical compound C1=2C(=O)N(C)C(=O)N(CC(C)C)C=2SC(CC=2C3=CC=CC=C3N=C(C)C=2)=C1C(=O)N1C[C@H](O)CO1 VFHHJCWOWISPED-KRWDZBQOSA-N 0.000 claims description 4
• HPEIANKQXRRLBL-AWEZNQCLSA-N 5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methylsulfanylbenzimidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CSC1=NC2=CC=CC=C2N1CC=1SC=2N(CC(C)C)C(=O)N(C)C(=O)C=2C=1C(=O)N1C[C@H](O)CO1 HPEIANKQXRRLBL-AWEZNQCLSA-N 0.000 claims description 4
• LCHHQJNRBXXZHG-ZDUSSCGKSA-N 5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methylsulfanylimidazo[4,5-b]pyridin-1-yl)methyl]thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CSC1=NC2=NC=CC=C2N1CC=1SC=2N(CC(C)C)C(=O)N(C)C(=O)C=2C=1C(=O)N1C[C@H](O)CO1 LCHHQJNRBXXZHG-ZDUSSCGKSA-N 0.000 claims description 4
• HIQNRBQEGNXQIY-ZDUSSCGKSA-N 5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methylsulfanylimidazo[4,5-b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CSC1=NC2=CC=CN=C2N1CC=1SC=2N(CC(C)C)C(=O)N(C)C(=O)C=2C=1C(=O)N1C[C@H](O)CO1 HIQNRBQEGNXQIY-ZDUSSCGKSA-N 0.000 claims description 4
• IBBQWKIRDFVRSO-ZDUSSCGKSA-N 5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-oxo-1,3-benzothiazol-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4-dione Chemical compound C1=2C(=O)N(C)C(=O)N(CC(C)C)C=2SC(CN2C(SC3=CC=CC=C32)=O)=C1C(=O)N1C[C@H](O)CO1 IBBQWKIRDFVRSO-ZDUSSCGKSA-N 0.000 claims description 4
• KDYIYJROCHINAC-ZDUSSCGKSA-N 5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-oxo-1,3-benzoxazol-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4-dione Chemical compound C1=2C(=O)N(C)C(=O)N(CC(C)C)C=2SC(CN2C(OC3=CC=CC=C32)=O)=C1C(=O)N1C[C@H](O)CO1 KDYIYJROCHINAC-ZDUSSCGKSA-N 0.000 claims description 4
• MONIFZUOJGZTAE-ZDUSSCGKSA-N 5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-oxo-3h-benzimidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-2,4-dione Chemical compound C1=2C(=O)N(C)C(=O)N(CC(C)C)C=2SC(CN2C(NC3=CC=CC=C32)=O)=C1C(=O)N1C[C@H](O)CO1 MONIFZUOJGZTAE-ZDUSSCGKSA-N 0.000 claims description 4
• WCXCSEWUMQNJDV-ZDUSSCGKSA-N 5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-6-[(2-methyl-1h-pyrrolo[2,3-b]pyridin-3-yl)methyl]-1-propan-2-ylthieno[2,3-d]pyrimidine-2,4-dione Chemical compound C1=2C(=O)N(C)C(=O)N(C(C)C)C=2SC(CC=2C3=CC=CN=C3NC=2C)=C1C(=O)N1C[C@H](O)CO1 WCXCSEWUMQNJDV-ZDUSSCGKSA-N 0.000 claims description 4
• LGTFKFFKZHGUGS-HNNXBMFYSA-N 5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-6-[(2-methylbenzimidazol-1-yl)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-dione Chemical compound C1=2C(=O)N(C)C(=O)N(CC(C)C)C=2SC(CN2C3=CC=CC=C3N=C2C)=C1C(=O)N1C[C@H](O)CO1 LGTFKFFKZHGUGS-HNNXBMFYSA-N 0.000 claims description 4
• YVJYZPRWQVUGQK-LBPRGKRZSA-N 5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-6-[(2-oxo-3h-benzimidazol-1-yl)methyl]-1-propan-2-ylthieno[2,3-d]pyrimidine-2,4-dione Chemical compound C1=2C(=O)N(C)C(=O)N(C(C)C)C=2SC(CN2C(NC3=CC=CC=C32)=O)=C1C(=O)N1C[C@H](O)CO1 YVJYZPRWQVUGQK-LBPRGKRZSA-N 0.000 claims description 4
• HAFALVDBJMSQDY-ZDUSSCGKSA-N 5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-6-[[2-(methylamino)benzimidazol-1-yl]methyl]-1-propan-2-ylthieno[2,3-d]pyrimidine-2,4-dione Chemical compound CNC1=NC2=CC=CC=C2N1CC=1SC=2N(C(C)C)C(=O)N(C)C(=O)C=2C=1C(=O)N1C[C@H](O)CO1 HAFALVDBJMSQDY-ZDUSSCGKSA-N 0.000 claims description 4
• MNNWRXMQFXOPNJ-LBPRGKRZSA-N 6-(benzotriazol-1-ylmethyl)-5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-propan-2-ylthieno[2,3-d]pyrimidine-2,4-dione Chemical compound C1=2C(=O)N(C)C(=O)N(C(C)C)C=2SC(CN2C3=CC=CC=C3N=N2)=C1C(=O)N1C[C@H](O)CO1 MNNWRXMQFXOPNJ-LBPRGKRZSA-N 0.000 claims description 4
• SALVKLFWQWNMJO-ZDUSSCGKSA-N 6-[(2-aminobenzimidazol-1-yl)methyl]-5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-dione Chemical compound C1=2C(=O)N(C)C(=O)N(CC(C)C)C=2SC(CN2C3=CC=CC=C3N=C2N)=C1C(=O)N1C[C@H](O)CO1 SALVKLFWQWNMJO-ZDUSSCGKSA-N 0.000 claims description 4
• OFTBDTAMUXEDOO-LBPRGKRZSA-N 6-[(2-aminobenzimidazol-1-yl)methyl]-5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-propan-2-ylthieno[2,3-d]pyrimidine-2,4-dione Chemical compound C1=2C(=O)N(C)C(=O)N(C(C)C)C=2SC(CN2C3=CC=CC=C3N=C2N)=C1C(=O)N1C[C@H](O)CO1 OFTBDTAMUXEDOO-LBPRGKRZSA-N 0.000 claims description 4
• ZHWJLKCQMOWILZ-LBPRGKRZSA-N 6-[(2-aminobenzimidazol-1-yl)methyl]-5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4-dione Chemical compound C1=2C(=O)N(C)C(=O)N(CCC)C=2SC(CN2C3=CC=CC=C3N=C2N)=C1C(=O)N1C[C@H](O)CO1 ZHWJLKCQMOWILZ-LBPRGKRZSA-N 0.000 claims description 4
• RECMMXWFDZIIOE-HNNXBMFYSA-N 6-[(2-ethylbenzimidazol-1-yl)methyl]-5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CCC1=NC2=CC=CC=C2N1CC=1SC=2N(CC(C)C)C(=O)N(C)C(=O)C=2C=1C(=O)N1C[C@H](O)CO1 RECMMXWFDZIIOE-HNNXBMFYSA-N 0.000 claims description 4
• NWDXTHRUMCBLPT-IBGZPJMESA-N 6-[(3,5-dimethyl-1-phenylpyrazol-4-yl)methyl]-5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-dione Chemical compound C([C@@H](O)C1)ON1C(=O)C=1C=2C(=O)N(C)C(=O)N(CC(C)C)C=2SC=1CC(=C1C)C(C)=NN1C1=CC=CC=C1 NWDXTHRUMCBLPT-IBGZPJMESA-N 0.000 claims description 4
• FXYDHGALICIHIR-ZDUSSCGKSA-N 6-[(3,5-dimethyl-1h-pyrazol-4-yl)methyl]-3-ethyl-5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-1-propan-2-ylthieno[2,3-d]pyrimidine-2,4-dione Chemical compound C([C@@H](O)C1)ON1C(=O)C=1C=2C(=O)N(CC)C(=O)N(C(C)C)C=2SC=1CC=1C(C)=NNC=1C FXYDHGALICIHIR-ZDUSSCGKSA-N 0.000 claims description 4
• UHGFWWYNEWEFMI-VIFPVBQESA-N 6-[(4,5-dichloro-2-methylimidazol-1-yl)methyl]-1-ethyl-5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methylthieno[2,3-d]pyrimidine-2,4-dione Chemical compound C([C@@H](O)C1)ON1C(=O)C=1C=2C(=O)N(C)C(=O)N(CC)C=2SC=1CN1C(C)=NC(Cl)=C1Cl UHGFWWYNEWEFMI-VIFPVBQESA-N 0.000 claims description 4
• JFIPQSAGONRHIK-JTQLQIEISA-N 6-[(4,5-dichloro-2-methylimidazol-1-yl)methyl]-5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4-dione Chemical compound C([C@@H](O)C1)ON1C(=O)C=1C=2C(=O)N(C)C(=O)N(CCC)C=2SC=1CN1C(C)=NC(Cl)=C1Cl JFIPQSAGONRHIK-JTQLQIEISA-N 0.000 claims description 4
• PTHUFRQNBGYBIG-NSHDSACASA-N 6-[(5,6-difluoro-2-oxo-3h-benzimidazol-1-yl)methyl]-5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-dione Chemical compound C1=2C(=O)N(C)C(=O)N(CC(C)C)C=2SC(CN2C(NC3=CC(F)=C(F)C=C32)=O)=C1C(=O)N1C[C@H](O)CO1 PTHUFRQNBGYBIG-NSHDSACASA-N 0.000 claims description 4
• 239000003814 drug Substances 0.000 claims description 4
• 125000000524 functional group Chemical group 0.000 claims description 4
• ZHWYUYWJISNICI-LBPRGKRZSA-N 1-ethyl-5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-6-[(2-methyl-1h-pyrrolo[2,3-b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4-dione Chemical compound C1=2C(=O)N(C)C(=O)N(CC)C=2SC(CC=2C3=CC=CN=C3NC=2C)=C1C(=O)N1C[C@H](O)CO1 ZHWYUYWJISNICI-LBPRGKRZSA-N 0.000 claims description 3
• JWADHAVOUUUADB-AWEZNQCLSA-N 1-ethyl-5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-6-[(2-propylbenzimidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CCCC1=NC2=CC=CC=C2N1CC=1SC=2N(CC)C(=O)N(C)C(=O)C=2C=1C(=O)N1C[C@H](O)CO1 JWADHAVOUUUADB-AWEZNQCLSA-N 0.000 claims description 3
• ZIQASVKKDANPDO-ABLWVSNPSA-N 5-(4-hydroxy-1,2-oxazolidine-2-carbonyl)-3-methyl-6-[[(2s)-6-methyl-3-oxo-2h-pyrazin-2-yl]methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-dione Chemical compound C1C(O)CON1C(=O)C=1C=2C(=O)N(C)C(=O)N(CC(C)C)C=2SC=1C[C@@H]1N=C(C)C=NC1=O ZIQASVKKDANPDO-ABLWVSNPSA-N 0.000 claims description 3
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• LPEDDCSWTHMDFK-UHFFFAOYSA-N methyl 1-ethyl-3,6-dimethyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate Chemical compound O=C1N(C)C(=O)N(CC)C2=C1C(C(=O)OC)=C(C)S2 LPEDDCSWTHMDFK-UHFFFAOYSA-N 0.000 description 1
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• RWKNVCIZFHCRKR-MRVPVSSYSA-N methyl 2-[(4r)-4-hydroxy-1,2-oxazolidine-2-carbonyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1C(=O)N1OC[C@H](O)C1 RWKNVCIZFHCRKR-MRVPVSSYSA-N 0.000 description 1
• RWKNVCIZFHCRKR-QMMMGPOBSA-N methyl 2-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1C(=O)N1OC[C@@H](O)C1 RWKNVCIZFHCRKR-QMMMGPOBSA-N 0.000 description 1
• ZOZLIRDDECXJGM-UHFFFAOYSA-N methyl 3,6-dimethyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate Chemical compound CC(C)CN1C(=O)N(C)C(=O)C2=C1SC(C)=C2C(=O)OC ZOZLIRDDECXJGM-UHFFFAOYSA-N 0.000 description 1
• MOBBVQRTKHTLCX-UHFFFAOYSA-N methyl 3,6-dimethyl-2,4-dioxo-1-propan-2-ylthieno[2,3-d]pyrimidine-5-carboxylate Chemical compound CC(C)N1C(=O)N(C)C(=O)C2=C1SC(C)=C2C(=O)OC MOBBVQRTKHTLCX-UHFFFAOYSA-N 0.000 description 1
• QZBMZXZAQVDMAM-UHFFFAOYSA-N methyl 3,6-dimethyl-2,4-dioxo-1-propylthieno[2,3-d]pyrimidine-5-carboxylate Chemical compound O=C1N(C)C(=O)N(CCC)C2=C1C(C(=O)OC)=C(C)S2 QZBMZXZAQVDMAM-UHFFFAOYSA-N 0.000 description 1
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• 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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• YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 1
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• HFGVPVHYMUHFRC-UHFFFAOYSA-N oxazinan-2-ium;chloride Chemical compound Cl.C1CCONC1 HFGVPVHYMUHFRC-UHFFFAOYSA-N 0.000 description 1
• 125000002971 oxazolyl group Chemical group 0.000 description 1
• 239000007800 oxidant agent Substances 0.000 description 1
• 230000003647 oxidation Effects 0.000 description 1
• 238000007254 oxidation reaction Methods 0.000 description 1
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• 229910052763 palladium Inorganic materials 0.000 description 1
• 229920002866 paraformaldehyde Polymers 0.000 description 1
• 238000007911 parenteral administration Methods 0.000 description 1
• 229940049954 penicillin Drugs 0.000 description 1
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• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
• 150000003014 phosphoric acid esters Chemical class 0.000 description 1
• 125000003367 polycyclic group Chemical group 0.000 description 1
• JCBJVAJGLKENNC-UHFFFAOYSA-M potassium ethyl xanthate Chemical compound [K+].CCOC([S-])=S JCBJVAJGLKENNC-UHFFFAOYSA-M 0.000 description 1
• LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
• 230000002062 proliferating effect Effects 0.000 description 1
• 230000000069 prophylactic effect Effects 0.000 description 1
• 238000010926 purge Methods 0.000 description 1
• ZZYXNRREDYWPLN-UHFFFAOYSA-N pyridine-2,3-diamine Chemical compound NC1=CC=CN=C1N ZZYXNRREDYWPLN-UHFFFAOYSA-N 0.000 description 1
• WUVXRNGXQRVRLV-UHFFFAOYSA-N pyridine-2,3-dione Chemical compound O=C1C=CC=NC1=O WUVXRNGXQRVRLV-UHFFFAOYSA-N 0.000 description 1
• 125000004076 pyridyl group Chemical group 0.000 description 1
• 238000005956 quaternization reaction Methods 0.000 description 1
• BNEVFKZLYCGDFG-UHFFFAOYSA-N quinoline-5-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=N1 BNEVFKZLYCGDFG-UHFFFAOYSA-N 0.000 description 1
• 239000002994 raw material Substances 0.000 description 1
• 208000002574 reactive arthritis Diseases 0.000 description 1
• 230000002829 reductive effect Effects 0.000 description 1
• 210000002345 respiratory system Anatomy 0.000 description 1
• 208000023504 respiratory system disease Diseases 0.000 description 1
• 238000002390 rotary evaporation Methods 0.000 description 1
• 208000008742 seborrheic dermatitis Diseases 0.000 description 1
• 238000000926 separation method Methods 0.000 description 1
• 238000013207 serial dilution Methods 0.000 description 1
• 210000002966 serum Anatomy 0.000 description 1
• 239000000377 silicon dioxide Substances 0.000 description 1
• VQHAJTIYQMZWCU-UHFFFAOYSA-M sodium 1-ethyl-3-methyl-6-[(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate Chemical compound C(C)N1C(N(C(C2=C1SC(=C2C(=O)[O-])CC1=C(NC2=NC=CC=C21)C)=O)C)=O.[Na+] VQHAJTIYQMZWCU-UHFFFAOYSA-M 0.000 description 1
• VGIANYKDYMXCNW-UHFFFAOYSA-M sodium 3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-[(2-oxo-1,3-benzoxazol-3-yl)methyl]thieno[2,3-d]pyrimidine-5-carboxylate Chemical compound [Na+].C12=CC=CC=C2OC(=O)N1CC(S1)=C(C([O-])=O)C2=C1N(CC(C)C)C(=O)N(C)C2=O VGIANYKDYMXCNW-UHFFFAOYSA-M 0.000 description 1
• LRZSMULLMDXTAU-UHFFFAOYSA-M sodium 3-methyl-2,4-dioxo-1-propan-2-yl-6-(quinolin-4-ylmethyl)thieno[2,3-d]pyrimidine-5-carboxylate Chemical compound CN1C(N(C2=C(C1=O)C(=C(S2)CC1=CC=NC2=CC=CC=C12)C(=O)[O-])C(C)C)=O.[Na+] LRZSMULLMDXTAU-UHFFFAOYSA-M 0.000 description 1
• NBKQJWKIHXNKPK-UHFFFAOYSA-M sodium 6-[(3,5-dimethyl-1-phenylpyrazol-4-yl)methyl]-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate Chemical compound [Na+].CC(C)Cn1c2sc(Cc3c(C)nn(c3C)-c3ccccc3)c(C([O-])=O)c2c(=O)n(C)c1=O NBKQJWKIHXNKPK-UHFFFAOYSA-M 0.000 description 1
• RPXVYIZKOKLMHH-UHFFFAOYSA-M sodium 6-[(4,5-dichloro-2-methylimidazol-1-yl)methyl]-1-ethyl-3-methyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate Chemical compound [Na+].ClC=1N=C(N(C=1Cl)CC1=C(C2=C(N(C(N(C2=O)C)=O)CC)S1)C(=O)[O-])C RPXVYIZKOKLMHH-UHFFFAOYSA-M 0.000 description 1
• JIOFPYBWQODQSA-UHFFFAOYSA-M sodium 6-[(4,5-dichloro-2-methylimidazol-1-yl)methyl]-3-methyl-2,4-dioxo-1-propan-2-ylthieno[2,3-d]pyrimidine-5-carboxylate Chemical compound ClC=1N=C(N(C=1Cl)CC1=C(C2=C(N(C(N(C2=O)C)=O)C(C)C)S1)C(=O)[O-])C.[Na+] JIOFPYBWQODQSA-UHFFFAOYSA-M 0.000 description 1
• XRZNXADIUKYNFP-UHFFFAOYSA-M sodium 6-[(6-fluoroquinolin-4-yl)methyl]-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate Chemical compound FC=1C=C2C(=CC=NC2=CC=1)CC1=C(C2=C(N(C(N(C2=O)C)=O)CC(C)C)S1)C(=O)[O-].[Na+] XRZNXADIUKYNFP-UHFFFAOYSA-M 0.000 description 1
• QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
• 239000011775 sodium fluoride Substances 0.000 description 1
• 235000013024 sodium fluoride Nutrition 0.000 description 1
• 239000001476 sodium potassium tartrate Substances 0.000 description 1
• 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
• AAMUWULJHBDPLE-UHFFFAOYSA-M sodium;3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-(quinolin-4-ylmethyl)thieno[2,3-d]pyrimidine-5-carboxylate Chemical compound [Na+].C1=CC=C2C(CC=3SC=4N(C(N(C)C(=O)C=4C=3C([O-])=O)=O)CC(C)C)=CC=NC2=C1 AAMUWULJHBDPLE-UHFFFAOYSA-M 0.000 description 1
• CPTNBXLVTIAIBE-UHFFFAOYSA-M sodium;3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-(quinolin-5-ylmethyl)thieno[2,3-d]pyrimidine-5-carboxylate Chemical compound [Na+].C1=CC=C2C(CC=3SC=4N(C(N(C)C(=O)C=4C=3C([O-])=O)=O)CC(C)C)=CC=CC2=N1 CPTNBXLVTIAIBE-UHFFFAOYSA-M 0.000 description 1
• PSGHVTLCCKCTRE-UHFFFAOYSA-M sodium;3-methyl-1-(2-methylpropyl)-6-[(2-methylsulfanylimidazo[4,5-b]pyridin-1-yl)methyl]-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate Chemical compound [Na+].CC(C)CN1C(=O)N(C)C(=O)C2=C1SC(CN1C3=CC=CN=C3N=C1SC)=C2C([O-])=O PSGHVTLCCKCTRE-UHFFFAOYSA-M 0.000 description 1
• CGIJMYISTIGMOS-UHFFFAOYSA-M sodium;3-methyl-2,4-dioxo-1-propyl-6-(quinolin-4-ylmethyl)thieno[2,3-d]pyrimidine-5-carboxylate Chemical compound [Na+].C1=CC=C2C(CC=3SC=4N(C(N(C)C(=O)C=4C=3C([O-])=O)=O)CCC)=CC=NC2=C1 CGIJMYISTIGMOS-UHFFFAOYSA-M 0.000 description 1
• XWJJZCJNRLLZIY-UHFFFAOYSA-M sodium;3-methyl-6-[(2-methyl-1h-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2,4-dioxo-1-propylthieno[2,3-d]pyrimidine-5-carboxylate Chemical compound [Na+].C1=CC=C2C(CC=3SC=4N(C(N(C)C(=O)C=4C=3C([O-])=O)=O)CCC)=C(C)NC2=N1 XWJJZCJNRLLZIY-UHFFFAOYSA-M 0.000 description 1
• XKRHCHZCEXRSMC-UHFFFAOYSA-M sodium;6-[(2-aminobenzimidazol-1-yl)methyl]-3-methyl-2,4-dioxo-1-propan-2-ylthieno[2,3-d]pyrimidine-5-carboxylate Chemical compound [Na+].NC1=NC2=CC=CC=C2N1CC(S1)=C(C([O-])=O)C2=C1N(C(C)C)C(=O)N(C)C2=O XKRHCHZCEXRSMC-UHFFFAOYSA-M 0.000 description 1
• OTKGWLRFTYGJGX-UHFFFAOYSA-M sodium;6-[(3,5-dimethyl-1h-pyrazol-4-yl)methyl]-3-methyl-2,4-dioxo-1-propylthieno[2,3-d]pyrimidine-5-carboxylate Chemical compound [Na+].[O-]C(=O)C=1C=2C(=O)N(C)C(=O)N(CCC)C=2SC=1CC=1C(C)=NNC=1C OTKGWLRFTYGJGX-UHFFFAOYSA-M 0.000 description 1
• SYCKQJKFFXBRNN-UHFFFAOYSA-M sodium;6-[(4,5-dichloro-2-methylimidazol-1-yl)methyl]-3-methyl-2,4-dioxo-1-propylthieno[2,3-d]pyrimidine-5-carboxylate Chemical compound [Na+].[O-]C(=O)C=1C=2C(=O)N(C)C(=O)N(CCC)C=2SC=1CN1C(C)=NC(Cl)=C1Cl SYCKQJKFFXBRNN-UHFFFAOYSA-M 0.000 description 1
• MANFKJGBAWSDPV-UHFFFAOYSA-M sodium;6-[(8-fluoroquinolin-4-yl)methyl]-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate Chemical compound [Na+].C1=CC=C2C(CC=3SC=4N(C(N(C)C(=O)C=4C=3C([O-])=O)=O)CC(C)C)=CC=NC2=C1F MANFKJGBAWSDPV-UHFFFAOYSA-M 0.000 description 1
• DEVTYVHEZULSDK-UHFFFAOYSA-M sodium;6-[[2-(hydroxymethyl)benzimidazol-1-yl]methyl]-3-methyl-2,4-dioxo-1-propylthieno[2,3-d]pyrimidine-5-carboxylate Chemical compound [Na+].OCC1=NC2=CC=CC=C2N1CC(S1)=C(C([O-])=O)C2=C1N(CCC)C(=O)N(C)C2=O DEVTYVHEZULSDK-UHFFFAOYSA-M 0.000 description 1
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• DTFTTXUDHBAYOZ-UHFFFAOYSA-N tert-butyl 6-[hydroxy-(2-methylquinolin-4-yl)methyl]-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate Chemical compound C1=CC=C2C(C(O)C=3SC=4N(C(N(C)C(=O)C=4C=3C(=O)OC(C)(C)C)=O)CC(C)C)=CC(C)=NC2=C1 DTFTTXUDHBAYOZ-UHFFFAOYSA-N 0.000 description 1
• REQWACMKKJVXAG-UHFFFAOYSA-N tert-butyl pyrimidine-5-carboxylate Chemical compound CC(C)(C)OC(=O)C1=CN=CN=C1 REQWACMKKJVXAG-UHFFFAOYSA-N 0.000 description 1
• BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
• 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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• 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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