JP7296318B2 - Sikインヒビターとしてのピリミドピリミジノンの使用 - Google Patents
Sikインヒビターとしてのピリミドピリミジノンの使用 Download PDFInfo
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- JP7296318B2 JP7296318B2 JP2019547113A JP2019547113A JP7296318B2 JP 7296318 B2 JP7296318 B2 JP 7296318B2 JP 2019547113 A JP2019547113 A JP 2019547113A JP 2019547113 A JP2019547113 A JP 2019547113A JP 7296318 B2 JP7296318 B2 JP 7296318B2
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- 239000003112 inhibitor Substances 0.000 title description 22
- RLJCWYYOGHGGBV-UHFFFAOYSA-N 1h-pyrimido[5,4-d]pyrimidin-2-one Chemical class C1=NC=C2NC(=O)N=CC2=N1 RLJCWYYOGHGGBV-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 186
- 150000003839 salts Chemical class 0.000 claims description 124
- 239000012453 solvate Substances 0.000 claims description 116
- 239000013078 crystal Substances 0.000 claims description 109
- 239000000203 mixture Substances 0.000 claims description 24
- 208000012641 Pigmentation disease Diseases 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 description 452
- 125000000623 heterocyclic group Chemical group 0.000 description 373
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 281
- 125000004452 carbocyclyl group Chemical group 0.000 description 207
- 229910052757 nitrogen Inorganic materials 0.000 description 201
- 125000001072 heteroaryl group Chemical group 0.000 description 199
- 125000004429 atom Chemical group 0.000 description 196
- 229910052717 sulfur Inorganic materials 0.000 description 182
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 181
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 172
- -1 bicyclic urea compounds Chemical class 0.000 description 162
- 125000000304 alkynyl group Chemical group 0.000 description 150
- 229910052760 oxygen Inorganic materials 0.000 description 146
- 239000001301 oxygen Substances 0.000 description 146
- 125000003342 alkenyl group Chemical group 0.000 description 144
- 239000011593 sulfur Substances 0.000 description 142
- 125000003118 aryl group Chemical group 0.000 description 140
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- 229910052739 hydrogen Inorganic materials 0.000 description 124
- 239000001257 hydrogen Substances 0.000 description 121
- 239000000651 prodrug Substances 0.000 description 107
- 229940002612 prodrug Drugs 0.000 description 107
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 106
- 125000001424 substituent group Chemical group 0.000 description 100
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 99
- 125000005842 heteroatom Chemical group 0.000 description 97
- 125000004432 carbon atom Chemical group C* 0.000 description 96
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 95
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 90
- 125000002950 monocyclic group Chemical group 0.000 description 67
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 66
- 125000002252 acyl group Chemical group 0.000 description 64
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- 125000004433 nitrogen atom Chemical group N* 0.000 description 57
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 56
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 54
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- 125000004430 oxygen atom Chemical group O* 0.000 description 45
- 125000004434 sulfur atom Chemical group 0.000 description 41
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- 210000003491 skin Anatomy 0.000 description 37
- 239000000460 chlorine Substances 0.000 description 36
- 150000004677 hydrates Chemical class 0.000 description 35
- 238000011282 treatment Methods 0.000 description 35
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 35
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 31
- 125000000547 substituted alkyl group Chemical group 0.000 description 31
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- 125000004404 heteroalkyl group Chemical group 0.000 description 30
- 229920006395 saturated elastomer Polymers 0.000 description 29
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 27
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 27
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 24
- 125000005017 substituted alkenyl group Chemical group 0.000 description 23
- 125000004426 substituted alkynyl group Chemical group 0.000 description 23
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 23
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 23
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- 125000003107 substituted aryl group Chemical group 0.000 description 20
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 229910052794 bromium Inorganic materials 0.000 description 15
- 229910052801 chlorine Inorganic materials 0.000 description 15
- 125000004122 cyclic group Chemical group 0.000 description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
- 229910052731 fluorine Inorganic materials 0.000 description 15
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- 125000000753 cycloalkyl group Chemical group 0.000 description 14
- 201000010099 disease Diseases 0.000 description 14
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 14
- GVBAXIVNAHMIGH-UHFFFAOYSA-N 1-cyclobutyl-3-(2,6-dimethylphenyl)-7-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-4H-pyrimido[4,5-d]pyrimidin-2-one Chemical compound COC1=C(NC2=NC3=C(CN(C(=O)N3C3CCC3)C3=C(C)C=CC=C3C)C=N2)C=CC(=C1)N1CCN(C)CC1 GVBAXIVNAHMIGH-UHFFFAOYSA-N 0.000 description 13
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 13
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- 230000014509 gene expression Effects 0.000 description 13
- 101150087532 mitF gene Proteins 0.000 description 13
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 13
- 125000004193 piperazinyl group Chemical group 0.000 description 13
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 13
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 13
- WTKQMHWYSBWUBE-UHFFFAOYSA-N (3-nitropyridin-2-yl) thiohypochlorite Chemical compound [O-][N+](=O)C1=CC=CN=C1SCl WTKQMHWYSBWUBE-UHFFFAOYSA-N 0.000 description 12
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 12
- 102100034377 Serine/threonine-protein kinase SIK2 Human genes 0.000 description 12
- 101710083836 Serine/threonine-protein kinase SIK2 Proteins 0.000 description 12
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
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- 229910052740 iodine Inorganic materials 0.000 description 12
- 239000011630 iodine Substances 0.000 description 12
- 108020004999 messenger RNA Proteins 0.000 description 12
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- 150000003254 radicals Chemical class 0.000 description 12
- 201000000849 skin cancer Diseases 0.000 description 12
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 11
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 11
- 102000001253 Protein Kinase Human genes 0.000 description 11
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- 239000002253 acid Substances 0.000 description 11
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 11
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 11
- 125000005003 perfluorobutyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 11
- 125000005004 perfluoroethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 11
- 125000005009 perfluoropropyl group Chemical group FC(C(C(F)(F)F)(F)F)(F)* 0.000 description 11
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- 201000001441 melanoma Diseases 0.000 description 10
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- 102000013760 Microphthalmia-Associated Transcription Factor Human genes 0.000 description 9
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 125000005647 linker group Chemical group 0.000 description 9
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| EP3589284A4 (en) | 2020-12-16 |
| EP3589284A1 (en) | 2020-01-08 |
| CN111163771A (zh) | 2020-05-15 |
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