IL217651A - Compounds of bi-cyclic urea - Google Patents

Info

Publication number

IL217651A

IL217651A IL217651A IL21765112A IL217651A IL 217651 A IL217651 A IL 217651A IL 217651 A IL217651 A IL 217651A IL 21765112 A IL21765112 A IL 21765112A IL 217651 A IL217651 A IL 217651A

Authority

IL

Israel

Prior art keywords

preparation

procedure described

obsd

title compound

fluoro

Prior art date

2009-08-06

Links

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• -1 Bicyclic urea compounds Chemical class 0.000 title description 125
• 150000001875 compounds Chemical class 0.000 claims description 350
• 150000003839 salts Chemical class 0.000 claims description 39
• 239000012453 solvate Substances 0.000 claims description 26
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
• 125000004434 sulfur atom Chemical group 0.000 claims description 8
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
• 229910052760 oxygen Inorganic materials 0.000 claims description 5
• 125000001424 substituent group Chemical group 0.000 claims description 5
• 125000004122 cyclic group Chemical group 0.000 claims description 4
• 239000004615 ingredient Substances 0.000 claims description 4
• 238000000034 method Methods 0.000 description 333
• 238000002360 preparation method Methods 0.000 description 323
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 280
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 73
• 239000007787 solid Substances 0.000 description 28
• 239000004202 carbamide Substances 0.000 description 26
• 238000006243 chemical reaction Methods 0.000 description 26
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
• 239000000543 intermediate Substances 0.000 description 22
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
• 206010028980 Neoplasm Diseases 0.000 description 21
• 239000000651 prodrug Substances 0.000 description 21
• 229940002612 prodrug Drugs 0.000 description 21
• 239000000203 mixture Substances 0.000 description 17
• 210000004027 cell Anatomy 0.000 description 16
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
• 239000000243 solution Substances 0.000 description 16
• 239000002253 acid Substances 0.000 description 15
• 238000004128 high performance liquid chromatography Methods 0.000 description 15
• 239000011541 reaction mixture Substances 0.000 description 15
• 241000124008 Mammalia Species 0.000 description 14
• 239000003112 inhibitor Substances 0.000 description 14
• 201000010099 disease Diseases 0.000 description 13
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
• 239000005441 aurora Substances 0.000 description 12
• 229910052731 fluorine Inorganic materials 0.000 description 12
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
• 150000001412 amines Chemical class 0.000 description 11
• 201000011510 cancer Diseases 0.000 description 11
• 239000012043 crude product Substances 0.000 description 11
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
• 230000000694 effects Effects 0.000 description 10
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
• 238000005160 1H NMR spectroscopy Methods 0.000 description 9
• XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 9
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
• 108091000080 Phosphotransferase Proteins 0.000 description 9
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
• 239000004480 active ingredient Substances 0.000 description 9
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 9
• GTTFJYUWPUKXJH-UHFFFAOYSA-N n-(4-aminophenyl)benzamide Chemical compound C1=CC(N)=CC=C1NC(=O)C1=CC=CC=C1 GTTFJYUWPUKXJH-UHFFFAOYSA-N 0.000 description 9
• 239000008194 pharmaceutical composition Substances 0.000 description 9
• 102000020233 phosphotransferase Human genes 0.000 description 9
• 238000002953 preparative HPLC Methods 0.000 description 9
• XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 9
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
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• QYAKZKZDJPNJNR-UHFFFAOYSA-N n-(4-aminophenyl)-4-fluoro-2-(trifluoromethyl)benzamide Chemical compound C1=CC(N)=CC=C1NC(=O)C1=CC=C(F)C=C1C(F)(F)F QYAKZKZDJPNJNR-UHFFFAOYSA-N 0.000 description 8
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• 239000000758 substrate Substances 0.000 description 8
• ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
• 239000003814 drug Substances 0.000 description 7
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
• 230000006870 function Effects 0.000 description 7
• 239000002244 precipitate Substances 0.000 description 7
• 108090000765 processed proteins & peptides Proteins 0.000 description 7
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
• 239000007858 starting material Substances 0.000 description 7
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• 150000007513 acids Chemical class 0.000 description 6
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
• 229910052794 bromium Inorganic materials 0.000 description 6
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
• 230000010261 cell growth Effects 0.000 description 6
• 239000003795 chemical substances by application Substances 0.000 description 6
• 239000000460 chlorine Substances 0.000 description 6
• 229910052801 chlorine Inorganic materials 0.000 description 6
• 125000000623 heterocyclic group Chemical group 0.000 description 6
• 229910052739 hydrogen Inorganic materials 0.000 description 6
• 150000002466 imines Chemical class 0.000 description 6
• 230000002401 inhibitory effect Effects 0.000 description 6
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
• 230000026731 phosphorylation Effects 0.000 description 6
• 238000006366 phosphorylation reaction Methods 0.000 description 6
• 108090000623 proteins and genes Proteins 0.000 description 6
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
• KDKUVYLMPJIGKA-UHFFFAOYSA-N 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide Chemical compound N=1N(C(=O)C=2C(=CC=CC=2F)F)C(N)=NC=1NC1=CC=C(S(N)(=O)=O)C=C1 KDKUVYLMPJIGKA-UHFFFAOYSA-N 0.000 description 5
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
• 102100039872 Inner centromere protein Human genes 0.000 description 5
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• 125000000217 alkyl group Chemical group 0.000 description 5
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• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 5
• WPJGHIVGAOVUAT-UHFFFAOYSA-N 1-(4-fluorophenyl)-2-oxopyridine-3-carboxylic acid Chemical compound O=C1C(C(=O)O)=CC=CN1C1=CC=C(F)C=C1 WPJGHIVGAOVUAT-UHFFFAOYSA-N 0.000 description 4
• 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 4
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• 239000002585 base Substances 0.000 description 4
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• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
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• ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
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