MXPA04011074A - Compuestos de pirimidinona, composiciones y metodos. - Google Patents
Compuestos de pirimidinona, composiciones y metodos.Info
- Publication number
- MXPA04011074A MXPA04011074A MXPA04011074A MXPA04011074A MXPA04011074A MX PA04011074 A MXPA04011074 A MX PA04011074A MX PA04011074 A MXPA04011074 A MX PA04011074A MX PA04011074 A MXPA04011074 A MX PA04011074A MX PA04011074 A MXPA04011074 A MX PA04011074A
- Authority
- MX
- Mexico
- Prior art keywords
- optionally substituted
- methyl
- alkyl
- propyl
- phenyl
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims description 88
- 238000000034 method Methods 0.000 title claims description 77
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 title description 44
- 150000001875 compounds Chemical class 0.000 claims abstract description 469
- 230000000694 effects Effects 0.000 claims abstract description 45
- 230000002062 proliferating effect Effects 0.000 claims abstract description 8
- -1 hydroxyl- Chemical group 0.000 claims description 712
- 239000001257 hydrogen Substances 0.000 claims description 100
- 229910052739 hydrogen Inorganic materials 0.000 claims description 100
- 125000000217 alkyl group Chemical group 0.000 claims description 97
- 150000002431 hydrogen Chemical class 0.000 claims description 60
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 59
- 125000001072 heteroaryl group Chemical group 0.000 claims description 55
- 125000003107 substituted aryl group Chemical group 0.000 claims description 55
- 102000010638 Kinesin Human genes 0.000 claims description 52
- 108010063296 Kinesin Proteins 0.000 claims description 52
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims description 44
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 43
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 40
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 39
- 125000003545 alkoxy group Chemical group 0.000 claims description 37
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 31
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 239000012453 solvate Substances 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- 206010028980 Neoplasm Diseases 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- 238000011282 treatment Methods 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 201000011510 cancer Diseases 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 14
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 13
- 230000004663 cell proliferation Effects 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 12
- 125000003944 tolyl group Chemical group 0.000 claims description 12
- 125000005518 carboxamido group Chemical group 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 208000035475 disorder Diseases 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 9
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- 125000005059 halophenyl group Chemical group 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- 206010061218 Inflammation Diseases 0.000 claims description 5
- 229940127089 cytotoxic agent Drugs 0.000 claims description 5
- 125000002636 imidazolinyl group Chemical group 0.000 claims description 5
- 230000004054 inflammatory process Effects 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 4
- 206010007572 Cardiac hypertrophy Diseases 0.000 claims description 4
- 208000006029 Cardiomegaly Diseases 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 206010020718 hyperplasia Diseases 0.000 claims description 4
- 208000026278 immune system disease Diseases 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 208000037803 restenosis Diseases 0.000 claims description 4
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 3
- 229940123237 Taxane Drugs 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000005422 alkyl sulfonamido group Chemical group 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- MFLYTCSVJYYAOR-UHFFFAOYSA-N (carbamimidoylazaniumyl)formate Chemical group NC(=N)NC(O)=O MFLYTCSVJYYAOR-UHFFFAOYSA-N 0.000 claims description 2
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 claims description 2
- UJHBVXDPRCBOAD-UHFFFAOYSA-N N-carbamoyl-2-pyridin-2-ylpyridine-3-carboxamide Chemical compound N1=C(C=CC=C1)C1=C(C(=O)NC(N)=O)C=CC=N1 UJHBVXDPRCBOAD-UHFFFAOYSA-N 0.000 claims description 2
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 claims description 2
- 125000004442 acylamino group Chemical group 0.000 claims description 2
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 2
- 125000006399 methylpyrazinyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 2
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 15
- 238000004519 manufacturing process Methods 0.000 claims 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 241000863480 Vinca Species 0.000 claims 1
- 229930013930 alkaloid Natural products 0.000 claims 1
- 150000003797 alkaloid derivatives Chemical class 0.000 claims 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 230000001413 cellular effect Effects 0.000 abstract description 5
- 208000037765 diseases and disorders Diseases 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 224
- 239000000243 solution Substances 0.000 description 180
- 238000006243 chemical reaction Methods 0.000 description 168
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 142
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 141
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 128
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 102
- 235000019439 ethyl acetate Nutrition 0.000 description 83
- 239000011541 reaction mixture Substances 0.000 description 82
- 239000000047 product Substances 0.000 description 79
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 76
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 70
- 239000002253 acid Substances 0.000 description 67
- 238000002360 preparation method Methods 0.000 description 62
- 210000004027 cell Anatomy 0.000 description 55
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 53
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 51
- 230000015572 biosynthetic process Effects 0.000 description 51
- 239000003795 chemical substances by application Substances 0.000 description 46
- 238000003786 synthesis reaction Methods 0.000 description 45
- 239000007787 solid Substances 0.000 description 44
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 43
- 229910052938 sodium sulfate Inorganic materials 0.000 description 43
- 235000011152 sodium sulphate Nutrition 0.000 description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 43
- 239000012044 organic layer Substances 0.000 description 42
- 235000002639 sodium chloride Nutrition 0.000 description 41
- YCIPQJTZJGUXND-UHFFFAOYSA-N Aglaia odorata Alkaloid Natural products C1=CC(OC)=CC=C1C1(C(C=2C(=O)N3CCCC3=NC=22)C=3C=CC=CC=3)C2(O)C2=C(OC)C=C(OC)C=C2O1 YCIPQJTZJGUXND-UHFFFAOYSA-N 0.000 description 40
- 238000000746 purification Methods 0.000 description 40
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- 230000027455 binding Effects 0.000 description 34
- 239000002904 solvent Substances 0.000 description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 32
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- 150000001412 amines Chemical class 0.000 description 28
- 239000000010 aprotic solvent Substances 0.000 description 28
- 239000002585 base Substances 0.000 description 28
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 26
- 125000005843 halogen group Chemical group 0.000 description 26
- 239000000741 silica gel Substances 0.000 description 25
- 229910002027 silica gel Inorganic materials 0.000 description 25
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 25
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 24
- 238000010992 reflux Methods 0.000 description 24
- 238000012360 testing method Methods 0.000 description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 22
- 102000029749 Microtubule Human genes 0.000 description 22
- 108091022875 Microtubule Proteins 0.000 description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 22
- 210000004688 microtubule Anatomy 0.000 description 22
- 239000008346 aqueous phase Substances 0.000 description 21
- 229920006395 saturated elastomer Polymers 0.000 description 21
- 230000002829 reductive effect Effects 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 18
- 235000019441 ethanol Nutrition 0.000 description 18
- 230000000394 mitotic effect Effects 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 239000012267 brine Substances 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 17
- 239000010410 layer Substances 0.000 description 17
- 108090000623 proteins and genes Proteins 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- 238000004587 chromatography analysis Methods 0.000 description 16
- 239000000543 intermediate Substances 0.000 description 16
- 239000002798 polar solvent Substances 0.000 description 16
- 235000018102 proteins Nutrition 0.000 description 16
- 102000004169 proteins and genes Human genes 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 229960000583 acetic acid Drugs 0.000 description 14
- 238000001704 evaporation Methods 0.000 description 14
- 230000008020 evaporation Effects 0.000 description 14
- 230000005764 inhibitory process Effects 0.000 description 14
- 230000011278 mitosis Effects 0.000 description 14
- 238000012216 screening Methods 0.000 description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- 239000003112 inhibitor Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- 229940079593 drug Drugs 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 11
- 125000004494 ethyl ester group Chemical group 0.000 description 11
- 238000003818 flash chromatography Methods 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 10
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 10
- 150000001299 aldehydes Chemical class 0.000 description 9
- 150000001408 amides Chemical class 0.000 description 9
- 229910021529 ammonia Inorganic materials 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 239000008121 dextrose Substances 0.000 description 9
- 239000012153 distilled water Substances 0.000 description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- 229910004373 HOAc Inorganic materials 0.000 description 8
- 101001008953 Homo sapiens Kinesin-like protein KIF11 Proteins 0.000 description 8
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 8
- 238000002835 absorbance Methods 0.000 description 8
- 208000009956 adenocarcinoma Diseases 0.000 description 8
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 8
- 238000011534 incubation Methods 0.000 description 8
- 239000003586 protic polar solvent Substances 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 7
- 108091006112 ATPases Proteins 0.000 description 7
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 7
- 206010025323 Lymphomas Diseases 0.000 description 7
- 206010039491 Sarcoma Diseases 0.000 description 7
- 150000001409 amidines Chemical class 0.000 description 7
- 230000022131 cell cycle Effects 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 150000004702 methyl esters Chemical class 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 239000012454 non-polar solvent Substances 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 238000004007 reversed phase HPLC Methods 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 6
- 201000009030 Carcinoma Diseases 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 6
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 230000003833 cell viability Effects 0.000 description 6
- 239000000460 chlorine Chemical group 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 238000009826 distribution Methods 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 102000055595 human KIF11 Human genes 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 230000009466 transformation Effects 0.000 description 6
- NQUVCRCCRXRJCK-UHFFFAOYSA-N 4-methylbenzoyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C=C1 NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 description 5
- 239000005695 Ammonium acetate Substances 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
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Classifications
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- 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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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
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- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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- 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
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- Health & Medical Sciences (AREA)
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| US37965802P | 2002-05-09 | 2002-05-09 | |
| PCT/US2003/013627 WO2003094839A2 (en) | 2002-05-09 | 2003-05-02 | Pyrimidinone compounds, compositions and methods |
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| MXPA04011074A MXPA04011074A (es) | 2002-05-09 | 2003-05-02 | Compuestos de pirimidinona, composiciones y metodos. |
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| TW (1) | TW200406387A (OSRAM) |
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| IL187528A0 (en) | 2008-03-20 |
| EP1503993A2 (en) | 2005-02-09 |
| WO2003094839A8 (en) | 2004-06-24 |
| NO20045043L (no) | 2005-02-08 |
| KR20050036911A (ko) | 2005-04-20 |
| WO2003094839A3 (en) | 2004-09-16 |
| NZ537076A (en) | 2007-06-29 |
| CN1665788A (zh) | 2005-09-07 |
| US20070135432A1 (en) | 2007-06-14 |
| AR039985A1 (es) | 2005-03-09 |
| ZA200409881B (en) | 2006-04-26 |
| IL165046A0 (en) | 2005-12-18 |
| AU2003223786A1 (en) | 2003-11-11 |
| IS7520A (is) | 2004-11-03 |
| US20040077662A1 (en) | 2004-04-22 |
| CA2485148A1 (en) | 2003-11-20 |
| PL373412A1 (en) | 2005-08-22 |
| RU2004135554A (ru) | 2006-01-20 |
| BR0309892A2 (pt) | 2011-04-05 |
| WO2003094839A2 (en) | 2003-11-20 |
| MY140767A (en) | 2010-01-15 |
| EP1503993A4 (en) | 2006-05-03 |
| CN100491358C (zh) | 2009-05-27 |
| US7482343B2 (en) | 2009-01-27 |
| US7166595B2 (en) | 2007-01-23 |
| TW200406387A (en) | 2004-05-01 |
| JP2006508030A (ja) | 2006-03-09 |
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