BG108453A - Пиролопиримидини като инхибитори на протеин киназа - Google Patents

Info

Publication number

BG108453A

BG108453A BG108453A BG10845303A BG108453A BG 108453 A BG108453 A BG 108453A BG 108453 A BG108453 A BG 108453A BG 10845303 A BG10845303 A BG 10845303A BG 108453 A BG108453 A BG 108453A

Authority

BG

Bulgaria

Prior art keywords

alkyl

group

heteroaryl

compounds

aryl

Prior art date

2001-06-23

Links

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• 239000003909 protein kinase inhibitor Substances 0.000 title description 3
• 150000004944 pyrrolopyrimidines Chemical class 0.000 title description 3
• 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 170
• 150000003839 salts Chemical class 0.000 claims abstract description 47
• 239000002253 acid Substances 0.000 claims abstract description 28
• 229940002612 prodrug Drugs 0.000 claims abstract description 12
• 239000000651 prodrug Substances 0.000 claims abstract description 12
• 150000001204 N-oxides Chemical class 0.000 claims abstract description 11
• 239000012453 solvate Substances 0.000 claims abstract description 10
• 125000000217 alkyl group Chemical group 0.000 claims description 79
• -1 cyclic acetal Chemical class 0.000 claims description 69
• 125000001072 heteroaryl group Chemical group 0.000 claims description 42
• 125000003118 aryl group Chemical group 0.000 claims description 37
• 229910005965 SO 2 Inorganic materials 0.000 claims description 35
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 30
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 30
• 229910052739 hydrogen Inorganic materials 0.000 claims description 27
• 239000001257 hydrogen Substances 0.000 claims description 27
• 125000005843 halogen group Chemical group 0.000 claims description 25
• 125000001041 indolyl group Chemical group 0.000 claims description 25
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 21
• 125000003342 alkenyl group Chemical group 0.000 claims description 20
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 19
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
• 150000002431 hydrogen Chemical class 0.000 claims description 17
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 14
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 14
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 11
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
• 125000000304 alkynyl group Chemical group 0.000 claims description 9
• 125000003545 alkoxy group Chemical group 0.000 claims description 8
• 229910052760 oxygen Inorganic materials 0.000 claims description 8
• 229910052717 sulfur Inorganic materials 0.000 claims description 8
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
• 125000003302 alkenyloxy group Chemical group 0.000 claims description 6
• 125000002252 acyl group Chemical group 0.000 claims description 5
• 125000005530 alkylenedioxy group Chemical group 0.000 claims description 5
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
• DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 4
• 125000003107 substituted aryl group Chemical group 0.000 claims description 2
• 238000000034 method Methods 0.000 abstract description 51
• 239000000203 mixture Substances 0.000 abstract description 26
• 238000011282 treatment Methods 0.000 abstract description 21
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 83
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 64
• 239000000243 solution Substances 0.000 description 52
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
• 238000006243 chemical reaction Methods 0.000 description 43
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 33
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 26
• 230000002829 reductive effect Effects 0.000 description 26
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
• 210000004027 cell Anatomy 0.000 description 18
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 18
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
• 235000019341 magnesium sulphate Nutrition 0.000 description 17
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
• 125000004432 carbon atom Chemical group C* 0.000 description 15
• 239000012074 organic phase Substances 0.000 description 15
• 238000010992 reflux Methods 0.000 description 15
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 14
• 230000008569 process Effects 0.000 description 14
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 13
• 238000003818 flash chromatography Methods 0.000 description 13
• 239000000377 silicon dioxide Substances 0.000 description 13
• 239000012312 sodium hydride Substances 0.000 description 13
• 229910000104 sodium hydride Inorganic materials 0.000 description 13
• 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 13
• YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 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 12
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
• 238000005859 coupling reaction Methods 0.000 description 12
• 239000011541 reaction mixture Substances 0.000 description 12
• 239000000126 substance Substances 0.000 description 12
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 11
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
• 206010028980 Neoplasm Diseases 0.000 description 11
• 238000009835 boiling Methods 0.000 description 11
• 230000008878 coupling Effects 0.000 description 11
• 238000010168 coupling process Methods 0.000 description 11
• IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 11
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
• 102000016621 Focal Adhesion Protein-Tyrosine Kinases Human genes 0.000 description 10
• 108010067715 Focal Adhesion Protein-Tyrosine Kinases Proteins 0.000 description 10
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
• 230000000694 effects Effects 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
• 239000002904 solvent Substances 0.000 description 10
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
• 239000002585 base Substances 0.000 description 9
• 239000012458 free base Substances 0.000 description 9
• 239000000543 intermediate Substances 0.000 description 9
• 239000003960 organic solvent Substances 0.000 description 9
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 8
• 108091000080 Phosphotransferase Proteins 0.000 description 8
• 230000029936 alkylation Effects 0.000 description 8
• 238000005804 alkylation reaction Methods 0.000 description 8
• 150000002148 esters Chemical class 0.000 description 8
• 229910052740 iodine Inorganic materials 0.000 description 8
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 8
• 102000020233 phosphotransferase Human genes 0.000 description 8
• 108090000461 Aurora Kinase A Proteins 0.000 description 7
• 102100032311 Aurora kinase A Human genes 0.000 description 7
• 102000001253 Protein Kinase Human genes 0.000 description 7
• 102000000551 Syk Kinase Human genes 0.000 description 7
• 108010016672 Syk Kinase Proteins 0.000 description 7
• 230000006978 adaptation Effects 0.000 description 7
• 125000001309 chloro group Chemical group Cl* 0.000 description 7
• 239000012442 inert solvent Substances 0.000 description 7
• 239000011630 iodine Substances 0.000 description 7
• 238000002360 preparation method Methods 0.000 description 7
• 108060006633 protein kinase Proteins 0.000 description 7
• 125000004076 pyridyl group Chemical group 0.000 description 7
• 235000017557 sodium bicarbonate Nutrition 0.000 description 7
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
• 239000007787 solid Substances 0.000 description 7
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
• 150000001450 anions Chemical class 0.000 description 6
• 239000000427 antigen Substances 0.000 description 6
• 108091007433 antigens Proteins 0.000 description 6
• 102000036639 antigens Human genes 0.000 description 6
• 239000012298 atmosphere Substances 0.000 description 6
• 238000010586 diagram Methods 0.000 description 6
• 150000004677 hydrates Chemical class 0.000 description 6
• 230000007062 hydrolysis Effects 0.000 description 6
• 238000006460 hydrolysis reaction Methods 0.000 description 6
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
• 210000005075 mammary gland Anatomy 0.000 description 6
• GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 6
• 229910052757 nitrogen Inorganic materials 0.000 description 6
• 239000000546 pharmaceutical excipient Substances 0.000 description 6
• 125000006239 protecting group Chemical group 0.000 description 6
• 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 description 6
• 230000004044 response Effects 0.000 description 6
• GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
• ZXUCBXRTRRIBSO-UHFFFAOYSA-L tetrabutylazanium;sulfate Chemical compound [O-]S([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC ZXUCBXRTRRIBSO-UHFFFAOYSA-L 0.000 description 6
• 230000001225 therapeutic effect Effects 0.000 description 6
• DWAQDRSOVMLGRQ-UHFFFAOYSA-N 5-methoxyindole Chemical compound COC1=CC=C2NC=CC2=C1 DWAQDRSOVMLGRQ-UHFFFAOYSA-N 0.000 description 5
• 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 5
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• 125000001931 aliphatic group Chemical group 0.000 description 5
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• 125000004122 cyclic group Chemical group 0.000 description 5
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• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
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