BR0308243B1 - Derivados de purina como inibidores de quinase, seu uso para tratar diabetes e doença de alzheimer, para estimular deposição óssea e inibir gsk-3, bem como formulação farmacêutica compreendendo os referidos derivados - Google Patents

Info

Publication number

BR0308243B1

BR0308243B1 BRPI0308243-1A BR0308243A BR0308243B1 BR 0308243 B1 BR0308243 B1 BR 0308243B1 BR 0308243 A BR0308243 A BR 0308243A BR 0308243 B1 BR0308243 B1 BR 0308243B1

Authority

BR

Brazil

Prior art keywords

mmol

add

alkyl

reduced pressure

optionally substituted

Prior art date

2002-03-05

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• 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 title claims description 29
• 102000002254 Glycogen Synthase Kinase 3 Human genes 0.000 title claims description 29
• 230000010256 bone deposition Effects 0.000 title claims description 13
• 239000008194 pharmaceutical composition Substances 0.000 title claims description 11
• 206010012601 diabetes mellitus Diseases 0.000 title claims description 8
• 208000024827 Alzheimer disease Diseases 0.000 title claims description 7
• 230000004936 stimulating effect Effects 0.000 title claims description 5
• 229940043355 kinase inhibitor Drugs 0.000 title abstract description 3
• 239000003757 phosphotransferase inhibitor Substances 0.000 title abstract description 3
• 229940083251 peripheral vasodilators purine derivative Drugs 0.000 title description 2
• 150000003212 purines Chemical class 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims description 334
• -1 tetrahydropyran-4-yl Chemical group 0.000 claims description 236
• 238000002360 preparation method Methods 0.000 claims description 128
• 229910052757 nitrogen Inorganic materials 0.000 claims description 52
• 229910052739 hydrogen Inorganic materials 0.000 claims description 31
• 239000001257 hydrogen Substances 0.000 claims description 30
• 125000000217 alkyl group Chemical group 0.000 claims description 25
• 241000124008 Mammalia Species 0.000 claims description 18
• 125000003545 alkoxy group Chemical group 0.000 claims description 18
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 18
• 125000002947 alkylene group Chemical group 0.000 claims description 13
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
• 125000001424 substituent group Chemical group 0.000 claims description 12
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 11
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
• 125000004076 pyridyl group Chemical group 0.000 claims description 9
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
• 150000002431 hydrogen Chemical class 0.000 claims description 8
• 150000003839 salts Chemical class 0.000 claims description 8
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 7
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 7
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
• 125000002883 imidazolyl group Chemical group 0.000 claims description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
• PIGFYZPCRLYGLF-UHFFFAOYSA-N Aluminum nitride Chemical compound [Al]#N PIGFYZPCRLYGLF-UHFFFAOYSA-N 0.000 claims description 5
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
• 230000002401 inhibitory effect Effects 0.000 claims description 4
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
• 239000003085 diluting agent Substances 0.000 claims description 3
• 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 3
• 125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 claims description 3
• 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 2
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
• 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
• 125000004043 oxo group Chemical group O=* 0.000 claims description 2
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 2
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
• 125000001425 triazolyl group Chemical group 0.000 claims description 2
• 125000004953 trihalomethyl group Chemical group 0.000 claims description 2
• 125000001475 halogen functional group Chemical group 0.000 claims 9
• NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims 1
• 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 545
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 213
• 239000012141 concentrate Substances 0.000 description 210
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• 230000002829 reductive effect Effects 0.000 description 204
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 194
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• 238000003756 stirring Methods 0.000 description 154
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• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 139
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 135
• 239000000243 solution Substances 0.000 description 125
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• 229920006395 saturated elastomer Polymers 0.000 description 118
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 105
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 94
• 239000000203 mixture Substances 0.000 description 85
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 84
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 83
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 81
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 75
• 239000011541 reaction mixture Substances 0.000 description 72
• 238000006243 chemical reaction Methods 0.000 description 71
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 71
• 239000011780 sodium chloride Substances 0.000 description 70
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 67
• 238000010992 reflux Methods 0.000 description 66
• 239000000284 extract Substances 0.000 description 64
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 56
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 55
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 47
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 45
• 235000019341 magnesium sulphate Nutrition 0.000 description 45
• 239000012044 organic layer Substances 0.000 description 44
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
• 238000010898 silica gel chromatography Methods 0.000 description 41
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 40
• 235000017557 sodium bicarbonate Nutrition 0.000 description 40
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 40
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 38
• 239000003921 oil Substances 0.000 description 37
• 235000019198 oils Nutrition 0.000 description 37
• 229910052938 sodium sulfate Inorganic materials 0.000 description 36
• 235000011152 sodium sulphate Nutrition 0.000 description 36
• 239000012074 organic phase Substances 0.000 description 35
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 30
• 239000000741 silica gel Substances 0.000 description 30
• 229910002027 silica gel Inorganic materials 0.000 description 30
• 238000000034 method Methods 0.000 description 26
• 229920005989 resin Polymers 0.000 description 26
• 239000011347 resin Substances 0.000 description 26
• DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 25
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
• XQVZDADGTFJAFM-UHFFFAOYSA-N Indole-7-carboxaldehyde Chemical class O=CC1=CC=CC2=C1NC=C2 XQVZDADGTFJAFM-UHFFFAOYSA-N 0.000 description 23
• 238000003818 flash chromatography Methods 0.000 description 23
• 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 description 23
• 239000010410 layer Substances 0.000 description 23
• 239000002904 solvent Substances 0.000 description 23
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 22
• 239000000047 product Substances 0.000 description 22
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 21
• 238000005481 NMR spectroscopy Methods 0.000 description 21
• 238000010791 quenching Methods 0.000 description 21
• 239000000725 suspension Substances 0.000 description 21
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 20
• HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 19
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• 238000003556 assay Methods 0.000 description 18
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