BRPI0708779A2 - derivados de pirrolopirimidina utilizados como inibidores de hsp90 - Google Patents

Info

Publication number

BRPI0708779A2

BRPI0708779A2 BRPI0708779-9A BRPI0708779A BRPI0708779A2 BR PI0708779 A2 BRPI0708779 A2 BR PI0708779A2 BR PI0708779 A BRPI0708779 A BR PI0708779A BR PI0708779 A2 BRPI0708779 A2 BR PI0708779A2

Authority

BR

Brazil

Prior art keywords

formula

pyrrolo

pyrimidine

phenyl

original document

Prior art date

2006-03-11

Links

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• 239000003481 heat shock protein 90 inhibitor Substances 0.000 title description 16
• 150000004944 pyrrolopyrimidines Chemical class 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 248
• 239000000460 chlorine Substances 0.000 claims abstract description 56
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 21
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 21
• 239000001257 hydrogen Substances 0.000 claims abstract description 19
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 15
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 15
• 201000011510 cancer Diseases 0.000 claims abstract description 12
• 229910052801 chlorine Inorganic materials 0.000 claims abstract description 12
• 229910052794 bromium Inorganic materials 0.000 claims abstract description 10
• 125000002837 carbocyclic group Chemical group 0.000 claims abstract description 9
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 9
• 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 9
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 9
• 238000011282 treatment Methods 0.000 claims abstract description 9
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 8
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 8
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 8
• 125000002947 alkylene group Chemical group 0.000 claims abstract description 8
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 8
• 239000011737 fluorine Substances 0.000 claims abstract description 8
• 229910052731 fluorine Inorganic materials 0.000 claims abstract description 8
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 5
• 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 4
• -1 methoxy, ethoxy, methylthio, ethylthio, hydroxyethylthio, methylamino, diethylaminomethylthio, methylaminocarbonylmethylthio Chemical group 0.000 claims description 137
• 238000000034 method Methods 0.000 claims description 83
• 230000000694 effects Effects 0.000 claims description 79
• 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 claims description 65
• 239000000203 mixture Substances 0.000 claims description 62
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
• 201000010099 disease Diseases 0.000 claims description 22
• 101710113864 Heat shock protein 90 Proteins 0.000 claims description 18
• 239000003814 drug Substances 0.000 claims description 17
• 125000001424 substituent group Chemical group 0.000 claims description 17
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
• 229940079593 drug Drugs 0.000 claims description 14
• 230000005764 inhibitory process Effects 0.000 claims description 14
• 125000004122 cyclic group Chemical group 0.000 claims description 13
• 125000003277 amino group Chemical group 0.000 claims description 12
• 150000003839 salts Chemical class 0.000 claims description 12
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 9
• 125000000623 heterocyclic group Chemical group 0.000 claims description 9
• 238000001727 in vivo Methods 0.000 claims description 9
• TVIVIEFSHFOWTE-UHFFFAOYSA-K tri(quinolin-8-yloxy)alumane Chemical compound [Al+3].C1=CN=C2C([O-])=CC=CC2=C1.C1=CN=C2C([O-])=CC=CC2=C1.C1=CN=C2C([O-])=CC=CC2=C1 TVIVIEFSHFOWTE-UHFFFAOYSA-K 0.000 claims description 9
• 238000002360 preparation method Methods 0.000 claims description 8
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
• 241000124008 Mammalia Species 0.000 claims description 6
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
• 101100507655 Canis lupus familiaris HSPA1 gene Proteins 0.000 claims description 5
• 125000003545 alkoxy group Chemical group 0.000 claims description 5
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
• 125000002757 morpholinyl group Chemical group 0.000 claims description 5
• 125000004076 pyridyl group Chemical group 0.000 claims description 5
• 201000004681 Psoriasis Diseases 0.000 claims description 4
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
• 238000000338 in vitro Methods 0.000 claims description 4
• 125000004193 piperazinyl group Chemical group 0.000 claims description 4
• 125000003386 piperidinyl group Chemical group 0.000 claims description 4
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
• 229920002554 vinyl polymer Polymers 0.000 claims description 4
• 201000003883 Cystic fibrosis Diseases 0.000 claims description 3
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• 201000009273 Endometriosis Diseases 0.000 claims description 3
• 206010021143 Hypoxia Diseases 0.000 claims description 3
• 206010062016 Immunosuppression Diseases 0.000 claims description 3
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 3
• 125000005336 allyloxy group Chemical group 0.000 claims description 3
• 230000033115 angiogenesis Effects 0.000 claims description 3
• 208000006673 asthma Diseases 0.000 claims description 3
• 210000004556 brain Anatomy 0.000 claims description 3
• 238000002512 chemotherapy Methods 0.000 claims description 3
• 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 201000011066 hemangioma Diseases 0.000 claims description 3
• 230000001506 immunosuppresive effect Effects 0.000 claims description 3
• 208000037906 ischaemic injury Diseases 0.000 claims description 3
• 206010025135 lupus erythematosus Diseases 0.000 claims description 3
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
• 231100000419 toxicity Toxicity 0.000 claims description 3
• 230000001988 toxicity Effects 0.000 claims description 3
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
• 230000003612 virological effect Effects 0.000 claims description 3
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
• 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
• 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
• 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
• 206010017533 Fungal infection Diseases 0.000 claims description 2
• 208000031888 Mycoses Diseases 0.000 claims description 2
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 2
• 125000001246 bromo group Chemical group Br* 0.000 claims description 2
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
• 208000027866 inflammatory disease Diseases 0.000 claims description 2
• 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 2
• 201000006417 multiple sclerosis Diseases 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims 2
• 208000014644 Brain disease Diseases 0.000 claims 1
• 208000032274 Encephalopathy Diseases 0.000 claims 1
• 239000003937 drug carrier Substances 0.000 claims 1
• 239000003112 inhibitor Substances 0.000 abstract description 3
• 125000004429 atom Chemical group 0.000 abstract description 2
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 212
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 191
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 168
• 239000000243 solution Substances 0.000 description 101
• 235000019439 ethyl acetate Nutrition 0.000 description 91
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
• 239000007787 solid Substances 0.000 description 75
• 238000005160 1H NMR spectroscopy Methods 0.000 description 57
• 238000003818 flash chromatography Methods 0.000 description 55
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 50
• 238000002875 fluorescence polarization Methods 0.000 description 50
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
• 101001016865 Homo sapiens Heat shock protein HSP 90-alpha Proteins 0.000 description 49
• 239000000047 product Substances 0.000 description 48
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 46
• 239000011541 reaction mixture Substances 0.000 description 43
• 239000012043 crude product Substances 0.000 description 41
• 239000000741 silica gel Substances 0.000 description 38
• 229910002027 silica gel Inorganic materials 0.000 description 38
• 229960001866 silicon dioxide Drugs 0.000 description 38
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 36
• 239000011734 sodium Substances 0.000 description 35
• 238000006243 chemical reaction Methods 0.000 description 34
• 108090000623 proteins and genes Proteins 0.000 description 31
• 239000002904 solvent Substances 0.000 description 30
• 102000004169 proteins and genes Human genes 0.000 description 27
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 26
• 235000018102 proteins Nutrition 0.000 description 26
• 229910004298 SiO 2 Inorganic materials 0.000 description 25
• 210000004027 cell Anatomy 0.000 description 22
• 230000002209 hydrophobic effect Effects 0.000 description 20
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• 235000019198 oils Nutrition 0.000 description 20
• 239000000706 filtrate Substances 0.000 description 19
• 239000012074 organic phase Substances 0.000 description 18
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 17
• 150000003254 radicals Chemical group 0.000 description 16
• 239000000725 suspension Substances 0.000 description 16
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
• 229920006395 saturated elastomer Polymers 0.000 description 15
• AVIJWXRQYVQJOA-UHFFFAOYSA-N 4-chloro-2-methylsulfanyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile Chemical compound CSC1=NC(Cl)=C2C(C#N)=CN(COCC[Si](C)(C)C)C2=N1 AVIJWXRQYVQJOA-UHFFFAOYSA-N 0.000 description 13
• 238000000746 purification Methods 0.000 description 13
• PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
• 238000003556 assay Methods 0.000 description 11
• 239000012230 colorless oil Substances 0.000 description 11
• 235000019441 ethanol Nutrition 0.000 description 11
• 230000006870 function Effects 0.000 description 11
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
• 125000004432 carbon atom Chemical group C* 0.000 description 10
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
• 239000002253 acid Substances 0.000 description 9
• 239000012467 final product Substances 0.000 description 9
• 150000003457 sulfones Chemical class 0.000 description 9
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
• QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
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• QTQAWLPCGQOSGP-KSRBKZBZSA-N geldanamycin Chemical class N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-KSRBKZBZSA-N 0.000 description 8
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