RU2008120850A - Соединения и композиции в качестве ингибиторов протеинкиназ - Google Patents
Соединения и композиции в качестве ингибиторов протеинкиназ Download PDFInfo
- Publication number
- RU2008120850A RU2008120850A RU2008120850/04A RU2008120850A RU2008120850A RU 2008120850 A RU2008120850 A RU 2008120850A RU 2008120850/04 A RU2008120850/04 A RU 2008120850/04A RU 2008120850 A RU2008120850 A RU 2008120850A RU 2008120850 A RU2008120850 A RU 2008120850A
- Authority
- RU
- Russia
- Prior art keywords
- phenyl
- yloxy
- trifluoromethylphenyl
- pyrrolo
- pyrimidin
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract 11
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title 1
- 239000000203 mixture Substances 0.000 title 1
- 239000003909 protein kinase inhibitor Substances 0.000 title 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract 6
- 238000000034 method Methods 0.000 claims abstract 4
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 claims abstract 3
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 claims abstract 3
- 101100481408 Danio rerio tie2 gene Proteins 0.000 claims abstract 3
- 102100023401 Dual specificity mitogen-activated protein kinase kinase 6 Human genes 0.000 claims abstract 3
- 101150036586 FES gene Proteins 0.000 claims abstract 3
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 claims abstract 3
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 claims abstract 3
- 101000624426 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 6 Proteins 0.000 claims abstract 3
- 101001074439 Homo sapiens Polycystin-2 Proteins 0.000 claims abstract 3
- 101000880439 Homo sapiens Serine/threonine-protein kinase 3 Proteins 0.000 claims abstract 3
- 101000777277 Homo sapiens Serine/threonine-protein kinase Chk2 Proteins 0.000 claims abstract 3
- 101001026882 Homo sapiens Serine/threonine-protein kinase D2 Proteins 0.000 claims abstract 3
- 101150003567 Mapk12 gene Proteins 0.000 claims abstract 3
- 101150060694 Mapk13 gene Proteins 0.000 claims abstract 3
- 102000056243 Mitogen-activated protein kinase 12 Human genes 0.000 claims abstract 3
- 108700015929 Mitogen-activated protein kinase 12 Proteins 0.000 claims abstract 3
- 102000056248 Mitogen-activated protein kinase 13 Human genes 0.000 claims abstract 3
- 108700015928 Mitogen-activated protein kinase 13 Proteins 0.000 claims abstract 3
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 claims abstract 3
- 101100091501 Mus musculus Ros1 gene Proteins 0.000 claims abstract 3
- 101100481410 Mus musculus Tek gene Proteins 0.000 claims abstract 3
- 101150056950 Ntrk2 gene Proteins 0.000 claims abstract 3
- 101100202399 Oryza sativa subsp. japonica SAPK4 gene Proteins 0.000 claims abstract 3
- 108091000080 Phosphotransferase Proteins 0.000 claims abstract 3
- 102000001393 Platelet-Derived Growth Factor alpha Receptor Human genes 0.000 claims abstract 3
- 108010068588 Platelet-Derived Growth Factor alpha Receptor Proteins 0.000 claims abstract 3
- 102100036142 Polycystin-2 Human genes 0.000 claims abstract 3
- 101150071831 RPS6KA1 gene Proteins 0.000 claims abstract 3
- 101100091511 Rhizobium radiobacter ros gene Proteins 0.000 claims abstract 3
- 102100039314 Rho-associated protein kinase 2 Human genes 0.000 claims abstract 3
- 101710088493 Rho-associated protein kinase 2 Proteins 0.000 claims abstract 3
- 101150105578 SAPK3 gene Proteins 0.000 claims abstract 3
- 102100037628 Serine/threonine-protein kinase 3 Human genes 0.000 claims abstract 3
- 102100031075 Serine/threonine-protein kinase Chk2 Human genes 0.000 claims abstract 3
- 101150110875 Syk gene Proteins 0.000 claims abstract 3
- 201000010099 disease Diseases 0.000 claims abstract 3
- 230000000694 effects Effects 0.000 claims abstract 3
- 102000020233 phosphotransferase Human genes 0.000 claims abstract 3
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 2
- -1 methoxy, imidazolyl Chemical group 0.000 claims 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 4
- 239000001257 hydrogen Substances 0.000 claims 4
- 229910052739 hydrogen Inorganic materials 0.000 claims 4
- 125000001072 heteroaryl group Chemical group 0.000 claims 3
- 208000031295 Animal disease Diseases 0.000 claims 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 230000007170 pathology Effects 0.000 claims 2
- 208000024891 symptom Diseases 0.000 claims 2
- 125000004191 (C1-C6) alkoxy group Chemical class 0.000 claims 1
- LICCVFXPSLEQPT-UHFFFAOYSA-N 1-(3,5-dimethoxyphenyl)-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea Chemical compound COC1=CC(OC)=CC(NC(=O)NC=2C=CC(OC=3C=4C=CNC=4N=CN=3)=CC=2)=C1 LICCVFXPSLEQPT-UHFFFAOYSA-N 0.000 claims 1
- KUUHELAXGDXSGL-UHFFFAOYSA-N 1-[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[4-(7h-purin-6-yloxy)phenyl]urea Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)NC=2C=CC(OC=3C=4N=CNC=4N=CN=3)=CC=2)=CC(C(F)(F)F)=C1 KUUHELAXGDXSGL-UHFFFAOYSA-N 0.000 claims 1
- XFRMNUYBPXLMNX-UHFFFAOYSA-N 1-[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)NC=2C=CC(OC=3C=4C=CNC=4N=CN=3)=CC=2)=CC(C(F)(F)F)=C1 XFRMNUYBPXLMNX-UHFFFAOYSA-N 0.000 claims 1
- IDOOWCFHQFYDNB-UHFFFAOYSA-N 1-[4-(7h-purin-6-yloxy)phenyl]-3-[3-(trifluoromethyl)phenyl]urea Chemical compound FC(F)(F)C1=CC=CC(NC(=O)NC=2C=CC(OC=3C=4N=CNC=4N=CN=3)=CC=2)=C1 IDOOWCFHQFYDNB-UHFFFAOYSA-N 0.000 claims 1
- CRNIURWEBLRATC-UHFFFAOYSA-N 1-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]-3-[3-(trifluoromethyl)phenyl]urea Chemical compound FC(F)(F)C1=CC=CC(NC(=O)NC=2C=CC(OC=3C=4C=CNC=4N=CN=3)=CC=2)=C1 CRNIURWEBLRATC-UHFFFAOYSA-N 0.000 claims 1
- VPDMGTIJUGETIM-UHFFFAOYSA-N 1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-(7h-purin-6-yloxy)phenyl]urea Chemical compound C1CN(CC)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)NC(C=C1)=CC=C1OC1=NC=NC2=C1N=CN2 VPDMGTIJUGETIM-UHFFFAOYSA-N 0.000 claims 1
- PEASZHCOKFXVSG-UHFFFAOYSA-N 1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea Chemical compound C1CN(CC)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)NC(C=C1)=CC=C1OC1=NC=NC2=C1C=CN2 PEASZHCOKFXVSG-UHFFFAOYSA-N 0.000 claims 1
- WDMGOMQPJYCQIL-UHFFFAOYSA-N 1-[5-(7h-pyrrolo[2,3-d]pyrimidin-4-yloxy)quinolin-8-yl]-3-[3-(trifluoromethyl)phenyl]urea Chemical compound FC(F)(F)C1=CC=CC(NC(=O)NC=2C3=NC=CC=C3C(OC=3C=4C=CNC=4N=CN=3)=CC=2)=C1 WDMGOMQPJYCQIL-UHFFFAOYSA-N 0.000 claims 1
- CHXBFAOJCNQFCH-UHFFFAOYSA-N 3-(4-methylimidazol-1-yl)-n-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]-5-(trifluoromethyl)benzamide Chemical compound C1=NC(C)=CN1C1=CC(C(=O)NC=2C=CC(OC=3C=4C=CNC=4N=CN=3)=CC=2)=CC(C(F)(F)F)=C1 CHXBFAOJCNQFCH-UHFFFAOYSA-N 0.000 claims 1
- 102000001253 Protein Kinase Human genes 0.000 claims 1
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 1
- 150000004677 hydrates Chemical class 0.000 claims 1
- 125000002883 imidazolyl group Chemical group 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- XGESRAICJZKRJU-UHFFFAOYSA-N n-[4-(7h-purin-6-yloxy)phenyl]-3-(trifluoromethyl)benzamide Chemical compound FC(F)(F)C1=CC=CC(C(=O)NC=2C=CC(OC=3C=4N=CNC=4N=CN=3)=CC=2)=C1 XGESRAICJZKRJU-UHFFFAOYSA-N 0.000 claims 1
- SEUVRZYXKVZISW-UHFFFAOYSA-N n-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]-3-(trifluoromethyl)benzamide Chemical compound FC(F)(F)C1=CC=CC(C(=O)NC=2C=CC(OC=3C=4C=CNC=4N=CN=3)=CC=2)=C1 SEUVRZYXKVZISW-UHFFFAOYSA-N 0.000 claims 1
- QBECTAAMEKAKDC-UHFFFAOYSA-N n-[5-(7h-purin-6-yloxy)quinolin-8-yl]-3-(trifluoromethyl)benzamide Chemical compound FC(F)(F)C1=CC=CC(C(=O)NC=2C3=NC=CC=C3C(OC=3C=4N=CNC=4N=CN=3)=CC=2)=C1 QBECTAAMEKAKDC-UHFFFAOYSA-N 0.000 claims 1
- 125000001624 naphthyl group Chemical group 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 108060006633 protein kinase Proteins 0.000 claims 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000012453 solvate Substances 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- 230000002159 abnormal effect Effects 0.000 abstract 2
- 208000035475 disorder Diseases 0.000 abstract 2
- 230000004913 activation Effects 0.000 abstract 1
- 230000002074 deregulated effect Effects 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- Life Sciences & Earth Sciences (AREA)
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- Transplantation (AREA)
Abstract
1. Соединение формулы I ! ! в котором Y выбран из азота и СН, ! R1 выбран из водорода и (С1-С6)алкила, ! R2 выбран из водорода и (С1-С6)алкила, или R1 и R2 совместно с фенильным циклом, к которому они присоединены, образуют (С6-С10)арил или (С5-С10)гетероарил, ! R3 выбран из NR4R5 и X1R5, где X1 выбран из связи и (С1-С4)алкилена, R4 выбран из водорода и (С1-С6)алкила, a R5 выбран из (С6-С10)арила, необязательно замещенного радикалами в количестве от 1 до 3, независимо выбранными из галоидзамещенного (С1-С6)алкила, (С1-С6)алкоксигрупы, (С5-С10)гетероарил(С0-С4)алкила и (С3-С8)гетероциклоалкил(С0-С4)алкила, где упомянутые гетероарильный и гетероциклоалкильный заместители в R5 необязательно замещены (С1-С6)алкилом, ! а также его фармацевтически приемлемые соли, гидраты, сольваты и изомеры. ! 2. Соединение согласно п.1, в котором R1 и R2 оба являются водородом или R1 и R2 совместно с фенильным циклом, к которому они присоединены, образуют хинолинил или нафтил, ! 3. Соединение согласно п.2, в котором R3 выбран из NHR5 и X1R5, где X1 выбран из связи и метилена, a R5 выбран из фенила, необязательно замещенного радикалами в количестве от 1 до 3, независимо выбранными из трифторметила, метоксигруппы, имидазолила и пиперазинилметила, где упомянутые имидазолильный или пиперазинильный заместители в R3 необязательно замещены метилом и этилом. ! 4. Соединение согласно п.1, выбранное из 1-[4-(7Н-пирроло[2,3-d]пиримидин-4-илокси)фенил]-3-(3-трифторметилфенил)мочевины, 1-[4-(4-этилпиперазин-1-илметил)-3-трифторметилфенил]-3-[4-(7Н-пирроло[2,3-d]пиримидин-4-илокси)фенил]мочевины, 1-[3-(4-метилимидазол-1-ил)-5-трифторметилфенил]-3-[4-(7Н-пирроло[2,3-d]пиримидин-4-илокси)фенил]мочевины, 1-(3,5-диметоксифенил)-3-[4-(7Н-пирроло[2,3-d]пиримидин-4-илокси)
Claims (8)
1. Соединение формулы I
в котором Y выбран из азота и СН,
R1 выбран из водорода и (С1-С6)алкила,
R2 выбран из водорода и (С1-С6)алкила, или R1 и R2 совместно с фенильным циклом, к которому они присоединены, образуют (С6-С10)арил или (С5-С10)гетероарил,
R3 выбран из NR4R5 и X1R5, где X1 выбран из связи и (С1-С4)алкилена, R4 выбран из водорода и (С1-С6)алкила, a R5 выбран из (С6-С10)арила, необязательно замещенного радикалами в количестве от 1 до 3, независимо выбранными из галоидзамещенного (С1-С6)алкила, (С1-С6)алкоксигрупы, (С5-С10)гетероарил(С0-С4)алкила и (С3-С8)гетероциклоалкил(С0-С4)алкила, где упомянутые гетероарильный и гетероциклоалкильный заместители в R5 необязательно замещены (С1-С6)алкилом,
а также его фармацевтически приемлемые соли, гидраты, сольваты и изомеры.
2. Соединение согласно п.1, в котором R1 и R2 оба являются водородом или R1 и R2 совместно с фенильным циклом, к которому они присоединены, образуют хинолинил или нафтил,
3. Соединение согласно п.2, в котором R3 выбран из NHR5 и X1R5, где X1 выбран из связи и метилена, a R5 выбран из фенила, необязательно замещенного радикалами в количестве от 1 до 3, независимо выбранными из трифторметила, метоксигруппы, имидазолила и пиперазинилметила, где упомянутые имидазолильный или пиперазинильный заместители в R3 необязательно замещены метилом и этилом.
4. Соединение согласно п.1, выбранное из 1-[4-(7Н-пирроло[2,3-d]пиримидин-4-илокси)фенил]-3-(3-трифторметилфенил)мочевины, 1-[4-(4-этилпиперазин-1-илметил)-3-трифторметилфенил]-3-[4-(7Н-пирроло[2,3-d]пиримидин-4-илокси)фенил]мочевины, 1-[3-(4-метилимидазол-1-ил)-5-трифторметилфенил]-3-[4-(7Н-пирроло[2,3-d]пиримидин-4-илокси)фенил]мочевины, 1-(3,5-диметоксифенил)-3-[4-(7Н-пирроло[2,3-d]пиримидин-4-илокси)фенил]мочевины, 1-[4-(9Н-пурин-6-илокси)фенил]-3-(3-трифторметилфенил)мочевины, 1-[3-(4-метилимидазол-1-ил)-5-трифторметилфенил]-3-[4-(9Н-пурин-6-илокси)фенил]мочевины, 1-[4-(4-этилпиперазин-1-илметил)-3-трифторметилфенил]-3-[4-(9Н-пурин-6-илокси)фенил]мочевины, 1-[5-(7Н-пирроло[2,3-d]пиримидин-4-илокси)хинолин-8-ил]-3-(3-трифторметилфенил)мочевины, N-[4-(7Н-пирроло[2,3-d]пиримидин-4-илокси)фенил]-2-(3-трифторметилфенил)ацетамида, 2-[3-(4-метилимидазол-1-ил)-5-трифторметилфенил]-N-[4-(9Н-пурин-6-илокси)фенил]ацетамида, N-[4-(7Н-пирроло[2,3-d]пиримидин-4-илокси)фенил]-3-трифторметилбензамида, 3-(4-метилимидазол-1-ил)-N-[4-(7Н-пирроло[2,3-d]пиримидин-4-илокси)фенил]-5-трифторметилбензамида, N-[4-(9Н-пурин-6-илокси)фенил]-3-трифторметилбензамида, 4-(4-этилпиперазин-1-илметил)-N-[4-(9Н-пурин-6-илокси)фенил]-3-трифторметилбензамида и N-[5-(9H-пурин-6-илокси)хинолин-8-ил]-3-трифторметилбензамида.
5. Фармацевтическая композиция, включающая терапевтически эффективное количество соединения согласно п.1 в сочетании с фармацевтически приемлемым наполнителем.
6. Способ лечения заболевания животного, при котором ингибирование киназной активности может предотвратить, ингибировать или облегчить патологию и/или симптоматику заболевания, каковой способ включает введение животному терапевтически эффективного количества соединения согласно п.1.
7. Способ согласно п.6, в котором киназа выбрана из Abl, Bcr-Abl, Aurora-А, Axl, BMX, СНК2, c-RAF, cSRC, Fes, FGFR3, Flt3, IKKα, IR, JNK2α2, Lck, Met, MKK6, MST2, p70S6K, PDGFRα, PKA, PKD2, ROCK-II, Ros, Rsk1, SAPK2α, SAPK2β, SAPK3, SAPK4, Syk, Tie2 и TrkB.
8. Применение соединения согласно п.1 в изготовлении лекарственного средства для лечения заболевания животного, при котором активность киназ Abl, Всr-Аbl, Аurоrа-А, Axl, BMX, CHK2, c-RAF, cSRC, Fes, FGFR3, Flt3, IKKα, IR, JNK2α2, Lck, Met, MKK6, MST2, p70S6K, PDGFRα, PKA, PKD2, ROCK-II, Ros, Rsk1, SAPK2α, SAPK2β, SAPK3, SAPK4, Syk, Tie2 и TrkB вносит вклад в патологию и/или симптоматику заболевания.
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WO2011023081A1 (en) * | 2009-08-24 | 2011-03-03 | Ascepion Pharmaceuticals, Inc. | 5,6-bicyclic heteroaryl-containing urea compounds as kinase inhibitors |
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