JP2007519694A - Ｐ３８キナーゼ阻害剤 - Google Patents
Ｐ３８キナーゼ阻害剤 Download PDFInfo
- Publication number
- JP2007519694A JP2007519694A JP2006550297A JP2006550297A JP2007519694A JP 2007519694 A JP2007519694 A JP 2007519694A JP 2006550297 A JP2006550297 A JP 2006550297A JP 2006550297 A JP2006550297 A JP 2006550297A JP 2007519694 A JP2007519694 A JP 2007519694A
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- methyl
- pyridin
- pyrazolo
- optionally substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 229940043355 kinase inhibitor Drugs 0.000 title description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 260
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 claims abstract description 36
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 claims abstract description 36
- 230000000694 effects Effects 0.000 claims abstract description 23
- 238000011282 treatment Methods 0.000 claims abstract description 19
- 230000001404 mediated effect Effects 0.000 claims abstract description 17
- 102000004127 Cytokines Human genes 0.000 claims abstract description 12
- 108090000695 Cytokines Proteins 0.000 claims abstract description 12
- 208000024891 symptom Diseases 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 98
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 69
- 229910052757 nitrogen Chemical group 0.000 claims description 56
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 55
- 125000001072 heteroaryl group Chemical group 0.000 claims description 54
- -1 —CONHR 22 Chemical group 0.000 claims description 51
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 43
- 229910052760 oxygen Inorganic materials 0.000 claims description 42
- 239000001301 oxygen Substances 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 40
- 150000002367 halogens Chemical class 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 39
- 125000001424 substituent group Chemical group 0.000 claims description 39
- 125000005842 heteroatom Chemical group 0.000 claims description 37
- 239000003814 drug Substances 0.000 claims description 29
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 125000000623 heterocyclic group Chemical group 0.000 claims description 26
- 229910052717 sulfur Inorganic materials 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 22
- 239000011593 sulfur Substances 0.000 claims description 22
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 17
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 16
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 16
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 239000000460 chlorine Substances 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 239000003085 diluting agent Substances 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 12
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 10
- 239000011737 fluorine Chemical group 0.000 claims description 10
- 229910052731 fluorine Chemical group 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 239000000969 carrier Substances 0.000 claims description 8
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 7
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 6
- FUCOMXCSIWZWMP-UHFFFAOYSA-N n-cyclopropyl-3-[1-(2-fluorophenyl)pyrazolo[3,4-c]pyridin-5-yl]-4-methylbenzamide Chemical compound CC1=CC=C(C(=O)NC2CC2)C=C1C(N=CC=12)=CC=1C=NN2C1=CC=CC=C1F FUCOMXCSIWZWMP-UHFFFAOYSA-N 0.000 claims description 5
- JXBGQOJIARFIEK-UHFFFAOYSA-N 3-(3-acetamido-1h-pyrazolo[3,4-b]pyridin-6-yl)-n-cyclopropyl-4-methylbenzamide Chemical compound C=1C=C2C(NC(=O)C)=NNC2=NC=1C(C(=CC=1)C)=CC=1C(=O)NC1CC1 JXBGQOJIARFIEK-UHFFFAOYSA-N 0.000 claims description 4
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 150000002429 hydrazines Chemical class 0.000 claims description 4
- CSYYIPJTYOBZRX-UHFFFAOYSA-N n-cyclopropyl-3-(1-cyclopropylsulfonylpyrazolo[3,4-c]pyridin-5-yl)-5-fluoro-4-methylbenzamide Chemical compound CC1=C(F)C=C(C(=O)NC2CC2)C=C1C(N=CC=12)=CC=1C=NN2S(=O)(=O)C1CC1 CSYYIPJTYOBZRX-UHFFFAOYSA-N 0.000 claims description 4
- IRXOVBVMJTWNEL-UHFFFAOYSA-N n-cyclopropyl-3-fluoro-4-methyl-5-[1-(3-methylphenyl)pyrazolo[3,4-c]pyridin-5-yl]benzamide Chemical compound CC1=CC=CC(N2C3=CN=C(C=C3C=N2)C=2C(=C(F)C=C(C=2)C(=O)NC2CC2)C)=C1 IRXOVBVMJTWNEL-UHFFFAOYSA-N 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- ODOAXTMBIZABMS-UHFFFAOYSA-N n-cyclopropyl-4-methyl-3-(1-propan-2-ylsulfonylpyrazolo[3,4-c]pyridin-5-yl)benzamide Chemical compound N=1C=C2N(S(=O)(=O)C(C)C)N=CC2=CC=1C(C(=CC=1)C)=CC=1C(=O)NC1CC1 ODOAXTMBIZABMS-UHFFFAOYSA-N 0.000 claims description 3
- IVZAVKISSSRRDM-UHFFFAOYSA-N n-cyclopropyl-4-methyl-3-(1-thiophen-2-ylsulfonylpyrazolo[3,4-c]pyridin-5-yl)benzamide Chemical compound CC1=CC=C(C(=O)NC2CC2)C=C1C(N=CC=12)=CC=1C=NN2S(=O)(=O)C1=CC=CS1 IVZAVKISSSRRDM-UHFFFAOYSA-N 0.000 claims description 3
- JPRFWXHDTCQHRD-UHFFFAOYSA-N n-cyclopropyl-4-methyl-3-[3-(2-methylpropanoylamino)-1h-pyrazolo[3,4-b]pyridin-6-yl]benzamide Chemical compound C=1C=C2C(NC(=O)C(C)C)=NNC2=NC=1C(C(=CC=1)C)=CC=1C(=O)NC1CC1 JPRFWXHDTCQHRD-UHFFFAOYSA-N 0.000 claims description 3
- NHPQXWRHCXVQNT-UHFFFAOYSA-N n-cyclopropyl-4-methyl-3-[3-(propanoylamino)-1h-pyrazolo[3,4-b]pyridin-6-yl]benzamide Chemical compound C=1C=C2C(NC(=O)CC)=NNC2=NC=1C(C(=CC=1)C)=CC=1C(=O)NC1CC1 NHPQXWRHCXVQNT-UHFFFAOYSA-N 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- ZUUPPBFBFQLCNJ-UHFFFAOYSA-N n-[6-[5-(cyclopropylcarbamoyl)-2-methylphenyl]-1h-pyrazolo[3,4-b]pyridin-3-yl]thiophene-2-carboxamide Chemical compound CC1=CC=C(C(=O)NC2CC2)C=C1C(N=C1NN=2)=CC=C1C=2NC(=O)C1=CC=CS1 ZUUPPBFBFQLCNJ-UHFFFAOYSA-N 0.000 claims description 2
- VJOHQXXMKNOOAX-UHFFFAOYSA-N n-cyclopropyl-3-fluoro-5-[3-(4-fluorophenyl)-2h-pyrazolo[3,4-b]pyridin-6-yl]-4-methylbenzamide Chemical compound CC1=C(F)C=C(C(=O)NC2CC2)C=C1C(N=C1NN=2)=CC=C1C=2C1=CC=C(F)C=C1 VJOHQXXMKNOOAX-UHFFFAOYSA-N 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims 2
- 239000003112 inhibitor Substances 0.000 abstract description 12
- 239000000126 substance Substances 0.000 abstract description 6
- 230000007170 pathology Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 197
- 239000000203 mixture Substances 0.000 description 93
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 82
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 82
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
- 239000000243 solution Substances 0.000 description 56
- 239000007787 solid Substances 0.000 description 48
- 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 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 43
- 235000002639 sodium chloride Nutrition 0.000 description 43
- 239000000377 silicon dioxide Substances 0.000 description 40
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 38
- 150000003839 salts Chemical class 0.000 description 36
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 34
- 239000002904 solvent Substances 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 32
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 30
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 28
- 230000002829 reductive effect Effects 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- 239000012299 nitrogen atmosphere Substances 0.000 description 22
- 239000003446 ligand Substances 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 20
- UUDUDVPUWBRXHD-UHFFFAOYSA-N 3-(3-amino-2h-pyrazolo[3,4-b]pyridin-6-yl)-n-cyclopropyl-4-methylbenzamide Chemical compound C1=C(C=2N=C3NN=C(N)C3=CC=2)C(C)=CC=C1C(=O)NC1CC1 UUDUDVPUWBRXHD-UHFFFAOYSA-N 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 229940079593 drug Drugs 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 18
- 108091000080 Phosphotransferase Proteins 0.000 description 17
- 102000020233 phosphotransferase Human genes 0.000 description 17
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 17
- 239000002253 acid Substances 0.000 description 16
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 16
- 238000009472 formulation Methods 0.000 description 16
- 230000002209 hydrophobic effect Effects 0.000 description 16
- 235000017557 sodium bicarbonate Nutrition 0.000 description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 239000012453 solvate Substances 0.000 description 15
- 238000002953 preparative HPLC Methods 0.000 description 13
- 239000003826 tablet Substances 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000007429 general method Methods 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 11
- 239000002552 dosage form Substances 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 11
- 239000012071 phase Substances 0.000 description 11
- 230000002441 reversible effect Effects 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- 229920002472 Starch Polymers 0.000 description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 235000019698 starch Nutrition 0.000 description 10
- 239000008107 starch Substances 0.000 description 10
- 239000000375 suspending agent Substances 0.000 description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 9
- 229940002612 prodrug Drugs 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- CBMTYCGVJICRKD-UHFFFAOYSA-M [I-].FC1=CC=C(C[Zn+])C=C1F Chemical compound [I-].FC1=CC=C(C[Zn+])C=C1F CBMTYCGVJICRKD-UHFFFAOYSA-M 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 230000001684 chronic effect Effects 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 239000003755 preservative agent Substances 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 description 7
- 0 C*1c2nc(C)ncc2C=*1 Chemical compound C*1c2nc(C)ncc2C=*1 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 6
- 229920000858 Cyclodextrin Polymers 0.000 description 6
- 241000282412 Homo Species 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 235000011054 acetic acid Nutrition 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000011230 binding agent Substances 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000006071 cream Substances 0.000 description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 6
- 238000010494 dissociation reaction Methods 0.000 description 6
- 230000005593 dissociations Effects 0.000 description 6
- 239000003937 drug carrier Substances 0.000 description 6
- 239000000314 lubricant Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000002480 mineral oil Substances 0.000 description 6
- 235000010446 mineral oil Nutrition 0.000 description 6
- 239000002674 ointment Substances 0.000 description 6
- 238000007911 parenteral administration Methods 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- DVAYVJGYZRYJEV-UHFFFAOYSA-M zinc;ethyl benzoate;iodide Chemical group I[Zn+].CCOC(=O)C1=CC=[C-]C=C1 DVAYVJGYZRYJEV-UHFFFAOYSA-M 0.000 description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 5
- 206010006895 Cachexia Diseases 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 208000002193 Pain Diseases 0.000 description 5
- 102000001708 Protein Isoforms Human genes 0.000 description 5
- 108010029485 Protein Isoforms Proteins 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 239000003086 colorant Substances 0.000 description 5
- 230000016396 cytokine production Effects 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 239000006210 lotion Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- UBSOWCULIXVZGE-UHFFFAOYSA-N n-ethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide Chemical compound CCNC(=O)C1=CC=C(C)C(B2OC(C)(C)C(C)(C)O2)=C1 UBSOWCULIXVZGE-UHFFFAOYSA-N 0.000 description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 235000011056 potassium acetate Nutrition 0.000 description 5
- 238000000159 protein binding assay Methods 0.000 description 5
- GSBPBXOLHIFRSE-UHFFFAOYSA-N (2,6-dichloropyridin-3-yl)-(4-fluorophenyl)methanone Chemical compound C1=CC(F)=CC=C1C(=O)C1=CC=C(Cl)N=C1Cl GSBPBXOLHIFRSE-UHFFFAOYSA-N 0.000 description 4
- ILMIEWNDXAKVNI-UHFFFAOYSA-N 4,6-dichloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=C(Cl)C=C1Cl ILMIEWNDXAKVNI-UHFFFAOYSA-N 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P11/02—Nasal agents, e.g. decongestants
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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| JP2007519694A true JP2007519694A (ja) | 2007-07-19 |
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| JP2009503037A (ja) * | 2005-08-04 | 2009-01-29 | アバンテイス・フアルマ・エス・アー | ７−置換アザ−インダゾール、これらを含む組成物、これらの製造方法および使用 |
| JP2015503546A (ja) * | 2011-12-28 | 2015-02-02 | サノフイ | Ｆｇｆ受容体（ｆｇｆｒ）アゴニスト二量体化合物、その製造方法及びその治療上の使用 |
| JP2018538355A (ja) * | 2015-09-30 | 2018-12-27 | シイエスピイシイ・チョンチ・ファーマシューティカル・テクノロジー・（シーチアチョワン）・カンパニー・リミテッド | ベンズアミド誘導体 |
| KR20190067795A (ko) * | 2016-09-09 | 2019-06-17 | 인사이트 코포레이션 | Hpk1 조절제로서의 피라졸로피리딘 유도체 및 암을 치료하기 위한 이의 용도 |
| JP2024525231A (ja) * | 2021-07-06 | 2024-07-10 | プレイザーセラピューティクス インコーポレイテッド | ｐ３８ ＭＡＰキナーゼ阻害剤で炎症性疾患の治療効果を示す新規な化合物 |
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| GB0124941D0 (en) | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
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| GB0124938D0 (en) | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
| GB0124933D0 (en) | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
| ATE375980T1 (de) | 2002-02-12 | 2007-11-15 | Smithkline Beecham Corp | Nicotinamide und deren verwendung als p38 inhibitoren |
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| US20080051416A1 (en) * | 2004-10-05 | 2008-02-28 | Smithkline Beecham Corporation | Novel Compounds |
| GB0512429D0 (en) * | 2005-06-17 | 2005-07-27 | Smithkline Beecham Corp | Novel compound |
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2004
- 2004-01-30 GB GBGB0402137.4A patent/GB0402137D0/en not_active Ceased
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2005
- 2005-01-27 US US10/587,989 patent/US20070161673A1/en not_active Abandoned
- 2005-01-27 EP EP05702029A patent/EP1709046B1/en not_active Expired - Lifetime
- 2005-01-27 WO PCT/GB2005/000274 patent/WO2005073232A1/en not_active Ceased
- 2005-01-27 JP JP2006550297A patent/JP2007519694A/ja active Pending
- 2005-01-27 AT AT05702029T patent/ATE517896T1/de not_active IP Right Cessation
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| WO1999021859A1 (en) * | 1997-10-10 | 1999-05-06 | Glaxo Group Limited | Azaoxindole derivatives |
| JP2002523459A (ja) * | 1998-08-31 | 2002-07-30 | メルク エンド カムパニー インコーポレーテッド | 新規血管形成阻害剤 |
| WO2004001974A1 (en) * | 2002-06-19 | 2003-12-31 | R & C Holding Aps | Phase-locked loop with incremental phase detectors and a converter for combining a logical operation with a digital to analog conversion |
| WO2004010995A1 (en) * | 2002-07-31 | 2004-02-05 | Smithkline Beecham Corporation | Fused heteroaryl derivatives for use as p38 kinase inhibitors in the treatment of i.a. rheumatoid arthristis |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009503037A (ja) * | 2005-08-04 | 2009-01-29 | アバンテイス・フアルマ・エス・アー | ７−置換アザ−インダゾール、これらを含む組成物、これらの製造方法および使用 |
| JP2015503546A (ja) * | 2011-12-28 | 2015-02-02 | サノフイ | Ｆｇｆ受容体（ｆｇｆｒ）アゴニスト二量体化合物、その製造方法及びその治療上の使用 |
| JP2018538355A (ja) * | 2015-09-30 | 2018-12-27 | シイエスピイシイ・チョンチ・ファーマシューティカル・テクノロジー・（シーチアチョワン）・カンパニー・リミテッド | ベンズアミド誘導体 |
| JP7028780B2 (ja) | 2015-09-30 | 2022-03-02 | シイエスピイシイ・チョンチ・ファーマシューティカル・テクノロジー・（シーチアチョワン）・カンパニー・リミテッド | ベンズアミド誘導体 |
| KR20190067795A (ko) * | 2016-09-09 | 2019-06-17 | 인사이트 코포레이션 | Hpk1 조절제로서의 피라졸로피리딘 유도체 및 암을 치료하기 위한 이의 용도 |
| JP2019530670A (ja) * | 2016-09-09 | 2019-10-24 | インサイト・コーポレイションＩｎｃｙｔｅ Ｃｏｒｐｏｒａｔｉｏｎ | Ｈｐｋ１調節薬としてのピラゾロピリジン誘導体及びがんの治療のためのその用法 |
| JP7076432B2 (ja) | 2016-09-09 | 2022-05-27 | インサイト・コーポレイション | Ｈｐｋ１調節薬としてのピラゾロピリジン誘導体及びがんの治療のためのその用法 |
| JP2022110095A (ja) * | 2016-09-09 | 2022-07-28 | インサイト・コーポレイション | Ｈｐｋ１調節薬としてのピラゾロピリジン誘導体及びがんの治療のためのその用法 |
| KR102507967B1 (ko) | 2016-09-09 | 2023-03-09 | 인사이트 코포레이션 | Hpk1 조절제로서의 피라졸로피리딘 유도체 및 암을 치료하기 위한 이의 용도 |
| JP7432655B2 (ja) | 2016-09-09 | 2024-02-16 | インサイト・コーポレイション | Ｈｐｋ１調節薬としてのピラゾロピリジン誘導体及びがんの治療のためのその用法 |
| JP2024525231A (ja) * | 2021-07-06 | 2024-07-10 | プレイザーセラピューティクス インコーポレイテッド | ｐ３８ ＭＡＰキナーゼ阻害剤で炎症性疾患の治療効果を示す新規な化合物 |
| JP7685803B2 (ja) | 2021-07-06 | 2025-05-30 | プレイザーセラピューティクス インコーポレイテッド | ｐ３８ ＭＡＰキナーゼ阻害剤で炎症性疾患の治療効果を示す新規な化合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1709046A1 (en) | 2006-10-11 |
| US20070161673A1 (en) | 2007-07-12 |
| GB0402137D0 (en) | 2004-03-03 |
| EP1709046B1 (en) | 2011-07-27 |
| WO2005073232A1 (en) | 2005-08-11 |
| ATE517896T1 (de) | 2011-08-15 |
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