WO2004096795A2 - C-fms kinase inhibitors - Google Patents
C-fms kinase inhibitors Download PDFInfo
- Publication number
- WO2004096795A2 WO2004096795A2 PCT/US2004/012729 US2004012729W WO2004096795A2 WO 2004096795 A2 WO2004096795 A2 WO 2004096795A2 US 2004012729 W US2004012729 W US 2004012729W WO 2004096795 A2 WO2004096795 A2 WO 2004096795A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phenyl
- amide
- carboxylic acid
- piperidin
- alkyl
- Prior art date
Links
- 229940043355 kinase inhibitor Drugs 0.000 title description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims abstract description 19
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims abstract description 18
- 108010058398 Macrophage Colony-Stimulating Factor Receptor Proteins 0.000 claims abstract description 14
- 239000012453 solvate Substances 0.000 claims abstract description 10
- 125000003118 aryl group Chemical group 0.000 claims description 82
- 125000001072 heteroaryl group Chemical group 0.000 claims description 82
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 58
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 57
- 125000003545 alkoxy group Chemical group 0.000 claims description 48
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 47
- 229910052736 halogen Inorganic materials 0.000 claims description 47
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 46
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 45
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 45
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 45
- 125000004104 aryloxy group Chemical group 0.000 claims description 45
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 45
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 45
- 150000002367 halogens Chemical class 0.000 claims description 44
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 42
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 42
- 229910003827 NRaRb Inorganic materials 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 28
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- 125000005842 heteroatom Chemical group 0.000 claims description 24
- 229910052717 sulfur Inorganic materials 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 23
- -1 -CORa Chemical group 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000001188 haloalkyl group Chemical group 0.000 claims description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- 241000124008 Mammalia Species 0.000 claims description 15
- 229910052705 radium Inorganic materials 0.000 claims description 14
- 229910052701 rubidium Inorganic materials 0.000 claims description 14
- 239000004305 biphenyl Substances 0.000 claims description 13
- 235000010290 biphenyl Nutrition 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- OYECAJPUPWFCSL-UHFFFAOYSA-N 2-piperidin-1-ylaniline Chemical compound NC1=CC=CC=C1N1CCCCC1 OYECAJPUPWFCSL-UHFFFAOYSA-N 0.000 claims description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
- 125000001624 naphthyl group Chemical group 0.000 claims description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 9
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 8
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 108091000080 Phosphotransferase Proteins 0.000 claims description 7
- 102000020233 phosphotransferase Human genes 0.000 claims description 7
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 6
- HJSQIQBSYVDUMX-UHFFFAOYSA-N [3-amino-4-(4-methylpiperidin-1-yl)phenyl]methanol Chemical compound C1CC(C)CCN1C1=CC=C(CO)C=C1N HJSQIQBSYVDUMX-UHFFFAOYSA-N 0.000 claims description 6
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 5
- 125000002636 imidazolinyl group Chemical group 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical group C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 4
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 claims description 4
- GVBBTRHDBRYGKO-UHFFFAOYSA-N 5-bromo-n-(2-piperidin-1-ylphenyl)furan-2-carboxamide Chemical compound O1C(Br)=CC=C1C(=O)NC1=CC=CC=C1N1CCCCC1 GVBBTRHDBRYGKO-UHFFFAOYSA-N 0.000 claims description 4
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 claims description 4
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 4
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
- 230000033115 angiogenesis Effects 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 4
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 4
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 claims description 4
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 claims description 4
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 4
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 claims description 4
- 229930192474 thiophene Natural products 0.000 claims description 4
- 150000003852 triazoles Chemical class 0.000 claims description 4
- NLEVWDAJRHRSKC-UHFFFAOYSA-N 5-cyano-n-(2-piperidin-1-ylphenyl)furan-2-carboxamide Chemical compound C=1C=C(C#N)OC=1C(=O)NC1=CC=CC=C1N1CCCCC1 NLEVWDAJRHRSKC-UHFFFAOYSA-N 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 208000037803 restenosis Diseases 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 201000000980 schizophrenia Diseases 0.000 claims description 3
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 3
- QTEOZRDIJORBHP-UHFFFAOYSA-N 3-nitro-n-(2-piperidin-1-ylphenyl)-1h-pyrazole-5-carboxamide Chemical compound N1N=C([N+](=O)[O-])C=C1C(=O)NC1=CC=CC=C1N1CCCCC1 QTEOZRDIJORBHP-UHFFFAOYSA-N 0.000 claims description 2
- OFRXFLCNWAKYTQ-UHFFFAOYSA-N 3-nitro-n-(2-piperidin-1-ylphenyl)benzamide Chemical compound [O-][N+](=O)C1=CC=CC(C(=O)NC=2C(=CC=CC=2)N2CCCCC2)=C1 OFRXFLCNWAKYTQ-UHFFFAOYSA-N 0.000 claims description 2
- DROVSAMYJYKNGZ-UHFFFAOYSA-N 4-nitro-n-(2-piperidin-1-ylphenyl)-1h-pyrazole-5-carboxamide Chemical compound C1=NNC(C(=O)NC=2C(=CC=CC=2)N2CCCCC2)=C1[N+](=O)[O-] DROVSAMYJYKNGZ-UHFFFAOYSA-N 0.000 claims description 2
- GVHCJWYUILSCPT-UHFFFAOYSA-N 4-nitro-n-(2-piperidin-1-ylphenyl)pyridine-2-carboxamide Chemical compound [O-][N+](=O)C1=CC=NC(C(=O)NC=2C(=CC=CC=2)N2CCCCC2)=C1 GVHCJWYUILSCPT-UHFFFAOYSA-N 0.000 claims description 2
- AWCOPJKGUSHZQS-UHFFFAOYSA-N 5-[(2-piperidin-1-ylphenyl)carbamoyl]furan-2-carboxylic acid Chemical compound O1C(C(=O)O)=CC=C1C(=O)NC1=CC=CC=C1N1CCCCC1 AWCOPJKGUSHZQS-UHFFFAOYSA-N 0.000 claims description 2
- ZLZOLLHPYUHXJX-UHFFFAOYSA-N 5-acetyl-n-(2-piperidin-1-ylphenyl)thiophene-2-carboxamide Chemical compound S1C(C(=O)C)=CC=C1C(=O)NC1=CC=CC=C1N1CCCCC1 ZLZOLLHPYUHXJX-UHFFFAOYSA-N 0.000 claims description 2
- VZFMTNFVLVJCCC-UHFFFAOYSA-N 5-chloro-n-(2-piperidin-1-ylphenyl)furan-2-carboxamide Chemical compound O1C(Cl)=CC=C1C(=O)NC1=CC=CC=C1N1CCCCC1 VZFMTNFVLVJCCC-UHFFFAOYSA-N 0.000 claims description 2
- ZVAQSZOXWQRADX-UHFFFAOYSA-N 5-cyano-n-(4-fluoro-2-piperidin-1-ylphenyl)furan-2-carboxamide Chemical compound C1CCCCN1C1=CC(F)=CC=C1NC(=O)C1=CC=C(C#N)O1 ZVAQSZOXWQRADX-UHFFFAOYSA-N 0.000 claims description 2
- LONZWZXDMYLWOG-UHFFFAOYSA-N 5-cyano-n-(5-cyano-2-piperidin-1-ylphenyl)furan-2-carboxamide Chemical compound C=1C=C(C#N)OC=1C(=O)NC1=CC(C#N)=CC=C1N1CCCCC1 LONZWZXDMYLWOG-UHFFFAOYSA-N 0.000 claims description 2
- MZFFCLRLFUULFH-UHFFFAOYSA-N 5-cyano-n-[2-(4-methylpiperidin-1-yl)phenyl]furan-2-carboxamide Chemical compound C1CC(C)CCN1C1=CC=CC=C1NC(=O)C1=CC=C(C#N)O1 MZFFCLRLFUULFH-UHFFFAOYSA-N 0.000 claims description 2
- PGPQSLHHTKQTOY-UHFFFAOYSA-N 5-cyano-n-[5-(hydroxymethyl)-2-piperidin-1-ylphenyl]furan-2-carboxamide Chemical compound C=1C=C(C#N)OC=1C(=O)NC1=CC(CO)=CC=C1N1CCCCC1 PGPQSLHHTKQTOY-UHFFFAOYSA-N 0.000 claims description 2
- HIPDRHWEKZGISM-UHFFFAOYSA-N 5-cyano-n-[5-[(2,3-dihydroxypropylamino)methyl]-2-piperidin-1-ylphenyl]furan-2-carboxamide Chemical compound C=1C=C(C#N)OC=1C(=O)NC1=CC(CNCC(O)CO)=CC=C1N1CCCCC1 HIPDRHWEKZGISM-UHFFFAOYSA-N 0.000 claims description 2
- CBUPZNJHZPSIBR-UHFFFAOYSA-N 5-cyano-n-[5-[(4-methylpiperazin-1-yl)methyl]-2-piperidin-1-ylphenyl]furan-2-carboxamide Chemical compound C1CN(C)CCN1CC(C=C1NC(=O)C=2OC(=CC=2)C#N)=CC=C1N1CCCCC1 CBUPZNJHZPSIBR-UHFFFAOYSA-N 0.000 claims description 2
- MEAUDYBXCRIMPW-UHFFFAOYSA-N 5-formyl-n-(2-piperidin-1-ylphenyl)furan-2-carboxamide Chemical compound O1C(C=O)=CC=C1C(=O)NC1=CC=CC=C1N1CCCCC1 MEAUDYBXCRIMPW-UHFFFAOYSA-N 0.000 claims description 2
- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 2
- VIZLEAPHFKXACR-UHFFFAOYSA-N n-(2-ethoxyphenyl)-5-nitrofuran-2-carboxamide Chemical compound CCOC1=CC=CC=C1NC(=O)C1=CC=C([N+]([O-])=O)O1 VIZLEAPHFKXACR-UHFFFAOYSA-N 0.000 claims description 2
- BIQWNNXDPVEAPZ-UHFFFAOYSA-N n-(2-morpholin-4-ylphenyl)-5-nitrofuran-2-carboxamide Chemical compound O1C([N+](=O)[O-])=CC=C1C(=O)NC1=CC=CC=C1N1CCOCC1 BIQWNNXDPVEAPZ-UHFFFAOYSA-N 0.000 claims description 2
- WXDDTTSLPVVQOT-UHFFFAOYSA-N n-(2-piperidin-1-ylphenyl)-1,2-oxazole-5-carboxamide Chemical compound C=1C=NOC=1C(=O)NC1=CC=CC=C1N1CCCCC1 WXDDTTSLPVVQOT-UHFFFAOYSA-N 0.000 claims description 2
- QCCOTCNQINYHRO-UHFFFAOYSA-N n-(4-chloro-2-piperidin-1-ylphenyl)-5-cyanofuran-2-carboxamide Chemical compound C1CCCCN1C1=CC(Cl)=CC=C1NC(=O)C1=CC=C(C#N)O1 QCCOTCNQINYHRO-UHFFFAOYSA-N 0.000 claims description 2
- GAKBUDJFUFUSED-UHFFFAOYSA-N n-[2-(3-methylpiperidin-1-yl)phenyl]-5-nitrofuran-2-carboxamide Chemical compound C1C(C)CCCN1C1=CC=CC=C1NC(=O)C1=CC=C([N+]([O-])=O)O1 GAKBUDJFUFUSED-UHFFFAOYSA-N 0.000 claims description 2
- DZBLHPFYHMMAOC-UHFFFAOYSA-N n-[2-(4-hydroxypiperidin-1-yl)phenyl]-5-nitrofuran-2-carboxamide Chemical compound C1CC(O)CCN1C1=CC=CC=C1NC(=O)C1=CC=C([N+]([O-])=O)O1 DZBLHPFYHMMAOC-UHFFFAOYSA-N 0.000 claims description 2
- ICWQOMBLDBHQHC-UHFFFAOYSA-N n-[2-(4-methylpiperazin-1-yl)phenyl]-5-nitrofuran-2-carboxamide Chemical compound C1CN(C)CCN1C1=CC=CC=C1NC(=O)C1=CC=C([N+]([O-])=O)O1 ICWQOMBLDBHQHC-UHFFFAOYSA-N 0.000 claims description 2
- VMDUQCSTUROBAE-UHFFFAOYSA-N n-[2-(azepan-1-yl)phenyl]-5-nitrofuran-2-carboxamide Chemical compound O1C([N+](=O)[O-])=CC=C1C(=O)NC1=CC=CC=C1N1CCCCCC1 VMDUQCSTUROBAE-UHFFFAOYSA-N 0.000 claims description 2
- VBRXABXYDNIKKL-TXEJJXNPSA-N n-[2-[(2s,6r)-2,6-dimethylmorpholin-4-yl]phenyl]-5-nitrofuran-2-carboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=CC=C1NC(=O)C1=CC=C([N+]([O-])=O)O1 VBRXABXYDNIKKL-TXEJJXNPSA-N 0.000 claims description 2
- GXDBMNMCRHJVBM-UHFFFAOYSA-N n-[2-[4-(hydroxymethyl)piperidin-1-yl]phenyl]-5-nitrofuran-2-carboxamide Chemical compound C1CC(CO)CCN1C1=CC=CC=C1NC(=O)C1=CC=C([N+]([O-])=O)O1 GXDBMNMCRHJVBM-UHFFFAOYSA-N 0.000 claims description 2
- NXMYHWUANSANME-UHFFFAOYSA-N n-[5-(hydroxymethyl)-2-piperidin-1-ylphenyl]-5-nitrofuran-2-carboxamide Chemical compound C=1C=C([N+]([O-])=O)OC=1C(=O)NC1=CC(CO)=CC=C1N1CCCCC1 NXMYHWUANSANME-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 7
- DUGGISWIWAQPLI-UHFFFAOYSA-N 2-(4-ethylpiperidin-1-yl)aniline Chemical compound C1CC(CC)CCN1C1=CC=CC=C1N DUGGISWIWAQPLI-UHFFFAOYSA-N 0.000 claims 3
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N Minaline Natural products OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 claims 3
- YUKCQPFOVIZCQL-UHFFFAOYSA-N [3-amino-4-(4-ethylpiperidin-1-yl)phenyl]methanol Chemical compound C1CC(CC)CCN1C1=CC=C(CO)C=C1N YUKCQPFOVIZCQL-UHFFFAOYSA-N 0.000 claims 3
- MOJQNIVEQAVVGV-UHFFFAOYSA-N 2-(4-methylpiperidin-1-yl)aniline Chemical compound C1CC(C)CCN1C1=CC=CC=C1N MOJQNIVEQAVVGV-UHFFFAOYSA-N 0.000 claims 2
- DSSUMPFRISORQN-UHFFFAOYSA-N 2-[1-[2-amino-4-(hydroxymethyl)phenyl]piperidin-4-yl]ethanol Chemical compound NC1=CC(CO)=CC=C1N1CCC(CCO)CC1 DSSUMPFRISORQN-UHFFFAOYSA-N 0.000 claims 2
- 239000002552 dosage form Substances 0.000 claims 2
- FHPKBJQLUKITJL-UHFFFAOYSA-N 2-[1-(2-aminophenyl)piperidin-4-yl]ethanol Chemical compound NC1=CC=CC=C1N1CCC(CCO)CC1 FHPKBJQLUKITJL-UHFFFAOYSA-N 0.000 claims 1
- 206010061218 Inflammation Diseases 0.000 claims 1
- TWWYCLWOXHOEGW-UHFFFAOYSA-N N-[(3-amino-4-piperidin-1-ylphenyl)methyl]methanesulfonamide Chemical compound NC1=CC(CNS(=O)(=O)C)=CC=C1N1CCCCC1 TWWYCLWOXHOEGW-UHFFFAOYSA-N 0.000 claims 1
- SFRWPOIGYKNCAT-UHFFFAOYSA-N [1-(2-aminophenyl)piperidin-4-yl]methanol Chemical compound NC1=CC=CC=C1N1CCC(CO)CC1 SFRWPOIGYKNCAT-UHFFFAOYSA-N 0.000 claims 1
- PFRHRZRURZQQAD-UHFFFAOYSA-N [1-[2-amino-4-(hydroxymethyl)phenyl]piperidin-4-yl]methanol Chemical compound NC1=CC(CO)=CC=C1N1CCC(CO)CC1 PFRHRZRURZQQAD-UHFFFAOYSA-N 0.000 claims 1
- 230000004054 inflammatory process Effects 0.000 claims 1
- QWZFSCWNCXRIBR-UHFFFAOYSA-N n-(2-morpholin-4-ylphenyl)-1,2-oxazole-5-carboxamide Chemical compound C=1C=NOC=1C(=O)NC1=CC=CC=C1N1CCOCC1 QWZFSCWNCXRIBR-UHFFFAOYSA-N 0.000 claims 1
- RVNRTOXBRIWYQO-UHFFFAOYSA-N n-[2-(2-chloro-1,1,2-trifluoroethyl)sulfanylphenyl]-5-nitrofuran-2-carboxamide Chemical compound O1C([N+](=O)[O-])=CC=C1C(=O)NC1=CC=CC=C1SC(F)(F)C(F)Cl RVNRTOXBRIWYQO-UHFFFAOYSA-N 0.000 claims 1
- ZBWQNLDDTPCSDQ-UHFFFAOYSA-N n-[2-(4-methylpiperidin-1-yl)phenyl]-5-nitrofuran-2-carboxamide Chemical compound C1CC(C)CCN1C1=CC=CC=C1NC(=O)C1=CC=C([N+]([O-])=O)O1 ZBWQNLDDTPCSDQ-UHFFFAOYSA-N 0.000 claims 1
- VBRXABXYDNIKKL-VXGBXAGGSA-N n-[2-[(2r,6r)-2,6-dimethylmorpholin-4-yl]phenyl]-5-nitrofuran-2-carboxamide Chemical compound C1[C@@H](C)O[C@H](C)CN1C1=CC=CC=C1NC(=O)C1=CC=C([N+]([O-])=O)O1 VBRXABXYDNIKKL-VXGBXAGGSA-N 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 150000004677 hydrates Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 32
- 125000004093 cyano group Chemical group *C#N 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 239000000203 mixture Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 150000002431 hydrogen Chemical class 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 239000011347 resin Substances 0.000 description 9
- 229920005989 resin Polymers 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 239000004793 Polystyrene Substances 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 230000003834 intracellular effect Effects 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 230000003389 potentiating effect Effects 0.000 description 6
- 239000012131 assay buffer Substances 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 0 **/C(/CCCCCC1)=C1\N(*)** Chemical compound **/C(/CCCCCC1)=C1\N(*)** 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- HHHCADSYQQJUGV-UHFFFAOYSA-N 5-cyanofuran-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(C#N)O1 HHHCADSYQQJUGV-UHFFFAOYSA-N 0.000 description 3
- SHNRXUWGUKDPMA-UHFFFAOYSA-N 5-formyl-2-furoic acid Chemical compound OC(=O)C1=CC=C(C=O)O1 SHNRXUWGUKDPMA-UHFFFAOYSA-N 0.000 description 3
- IODMEDPPCXSFLD-UHFFFAOYSA-N 5-nitrofuran-2-carboxylic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)O1 IODMEDPPCXSFLD-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 102000001253 Protein Kinase Human genes 0.000 description 3
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 3
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 3
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 3
- CPGZBKYOATXYFO-UHFFFAOYSA-N [4-(4-methylpiperidin-1-yl)-3-nitrophenyl]methanol Chemical compound C1CC(C)CCN1C1=CC=C(CO)C=C1[N+]([O-])=O CPGZBKYOATXYFO-UHFFFAOYSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002875 fluorescence polarization Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 108060006633 protein kinase Proteins 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- MIIQJAUWHSUTIT-UHFFFAOYSA-N 1,2-oxazole-5-carboxylic acid Chemical compound OC(=O)C1=CC=NO1 MIIQJAUWHSUTIT-UHFFFAOYSA-N 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- UUINESKHLDZZRQ-UHFFFAOYSA-N 4-oxo-6-piperidin-1-yl-5h-furo[2,3-c]quinoline-2-carbaldehyde Chemical compound O1C(C=O)=CC(C2=CC=C3)=C1C(=O)NC2=C3N1CCCCC1 UUINESKHLDZZRQ-UHFFFAOYSA-N 0.000 description 2
- SXINBFXPADXIEY-UHFFFAOYSA-N 5-Nitrofurfural Chemical compound [O-][N+](=O)C1=CC=C(C=O)O1 SXINBFXPADXIEY-UHFFFAOYSA-N 0.000 description 2
- NNPCFFIJVKYGHR-UHFFFAOYSA-N 5-cyano-furan-2-carboxylic acid [5-hydroxymethyl-2-(4-methyl-piperidin-1-yl)-phenyl]-amide Chemical compound C1CC(C)CCN1C1=CC=C(CO)C=C1NC(=O)C1=CC=C(C#N)O1 NNPCFFIJVKYGHR-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 2
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 2
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) Substances [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000007942 carboxylates Chemical group 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- IRSSSGJWQKONBA-UHFFFAOYSA-N diethyl 3-(2-nitro-3-piperidin-1-ylphenyl)-2,5-dioxohexanedioate Chemical compound CCOC(=O)C(=O)CC(C(=O)C(=O)OCC)C1=CC=CC(N2CCCCC2)=C1[N+]([O-])=O IRSSSGJWQKONBA-UHFFFAOYSA-N 0.000 description 2
- CKWLDHWJFIRFJM-UHFFFAOYSA-N ethyl 3-(2-nitro-3-piperidin-1-ylphenyl)-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CC1=CC=CC(N2CCCCC2)=C1[N+]([O-])=O CKWLDHWJFIRFJM-UHFFFAOYSA-N 0.000 description 2
- MZISOBNPONYUIY-UHFFFAOYSA-N ethyl 4-oxo-6-piperidin-1-yl-5h-furo[2,3-c]quinoline-2-carboxylate Chemical compound O1C(C(=O)OCC)=CC(C2=CC=C3)=C1C(=O)NC2=C3N1CCCCC1 MZISOBNPONYUIY-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 2
- 239000012286 potassium permanganate Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 230000036515 potency Effects 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 125000004354 sulfur functional group Chemical group 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- SPFMQWBKVUQXJV-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;hydrate Chemical compound O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O SPFMQWBKVUQXJV-BTVCFUMJSA-N 0.000 description 1
- MKWJZTFMDWSRIH-UHFFFAOYSA-N (4-fluoro-3-nitrophenyl)methanol Chemical compound OCC1=CC=C(F)C([N+]([O-])=O)=C1 MKWJZTFMDWSRIH-UHFFFAOYSA-N 0.000 description 1
- NASLINFISOTVJJ-UHFFFAOYSA-N 1,2-oxazole-5-carbonyl chloride Chemical compound ClC(=O)C1=CC=NO1 NASLINFISOTVJJ-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- BKCBTVSSPKFFPF-UHFFFAOYSA-N 1-(3-methyl-2-nitrophenyl)piperidine Chemical compound CC1=CC=CC(N2CCCCC2)=C1[N+]([O-])=O BKCBTVSSPKFFPF-UHFFFAOYSA-N 0.000 description 1
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 1
- XDKMDDOCVPNVMB-UHFFFAOYSA-N 1-bromo-3-methyl-2-nitrobenzene Chemical compound CC1=CC=CC(Br)=C1[N+]([O-])=O XDKMDDOCVPNVMB-UHFFFAOYSA-N 0.000 description 1
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- SXRKNKLAGDXHDA-UHFFFAOYSA-N 2-bromoethyl 2-oxopropanoate Chemical compound CC(=O)C(=O)OCCBr SXRKNKLAGDXHDA-UHFFFAOYSA-N 0.000 description 1
- HTUUAZYBRLAVBE-UHFFFAOYSA-N 4-cyano-n-(2-piperidin-1-ylphenyl)-1h-pyrrole-2-carboxamide Chemical compound C=1C(C#N)=CNC=1C(=O)NC1=CC=CC=C1N1CCCCC1 HTUUAZYBRLAVBE-UHFFFAOYSA-N 0.000 description 1
- ORUZNQLJCNUUCR-UHFFFAOYSA-N 4-cyano-n-[2-(4-ethylpiperidin-1-yl)-5-(hydroxymethyl)phenyl]-1h-pyrrole-2-carboxamide Chemical compound C1CC(CC)CCN1C1=CC=C(CO)C=C1NC(=O)C1=CC(C#N)=CN1 ORUZNQLJCNUUCR-UHFFFAOYSA-N 0.000 description 1
- NKZBGPXMNUBFDS-UHFFFAOYSA-N 4-cyano-n-[2-(4-ethylpiperidin-1-yl)phenyl]-1h-pyrrole-2-carboxamide Chemical compound C1CC(CC)CCN1C1=CC=CC=C1NC(=O)C1=CC(C#N)=CN1 NKZBGPXMNUBFDS-UHFFFAOYSA-N 0.000 description 1
- CPHVPCBCLPLAAW-UHFFFAOYSA-N 4-cyano-n-[2-(4-methylpiperidin-1-yl)phenyl]-1h-pyrrole-2-carboxamide Chemical compound C1CC(C)CCN1C1=CC=CC=C1NC(=O)C1=CC(C#N)=CN1 CPHVPCBCLPLAAW-UHFFFAOYSA-N 0.000 description 1
- GLGJFLQSXQTLRP-UHFFFAOYSA-N 4-cyano-n-[2-[4-(2-hydroxyethyl)piperidin-1-yl]-5-(hydroxymethyl)phenyl]-1h-pyrrole-2-carboxamide Chemical compound C1CC(CCO)CCN1C1=CC=C(CO)C=C1NC(=O)C1=CC(C#N)=CN1 GLGJFLQSXQTLRP-UHFFFAOYSA-N 0.000 description 1
- RSLPIOLEICYFGI-UHFFFAOYSA-N 4-cyano-n-[5-(hydroxymethyl)-2-(4-methylpiperidin-1-yl)phenyl]-1h-pyrrole-2-carboxamide Chemical compound C1CC(C)CCN1C1=CC=C(CO)C=C1NC(=O)C1=CC(C#N)=CN1 RSLPIOLEICYFGI-UHFFFAOYSA-N 0.000 description 1
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 description 1
- RPEGOIBVNSWRQC-UHFFFAOYSA-N 4-oxo-6-piperidin-1-yl-5h-furo[2,3-c]quinoline-2-carbonitrile Chemical compound C1=CC=C2C=3C=C(C#N)OC=3C(=O)NC2=C1N1CCCCC1 RPEGOIBVNSWRQC-UHFFFAOYSA-N 0.000 description 1
- YVTQHZDUDUCGRD-UHFFFAOYSA-N 5-bromofuran-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Br)O1 YVTQHZDUDUCGRD-UHFFFAOYSA-N 0.000 description 1
- AZXQEVPOTUJYKW-UHFFFAOYSA-N 5-cyano-n-[2-(4-ethylpiperidin-1-yl)phenyl]furan-2-carboxamide Chemical compound C1CC(CC)CCN1C1=CC=CC=C1NC(=O)C1=CC=C(C#N)O1 AZXQEVPOTUJYKW-UHFFFAOYSA-N 0.000 description 1
- GAVALYPQKRALAR-UHFFFAOYSA-N 5-cyano-n-[2-[4-(2-hydroxyethyl)piperidin-1-yl]-5-(hydroxymethyl)phenyl]furan-2-carboxamide Chemical compound C1CC(CCO)CCN1C1=CC=C(CO)C=C1NC(=O)C1=CC=C(C#N)O1 GAVALYPQKRALAR-UHFFFAOYSA-N 0.000 description 1
- KFRVXUZPIRGPKD-UHFFFAOYSA-N 5-cyano-n-[2-[4-(2-hydroxyethyl)piperidin-1-yl]phenyl]furan-2-carboxamide Chemical compound C1CC(CCO)CCN1C1=CC=CC=C1NC(=O)C1=CC=C(C#N)O1 KFRVXUZPIRGPKD-UHFFFAOYSA-N 0.000 description 1
- KPQDMEUGYKVMLJ-UHFFFAOYSA-N 5-cyano-n-[2-[4-(hydroxymethyl)piperidin-1-yl]phenyl]furan-2-carboxamide Chemical compound C1CC(CO)CCN1C1=CC=CC=C1NC(=O)C1=CC=C(C#N)O1 KPQDMEUGYKVMLJ-UHFFFAOYSA-N 0.000 description 1
- DGICBILOARQTCD-UHFFFAOYSA-N 5-cyano-n-[5-(hydroxymethyl)-2-[4-(hydroxymethyl)piperidin-1-yl]phenyl]furan-2-carboxamide Chemical compound C1CC(CO)CCN1C1=CC=C(CO)C=C1NC(=O)C1=CC=C(C#N)O1 DGICBILOARQTCD-UHFFFAOYSA-N 0.000 description 1
- UNJWUJSFLSUHRH-UHFFFAOYSA-N 5-cyano-n-[5-(methanesulfonamidomethyl)-2-piperidin-1-ylphenyl]furan-2-carboxamide Chemical compound C=1C=C(C#N)OC=1C(=O)NC1=CC(CNS(=O)(=O)C)=CC=C1N1CCCCC1 UNJWUJSFLSUHRH-UHFFFAOYSA-N 0.000 description 1
- QCYCZUIFRXZOAE-UHFFFAOYSA-N 5-cyano-n-[5-[(diaminomethylideneamino)methyl]-2-piperidin-1-ylphenyl]furan-2-carboxamide Chemical compound C=1C=C(C#N)OC=1C(=O)NC1=CC(CNC(=N)N)=CC=C1N1CCCCC1 QCYCZUIFRXZOAE-UHFFFAOYSA-N 0.000 description 1
- VLZZMVPPSQPHMQ-UHFFFAOYSA-N 5-cyanofuran-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=C(C#N)O1 VLZZMVPPSQPHMQ-UHFFFAOYSA-N 0.000 description 1
- BEEHSUPOPGWGQH-UHFFFAOYSA-N 5-nitro-n-(2-piperidin-1-ylphenyl)furan-2-carboxamide Chemical compound O1C([N+](=O)[O-])=CC=C1C(=O)NC1=CC=CC=C1N1CCCCC1 BEEHSUPOPGWGQH-UHFFFAOYSA-N 0.000 description 1
- XFEREKDDQIUTOE-UHFFFAOYSA-N 5-nitro-n-(2-piperidin-1-ylphenyl)thiophene-2-carboxamide Chemical compound S1C([N+](=O)[O-])=CC=C1C(=O)NC1=CC=CC=C1N1CCCCC1 XFEREKDDQIUTOE-UHFFFAOYSA-N 0.000 description 1
- BPZNHKQKNUUVQA-UHFFFAOYSA-N 5-nitro-n-phenylfuran-2-carboxamide Chemical class O1C([N+](=O)[O-])=CC=C1C(=O)NC1=CC=CC=C1 BPZNHKQKNUUVQA-UHFFFAOYSA-N 0.000 description 1
- OLEFNFXYGGTROA-UHFFFAOYSA-N 5-nitrofuran-2-carbonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)O1 OLEFNFXYGGTROA-UHFFFAOYSA-N 0.000 description 1
- GUOMINFEASCICM-UHFFFAOYSA-N 5-phenylfuran-2-carboxylic acid Chemical compound O1C(C(=O)O)=CC=C1C1=CC=CC=C1 GUOMINFEASCICM-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 101100381481 Caenorhabditis elegans baz-2 gene Proteins 0.000 description 1
- 101100123850 Caenorhabditis elegans her-1 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 101100481404 Danio rerio tie1 gene Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 102000054300 EC 2.7.11.- Human genes 0.000 description 1
- 108700035490 EC 2.7.11.- Proteins 0.000 description 1
- 102100030013 Endoribonuclease Human genes 0.000 description 1
- 101710199605 Endoribonuclease Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 108010031794 IGF Type 1 Receptor Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 102100036721 Insulin receptor Human genes 0.000 description 1
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 101100481410 Mus musculus Tek gene Proteins 0.000 description 1
- 101100481406 Mus musculus Tie1 gene Proteins 0.000 description 1
- 102000008300 Mutant Proteins Human genes 0.000 description 1
- 108010021466 Mutant Proteins Proteins 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 1
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 101100372762 Rattus norvegicus Flt1 gene Proteins 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 206010038934 Retinopathy proliferative Diseases 0.000 description 1
- 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 102000016663 Vascular Endothelial Growth Factor Receptor-3 Human genes 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- JYKWPPFMIWMTPT-UHFFFAOYSA-N [O-][N+](c1ccc(CNc(cccc2)c2N2CCCCC2)[o]1)=O Chemical compound [O-][N+](c1ccc(CNc(cccc2)c2N2CCCCC2)[o]1)=O JYKWPPFMIWMTPT-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 201000011529 cardiovascular cancer Diseases 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- JCWIWBWXCVGEAN-UHFFFAOYSA-L cyclopentyl(diphenyl)phosphane;dichloropalladium;iron Chemical compound [Fe].Cl[Pd]Cl.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1 JCWIWBWXCVGEAN-UHFFFAOYSA-L 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 239000013024 dilution buffer Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- VXHSQWIWUZWWBC-UHFFFAOYSA-N n-[2-(4-ethylpiperidin-1-yl)-5-(hydroxymethyl)phenyl]-4-nitro-1h-pyrrole-2-carboxamide Chemical compound C1CC(CC)CCN1C1=CC=C(CO)C=C1NC(=O)C1=CC([N+]([O-])=O)=CN1 VXHSQWIWUZWWBC-UHFFFAOYSA-N 0.000 description 1
- PQUDAAISFZLLMB-UHFFFAOYSA-N n-[2-(4-ethylpiperidin-1-yl)phenyl]-4-nitro-1h-pyrrole-2-carboxamide Chemical compound C1CC(CC)CCN1C1=CC=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CN1 PQUDAAISFZLLMB-UHFFFAOYSA-N 0.000 description 1
- HSSSNQPZBNYEAY-UHFFFAOYSA-N n-[2-(4-methylpiperidin-1-yl)phenyl]-4-nitro-1h-pyrrole-2-carboxamide Chemical compound C1CC(C)CCN1C1=CC=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CN1 HSSSNQPZBNYEAY-UHFFFAOYSA-N 0.000 description 1
- HZPJHDOUJRTBHL-UHFFFAOYSA-N n-[2-[4-(2-hydroxyethyl)piperidin-1-yl]-5-(hydroxymethyl)phenyl]-4-nitro-1h-pyrrole-2-carboxamide Chemical compound C1CC(CCO)CCN1C1=CC=C(CO)C=C1NC(=O)C1=CC([N+]([O-])=O)=CN1 HZPJHDOUJRTBHL-UHFFFAOYSA-N 0.000 description 1
- 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 230000010644 positive regulation of cell differentiation Effects 0.000 description 1
- 230000034918 positive regulation of cell growth Effects 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000006785 proliferative vitreoretinopathy Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229960004441 tyrosine Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 235000002374 tyrosine Nutrition 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 230000004862 vasculogenesis Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/02—1,2-Oxazines; Hydrogenated 1,2-oxazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/70—Nitro radicals
- C07D307/71—Nitro radicals attached in position 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
Definitions
- the invention relates to novel compounds that function as protein tyro sine kinase inhibitors. More particularly, the invention relates to novel compounds that function as inhibitors of c-fms kinase.
- Protein kinases are enzymes that serve as key components of signal transduction pathways by catalyzing the transfer of the terminal phosphate from ATP to the hydroxy group of tyrosine, serine and threonine residues of proteins. As a consequence, protein kinase inhibitors and substrates are valuable tools for assessing the physiological consequences of protein kinase activation.
- the overexpression or inappropriate expression of normal or mutant protein kinases in mammals has been demonstrated to play significant roles in the development of many diseases, including cancer and diabetes.
- Protein kinases can be divided into two classes: those which preferentially phosphorylate tyrosine residues (protein tyrosine kinases) and those which preferentially phosphorylate serine and/or threonine residues (protein serine/threonine kinases). Protein tyrosine kinases perform diverse functions ranging from stimulation of cell growth and differentiation to arrest of cell proliferation. They can be classified as either receptor protein tyrosine kinases or intracellular protein tyrosine kinases. The receptor protein tyrosine kinases, which possess an extracellular ligand binding domain and an intracellular catalytic domain with intrinsic tyrosine kinase activity, are distributed among 20 subfamilies.
- Receptor tyrosine kinases of the epidermal growth factor (“EGF”) family which includes HER-1, HER-2/neu and HER-3 receptors, contain an extracellular binding domain, a transmembrane domain and an intracellular cytoplasmic catalytic domain. Receptor binding leads to the initiation of multiple intracellular tyrosine kinase dependent phosphorylation processes, which ultimately results in oncogene transcription.
- EGF epidermal growth factor
- HER-1 epidermal growth factor
- HER-3 receptors contain an extracellular binding domain, a transmembrane domain and an intracellular cytoplasmic catalytic domain. Receptor binding leads to the initiation of multiple intracellular tyrosine kinase dependent phosphorylation processes, which ultimately results in oncogene transcription.
- Breast, colorectal and prostate cancers have been linked to this family of receptors. Insulin receptor ('TR”) and insulin-like growth factor I receptor (“IGF-1R”) are structurally and functionally related
- Platelet derived growth factor (“PDGF”) receptors mediate cellular responses that include proliferation, migration and survival and include PDGFR, the stem cell factor receptor (c-kit) and c-fms. These receptors have been linked to diseases such as atherosclerosis, fibrosis and proliferative vitreoretinopathy.
- PDGF Platelet derived growth factor
- Fibroblast growth factor (“FGR”) receptors consist of four receptors which are responsible for the production of blood vessels, for limb outgrowth, and for the growth and differentiation of numerous cell types.
- VEGF Vascular endothelial growth factor
- ovarian carcinomas a potent mitogen of endothelial cells
- VEGFR-1 Flt-1
- VEGFR-2 VEGFR-2
- KDR VEGFR-3
- Flt-4 VEGFR-3
- a related group of receptors, tie-1 and tie-2 kinases, have been identified in vascular endothelium and hematopoietic cells.
- VEGF receptors have been linked to vasculogenesis and angiogenesis.
- Intracellular protein tyrosine kinases are also known as non-receptor protein tyrosine kinases. Over 24 such kinases have been identified and have been classified into 11 subfamilies. The serine/threonine protein kinases, like the cellular protein tyrosine kinases, are predominantly intracellular. Diabetes, angiogenesis, psoriasis, restenosis, ocular diseases, schizophrenia, rheumatoid arthritis, cardiovascular disease and cancer are exemplary of pathogenic conditions that have been linked with abnormal protein tyrosine kinase activity. Thus, a need exists for selective and potent small-molecule protein tyrosine kinase inhibitors.
- U.S. Patent Nos. 6,383,790; 6,346,625; 6,235,746; 6,100,254 and PCT International Applications WO 01/47897, WO 00/27820 and WO 02/068406 are indicative of recent attempts to synthesize such inhibitors.
- the invention addresses the current need for selective and potent protein tyrosine kinase inhibitors by providing potent inhibitors of c-fms kinase.
- One embodiment of the invention is directed to the novel compounds of Formula I:
- A is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR a , -CN, -C(NH)NH 2 , -COOR a , -CONR a R b , -N(R a )COR b , -NO 2 , -SO 2 R a , -SO 3 R a or
- a 5- to 7-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with one or more of -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR a , -CN, -C(NH)NH 2 , -COORa, -CONR a R b , -N(R a )COR b , -NO 2 , -SO ⁇ , -SO 3 R a or -SO 2 NR a
- R 2 and R 3 are independently
- R 2 and R 3 taken together with the attached nitrogen, form a 5- to 7-membered heterocyclic or heteroaromatic ring containing from one to three heteroatoms selected from N, O or S, which may be optionally substituted with -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -COR a , -CN, -COOR a ,
- W is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C 1-4 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxy, -CF 3 , alkoxy, aryloxy, arylalkoxy, -OCF 3 , -COR a , -CN, -C(NH)NH 2 , -COOR a , -CONR a R b , -NHCOR a R b , -NHSO 2 R a , -NO 2 , -SOR a , -SOsR, or -SO 2 NR a R b ; or
- Ra and R b are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
- the invention is directed to the novel compounds of Formula II:
- A is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR a , -CN,
- a 5- to 7-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with one or more of -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 ,
- Ri is -H, aryl, -CORa, -COR a , -COOR a , -CONR a R b , -SO 2 R a or -SO 2 NR a R b ;
- R 2 is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which may be optionally substituted with one or more halogens;
- W is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C 1- alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxy, -CF 3 , alkoxy, aryloxy, arylalkoxy, -OCF 3 , -COR a , -CN, -C(NH)NH 2 , -COOR a , -CONR a R b , -NHCOR a R b , -NHSO 2 R a , -NO 2 , -SOR a , -SOsR, or -SO 2 NR a R ; or
- R a and R b are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
- A is a 5- to 6-membered heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido,
- Y is direct bond, -CH 2 -, -CH 2 CH 2 -, -CE CH-, -NR a -, -O-, -S-, -SO-, -SO 2 -, -CH 2 O-,
- R 2 and R 3 are independently -H, -C 1-6 alkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, -COR a , -COR a ,
- R 2 and R 3j taken together with the attached nitrogen, form a 5- to 7-membered heterocyclic or heteroaromatic ring containing from one to three heteroatoms selected from N, O or S, which may be optionally substituted with -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -COR a , -CN, -COOR a , -CONR a R , -N(R a )COR b , -NO 2 , -SO 2 R a , -SO 3 R a or -SO 2 NR a R b ,
- R is one or more of -H, -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR a , -CN, -COOR a , -CONR a R b , -N(R a )COR b , -NO 2 , -SO 2 R a , -SO 3 R a or -SOiNRaRi,
- R a and R b are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
- the compounds of Formulae I and II are especially potent inhibitors of the c- fms protein tyrosine kinase.
- the compounds of Formula 111 are expected to exhibit similar inhibitory potencies.
- the invention also relates to methods of inhibiting protein tyrosme kinase activity in a mammal by administration of a therapeutically effective amount of at least one compound of Formula I, II or III.
- A is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR a ,
- a 5- to 7-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with one or more of -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR a , -CN, -C(NH)NH 2 , -COOR a , -CONR a R , -N(R a )COR b , -NO 2 , -SO 2 R a , -SO 3 R a or -SO 2
- R 2 and R 3 are independently
- R 2 and R 3 taken together with the attached nitrogen, form a 5- to 7-membered heterocyclic or heteroaromatic ring containing from one to three heteroatoms selected from N, O or S, which may be optionally substituted with -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -COR a , -CN, -COOR a , -CONR a R b , -N(R a )COR b , -NO 2 , -SO 2 R a , -SO 3 R a or -SO 2 NR a R b
- W is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C 1- alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxy, -CF 3 , alkoxy, aryloxy, arylalkoxy, -OCF 3 , -COR a , -CN, -C(NH)NH 2 , -COOR a , -CONR a R b , -NHCOR a R b , -NHSO 2 R a , -NO 2 , -SOR a , -SO 3 R a or -SO 2 NR a R b ; or
- the invention is directed to the novel compounds of Formula II:
- A is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR a , -CN, -C(NH)NH 2 , -COOR a , -CONR a R , -N(R a )COR b , -NO 2 , -SO 2 R a , -SO 3 R a or
- a 5- to 7-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with one or more of -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR a , -CN,-C(NH)NH 2 , -COOR a , -CONR a R b , -N(R a )COR b , -NO 2 , -SO 2 Ra, -SO 3 R a or -SO 2 NR
- Ri is -H, aryl, -COR a , -COR a , -COOR a , -CONR a R b , -SO 2 R a or -SO 2 NR a R b ;
- R 2 is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which may be optionally substituted with one or more halogens;
- W is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C 1-4 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxy, -CF 3 , alkoxy, aryloxy, arylalkoxy, -OCF 3 , -COR a , -CN, -C(NH)NH 2 , -COOR a , -CONR a R b , -NHCOR a R b , -NHSO 2 R a , -NO 2 , -SOR a , -SO 3 R a or -SO 2 NR a R b ; or
- R a and R b are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
- A is a 5- to 6-membered heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -COR a ,
- R 2 and R 3 are independently
- R 2 and R 3 taken together with the attached nitrogen, form a 5- to 7-membered heterocyclic or heteroaromatic ring containing from one to three heteroatoms selected from N, O or S, which may be optionally substituted with -C ⁇ - 6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy,-OCF 3 , -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -COR a , -CN, -COOR a , -CONR a R b , -N(R a )COR , -NO 2 , -SO 2 R a , -SO 3 R a or -SO 2 NR a R b , and
- -H, -C 1-6 alkyl is one or more of -H, -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR a , -CN,
- R a and R b are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
- Preferred compounds of Formula I are those wherein A is phenyl; R ⁇ is -H; and
- R 2 and R 3 taken together with the attached nitrogen, form a piperidine, piperazine, morpholine, thiomorpho ne, pyrrolidine, pyrroline, pyrazolidine, pyrazoline, imidazolidine or imidazoline ring which may be optionally substituted with -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -COR a , -CN, -COOR a , -CONR a R b , -N(R a )COR b , -NO 2 , -SO 2 R a
- R a and R b are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
- Particularly preferred compounds of Formula I are those wherein
- A is phenyl
- R ⁇ is -H; R 2 and R , taken together with the attached nitrogen, form a piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, pyrroline, pyrazolidine, pyrazoline, imidazolidine or imidazoline ring which may be optionally substituted with -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF , -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -COR a , -CN, -C(NH)NH 2 , -COORa, -CONR a R , -N(R a )COR b , -NO
- W is a phenyl, furan, thiophene, isoxazole, pyrrole, oxazole, thiazole, imidazole, pyrazole, isothiazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine ring which may be optionally substituted with -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -OCO-alkylamino, -OCO- alkylamido, -COR a , -CN, -C(NH)NH 2 , -COOR a , -CONR a R b ,
- R a and R b are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
- Preferred compounds of Formula II are those wherein
- A is phenyl
- Ri is -H
- W is a phenyl, furan, thiophene, isoxazole, pyrrole, oxazole, thiazole, imidazole, pyrazole, isothiazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine ring which may be optionally substituted with -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -OCO-alkylamino, -OCO- alkylamido, -CORa, -CN, -C(NH)NH 2 , -COOR a , -CONR a R b , -
- Ra and R b are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl. It is expected that the preferred compounds of Formula III will have similar or identical R 2 and R 3 substituents as compared to the preferred compounds of Formulae I and II.
- the most preferred compounds of Formula I include, but are not limited to, 5- nitro-furan-2-carboxylic acid (2-piperidin-l-yl-phenyl)-amide; isoxazole-5-carboxylic acid (2-piperidin-l-yl-phenyl)-amide; 5-nitro-furan-2-carboxylic acid (5- hydroxymethyl-2-piperidin-l-yl-phenyl)-amide; 5-nitro-furan-2-carboxylic acid [2-(3- methyl-piperidin-l-yl)-phenyl]-amide; 4-nitro-pyridine-2-carboxylic acid (2- piperidin-l-yl-phenyl)-amide; 5-nitro-furan-2-carboxylic acid (2-morpholin-4-yl- phenyl)-amide; 5-chloro-furan-2-carboxylic acid (2-piperidin-l-yl-phenyl)-amide; 5- nitro-furan-2-carboxylic acid [2-
- the most preferred compounds of Formula II include 5-nitro-furan-2- carboxylic acid [2-(2-chloro-l,l,2-trifluoro-ethylsulfanyl)-phenyl]-amide; 5-nitro- furan-2-carboxylic acid (2-ethoxyphenyl)-amide and pharmaceutically acceptable salts thereof.
- the invention also relates to methods of inhibiting protein tyrosine kinase activity in a mammal by administration of a therapeutically effective amount of at least one compound of Formula I, II or III.
- a preferred tyrosme kinase is c-fms.
- the invention is considered to include the enantiomeric, diastereomeric and tautomeric forms of all compounds of Formulae I, II and III as well as their racemic mixtures.
- some of the compounds represented by Formulae I, II and III may be prodrugs, i. e. , derivatives of an acting drug that possess superior delivery capabilities and therapeutic value as compared to the acting drug. Prodrugs are transfonned into active drugs by in vivo enzymatic or chemical processes.
- alkyl refers to both linear and branched chain radicals of up to 12 carbon atoms, unless otherwise indicated, and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl.
- cycloalkyl refers to a saturated or partially unsaturated ring composed of from 3 to 8 carbon atoms. Alkyl substituents may optionally be present on the ring. Examples include cyclopropyl, 1,1 -dimethyl cyclobutyl, 1,2,3- trimethylcyclopentyl, cyclohexyl and cyclohexenyl.
- heterocyclyl refers to a nonaromatic (i. e. saturated or partially unsaturated) ring composed of from 3 to 7 carbon atoms and at least one heteroatom selected from N, O or S. Alkyl substituents may optionally be present on the ring.
- Examples include tetrahydrofuryl, dihydropyranyl, piperidyl, 2,5-dimethypiperidyl, morpholinyl, piperazinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl and imidazolinyl.
- heterocyclylalkyl refers to a C 1-6 alkyl group containing a heterocyclyl substituent. Examples include dihydropyranylethyl and 2- morpholinylpropyl.
- hydroxyalkyl refers to at least one hydroxyl group bonded to any carbon atom along an alkyl chain.
- aminoalkyl refers to at least one primary or secondary amino group bonded to any carbon atom along an alkyl chain.
- alkoxyalkyl refers to at least one alkoxy group bonded to any carbon atom along an alkyl chain.
- polyalkoxyalkyl refers to long-chain alkoxy compounds and ' includes polyethylene glycols of discreet or monodispersed sizes.
- thioalkyl refers to at least one sulfur group bonded to any carbon atom along an alkyl chain. The sulfur group may be at any oxidation state and includes sulfoxides, sulfones and sulfates.
- Carboxyalkyl refers to at least one carboxylate group bonded to any carbon atom along an alkyl chain.
- carboxylate group includes carboxylic acids and alkyl, cycloalkyl, aryl or aralkyl carboxylate esters.
- heteroaryl refers to 5- to 7-membered mono- or 8- to 10-membered bicyclic aromatic ring systems, any ring of which may consist of from one to four heteroatoms selected from N, O or S where the nitrogen and sulfur atoms can exist in any allowed oxidation state.
- Examples include benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, py ⁇ olyl, quinolinyl, thiazolyl and thienyl.
- heteroarylkyl refers to a C 1-6 alkyl group having a heteroaryl substituent. Examples include furylethyl and 2-quinolinylpropyl.
- heteroatom refers to a nitrogen atom, an oxygen atom or a sulfur atom wherein the nitrogen and sulfur atoms can exist in any allowed oxidation states.
- alkoxy refers to straight or branched chain radicals of up to 12 carbon atoms, unless otherwise indicated, bonded to an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy and butoxy.
- aryl refers to monocyclic or bicyclic aromatic ring systems containing from 6 to 12 carbons in the ring. Alkyl substituents may optionally be present on the ring. Examples include benzene, biphenyl and napththalene.
- aralkyl refers to a C 1-6 alkyl group containing an aryl substituent. Examples include benzyl, phenylethyl or 2-naphthylmethyl.
- heteroarylkyl refers to a C 1-6 alkyl group containing a heteroaryl substituent. Examples include furylmethyl and pyridylpropyl.
- aryloxy refers to an oxygen atom bound to an aryl substituent. Examples include phenoxy and benzyloxy.
- arylalkoxy refers to an alkoxy group bound to an aryl substituent.
- acyl refers to the group -C(O)R a , where R a is alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl.
- An “acylating agent” adds the -C(O)R a group to a molecule.
- sulfonyl refers to the group -S(O) 2 R a , where R a is hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl.
- a "sulfonylating agent” adds the -S(O) 2 R a group to a molecule.
- the compounds of Formulae I, II and III represent novel potent inhibitors of protein tyrosine kinases, such as c-fms, and may be useful in the prevention and treatment of disorders resulting from actions of these kinases.
- the invention also provides methods of inhibiting a protein tyrosine kinase comprising contacting the protein tyrosine kinase with an effective inhibitory amount of at least one of the compounds of Formula I, II or III.
- a preferred tyrosine kinase is c-fms.
- at least one of the compounds of Formula I, II or III is combined with a known tyrosine kinase inhibitor.
- the protein tyrosine kinases inhibited by the compounds of Formulae I, II and III are located in cells, in a mammal or in vitro. In the case of mammals, which includes humans, a therapeutically effective amount of a pharmaceutically acceptable form of at least one of the compounds of Formula I, II or III is administered.
- the invention further provides methods of treating cancer in mammals, including humans, by administration of a therapeutically effective amount of a pharmaceutically acceptable composition of least one compound of Formula I, II or III.
- exemplary cancers include, but are not limited to, breast cancer, colon cancer, stomach cancer, hairy cell leukemia and non-small lung carcinoma.
- an effective amount of at least one compound of Formula I, II or III is administered in combination with an effective amount of a chemotherapeutic agent.
- the invention also provides methods of treating cardiovascular and inflammatory diseases in mammals, including humans, by administration of a therapeutically effective amount of a pharmaceutically acceptable form of at least one of the compounds of Fo ⁇ nula I, II or III.
- diseases that may be effectively treated include glomerulonephritis, rheumatoid arthritis, psoriasis, diabetes, tumor related angiogenesis, restenosis, schizophrenia and Alzheimer's dementia.
- the compounds of the invention may be administered in an effective amount within the dosage range of about 0.5 mg to about 10 g, preferably between about 0.5 mg to about 5 g, in single or divided daily doses.
- the dosage administered will be affected by factors such as the route of administration, the health, weight and age of the recipient, the frequency of the treatment and the presence of concurrent and unrelated treatments.
- the compounds of Formulae I, II and III may be formulated into pharmaceutical compositions comprising any known pharmaceutically acceptable carriers.
- Exemplary carriers include, but are not limited to, any suitable solvents, dispersion media, coatings, antibacterial and antifungal agents and isotonic agents.
- Exemplary excipients that may also be components of the formulation include fillers, binders, disintegrating agents and lubricants.
- the pharmaceutically-acceptable salts of the compounds of Formulae I, II and HI include the conventional non-toxic salts or the quaternary ammonium salts which are formed from inorganic or organic acids or bases.
- acid addition salts include acetate, adipate, benzoate, benzenesulfonate, citrate, camphorate, dodecylsulfate, hydrochloride, hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate, pivalate, propionate, succinate, sulfate and tartrate.
- Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts and salts with amino acids such as arginine. Also, the basic nitrogen-containing groups may be quaternized with, for example, alkyl halides.
- compositions of the invention may be administered by any means that accomplish their intended purpose. Examples include administration by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal or ocular routes. Alternatively or concurrently, administration may be by the oral route.
- suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts, acidic solutions, alkaline solutions, dextrose-water solutions, isotonic carbohydrate solutions and cyclodextrin inclusion complexes.
- the compounds of Formulae I, II and III may be prepared by either solid phase support methodology or by solution-phase synthesis. Exemplary synthetic routes for generating amides of the invention are described below.
- each well received 10 ⁇ L of a 1:1:3 mixture of anti-phosphotyrosine antibody, 10X, PTK green tracer, 10X (vortexed), FP dilution buffer, respectively (all from PanVera, cat. # P2837).
- the plate was covered, incubated for 30 min at room temperature and the fluorescence polarization was read on the Analyst.
- the instrument settings were: 485 nm excitation filter; 530 nm emission filter; Z height: middle of well; G factor: 0.93. Under these conditions, the fluorescence polarization values for positive and negative controls were approximately 300 and 150, respectively, and were used to define the 100 % and 0 % inhibition of the c-fms reaction. The reported IC 50 values are averages of three independent measurements.
- Table 1 lists representative compounds of Formulae I and II of the invention. TABLE 1
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Diabetes (AREA)
- Psychiatry (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Emergency Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Cardiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Furan Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04750617A EP1631560A2 (en) | 2003-04-25 | 2004-04-26 | C-fms kinase inhibitors |
JP2006513302A JP2007525460A (en) | 2003-04-25 | 2004-04-26 | c-fms kinase inhibitor |
MXPA05011503A MXPA05011503A (en) | 2003-04-25 | 2004-04-26 | C-fms kinase inhibitors. |
CA002536964A CA2536964A1 (en) | 2003-04-25 | 2004-04-26 | C-fms kinase inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US46520403P | 2003-04-25 | 2003-04-25 | |
US60/465,204 | 2003-04-25 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2004096795A2 true WO2004096795A2 (en) | 2004-11-11 |
WO2004096795A3 WO2004096795A3 (en) | 2005-03-10 |
Family
ID=33418203
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2004/012729 WO2004096795A2 (en) | 2003-04-25 | 2004-04-26 | C-fms kinase inhibitors |
Country Status (6)
Country | Link |
---|---|
US (1) | US7429603B2 (en) |
EP (1) | EP1631560A2 (en) |
JP (1) | JP2007525460A (en) |
CA (1) | CA2536964A1 (en) |
MX (1) | MXPA05011503A (en) |
WO (1) | WO2004096795A2 (en) |
Cited By (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006047503A2 (en) * | 2004-10-22 | 2006-05-04 | Janssen Pharmaceutica | Inhibitors of c-fms kinase |
WO2006047479A2 (en) * | 2004-10-22 | 2006-05-04 | Janssen Pharmaceutica, N.V. | C-fms kinase inhibitors |
WO2006047504A1 (en) * | 2004-10-22 | 2006-05-04 | Janssen Pharmaceutica, N.V. | Aromatic amides as inhibitors of c-fms kinase |
WO2006047505A2 (en) * | 2004-10-22 | 2006-05-04 | Janssen Pharmaceutica, N.V. | Crystal structure of the c-fms kinase domain |
EP1757290A1 (en) | 2005-08-16 | 2007-02-28 | Zentaris GmbH | Novel triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors |
WO2007124319A1 (en) * | 2006-04-20 | 2007-11-01 | Janssen Pharmaceutica N.V. | Inhibitors of c-fms kinase |
WO2007123269A1 (en) | 2006-04-19 | 2007-11-01 | Astellas Pharma Inc. | Azolecarboxamide derivative |
WO2007123516A1 (en) * | 2006-04-20 | 2007-11-01 | Janssen Pharmaceutica, N.V. | C-fms kinase inhibitors |
WO2007124318A1 (en) * | 2006-04-20 | 2007-11-01 | Janssen Pharmaceutica N.V. | Inhibitors of c-fms kinase |
US7429603B2 (en) | 2003-04-25 | 2008-09-30 | 3-Dimensional Pharmaceuticals, Inc. | C-fms kinase inhibitors |
US7569536B2 (en) * | 2003-12-26 | 2009-08-04 | Masatoshi Hagiwara | Method for controlling SR protein phosphorylation, and antiviral agents whose active ingredients comprise agents that control SR protein activity |
US7790724B2 (en) | 2003-04-25 | 2010-09-07 | Janssen Pharmaceutica N.V. | c-fms kinase inhibitors |
US7973035B2 (en) | 2006-04-20 | 2011-07-05 | Janssen Pharmaceutica, N.V. | Inhibitors of C-FMS kinase |
US8084614B2 (en) | 2007-04-06 | 2011-12-27 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
EP2431035A1 (en) | 2010-09-16 | 2012-03-21 | Æterna Zentaris GmbH | Novel Triazole Derivatives with Improved Receptor Activity and Bioavailability Properties as Ghrelin Antagonists of Growth Hormone Secretagogue Receptors |
US8168630B2 (en) | 2007-04-24 | 2012-05-01 | Shionogi & Co., Ltd. | Aminodihydrothiazine derivatives substituted with a cyclic group |
US8173642B2 (en) | 2005-10-25 | 2012-05-08 | Shionogi & Co., Ltd. | Aminodihydrothiazine derivatives |
US8263588B2 (en) | 2007-04-06 | 2012-09-11 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
EP2518063A1 (en) * | 2006-12-21 | 2012-10-31 | Sloan-Kettering Institute For Cancer Research | Pyridazinones and furan-containing compounds |
US8304547B2 (en) | 2007-10-24 | 2012-11-06 | Astellas Pharma Inc. | Azolecarboxamide compound or salt thereof |
US8497376B2 (en) | 2007-10-17 | 2013-07-30 | Janssen Pharmaceutica N.V. | Inhibitors of c-fms kinase |
US8557847B2 (en) | 2005-06-10 | 2013-10-15 | Janssen Pharmaceutica, N.V. | Synergistic modulation of FLT3 kinase using a FLT3 inhibitor and a farnesyl transferase inhibitor |
AU2013200528B2 (en) * | 2006-04-20 | 2014-05-08 | Janssen Pharmaceutica N.V. | Inhibitors of C-FMS kinase |
US8933091B2 (en) | 2006-04-20 | 2015-01-13 | Janssen Pharmaceutica Nv | Method of inhibiting C-KIT kinase |
US9029352B2 (en) | 2012-08-07 | 2015-05-12 | Janssen Pharmaceutica Nv | Process for the preparation of C-FMS kinase inhibitors |
US9290466B2 (en) | 2009-12-11 | 2016-03-22 | Shionogi & Co., Ltd. | Oxazine derivatives |
US9303046B2 (en) | 2012-08-07 | 2016-04-05 | Janssen Pharmaceutica Nv | Process for the preparation of heterocyclic ester derivatives |
US9452998B2 (en) | 2014-08-06 | 2016-09-27 | Novartis Ag | Protein kinase C inhibitors and methods of their use |
US9650371B2 (en) | 2008-06-13 | 2017-05-16 | Shionogi & Co., Ltd. | Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity |
US9758513B2 (en) | 2012-10-24 | 2017-09-12 | Shionogi & Co., Ltd. | Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity |
US10047096B2 (en) | 2014-11-25 | 2018-08-14 | Bayer Pharma Aktiengesellschaft | Substituted pyridobenzodiazepinone-derivatives and use thereof |
US20220389015A1 (en) * | 2017-09-27 | 2022-12-08 | Exonate Limited | Srpk1 inhibitors |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080090836A1 (en) * | 2004-09-20 | 2008-04-17 | Peter Nilsson | Pyrazole Compounds Useful In The Treatment Of Inflammation |
WO2006032851A1 (en) * | 2004-09-20 | 2006-03-30 | Biolipox Ab | Pyrazole compounds useful in the treatment of inflammation |
EP1807077B1 (en) * | 2004-10-22 | 2016-11-23 | Janssen Pharmaceutica NV | Inhibitors of c-fms kinase |
US7662837B2 (en) * | 2004-10-22 | 2010-02-16 | Janssen Pharmaceutica N.V. | Inhibitors of c-fms kinase |
US7645755B2 (en) * | 2004-10-22 | 2010-01-12 | Janssen Pharmaceutical N.V. | Inhibitors of c-fms kinase |
KR101443651B1 (en) * | 2005-10-18 | 2014-09-23 | 얀센 파마슈티카 엔.브이. | Method of inhibiting flt-3 kinase |
TW200800911A (en) * | 2005-10-20 | 2008-01-01 | Biolipox Ab | Pyrazoles useful in the treatment of inflammation |
ZA200803636B (en) * | 2005-10-31 | 2009-10-28 | Biolipox Ab | Triazole compounds as lipoxygenase inhibitors |
TW200732320A (en) * | 2005-10-31 | 2007-09-01 | Biolipox Ab | Pyrazoles useful in the treatment of inflammation |
EP1943225A1 (en) * | 2005-11-01 | 2008-07-16 | Biolipox AB | Pyrazoles useful in the treatment of inflammation |
WO2008055013A2 (en) * | 2006-10-31 | 2008-05-08 | Janssen Pharmaceutica N.V. | 5-oxo-5,8 - dihydro - pyrido - pyrimidines as inhibitors of c-fms kinase |
JP5383483B2 (en) | 2007-04-24 | 2014-01-08 | 塩野義製薬株式会社 | Pharmaceutical composition for the treatment of Alzheimer's disease |
JPWO2010047372A1 (en) | 2008-10-22 | 2012-03-22 | 塩野義製薬株式会社 | 2-Aminopyrimidin-4-one and 2-aminopyridine derivatives having BACE1 inhibitory activity |
JP5766198B2 (en) | 2010-10-29 | 2015-08-19 | 塩野義製薬株式会社 | Condensed aminodihydropyrimidine derivatives |
US8927721B2 (en) | 2010-10-29 | 2015-01-06 | Shionogi & Co., Ltd. | Naphthyridine derivative |
US8883779B2 (en) | 2011-04-26 | 2014-11-11 | Shinogi & Co., Ltd. | Oxazine derivatives and a pharmaceutical composition for inhibiting BACE1 containing them |
CN114874166B (en) * | 2022-06-13 | 2023-11-21 | 河北工业大学 | Method for safely synthesizing 5-hydroxymethyl furnitrile under low temperature condition |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2635818A1 (en) * | 1976-04-30 | 1977-11-17 | Ihara Chemical Ind Co | PROCESS FOR THE PREPARATION OF 2-SUBSTITUTED BENZANILIDE |
US4172947A (en) * | 1977-01-07 | 1979-10-30 | Westwood Pharmaceuticals, Inc. | 1-(2-Acylaminophenyl)imidazoles |
WO1995019169A2 (en) * | 1994-01-07 | 1995-07-20 | Sugen, Inc. | Treatment of platelet derived growth factor related disorders such as cancer using inhibitors of platelet derived growth factor receptor |
WO2000062778A1 (en) * | 1999-04-15 | 2000-10-26 | Bristol-Myers Squibb Co. | Cyclic protein tyrosine kinase inhibitors |
EP1193246A1 (en) * | 1999-07-01 | 2002-04-03 | Taisho Pharmaceutical Co., Ltd | Aminobenzoic acid derivatives |
WO2003103648A1 (en) * | 2002-06-05 | 2003-12-18 | 株式会社医薬分子設計研究所 | Therapeutic drug for diabetes |
WO2003103658A1 (en) * | 2002-06-05 | 2003-12-18 | 株式会社医薬分子設計研究所 | Immunity-related protein kinase inhibitors |
Family Cites Families (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3717579A (en) * | 1970-10-05 | 1973-02-20 | Goldschmidt Ag Th | Biocidal preparation |
JPS555502B1 (en) * | 1971-07-31 | 1980-02-07 | ||
US4186199A (en) * | 1978-11-02 | 1980-01-29 | American Hoechst Corporation | Indolo-,1,2-dihydroindolo-, and 1,2,6,7-tetrahydroindolo [1,7-ab][1,5] benzodiazepines |
US4361572A (en) * | 1981-12-21 | 1982-11-30 | Chugai Seiyaku Kabushiki Kaisha | Tetrahydronicotinamide derivative, pharmaceutical compositions and use |
US5962490A (en) * | 1987-09-25 | 1999-10-05 | Texas Biotechnology Corporation | Thienyl-, furyl- and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin |
US5258357A (en) * | 1989-10-07 | 1993-11-02 | Basf Aktiengesellschaft | Carboxamides, their preparation and their use as herbicides |
CA2297592A1 (en) * | 1993-01-15 | 1994-07-21 | G.D. Searle & Co. | Novel 3,4-diaryl thiophenes and analogs thereof having use as antiinflammatory agents |
US5977168A (en) * | 1994-04-15 | 1999-11-02 | Sankyo Company, Limited | Wood preservative compositions containing dimethylfurancarboxyanilide derivatives |
GB9603095D0 (en) * | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline derivatives |
US6191165B1 (en) * | 1996-05-31 | 2001-02-20 | Allelix Neuroscience Inc. | Pharmaceutical for treatment of neurological and neuropsychiatric disorders |
US5854285A (en) * | 1997-04-03 | 1998-12-29 | Natpro, Inc. | Protein kinase inhibitor |
JP4344960B2 (en) * | 1997-05-23 | 2009-10-14 | バイエル、コーポレイション | Inhibition of p38 kinase activity by arylureas |
US7041702B1 (en) * | 1997-10-21 | 2006-05-09 | Scion Pharmaceuticals, Inc. | Pharmaceutically active compounds and methods of use |
DE69828197T2 (en) * | 1997-10-27 | 2005-12-08 | Sumitomo Pharmaceuticals Co., Ltd. | AMID DERIVATIVES FOR THE TREATMENT OF NEURODEEGENERATIVE DISORDERS OF THE NETWORK |
HUP0004151A3 (en) * | 1997-10-27 | 2001-12-28 | Isk Americas Inc Concord | Herbicidal substituted benzene derivatives, intermediates, preparation and use thereof |
JP2002179651A (en) * | 1998-06-19 | 2002-06-26 | Wakamoto Pharmaceut Co Ltd | Benzanilide derivative and medicine composition |
TR200100631T2 (en) * | 1998-08-20 | 2002-08-21 | Agouron Pharmaceuticals,Inc. | Non-peptide GnRH substances |
GB9824579D0 (en) | 1998-11-10 | 1999-01-06 | Novartis Ag | Organic compounds |
JP3828364B2 (en) * | 1999-03-10 | 2006-10-04 | 塩野義製薬株式会社 | [2.2.1] and [3.1.1] PGD2 / TXA2 Receptor Antagonistic Pharmaceutical Composition Having Bicyclo Skeleton |
JP2001072653A (en) * | 1999-07-01 | 2001-03-21 | Taisho Pharmaceut Co Ltd | Aminobenzoic acid derivative |
US7115660B2 (en) * | 2001-03-27 | 2006-10-03 | The Scripps Research Institute | Methods for inhibiting angiogenesis and tumor growth |
UA75093C2 (en) | 2000-10-06 | 2006-03-15 | Dimensional Pharm Inc | Aminopyridinyl-,aminoguanidinyl-, and alkoxyguanidinesubstituted phenylsubstituted phenylacetamides as protease inhibitors |
US7105682B2 (en) | 2001-01-12 | 2006-09-12 | Amgen Inc. | Substituted amine derivatives and methods of use |
US6734207B2 (en) * | 2001-04-20 | 2004-05-11 | Parker Hughes Institute | Cytotoxic compounds |
DE10129725A1 (en) * | 2001-06-20 | 2003-01-02 | Bayer Ag | Combination therapy of substituted oxazolidinones |
SE0102617D0 (en) * | 2001-07-25 | 2001-07-25 | Astrazeneca Ab | Novel compounds |
JP2003137866A (en) * | 2001-11-01 | 2003-05-14 | Sankyo Co Ltd | Phenylenediamine derivative |
WO2003075853A2 (en) * | 2002-03-08 | 2003-09-18 | Bristol-Myers Squibb Company | Cyclic derivatives as modulators of chemokine receptor activity |
DE10222884A1 (en) * | 2002-05-23 | 2003-12-04 | Bayer Cropscience Ag | furancarboxamides |
WO2004018461A2 (en) | 2002-08-23 | 2004-03-04 | Pharmacia & Upjohn Company Llc | Antibacterial benzoic acid derivatives |
WO2004022525A1 (en) | 2002-09-05 | 2004-03-18 | Neurosearch A/S | Amide derivatives and their use as chloride channel blockers |
WO2004047743A2 (en) * | 2002-11-22 | 2004-06-10 | Bristol-Myers Squibb Company | 1-aryl-2-hydroxyethyl amides as potassium channel openers |
US7109243B2 (en) * | 2003-03-24 | 2006-09-19 | Irm Llc | Inhibitors of cathepsin S |
JP2007525460A (en) | 2003-04-25 | 2007-09-06 | オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド | c-fms kinase inhibitor |
US7427683B2 (en) * | 2003-04-25 | 2008-09-23 | Ortho-Mcneil Pharmaceutical, Inc. | c-fms kinase inhibitors |
US20050113566A1 (en) * | 2003-04-25 | 2005-05-26 | Player Mark R. | Inhibitors of C-FMS kinase |
DE602005015742D1 (en) | 2004-10-22 | 2009-09-10 | Janssen Pharmaceutica Nv | AROMATIC AMIDES AS INHIBITORS OF C-FMS KINASE |
EP1807077B1 (en) | 2004-10-22 | 2016-11-23 | Janssen Pharmaceutica NV | Inhibitors of c-fms kinase |
-
2004
- 2004-04-26 JP JP2006513302A patent/JP2007525460A/en active Pending
- 2004-04-26 WO PCT/US2004/012729 patent/WO2004096795A2/en active Application Filing
- 2004-04-26 CA CA002536964A patent/CA2536964A1/en not_active Abandoned
- 2004-04-26 MX MXPA05011503A patent/MXPA05011503A/en unknown
- 2004-04-26 EP EP04750617A patent/EP1631560A2/en not_active Withdrawn
- 2004-04-26 US US10/831,216 patent/US7429603B2/en active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2635818A1 (en) * | 1976-04-30 | 1977-11-17 | Ihara Chemical Ind Co | PROCESS FOR THE PREPARATION OF 2-SUBSTITUTED BENZANILIDE |
US4172947A (en) * | 1977-01-07 | 1979-10-30 | Westwood Pharmaceuticals, Inc. | 1-(2-Acylaminophenyl)imidazoles |
WO1995019169A2 (en) * | 1994-01-07 | 1995-07-20 | Sugen, Inc. | Treatment of platelet derived growth factor related disorders such as cancer using inhibitors of platelet derived growth factor receptor |
WO2000062778A1 (en) * | 1999-04-15 | 2000-10-26 | Bristol-Myers Squibb Co. | Cyclic protein tyrosine kinase inhibitors |
EP1193246A1 (en) * | 1999-07-01 | 2002-04-03 | Taisho Pharmaceutical Co., Ltd | Aminobenzoic acid derivatives |
WO2003103648A1 (en) * | 2002-06-05 | 2003-12-18 | 株式会社医薬分子設計研究所 | Therapeutic drug for diabetes |
WO2003103658A1 (en) * | 2002-06-05 | 2003-12-18 | 株式会社医薬分子設計研究所 | Immunity-related protein kinase inhibitors |
Non-Patent Citations (25)
Title |
---|
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002307089 & CHEM. BER., vol. 24, 1891, page 2101, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002307090 & J. CHEM. SOC., 1963, pages 4666-4669, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002307091 & J. CHEM. SOC., 1964, page 2609, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002307092 & J. CHEM. SOC. C, 1969, pages 1444-1448, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002307093 & JUSTUS LIEBIGS ANN. CHEM., vol. 699, 1966, page 88, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002307094 & J. CHEM. SOC. B, 1971, page 696, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002307095 & CHEM. PHARM. BULL., vol. 31, no. 9, 1983, pages 3160-3167, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002307096 & CHEM. PHARM. BULL., vol. 36, no. 9, 1988, pages 3248-3252, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002307097 & HELV. CHIM. ACTA, vol. 61, 1978, page 2887, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002307098 & FARMACO ED. SCI., vol. 42, no. 3, 1987, pages 231-236, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002307099 & BULL. SOC. CHIM. FR., 1973, pages 3017-3018, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002307100 & J. MED. CHEM., vol. 35, no. 5, 1992, pages 804-807, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002307101 & ARH. CHEM., vol. 27, 1955, page 33, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002307102 & PROC.-INDIAN ACAD. SCI. SECT. A, vol. 38, 1953, page 58, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002307103 & J. AM. CHEM. SOC., vol. 40, 1980, page 566, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002307104 & GAZZ. CHIM. ITAL., vol. 80, 1950, page 456, * |
DATABASE CHEMCATS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002307105 retrieved from STN & "Interchim Intermediates" 9 July 2002 (2002-07-09), INTERCHIM , 213 AVENUE KENNEDY, BP 1140, MONTLUCON, CEDEX, 03103, FRANCE * |
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002307086 & "Ambinter Stock Screening Collection" 1 January 2004 (2004-01-01), AMBINTER , 46 QUAI LOIUS BLERIOT, F-75016 PARIS, FRANCE * |
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002307088 & "ChemStar Product List" 24 April 2003 (2003-04-24), CHEMSTAR, LTD. , LENINGRADSKII PROSPEKT 47, OFFICE 465, MOSKOW, 125167, RUSSIA * |
HODSON, S. J. ET AL.: "Alpha1-Adrenoceptor Activation: A Comparison of 4-(Anilinomethyl)imidazoles and 4-(Phenoxymethyl)imidazoles to Related 2-Imidazolines" BIOORG. MED. CHEM. LETT., vol. 12, 2002, pages 3449-3452, XP002307084 * |
KLUNDER, J. M. ET AL.: "Novel Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase. 2. Tricyclic Pyridobenzoxazepinones and Dibenzoxazepinones." J. MED. CHEM., vol. 35, 1992, pages 1887-1897, XP002307085 * |
MELIK-ORGANDZHANYAN, R. G. ET AL.: "New Method for the Synthesis of Polyfunctional 5-Aminopyrimidines" CHEM. HETEROCYCL. COMPD. ENGL. TRANSL., 1983, pages 100-102, XP009040286 * |
SHOWALTER ET AL: "Tyrosine Kinase Inhibitors. 16. 6,5,6-Tricyclic Benzothieno[3,2-d]pyrimidines and Pyrimido[5,4-b]- and -[4,5-b]indoles as Potent Inhibitors of the Epidermal Growth Factor Receptor Tyrosine Kinase" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 42, 1999, pages 5464-5474, XP002210181 ISSN: 0022-2623 * |
TRAXLER P: "TYROSINE KINASE INHIBITORS IN CANCER TREATMENT (PART II)" EXPERT OPINION ON THERAPEUTIC PATENTS, ASHLEY PUBLICATIONS, GB, vol. 8, no. 12, 1998, pages 1599-1625, XP001183544 ISSN: 1354-3776 * |
YOSHINO, H. ET AL.: "Novel Sulfonamides as Potential, Systematically Active Antitumor Agents" J. MED. CHEM., vol. 35, 1992, pages 2496-2497, XP002307083 * |
Cited By (83)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7790724B2 (en) | 2003-04-25 | 2010-09-07 | Janssen Pharmaceutica N.V. | c-fms kinase inhibitors |
US7429603B2 (en) | 2003-04-25 | 2008-09-30 | 3-Dimensional Pharmaceuticals, Inc. | C-fms kinase inhibitors |
US7427683B2 (en) | 2003-04-25 | 2008-09-23 | Ortho-Mcneil Pharmaceutical, Inc. | c-fms kinase inhibitors |
US8816089B2 (en) | 2003-12-26 | 2014-08-26 | Masatoshi Hagiwara | Methods for controlling SR protein phosphorylation, and antiviral agents whose active ingredients comprise agents that control SR protein activity |
US8338362B2 (en) * | 2003-12-26 | 2012-12-25 | Masatoshi Hagiwara | Methods for controlling SR protein phosphorylation, and antiviral agents whose active ingredients comprise agents that control SR protein activity |
US7569536B2 (en) * | 2003-12-26 | 2009-08-04 | Masatoshi Hagiwara | Method for controlling SR protein phosphorylation, and antiviral agents whose active ingredients comprise agents that control SR protein activity |
WO2006047479A3 (en) * | 2004-10-22 | 2007-01-04 | Janssen Pharmaceutica Nv | C-fms kinase inhibitors |
WO2006047503A3 (en) * | 2004-10-22 | 2006-09-28 | Janssen Pharmaceutica Nv | Inhibitors of c-fms kinase |
WO2006047479A2 (en) * | 2004-10-22 | 2006-05-04 | Janssen Pharmaceutica, N.V. | C-fms kinase inhibitors |
WO2006047505A3 (en) * | 2004-10-22 | 2007-01-25 | Janssen Pharmaceutica Nv | Crystal structure of the c-fms kinase domain |
WO2006047504A1 (en) * | 2004-10-22 | 2006-05-04 | Janssen Pharmaceutica, N.V. | Aromatic amides as inhibitors of c-fms kinase |
WO2006047505A2 (en) * | 2004-10-22 | 2006-05-04 | Janssen Pharmaceutica, N.V. | Crystal structure of the c-fms kinase domain |
WO2006047503A2 (en) * | 2004-10-22 | 2006-05-04 | Janssen Pharmaceutica | Inhibitors of c-fms kinase |
JP2008517945A (en) * | 2004-10-22 | 2008-05-29 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Aromatic amides as inhibitors of C-FMS kinase |
US7705042B2 (en) | 2004-10-22 | 2010-04-27 | Janssen Pharmaceutica Nv | Class of arylamide compounds useful as inhibitors of c-fms kinase |
US8557847B2 (en) | 2005-06-10 | 2013-10-15 | Janssen Pharmaceutica, N.V. | Synergistic modulation of FLT3 kinase using a FLT3 inhibitor and a farnesyl transferase inhibitor |
US8710089B2 (en) | 2005-08-15 | 2014-04-29 | Zentaris Gmbh | Triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors |
US7829724B2 (en) | 2005-08-15 | 2010-11-09 | Zentaris Gmbh | Triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors |
EP1757290A1 (en) | 2005-08-16 | 2007-02-28 | Zentaris GmbH | Novel triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors |
US8173642B2 (en) | 2005-10-25 | 2012-05-08 | Shionogi & Co., Ltd. | Aminodihydrothiazine derivatives |
US9029358B2 (en) | 2005-10-25 | 2015-05-12 | Shionogi & Co., Ltd. | Aminodihydrothiazine derivatives |
WO2007123269A1 (en) | 2006-04-19 | 2007-11-01 | Astellas Pharma Inc. | Azolecarboxamide derivative |
US8163746B2 (en) | 2006-04-19 | 2012-04-24 | Astellas Pharma Inc. | Azolecarboxamide derivative |
RU2475483C2 (en) * | 2006-04-20 | 2013-02-20 | Янссен Фармацевтика Н.В. | C-fmc kinase inhibitors |
US9403804B2 (en) | 2006-04-20 | 2016-08-02 | Janssen Pharmaceutica Nv | Inhibitors of c-fms kinase |
JP2009534407A (en) * | 2006-04-20 | 2009-09-24 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Inhibitors of c-fms kinase |
US7973035B2 (en) | 2006-04-20 | 2011-07-05 | Janssen Pharmaceutica, N.V. | Inhibitors of C-FMS kinase |
US9452996B2 (en) | 2006-04-20 | 2016-09-27 | Janssen Pharmaceutica Nv | Inhibitors of c-fms kinase |
JP2009534404A (en) * | 2006-04-20 | 2009-09-24 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Inhibitors of c-fms kinase |
US9394289B2 (en) | 2006-04-20 | 2016-07-19 | Janssen Pharmaceutica Nv | Inhibitors of c-fms kinase |
JP2009534380A (en) * | 2006-04-20 | 2009-09-24 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | c-fms kinase inhibitor |
US9296726B2 (en) | 2006-04-20 | 2016-03-29 | Janssen Pharmaceutica Nv | Inhibitors of c-fms kinase |
JP2009534405A (en) * | 2006-04-20 | 2009-09-24 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Inhibitors of c-fms kinase |
AU2007240442B2 (en) * | 2006-04-20 | 2012-09-06 | Janssen Pharmaceutica N.V. | Inhibitors of c-fms kinase |
US9221797B2 (en) | 2006-04-20 | 2015-12-29 | Janssen Pharmaceutica Nv | Inhibitors of c-fms kinase |
AU2007240440B2 (en) * | 2006-04-20 | 2012-09-20 | Janssen Pharmaceutica N.V. | Inhibitors of c-fms kinase |
AU2007240439B2 (en) * | 2006-04-20 | 2012-10-11 | Janssen Pharmaceutica N.V. | Inhibitors of c-fms kinase |
WO2007124319A1 (en) * | 2006-04-20 | 2007-11-01 | Janssen Pharmaceutica N.V. | Inhibitors of c-fms kinase |
AU2007240443B2 (en) * | 2006-04-20 | 2012-11-01 | Janssen Pharmaceutica N.V. | Inhibitors of c-fms kinase |
KR101491564B1 (en) * | 2006-04-20 | 2015-02-09 | 얀센 파마슈티카 엔.브이. | Inhibitors of c-fms kinase |
JP2009534406A (en) * | 2006-04-20 | 2009-09-24 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Inhibitors of c-fms kinase |
WO2007124318A1 (en) * | 2006-04-20 | 2007-11-01 | Janssen Pharmaceutica N.V. | Inhibitors of c-fms kinase |
US8933091B2 (en) | 2006-04-20 | 2015-01-13 | Janssen Pharmaceutica Nv | Method of inhibiting C-KIT kinase |
US8895584B2 (en) | 2006-04-20 | 2014-11-25 | Janssen Pharmaceutica Nv | Inhibitors of c-fms kinase |
KR101462393B1 (en) * | 2006-04-20 | 2014-11-18 | 얀센 파마슈티카 엔.브이. | Inhibitors of c-fms kinase |
TWI411612B (en) * | 2006-04-20 | 2013-10-11 | Janssen Pharmaceutica Nv | Inhibitors of c-fms kinase |
WO2007123516A1 (en) * | 2006-04-20 | 2007-11-01 | Janssen Pharmaceutica, N.V. | C-fms kinase inhibitors |
EP2687516A1 (en) | 2006-04-20 | 2014-01-22 | Janssen Pharmaceutica N.V. | Inhibitors of C-FMS Kinase |
KR101367646B1 (en) * | 2006-04-20 | 2014-02-27 | 얀센 파마슈티카 엔.브이. | Inhibitors of c-fms kinase |
US8674100B2 (en) | 2006-04-20 | 2014-03-18 | Janssen Pharmaceutica, N.V. | Inhibitors of C-FMS kinase |
JP2014074030A (en) * | 2006-04-20 | 2014-04-24 | Janssen Pharmaceutica Nv | Inhibitors of c-fms kinase |
WO2007124322A1 (en) * | 2006-04-20 | 2007-11-01 | Janssen Pharmaceutica N.V. | Inhibitors of c-fms kinase |
AU2013200528B2 (en) * | 2006-04-20 | 2014-05-08 | Janssen Pharmaceutica N.V. | Inhibitors of C-FMS kinase |
KR101406877B1 (en) * | 2006-04-20 | 2014-06-13 | 얀센 파마슈티카 엔.브이. | Inhibitors of c-fms kinase |
WO2007124321A1 (en) * | 2006-04-20 | 2007-11-01 | Janssen Pharmaceutica N.V. | Inhibitors of c-fms kinase |
EP2518063A1 (en) * | 2006-12-21 | 2012-10-31 | Sloan-Kettering Institute For Cancer Research | Pyridazinones and furan-containing compounds |
US10336769B2 (en) | 2007-04-06 | 2019-07-02 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
US11713324B2 (en) | 2007-04-06 | 2023-08-01 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
US9422310B2 (en) | 2007-04-06 | 2016-08-23 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
US8952161B2 (en) | 2007-04-06 | 2015-02-10 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
US10941159B2 (en) | 2007-04-06 | 2021-03-09 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
US8263588B2 (en) | 2007-04-06 | 2012-09-11 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
US8481738B2 (en) | 2007-04-06 | 2013-07-09 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
US8084614B2 (en) | 2007-04-06 | 2011-12-27 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
US8507536B2 (en) | 2007-04-06 | 2013-08-13 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
US8168630B2 (en) | 2007-04-24 | 2012-05-01 | Shionogi & Co., Ltd. | Aminodihydrothiazine derivatives substituted with a cyclic group |
US8497376B2 (en) | 2007-10-17 | 2013-07-30 | Janssen Pharmaceutica N.V. | Inhibitors of c-fms kinase |
US8304547B2 (en) | 2007-10-24 | 2012-11-06 | Astellas Pharma Inc. | Azolecarboxamide compound or salt thereof |
US9650371B2 (en) | 2008-06-13 | 2017-05-16 | Shionogi & Co., Ltd. | Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity |
US9290466B2 (en) | 2009-12-11 | 2016-03-22 | Shionogi & Co., Ltd. | Oxazine derivatives |
US9656974B2 (en) | 2009-12-11 | 2017-05-23 | Shionogi & Co., Ltd. | Oxazine derivatives |
WO2012035124A1 (en) | 2010-09-16 | 2012-03-22 | Æterna Zentaris Gmbh | Novel triazole derivatives with improved receptor activity and bioavailability properties as ghrelin antagonists of growth hormone secretagogue receptors |
EP2431035A1 (en) | 2010-09-16 | 2012-03-21 | Æterna Zentaris GmbH | Novel Triazole Derivatives with Improved Receptor Activity and Bioavailability Properties as Ghrelin Antagonists of Growth Hormone Secretagogue Receptors |
US9029352B2 (en) | 2012-08-07 | 2015-05-12 | Janssen Pharmaceutica Nv | Process for the preparation of C-FMS kinase inhibitors |
US9303046B2 (en) | 2012-08-07 | 2016-04-05 | Janssen Pharmaceutica Nv | Process for the preparation of heterocyclic ester derivatives |
US9758513B2 (en) | 2012-10-24 | 2017-09-12 | Shionogi & Co., Ltd. | Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity |
US9845309B2 (en) | 2014-08-06 | 2017-12-19 | Novartis Ag | Protein kinase C inhibitors and methods of their use |
US10508101B2 (en) | 2014-08-06 | 2019-12-17 | Novartis Ag | Protein kinase C inhibitors and methods of their use |
US11059804B2 (en) | 2014-08-06 | 2021-07-13 | Novartis Ag | Protein kinase C inhibitors and methods of their use |
US11505541B2 (en) | 2014-08-06 | 2022-11-22 | Novartis Ag | Protein kinase C inhibitors and methods of their use |
US9452998B2 (en) | 2014-08-06 | 2016-09-27 | Novartis Ag | Protein kinase C inhibitors and methods of their use |
US10047096B2 (en) | 2014-11-25 | 2018-08-14 | Bayer Pharma Aktiengesellschaft | Substituted pyridobenzodiazepinone-derivatives and use thereof |
US20220389015A1 (en) * | 2017-09-27 | 2022-12-08 | Exonate Limited | Srpk1 inhibitors |
Also Published As
Publication number | Publication date |
---|---|
EP1631560A2 (en) | 2006-03-08 |
WO2004096795A3 (en) | 2005-03-10 |
US20050004112A1 (en) | 2005-01-06 |
MXPA05011503A (en) | 2006-05-31 |
US7429603B2 (en) | 2008-09-30 |
JP2007525460A (en) | 2007-09-06 |
CA2536964A1 (en) | 2004-11-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1631560A2 (en) | C-fms kinase inhibitors | |
AU2005299500A1 (en) | Inhibitors of c-fms kinase | |
AU2005299476A1 (en) | c-fms kinase inhibitors | |
EP1807407B1 (en) | Aromatic amides as inhibitors of c-fms kinase | |
JP5331679B2 (en) | Inhibitors of c-fms kinase | |
CN100391958C (en) | Chemical compounds | |
US7790724B2 (en) | c-fms kinase inhibitors | |
KR20060097105A (en) | Quinolinone derivatives as inhibitors of c-fms kinase | |
JP5480619B2 (en) | Inhibitors of c-fms kinase | |
WO2007123516A1 (en) | C-fms kinase inhibitors | |
WO2005082001A2 (en) | Advanced isothiazole based protein kinase inhibitors | |
KR20200127223A (en) | Oxazino-quinazoline and oxazino-quinoline type compound, preparation method and use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DPEN | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101) | ||
ENP | Entry into the national phase |
Ref document number: 2536964 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006513302 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2005/011503 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004750617 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 2004750617 Country of ref document: EP |