SK3452003A3 - Pyridine derivatives with IKB-kinase (IKK-beta) inhibiting activity - Google Patents
Pyridine derivatives with IKB-kinase (IKK-beta) inhibiting activity Download PDFInfo
- Publication number
- SK3452003A3 SK3452003A3 SK345-2003A SK3452003A SK3452003A3 SK 3452003 A3 SK3452003 A3 SK 3452003A3 SK 3452003 A SK3452003 A SK 3452003A SK 3452003 A3 SK3452003 A3 SK 3452003A3
- Authority
- SK
- Slovakia
- Prior art keywords
- carbon atoms
- group
- alkyl
- amino
- piperidinyl
- Prior art date
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- 150000003222 pyridines Chemical class 0.000 title claims description 12
- 230000002401 inhibitory effect Effects 0.000 title description 7
- 102000001284 I-kappa-B kinase Human genes 0.000 title description 3
- 108060006678 I-kappa-B kinase Proteins 0.000 title description 3
- -1 2-amino-4,6-disubstituted nicotinic acid ester Chemical class 0.000 claims abstract description 230
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 181
- 238000000034 method Methods 0.000 claims abstract description 37
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 376
- 229910052739 hydrogen Inorganic materials 0.000 claims description 185
- 150000001875 compounds Chemical class 0.000 claims description 144
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 75
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 73
- 239000001257 hydrogen Substances 0.000 claims description 51
- 125000003545 alkoxy group Chemical group 0.000 claims description 50
- 229920006395 saturated elastomer Polymers 0.000 claims description 49
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 45
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 32
- 229910052757 nitrogen Chemical group 0.000 claims description 32
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 28
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 25
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 23
- 125000001589 carboacyl group Chemical group 0.000 claims description 22
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 229910052717 sulfur Inorganic materials 0.000 claims description 20
- 239000011593 sulfur Substances 0.000 claims description 20
- 125000003282 alkyl amino group Chemical group 0.000 claims description 19
- 125000003277 amino group Chemical group 0.000 claims description 19
- 125000005842 heteroatom Chemical group 0.000 claims description 19
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 17
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 17
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 239000001301 oxygen Chemical group 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 16
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 16
- 239000004480 active ingredient Substances 0.000 claims description 15
- 125000005167 cycloalkylaminocarbonyl group Chemical group 0.000 claims description 14
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 claims description 13
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 12
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 12
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 11
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 9
- 150000001721 carbon Chemical group 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- FTAHXMZRJCZXDL-UHFFFAOYSA-N 3-piperideine Chemical group C1CC=CCN1 FTAHXMZRJCZXDL-UHFFFAOYSA-N 0.000 claims description 7
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
- 208000006673 asthma Diseases 0.000 claims description 7
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 7
- 125000003386 piperidinyl group Chemical group 0.000 claims description 7
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 5
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 claims description 5
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 5
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 201000001981 dermatomyositis Diseases 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 4
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 4
- 125000005163 aryl sulfanyl group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 206010009887 colitis Diseases 0.000 claims description 4
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 4
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- VRTFOUDCQHOCPY-UHFFFAOYSA-N 2-[6-amino-5-(hydroxymethyl)-4-piperidin-3-ylpyridin-2-yl]-3-(cyclopropylmethoxy)phenol Chemical compound OCC=1C(N)=NC(C=2C(=CC=CC=2O)OCC2CC2)=CC=1C1CCCNC1 VRTFOUDCQHOCPY-UHFFFAOYSA-N 0.000 claims description 3
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 3
- MWJZCWXDCPUUKA-UHFFFAOYSA-N 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(1-methylpiperidin-3-yl)pyridine-3-carbonitrile Chemical compound C1N(C)CCCC1C1=CC(C=2C(=CC=CC=2O)OCC2CC2)=NC(N)=C1C#N MWJZCWXDCPUUKA-UHFFFAOYSA-N 0.000 claims description 3
- XVDVGCLXFIUCFT-UHFFFAOYSA-N 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-piperidin-3-yl-1H-1,8-naphthyridin-2-one Chemical compound C=1C(C2CNCCC2)=C2C=CC(=O)NC2=NC=1C=1C(O)=CC=CC=1OCC1CC1 XVDVGCLXFIUCFT-UHFFFAOYSA-N 0.000 claims description 3
- 206010010741 Conjunctivitis Diseases 0.000 claims description 3
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 3
- 201000005569 Gout Diseases 0.000 claims description 3
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 3
- 206010040047 Sepsis Diseases 0.000 claims description 3
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 3
- 201000010105 allergic rhinitis Diseases 0.000 claims description 3
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 3
- 201000008937 atopic dermatitis Diseases 0.000 claims description 3
- OCGWPIHFDXWNCJ-UHFFFAOYSA-N ethyl 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-piperidin-3-yl-1,4-dihydropyrido[2,3-d]pyrimidine-3-carboxylate Chemical compound N1C(=O)N(C(=O)OCC)CC2=C1N=C(C=1C(=CC=CC=1O)OCC1CC1)C=C2C1CCCNC1 OCGWPIHFDXWNCJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 208000005987 polymyositis Diseases 0.000 claims description 3
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 3
- 208000018464 vernal keratoconjunctivitis Diseases 0.000 claims description 3
- CETGRCDGYVBQML-UHFFFAOYSA-N 2-[6-amino-5-(hydroxymethyl)-4-(1,2,3,6-tetrahydropyridin-5-yl)pyridin-2-yl]phenol Chemical compound OCC=1C(N)=NC(C=2C(=CC=CC=2)O)=CC=1C1=CCCNC1 CETGRCDGYVBQML-UHFFFAOYSA-N 0.000 claims description 2
- ICGXFLJTVZTHPV-UHFFFAOYSA-N 2-[6-amino-5-(hydroxymethyl)-4-piperidin-3-ylpyridin-2-yl]-3-(2,2-dimethylpropoxy)phenol Chemical compound CC(C)(C)COC1=CC=CC(O)=C1C1=CC(C2CNCCC2)=C(CO)C(N)=N1 ICGXFLJTVZTHPV-UHFFFAOYSA-N 0.000 claims description 2
- FQNVEBJCAOPRMX-UHFFFAOYSA-N 2-[6-amino-5-(hydroxymethyl)-4-piperidin-3-ylpyridin-2-yl]-3-phenylmethoxyphenol Chemical compound OCC=1C(N)=NC(C=2C(=CC=CC=2O)OCC=2C=CC=CC=2)=CC=1C1CCCNC1 FQNVEBJCAOPRMX-UHFFFAOYSA-N 0.000 claims description 2
- DMACSHODVXTYON-UHFFFAOYSA-N 2-[6-amino-5-(hydroxymethyl)-4-piperidin-3-ylpyridin-2-yl]pyridin-3-ol Chemical compound OCC=1C(N)=NC(C=2C(=CC=CN=2)O)=CC=1C1CCCNC1 DMACSHODVXTYON-UHFFFAOYSA-N 0.000 claims description 2
- QZUAQCKUXDWPHT-UHFFFAOYSA-N 2-[6-amino-5-(hydroxymethyl)-4-piperidin-4-ylpyridin-2-yl]-3-(cyclopropylmethoxy)phenol Chemical compound OCC=1C(N)=NC(C=2C(=CC=CC=2O)OCC2CC2)=CC=1C1CCNCC1 QZUAQCKUXDWPHT-UHFFFAOYSA-N 0.000 claims description 2
- WZGFRSBFQANORR-UHFFFAOYSA-N 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-3-ylpyridine-3-carbonitrile 2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.Nc1nc(cc(C2CCCNC2)c1C#N)-c1c(O)cccc1OCC1CC1 WZGFRSBFQANORR-UHFFFAOYSA-N 0.000 claims description 2
- BCAHWVMQDYMSQK-UHFFFAOYSA-N 2-amino-6-[2-hydroxy-6-(4-methylpentoxy)phenyl]-4-piperidin-4-ylpyridine-3-carbonitrile Chemical compound CC(C)CCCOC1=CC=CC(O)=C1C1=CC(C2CCNCC2)=C(C#N)C(N)=N1 BCAHWVMQDYMSQK-UHFFFAOYSA-N 0.000 claims description 2
- UZBXYMHLKCOBOS-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-2-(5-piperidin-3-yl-2,4-dihydro-1H-pyrido[2,3-d][1,3]oxazin-7-yl)phenol Chemical compound C=1C(C2CNCCC2)=C2COCNC2=NC=1C=1C(O)=CC=CC=1OCC1CC1 UZBXYMHLKCOBOS-UHFFFAOYSA-N 0.000 claims description 2
- GSWTYFPALXHXJD-UHFFFAOYSA-N 7-(2-hydroxy-6-propoxyphenyl)-5-piperidin-3-yl-1,4-dihydropyrido[2,3-d][1,3]oxazin-2-one Chemical compound CCCOC1=CC=CC(O)=C1C1=CC(C2CNCCC2)=C(COC(=O)N2)C2=N1 GSWTYFPALXHXJD-UHFFFAOYSA-N 0.000 claims description 2
- VWSSLCXIHNUQTG-UHFFFAOYSA-N 7-(2-hydroxy-6-propoxyphenyl)-5-piperidin-4-yl-1,4-dihydropyrido[2,3-d][1,3]oxazin-2-one Chemical compound CCCOC1=CC=CC(O)=C1C1=CC(C2CCNCC2)=C(COC(=O)N2)C2=N1 VWSSLCXIHNUQTG-UHFFFAOYSA-N 0.000 claims description 2
- DTUKQSNELAAPEW-UHFFFAOYSA-N 7-(2-hydroxyphenyl)-5-piperidin-3-yl-1,4-dihydropyrido[2,3-d][1,3]oxazin-2-one Chemical compound OC1=CC=CC=C1C1=CC(C2CNCCC2)=C(COC(=O)N2)C2=N1 DTUKQSNELAAPEW-UHFFFAOYSA-N 0.000 claims description 2
- AYEHKYACNQAKGD-UHFFFAOYSA-N 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-piperidin-3-yl-3,4-dihydro-1H-1,8-naphthyridine-3-carboxamide Chemical compound N1C(=O)C(C(=O)N)CC2=C1N=C(C=1C(=CC=CC=1O)OCC1CC1)C=C2C1CCCNC1 AYEHKYACNQAKGD-UHFFFAOYSA-N 0.000 claims description 2
- DZDSBMRWUTWDRF-UHFFFAOYSA-N 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-fluoro-5-piperidin-3-yl-1H-1,8-naphthyridin-2-one Chemical compound C=1C(C2CNCCC2)=C2C=C(F)C(=O)NC2=NC=1C=1C(O)=CC=CC=1OCC1CC1 DZDSBMRWUTWDRF-UHFFFAOYSA-N 0.000 claims description 2
- IGJVFGZEWDGDOO-UHFFFAOYSA-N 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-piperidin-3-yl-1,4-dihydropyrido[2,3-d][1,3]oxazin-2-one Chemical compound C=1C(C2CNCCC2)=C2COC(=O)NC2=NC=1C=1C(O)=CC=CC=1OCC1CC1 IGJVFGZEWDGDOO-UHFFFAOYSA-N 0.000 claims description 2
- PABIFKJGFAZMJW-UHFFFAOYSA-N 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-piperidin-3-yl-3,4-dihydro-1H-1,8-naphthyridin-2-one Chemical compound C=1C(C2CNCCC2)=C2CCC(=O)NC2=NC=1C=1C(O)=CC=CC=1OCC1CC1 PABIFKJGFAZMJW-UHFFFAOYSA-N 0.000 claims description 2
- PONMWDXRKJKNES-UHFFFAOYSA-N 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-piperidin-4-yl-1,4-dihydropyrido[2,3-d][1,3]oxazin-2-one Chemical compound C=1C(C2CCNCC2)=C2COC(=O)NC2=NC=1C=1C(O)=CC=CC=1OCC1CC1 PONMWDXRKJKNES-UHFFFAOYSA-N 0.000 claims description 2
- RPWVNHVSOTXEMN-UHFFFAOYSA-N 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-piperidin-4-yl-3,4-dihydro-1H-1,8-naphthyridin-2-one Chemical compound C=1C(C2CCNCC2)=C2CCC(=O)NC2=NC=1C=1C(O)=CC=CC=1OCC1CC1 RPWVNHVSOTXEMN-UHFFFAOYSA-N 0.000 claims description 2
- TUCPPAVGTSUQIW-UHFFFAOYSA-N 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-N-ethyl-2-oxo-5-piperidin-3-yl-1,4-dihydropyrido[2,3-d]pyrimidine-3-carboxamide Chemical compound N1C(=O)N(C(=O)NCC)CC2=C1N=C(C=1C(=CC=CC=1O)OCC1CC1)C=C2C1CCCNC1 TUCPPAVGTSUQIW-UHFFFAOYSA-N 0.000 claims description 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 2
- 102100021854 Inhibitor of nuclear factor kappa-B kinase subunit beta Human genes 0.000 claims description 2
- 101710205525 Inhibitor of nuclear factor kappa-B kinase subunit beta Proteins 0.000 claims description 2
- CPWGGAVZGQHHGK-UHFFFAOYSA-N N-[[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-3-ylpyridin-3-yl]methyl]acetamide Chemical compound CC(=O)NCC1=C(N)N=C(C=2C(=CC=CC=2O)OCC2CC2)C=C1C1CCCNC1 CPWGGAVZGQHHGK-UHFFFAOYSA-N 0.000 claims description 2
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- MOMLCJXOIMMUMB-UHFFFAOYSA-N chembl181334 Chemical compound CCCOC1=CC=CC(O)=C1C1=CC(C2CNCCC2)=C(C#N)C(N)=N1 MOMLCJXOIMMUMB-UHFFFAOYSA-N 0.000 claims description 2
- SMBKYSLSHYPLDQ-UHFFFAOYSA-N chembl361233 Chemical compound N#CC=1C(N)=NC(C=2C(=CC=CC=2O)OCC=2C=CC=CC=2)=CC=1C1CCCNC1 SMBKYSLSHYPLDQ-UHFFFAOYSA-N 0.000 claims description 2
- DYVFBWXIOCLHPP-UHFFFAOYSA-N chembl368427 Chemical compound N#CC=1C(N)=NC(C=2C(=CC=CC=2O)OCC2CC2)=CC=1C1CCNCC1 DYVFBWXIOCLHPP-UHFFFAOYSA-N 0.000 claims description 2
- 210000002808 connective tissue Anatomy 0.000 claims description 2
- RCUGCDPYJHBMHI-UHFFFAOYSA-N ethyl 7-(2-hydroxy-6-propoxyphenyl)-2-oxo-5-piperidin-3-yl-3,4-dihydro-1H-1,8-naphthyridine-3-carboxylate Chemical compound CCCOC1=CC=CC(O)=C1C1=CC(C2CNCCC2)=C(CC(C(=O)OCC)C(=O)N2)C2=N1 RCUGCDPYJHBMHI-UHFFFAOYSA-N 0.000 claims description 2
- DAUFKTSKCPJBHA-UHFFFAOYSA-N ethyl 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-piperidin-3-yl-3,4-dihydro-1H-1,8-naphthyridine-3-carboxylate Chemical compound N1C(=O)C(C(=O)OCC)CC2=C1N=C(C=1C(=CC=CC=1O)OCC1CC1)C=C2C1CCCNC1 DAUFKTSKCPJBHA-UHFFFAOYSA-N 0.000 claims description 2
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 2
- 208000028867 ischemia Diseases 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 230000000451 tissue damage Effects 0.000 claims description 2
- 231100000827 tissue damage Toxicity 0.000 claims description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims 1
- 125000000172 C5-C10 aryl group Chemical group 0.000 claims 1
- AARPAUSAUTWCNJ-UHFFFAOYSA-N [2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-3-ylpyridin-3-yl]methylurea Chemical compound NC(=O)NCC1=C(N)N=C(C=2C(=CC=CC=2O)OCC2CC2)C=C1C1CCCNC1 AARPAUSAUTWCNJ-UHFFFAOYSA-N 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- ANBQYFIVLNNZCU-CQCLMDPOSA-N alpha-L-Fucp-(1->2)-[alpha-D-GalpNAc-(1->3)]-beta-D-Galp-(1->3)-[alpha-L-Fucp-(1->4)]-beta-D-GlcpNAc-(1->3)-beta-D-Galp Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@H]2[C@@H]([C@@H](O[C@@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)NC(C)=O)[C@@H](O)[C@@H](CO)O2)O[C@H]2[C@H]([C@H](O)[C@H](O)[C@H](C)O2)O)[C@@H](NC(C)=O)[C@H](O[C@H]2[C@H]([C@@H](CO)O[C@@H](O)[C@@H]2O)O)O[C@@H]1CO ANBQYFIVLNNZCU-CQCLMDPOSA-N 0.000 claims 1
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- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 62
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- 238000009795 derivation Methods 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
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- FUGMZKAIEBPRKK-UHFFFAOYSA-N tert-butyl 3-[3-acetyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-1,4-dihydropyrido[2,3-d]pyrimidin-5-yl]piperidine-1-carboxylate Chemical compound N1C(=O)N(C(=O)C)CC2=C1N=C(C=1C(=CC=CC=1O)OCC1CC1)C=C2C1CCCN(C(=O)OC(C)(C)C)C1 FUGMZKAIEBPRKK-UHFFFAOYSA-N 0.000 description 1
- FLPQJANYBBMRDX-UHFFFAOYSA-N tert-butyl 3-[3-amino-6-(2-phenylmethoxyphenyl)-2h-pyrazolo[3,4-b]pyridin-4-yl]piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC1C1=CC(C=2C(=CC=CC=2)OCC=2C=CC=CC=2)=NC2=C1C(N)=NN2 FLPQJANYBBMRDX-UHFFFAOYSA-N 0.000 description 1
- MYMKNSSNNCHSLX-UHFFFAOYSA-N tert-butyl 3-[3-cyano-6-(2-hydroxyphenyl)-2-(propylamino)pyridin-4-yl]piperidine-1-carboxylate Chemical compound N#CC=1C(NCCC)=NC(C=2C(=CC=CC=2)O)=CC=1C1CCCN(C(=O)OC(C)(C)C)C1 MYMKNSSNNCHSLX-UHFFFAOYSA-N 0.000 description 1
- ZFBPJMKVHNOJTP-UHFFFAOYSA-N tert-butyl 3-[3-cyano-6-(2-phenylmethoxyphenyl)-2-(propylamino)pyridin-4-yl]piperidine-1-carboxylate Chemical compound N#CC=1C(NCCC)=NC(C=2C(=CC=CC=2)OCC=2C=CC=CC=2)=CC=1C1CCCN(C(=O)OC(C)(C)C)C1 ZFBPJMKVHNOJTP-UHFFFAOYSA-N 0.000 description 1
- PXUIROTZYWBKNB-UHFFFAOYSA-N tert-butyl 3-[7-(2,6-dihydroxyphenyl)-2-oxo-1,4-dihydropyrido[2,3-d][1,3]oxazin-5-yl]piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC1C1=CC(C=2C(=CC=CC=2O)O)=NC2=C1COC(=O)N2 PXUIROTZYWBKNB-UHFFFAOYSA-N 0.000 description 1
- WRJGNDZRUMAYFZ-UHFFFAOYSA-N tert-butyl 3-[7-(2-hydroxyphenyl)-2-oxo-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-5-yl]piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC1C1=CC(C=2C(=CC=CC=2)O)=NC2=C1CNC(=O)N2 WRJGNDZRUMAYFZ-UHFFFAOYSA-N 0.000 description 1
- GFIQXPZTOFYEMI-UHFFFAOYSA-N tert-butyl 3-formyl-3-methylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(C)(C=O)C1 GFIQXPZTOFYEMI-UHFFFAOYSA-N 0.000 description 1
- KUDYDGWGDRZATE-UHFFFAOYSA-N tert-butyl 5-formyl-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC=C(C=O)C1 KUDYDGWGDRZATE-UHFFFAOYSA-N 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- JAXGMBUVQWCKRW-UHFFFAOYSA-N tert-butyl n-(3-formylcyclohexyl)-n-methylcarbamate Chemical compound CC(C)(C)OC(=O)N(C)C1CCCC(C=O)C1 JAXGMBUVQWCKRW-UHFFFAOYSA-N 0.000 description 1
- ZJTYRNPLVNMVPQ-LBPRGKRZSA-N tert-butyl n-[(2s)-1-oxo-3-phenylpropan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C=O)CC1=CC=CC=C1 ZJTYRNPLVNMVPQ-LBPRGKRZSA-N 0.000 description 1
- VCBQHUZBBTUJQR-UHFFFAOYSA-N tert-butyl n-[1-[2-oxo-7-(2-phenylmethoxyphenyl)-1,4-dihydropyrido[2,3-d][1,3]oxazin-5-yl]-2-phenylethyl]carbamate Chemical compound C=1C(C=2C(=CC=CC=2)OCC=2C=CC=CC=2)=NC=2NC(=O)OCC=2C=1C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 VCBQHUZBBTUJQR-UHFFFAOYSA-N 0.000 description 1
- JGGNEBWEXSLKCK-UHFFFAOYSA-N tert-butyl n-[3-[methoxy(methyl)carbamoyl]cyclohexyl]-n-methylcarbamate Chemical compound CON(C)C(=O)C1CCCC(N(C)C(=O)OC(C)(C)C)C1 JGGNEBWEXSLKCK-UHFFFAOYSA-N 0.000 description 1
- CNTQVZYSRYLVBU-UHFFFAOYSA-N tert-butyl n-[3-[methoxy(methyl)carbamoyl]cyclohexyl]carbamate Chemical compound CON(C)C(=O)C1CCCC(NC(=O)OC(C)(C)C)C1 CNTQVZYSRYLVBU-UHFFFAOYSA-N 0.000 description 1
- AZAKMLHUDVIDFN-UHFFFAOYSA-N tert-butyl nitrate Chemical compound CC(C)(C)O[N+]([O-])=O AZAKMLHUDVIDFN-UHFFFAOYSA-N 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 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
- 238000011144 upstream manufacturing Methods 0.000 description 1
- LSGOVYNHVSXFFJ-UHFFFAOYSA-N vanadate(3-) Chemical compound [O-][V]([O-])([O-])=O LSGOVYNHVSXFFJ-UHFFFAOYSA-N 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
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- 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
- C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/08—Preparation by ring-closure
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- C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/08—Preparation by ring-closure
- C07D213/09—Preparation by ring-closure involving the use of ammonia, amines, amine salts, or nitriles
- C07D213/10—Preparation by ring-closure involving the use of ammonia, amines, amine salts, or nitriles from acetaldehyde or cyclic polymers thereof
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- 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
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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- 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
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- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/80—Acids; Esters in position 3
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- 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
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- 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
- C07D231/12—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
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- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D515/04—Ortho-condensed systems
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
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| JP2000289173A JP4272338B2 (ja) | 2000-09-22 | 2000-09-22 | ピリジン誘導体 |
| PCT/EP2001/010405 WO2002024679A1 (fr) | 2000-09-22 | 2001-09-10 | Derives de pyridine avec activite inhibitrice de l'ikb-kinase (ikk-kinase9 |
Publications (1)
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| SK3452003A3 true SK3452003A3 (en) | 2004-01-08 |
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| SK345-2003A SK3452003A3 (en) | 2000-09-22 | 2001-09-10 | Pyridine derivatives with IKB-kinase (IKK-beta) inhibiting activity |
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| EP (1) | EP1326856B1 (fr) |
| JP (1) | JP4272338B2 (fr) |
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| AT (1) | ATE381556T1 (fr) |
| AU (3) | AU2001289873A1 (fr) |
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| BR (1) | BR0114073A (fr) |
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| EE (1) | EE200300113A (fr) |
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| MX (1) | MXPA03002491A (fr) |
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| AU2016250976B2 (en) | 2015-04-21 | 2020-02-27 | Jiangsu Hengrui Medicine Co., Ltd. | Imidazo isoindole derivative, preparation method therefor and medical use thereof |
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| ES2805232T3 (es) | 2015-06-19 | 2021-02-11 | Novartis Ag | Compuestos y composiciones para inhibir la actividad de SHP2 |
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| HUE072191T2 (hu) | 2015-12-04 | 2025-10-28 | Global Blood Therapeutics Inc | A 2-hidoxi-6-((2-(1-izopropil-1H-pirazol-5-il)piridin-3-il)metoxi)benzaldehid adagolási rendje |
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| US20190343836A1 (en) | 2017-01-10 | 2019-11-14 | Novartis Ag | Pharmaceutical combination comprising an alk inhibitor and a shp2 inhibitor |
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| RU2669348C1 (ru) * | 2017-11-15 | 2018-10-10 | Федеральное государственное автономное образовательное учреждение высшего образования "Белгородский государственный национальный исследовательский университет" (НИУ "БелГУ") | Способ ингибирования нуклеарного фактора каппа В с использованием 2-этил-6-метил-3-гидроксипиридиния L-2,6-диаминогексаноата в культуре клеток |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4003908A (en) * | 1976-03-11 | 1977-01-18 | E. R. Squibb & Sons, Inc. | Derivatives of imidazo(4,5-b)pyridines |
| ECSP003699A (es) * | 1999-10-08 | 2002-04-23 | Smithkline Beecham Corp | Inhibidores de fab i |
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