HRP20030214A2 - Pharmaceutically active sulfonamide derivatives bearing both lipohilic and ionisable moieties as inhibitors of protein junkinases - Google Patents
Pharmaceutically active sulfonamide derivatives bearing both lipohilic and ionisable moieties as inhibitors of protein junkinases Download PDFInfo
- Publication number
- HRP20030214A2 HRP20030214A2 HR20030214A HRP20030214A HRP20030214A2 HR P20030214 A2 HRP20030214 A2 HR P20030214A2 HR 20030214 A HR20030214 A HR 20030214A HR P20030214 A HRP20030214 A HR P20030214A HR P20030214 A2 HRP20030214 A2 HR P20030214A2
- Authority
- HR
- Croatia
- Prior art keywords
- methyl
- sulfonyl
- amino
- thien
- benzamide
- Prior art date
Links
- 229940124530 sulfonamide Drugs 0.000 title claims description 52
- 150000003456 sulfonamides Chemical class 0.000 title claims description 43
- 101000950669 Homo sapiens Mitogen-activated protein kinase 9 Proteins 0.000 title claims description 17
- 102100037809 Mitogen-activated protein kinase 9 Human genes 0.000 title claims description 17
- 239000003112 inhibitor Substances 0.000 title description 6
- -1 nitro, sulfonyl Chemical group 0.000 claims description 77
- 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 claims description 65
- 239000000203 mixture Substances 0.000 claims description 50
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 33
- 150000001412 amines Chemical class 0.000 claims description 31
- 238000002360 preparation method Methods 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 23
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 17
- 230000014509 gene expression Effects 0.000 claims description 15
- 101000628949 Homo sapiens Mitogen-activated protein kinase 10 Proteins 0.000 claims description 13
- 208000035475 disorder Diseases 0.000 claims description 13
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 13
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 12
- 102100026931 Mitogen-activated protein kinase 10 Human genes 0.000 claims description 11
- 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 claims description 11
- 150000002431 hydrogen Chemical group 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- HEHMZUQCKMARIT-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[[4-(trifluoromethyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=CC(=CC=2)C(F)(F)F)=C1 HEHMZUQCKMARIT-UHFFFAOYSA-N 0.000 claims description 9
- 210000004556 brain Anatomy 0.000 claims description 9
- 208000028867 ischemia Diseases 0.000 claims description 9
- VRJHQPZVIGNGMX-UHFFFAOYSA-N piperidine-4-one Chemical group O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 claims description 9
- 125000001544 thienyl group Chemical group 0.000 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical group 0.000 claims description 7
- OGLWFGSKCPERGG-UHFFFAOYSA-N 2-oxo-n-[[5-[4-[[4-(trifluoromethyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-1h-pyridine-3-carboxamide Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C(NC=CC=3)=O)=CC=2)CC1 OGLWFGSKCPERGG-UHFFFAOYSA-N 0.000 claims description 6
- 208000023275 Autoimmune disease Diseases 0.000 claims description 6
- 230000000302 ischemic effect Effects 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- XPPZCVNVUAJANR-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[methyl-[[4-(trifluoromethyl)phenyl]methyl]amino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)N(C)CC=2C=CC(=CC=2)C(F)(F)F)=C1 XPPZCVNVUAJANR-UHFFFAOYSA-N 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 206010040070 Septic Shock Diseases 0.000 claims description 5
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 210000002216 heart Anatomy 0.000 claims description 5
- 210000003734 kidney Anatomy 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 4
- 125000004442 acylamino group Chemical group 0.000 claims description 4
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical group C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 201000006370 kidney failure Diseases 0.000 claims description 4
- 210000004185 liver Anatomy 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000005309 thioalkoxy group Chemical group 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 208000023105 Huntington disease Diseases 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- 206010063837 Reperfusion injury Diseases 0.000 claims description 3
- 230000002159 abnormal effect Effects 0.000 claims description 3
- 125000005036 alkoxyphenyl group Chemical group 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 230000006806 disease prevention Effects 0.000 claims description 3
- 206010015037 epilepsy Diseases 0.000 claims description 3
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 125000006501 nitrophenyl group Chemical group 0.000 claims description 3
- BCIIMDOZSUCSEN-UHFFFAOYSA-N piperidin-4-amine Chemical group NC1CCNCC1 BCIIMDOZSUCSEN-UHFFFAOYSA-N 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 claims description 3
- NGXSWUFDCSEIOO-UHFFFAOYSA-N pyrrolidin-3-amine Chemical group NC1CCNC1 NGXSWUFDCSEIOO-UHFFFAOYSA-N 0.000 claims description 3
- QGKLPGKXAVVPOJ-UHFFFAOYSA-N pyrrolidin-3-one Chemical group O=C1CCNC1 QGKLPGKXAVVPOJ-UHFFFAOYSA-N 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 230000036303 septic shock Effects 0.000 claims description 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- ZXDHMWKKHWUGNF-UHFFFAOYSA-N 2-sulfanylidene-n-[[5-[4-[[4-(trifluoromethyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-1h-pyridine-3-carboxamide Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C(NC=CC=3)=S)=CC=2)CC1 ZXDHMWKKHWUGNF-UHFFFAOYSA-N 0.000 claims description 2
- WNDVUNAGTFREDB-UHFFFAOYSA-N 3-methoxy-n-[[5-[3-(2-pyridin-2-ylethylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CC(CC2)NCCC=2N=CC=CC=2)=C1 WNDVUNAGTFREDB-UHFFFAOYSA-N 0.000 claims description 2
- KPOIREPMXZFSNV-UHFFFAOYSA-N 3-methoxy-n-[[5-[3-(3-morpholin-4-ylpropylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CC(CC2)NCCCN2CCOCC2)=C1 KPOIREPMXZFSNV-UHFFFAOYSA-N 0.000 claims description 2
- CWRSKSUXNCINND-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(2-pyridin-2-ylethylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CCC2)NCCC=2N=CC=CC=2)=C1 CWRSKSUXNCINND-UHFFFAOYSA-N 0.000 claims description 2
- AABAJDPRRHYOAV-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(2-pyridin-2-ylethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCCC=2N=CC=CC=2)=C1 AABAJDPRRHYOAV-UHFFFAOYSA-N 0.000 claims description 2
- WJVPSLHIPHKJGR-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(3-morpholin-4-ylpropylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCCCN2CCOCC2)=C1 WJVPSLHIPHKJGR-UHFFFAOYSA-N 0.000 claims description 2
- IEVZPTYBQVKDGM-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[(2,3,4,5,6-pentamethylphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C(=C(C)C(C)=C(C)C=2C)C)=C1 IEVZPTYBQVKDGM-UHFFFAOYSA-N 0.000 claims description 2
- LKMMJRSDKDNVCD-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[(4-methylphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=CC(C)=CC=2)=C1 LKMMJRSDKDNVCD-UHFFFAOYSA-N 0.000 claims description 2
- HWVOMCVAQLMXEP-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[(4-methylsulfonylphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=CC(=CC=2)S(C)(=O)=O)=C1 HWVOMCVAQLMXEP-UHFFFAOYSA-N 0.000 claims description 2
- SIPDDBKNGXEADC-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[(4-phenoxyphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=CC(OC=3C=CC=CC=3)=CC=2)=C1 SIPDDBKNGXEADC-UHFFFAOYSA-N 0.000 claims description 2
- YDWAZMSGTWOJKZ-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[(4-propoxyphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(OCCC)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=C(OC)C=CC=3)=CC=2)CC1 YDWAZMSGTWOJKZ-UHFFFAOYSA-N 0.000 claims description 2
- POXCZVSHFWOHHK-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[1-[4-(trifluoromethyl)phenyl]ethylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NC(C)C=2C=CC(=CC=2)C(F)(F)F)=C1 POXCZVSHFWOHHK-UHFFFAOYSA-N 0.000 claims description 2
- WCFANFOWTKGWNV-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[1-[4-(trifluoromethyl)phenyl]propylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C=1C=C(C(F)(F)F)C=CC=1C(CC)NC(CC1)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 WCFANFOWTKGWNV-UHFFFAOYSA-N 0.000 claims description 2
- IBUQXYBAGPSJJO-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[2-(4-methylphenyl)ethylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCCC=2C=CC(C)=CC=2)=C1 IBUQXYBAGPSJJO-UHFFFAOYSA-N 0.000 claims description 2
- UNWNZJPKLZSKCV-RPBOFIJWSA-N 3-methoxy-n-[[5-[4-[[(1s,2r)-2-phenylcyclopropyl]amino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)N[C@@H]2[C@H](C2)C=2C=CC=CC=2)=C1 UNWNZJPKLZSKCV-RPBOFIJWSA-N 0.000 claims description 2
- ZWFPICDMSOAGLH-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[[2-(trifluoromethyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C(=CC=CC=2)C(F)(F)F)=C1 ZWFPICDMSOAGLH-UHFFFAOYSA-N 0.000 claims description 2
- HMZNUBAPMAOCOT-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[[3-(trifluoromethyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=C(C=CC=2)C(F)(F)F)=C1 HMZNUBAPMAOCOT-UHFFFAOYSA-N 0.000 claims description 2
- CMSNSJKESAFZTI-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[[3-(trifluoromethylsulfanyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=C(SC(F)(F)F)C=CC=2)=C1 CMSNSJKESAFZTI-UHFFFAOYSA-N 0.000 claims description 2
- XPBMHMIVWLMSSJ-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[[4-(trifluoromethylsulfanyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=CC(SC(F)(F)F)=CC=2)=C1 XPBMHMIVWLMSSJ-UHFFFAOYSA-N 0.000 claims description 2
- WQYNKWNGMHSGNT-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[[6-(trifluoromethyl)pyridin-3-yl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=NC(=CC=2)C(F)(F)F)=C1 WQYNKWNGMHSGNT-UHFFFAOYSA-N 0.000 claims description 2
- BLHCGACBVVBQJQ-GOSISDBHSA-N 4-chloro-n-[[5-[(3r)-3-[(hexylamino)methyl]pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1[C@@H](CNCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 BLHCGACBVVBQJQ-GOSISDBHSA-N 0.000 claims description 2
- ISDZJHKRZJOPFG-GOSISDBHSA-N 4-chloro-n-[[5-[(3r)-3-[[[4-(trifluoromethyl)phenyl]methylamino]methyl]pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC[C@@H]1CN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CC1 ISDZJHKRZJOPFG-GOSISDBHSA-N 0.000 claims description 2
- PJRYNEPWNXFQGP-UHFFFAOYSA-N 4-chloro-n-[[5-[2-[[[4-(trifluoromethyl)phenyl]methylamino]methyl]pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(C(F)(F)F)=CC=C1CNCC1N(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CCC1 PJRYNEPWNXFQGP-UHFFFAOYSA-N 0.000 claims description 2
- ZMWLJQDAWIGXOC-UHFFFAOYSA-N 4-chloro-n-[[5-[3-(2-pyridin-2-ylethylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CC(CC2)NCCC=2N=CC=CC=2)S1 ZMWLJQDAWIGXOC-UHFFFAOYSA-N 0.000 claims description 2
- QFDUJWBLOQNNFF-UHFFFAOYSA-N 4-chloro-n-[[5-[3-[(1-hydroxycyclohexyl)methylamino]pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CC1NCC1(O)CCCCC1 QFDUJWBLOQNNFF-UHFFFAOYSA-N 0.000 claims description 2
- JUECCJMELXTEIW-UHFFFAOYSA-N 4-chloro-n-[[5-[3-[[[4-(trifluoromethyl)phenyl]methylamino]methyl]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(C(F)(F)F)=CC=C1CNCC1CN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CCC1 JUECCJMELXTEIW-UHFFFAOYSA-N 0.000 claims description 2
- BNBVRPMOIVJFGS-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[(4-propylphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(CCC)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CC1 BNBVRPMOIVJFGS-UHFFFAOYSA-N 0.000 claims description 2
- OPNYMHLOHHVHJC-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[1-[4-(trifluoromethyl)phenyl]ethylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C=1C=C(C(F)(F)F)C=CC=1C(C)NC(CC1)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 OPNYMHLOHHVHJC-UHFFFAOYSA-N 0.000 claims description 2
- DIDQABDFIWEKRS-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[2-[4-(trifluoromethyl)phenyl]propan-2-ylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C=1C=C(C(F)(F)F)C=CC=1C(C)(C)NC(CC1)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 DIDQABDFIWEKRS-UHFFFAOYSA-N 0.000 claims description 2
- ZPKZTRKUOSQDAN-GOSISDBHSA-N 4-chloro-n-[[5-[4-[[(1r)-1-cyclohexylethyl]amino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound N([C@H](C)C1CCCCC1)C(CC1)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 ZPKZTRKUOSQDAN-GOSISDBHSA-N 0.000 claims description 2
- JWLSFCHUCJLYLD-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[[4-(trifluoromethoxy)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(OC(F)(F)F)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CC1 JWLSFCHUCJLYLD-UHFFFAOYSA-N 0.000 claims description 2
- BVFJKTWMNUHVDO-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[[4-(trifluoromethyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CC1 BVFJKTWMNUHVDO-UHFFFAOYSA-N 0.000 claims description 2
- YRSBUPXJFZUIJU-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[[4-(trifluoromethylsulfanyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(SC(F)(F)F)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CC1 YRSBUPXJFZUIJU-UHFFFAOYSA-N 0.000 claims description 2
- SWWYYUFJDBPSCO-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[hexyl(3-phenylpropyl)amino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CCC1N(CCCCCC)CCCC1=CC=CC=C1 SWWYYUFJDBPSCO-UHFFFAOYSA-N 0.000 claims description 2
- SFFWJQKPFTWBOT-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[hexyl(pyridin-4-ylmethyl)amino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CCC1N(CCCCCC)CC1=CC=NC=C1 SFFWJQKPFTWBOT-UHFFFAOYSA-N 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 206010019196 Head injury Diseases 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- 208000017442 Retinal disease Diseases 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 210000000481 breast Anatomy 0.000 claims description 2
- 210000001072 colon Anatomy 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 210000004072 lung Anatomy 0.000 claims description 2
- VHUXUXYRKSWDAU-UHFFFAOYSA-N n-[[4-chloro-5-[4-(hexylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(NCCCCCC)CCN1S(=O)(=O)C1=C(Cl)C=C(CNC(=O)C=2C=C(OC)C=CC=2)S1 VHUXUXYRKSWDAU-UHFFFAOYSA-N 0.000 claims description 2
- AUMSGNKKNYYDPO-UHFFFAOYSA-N n-[[5-[3-(1-adamantylmethylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CC(CC2)NCC23CC4CC(CC(C4)C2)C3)=C1 AUMSGNKKNYYDPO-UHFFFAOYSA-N 0.000 claims description 2
- HAXYDEDKPDXTRY-UHFFFAOYSA-N n-[[5-[3-(1-adamantylmethylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]-4-chlorobenzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CC(CC2)NCC23CC4CC(CC(C4)C2)C3)S1 HAXYDEDKPDXTRY-UHFFFAOYSA-N 0.000 claims description 2
- PEDDBRJLQYOUOZ-UHFFFAOYSA-N n-[[5-[3-(2-cyclohexylethylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CC(CC2)NCCC2CCCCC2)=C1 PEDDBRJLQYOUOZ-UHFFFAOYSA-N 0.000 claims description 2
- UJZBPGBILAFJTQ-UHFFFAOYSA-N n-[[5-[3-(butylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]-4-chlorobenzamide Chemical compound C1C(NCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 UJZBPGBILAFJTQ-UHFFFAOYSA-N 0.000 claims description 2
- BJCCBOGODWMYNF-ITUIMRKVSA-N n-[[5-[3-[[(1r)-1-cyclohexylethyl]amino]pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CC(CC2)N[C@H](C)C2CCCCC2)=C1 BJCCBOGODWMYNF-ITUIMRKVSA-N 0.000 claims description 2
- BDTCTRHEDIAZLI-WEWZKHDXSA-N n-[[5-[3-[[(1s,3r,4r)-3-bicyclo[2.2.1]heptanyl]amino]pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound N([C@H]1[C@]2([H])CC[C@@](C2)(C1)[H])C(C1)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 BDTCTRHEDIAZLI-WEWZKHDXSA-N 0.000 claims description 2
- BYZMUFLFKDVUJW-UHFFFAOYSA-N n-[[5-[4-(2,3-dihydro-1,4-benzodioxin-6-ylmethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=C3OCCOC3=CC=2)=C1 BYZMUFLFKDVUJW-UHFFFAOYSA-N 0.000 claims description 2
- UFPYTBMPRFMEQT-UHFFFAOYSA-N n-[[5-[4-(2,3-dihydro-1-benzofuran-5-ylmethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=C3CCOC3=CC=2)=C1 UFPYTBMPRFMEQT-UHFFFAOYSA-N 0.000 claims description 2
- KLYZWURVWSWFLY-UHFFFAOYSA-N n-[[5-[4-(2-cyclohexylethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCCC2CCCCC2)=C1 KLYZWURVWSWFLY-UHFFFAOYSA-N 0.000 claims description 2
- CKXLOOSPQMRJMK-UHFFFAOYSA-N n-[[5-[4-(3,3-diethoxypropylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(NCCC(OCC)OCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 CKXLOOSPQMRJMK-UHFFFAOYSA-N 0.000 claims description 2
- IJSNIBWPXCQGHM-UHFFFAOYSA-N n-[[5-[4-(benzylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=CC=CC=2)=C1 IJSNIBWPXCQGHM-UHFFFAOYSA-N 0.000 claims description 2
- QRMFLENACLOUIF-UHFFFAOYSA-N n-[[5-[4-(butylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-2-oxo-1h-pyridine-3-carboxamide Chemical compound C1CC(NCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CNC1=O QRMFLENACLOUIF-UHFFFAOYSA-N 0.000 claims description 2
- QUPGNQAAPYBLQS-UHFFFAOYSA-N n-[[5-[4-(hexylamino)piperidin-1-yl]sulfonyl-4-[hydroxy(phenyl)methyl]thiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(NCCCCCC)CCN1S(=O)(=O)C1=C(C(O)C=2C=CC=CC=2)C=C(CNC(=O)C=2C=C(OC)C=CC=2)S1 QUPGNQAAPYBLQS-UHFFFAOYSA-N 0.000 claims description 2
- GCTUKULTSHXALR-UHFFFAOYSA-N n-[[5-[4-(hexylamino)piperidin-1-yl]sulfonyl-4-trimethylsilylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(NCCCCCC)CCN1S(=O)(=O)C1=C([Si](C)(C)C)C=C(CNC(=O)C=2C=C(OC)C=CC=2)S1 GCTUKULTSHXALR-UHFFFAOYSA-N 0.000 claims description 2
- YHENMXCQEQDMCT-UHFFFAOYSA-N n-[[5-[4-(hexylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-2-sulfanylidene-1h-pyridine-3-carboxamide Chemical compound C1CC(NCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CNC1=S YHENMXCQEQDMCT-UHFFFAOYSA-N 0.000 claims description 2
- IHASYAHJFDYBCN-UHFFFAOYSA-N n-[[5-[4-[(2,2-difluoro-1,3-benzodioxol-5-yl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=C3OC(F)(F)OC3=CC=2)=C1 IHASYAHJFDYBCN-UHFFFAOYSA-N 0.000 claims description 2
- IYOIXTJUBKEFFP-UHFFFAOYSA-N n-[[5-[4-[(4-butoxyphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-4-chlorobenzamide Chemical compound C1=CC(OCCCC)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CC1 IYOIXTJUBKEFFP-UHFFFAOYSA-N 0.000 claims description 2
- NMGGSYPIVVODTC-UHFFFAOYSA-N n-[[5-[4-[(4-ethylphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1=CC(CC)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=C(OC)C=CC=3)=CC=2)CC1 NMGGSYPIVVODTC-UHFFFAOYSA-N 0.000 claims description 2
- DVOAIIHBNXHFHN-UHFFFAOYSA-N n-[[5-[4-[(4-ethylsulfanylphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1=CC(SCC)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=C(OC)C=CC=3)=CC=2)CC1 DVOAIIHBNXHFHN-UHFFFAOYSA-N 0.000 claims description 2
- JNSJAYIEHBECRH-UHFFFAOYSA-N n-[[5-[4-[(5-bromofuran-2-yl)methyl-hexylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-4-chlorobenzamide Chemical compound C1CN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CCC1N(CCCCCC)CC1=CC=C(Br)O1 JNSJAYIEHBECRH-UHFFFAOYSA-N 0.000 claims description 2
- MQVGWGTYVZGDHS-UHFFFAOYSA-N n-[[5-[4-[2-(4-hydroxyphenyl)ethylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCCC=2C=CC(O)=CC=2)=C1 MQVGWGTYVZGDHS-UHFFFAOYSA-N 0.000 claims description 2
- IYMXZYMDKGDVCP-PPUHSXQSSA-N n-[[5-[4-[[(1r)-1-cyclohexylethyl]amino]azepan-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CCC2)N[C@H](C)C2CCCCC2)=C1 IYMXZYMDKGDVCP-PPUHSXQSSA-N 0.000 claims description 2
- WJRKVPQBYULJLZ-LJQANCHMSA-N n-[[5-[4-[[(1r)-1-cyclohexylethyl]amino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)N[C@H](C)C2CCCCC2)=C1 WJRKVPQBYULJLZ-LJQANCHMSA-N 0.000 claims description 2
- SPYAWOKUARADJQ-GDHBDLSCSA-N n-[[5-[4-[[(1s,3r,4r)-3-bicyclo[2.2.1]heptanyl]amino]azepan-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound N([C@H]1[C@]2([H])CC[C@@](C2)(C1)[H])C(CC1)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 SPYAWOKUARADJQ-GDHBDLSCSA-N 0.000 claims description 2
- FJRFRBOTFXORHP-WTUOIENSSA-N n-[[5-[4-[[(1s,3r,4r)-3-bicyclo[2.2.1]heptanyl]amino]azepan-1-yl]sulfonylthiophen-2-yl]methyl]-4-chlorobenzamide Chemical compound N([C@H]1[C@]2([H])CC[C@@](C2)(C1)[H])C(CC1)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 FJRFRBOTFXORHP-WTUOIENSSA-N 0.000 claims description 2
- MHXQUNHXLFOURQ-YZZKKUAISA-N n-[[5-[4-[[(1s,3r,4r)-3-bicyclo[2.2.1]heptanyl]amino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound N([C@H]1[C@]2([H])CC[C@@](C2)(C1)[H])C(CC1)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 MHXQUNHXLFOURQ-YZZKKUAISA-N 0.000 claims description 2
- PAINNEQTKSSEME-AQOAWAETSA-N n-[[5-[4-[[(1s,3r,4r)-3-bicyclo[2.2.1]heptanyl]amino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-4-chlorobenzamide Chemical compound N([C@H]1[C@]2([H])CC[C@@](C2)(C1)[H])C(CC1)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 PAINNEQTKSSEME-AQOAWAETSA-N 0.000 claims description 2
- QFYMBOHCUQXBMB-UHFFFAOYSA-N n-[[5-[4-[[2,5-bis(trifluoromethyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C(=CC=C(C=2)C(F)(F)F)C(F)(F)F)=C1 QFYMBOHCUQXBMB-UHFFFAOYSA-N 0.000 claims description 2
- BGFKIMXHVHKPNG-UHFFFAOYSA-N n-[[5-[4-[[4-(difluoromethoxy)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=CC(OC(F)F)=CC=2)=C1 BGFKIMXHVHKPNG-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 210000000056 organ Anatomy 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 230000037361 pathway Effects 0.000 claims description 2
- 210000002307 prostate Anatomy 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 238000006268 reductive amination reaction Methods 0.000 claims description 2
- 208000020431 spinal cord injury Diseases 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 210000001550 testis Anatomy 0.000 claims description 2
- HFFXLYHRNRKAPM-UHFFFAOYSA-N 2,4,5-trichloro-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C(=CC(Cl)=C(Cl)C=2)Cl)=N1 HFFXLYHRNRKAPM-UHFFFAOYSA-N 0.000 claims 14
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims 4
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 3
- 102000019145 JUN kinase activity proteins Human genes 0.000 claims 2
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 claims 1
- WFCHEWUYHIIPDU-UHFFFAOYSA-N 3-methoxy-N-[[5-[4-[[4-(2-methylpropyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide 3-methoxy-N-[[5-[4-[(4-propan-2-ylphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C(C(C)C)C1=CC=C(CNC2CCN(CC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC(=CC=C2)OC)=O)C=C1.C(C)(C)C1=CC=C(CNC2CCN(CC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC(=CC=C2)OC)=O)C=C1 WFCHEWUYHIIPDU-UHFFFAOYSA-N 0.000 claims 1
- WKAUASPRERVXBS-UHFFFAOYSA-N 4-chloro-N-[[5-[4-[[4-(difluoromethoxy)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide 4-chloro-N-[[5-[4-[(4-propoxyphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC2=CC=C(C=C2)OCCC)C=C1.ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC2=CC=C(C=C2)OC(F)F)C=C1 WKAUASPRERVXBS-UHFFFAOYSA-N 0.000 claims 1
- NQGJYCKIXCESDA-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(2-cyclohexylethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide;4-chloro-n-[[5-[4-(cyclohexylmethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CCC(CC2)NCC2CCCCC2)S1.C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CCC(CC2)NCCC2CCCCC2)S1 NQGJYCKIXCESDA-UHFFFAOYSA-N 0.000 claims 1
- PEOPOFHAAWDBLO-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(2-ethylhexylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]benzamide;4-chloro-n-[[5-[4-(2-propoxyethylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCOCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1.C1CC(NCC(CC)CCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 PEOPOFHAAWDBLO-UHFFFAOYSA-N 0.000 claims 1
- ZZAINDHFFCGOPR-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(2-ethylhexylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide;4-chloro-n-[[5-[4-(3-imidazol-1-ylpropylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCC(CC)CCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1.C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CCC(CC2)NCCCN2C=NC=C2)S1 ZZAINDHFFCGOPR-UHFFFAOYSA-N 0.000 claims 1
- BSYLQPYKXIPKGD-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(heptylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]benzamide;4-chloro-n-[[5-[4-(octylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCCCCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1.C1CC(NCCCCCCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 BSYLQPYKXIPKGD-UHFFFAOYSA-N 0.000 claims 1
- ZAJCFNGTGLBWQU-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(hexylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]benzamide;n-[[5-[4-(hexylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(NCCCCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1.C1CC(NCCCCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 ZAJCFNGTGLBWQU-UHFFFAOYSA-N 0.000 claims 1
- NGVMCDWZEGDTKT-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(octylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide;n-[[5-[4-(heptylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(NCCCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1.C1CC(NCCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 NGVMCDWZEGDTKT-UHFFFAOYSA-N 0.000 claims 1
- SBTVUGWQXLXMON-UHFFFAOYSA-N 5-[[(3-methoxybenzoyl)amino]methyl]-2-[4-[[4-(trifluoromethyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophene-3-carboxylic acid Chemical class COC1=CC=CC(C(=O)NCC=2SC(=C(C(O)=O)C=2)S(=O)(=O)N2CCC(CC2)NCC=2C=CC(=CC=2)C(F)(F)F)=C1 SBTVUGWQXLXMON-UHFFFAOYSA-N 0.000 claims 1
- DSRHCPAMEKHQLU-UHFFFAOYSA-N C(C)C(CNC1CCN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O)CCCC.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCCN2CCCCC2)C=CC1 Chemical compound C(C)C(CNC1CCN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O)CCCC.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCCN2CCCCC2)C=CC1 DSRHCPAMEKHQLU-UHFFFAOYSA-N 0.000 claims 1
- XRYLCMKFQVPZOQ-UHFFFAOYSA-N C(C)C(CNC1CN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O)CCCC.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CC(CC2)NCCN2CCCCC2)C=CC1 Chemical compound C(C)C(CNC1CN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O)CCCC.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CC(CC2)NCCN2CCCCC2)C=CC1 XRYLCMKFQVPZOQ-UHFFFAOYSA-N 0.000 claims 1
- YWTIDRAHRAMOCK-UHFFFAOYSA-N C(C)OC=1C=C(CNC2CCN(CC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC(=CC=C2)OC)=O)C=CC1.C(C)(C)(C)C1=CC=C(CNC2CCN(CC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC(=CC=C2)OC)=O)C=C1 Chemical compound C(C)OC=1C=C(CNC2CCN(CC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC(=CC=C2)OC)=O)C=CC1.C(C)(C)(C)C1=CC=C(CNC2CCN(CC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC(=CC=C2)OC)=O)C=C1 YWTIDRAHRAMOCK-UHFFFAOYSA-N 0.000 claims 1
- SWJYEAFPMGNSCW-UHFFFAOYSA-N C(C1=CC=CC=C1)OC1=CC=C(CNC2CCN(CC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC(=CC=C2)OC)=O)C=C1.IC1=CC=C(CNC2CCN(CC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC(=CC=C2)OC)=O)C=C1 Chemical compound C(C1=CC=CC=C1)OC1=CC=C(CNC2CCN(CC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC(=CC=C2)OC)=O)C=C1.IC1=CC=C(CNC2CCN(CC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC(=CC=C2)OC)=O)C=C1 SWJYEAFPMGNSCW-UHFFFAOYSA-N 0.000 claims 1
- SYGKFXFHPPDWSX-UHFFFAOYSA-N C(CCC)N(C1CCN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC=C(C=C1)Cl)=O)CCCCCC.ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)N(CC2=NC=CC=C2)CCCCCC)C=C1 Chemical compound C(CCC)N(C1CCN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC=C(C=C1)Cl)=O)CCCCCC.ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)N(CC2=NC=CC=C2)CCCCCC)C=C1 SYGKFXFHPPDWSX-UHFFFAOYSA-N 0.000 claims 1
- NJARXDSIZAEXHI-UHFFFAOYSA-N C(CCC)NC1CCN(CCC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CCC2)NCCCCC)C=CC1 Chemical compound C(CCC)NC1CCN(CCC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CCC2)NCCCCC)C=CC1 NJARXDSIZAEXHI-UHFFFAOYSA-N 0.000 claims 1
- LHNKGTSELYJPAR-UHFFFAOYSA-N C(CCC)NC1CCN(CCC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC=C(C=C1)Cl)=O.ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CCC2)NCCCCC)C=C1 Chemical compound C(CCC)NC1CCN(CCC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC=C(C=C1)Cl)=O.ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CCC2)NCCCCC)C=C1 LHNKGTSELYJPAR-UHFFFAOYSA-N 0.000 claims 1
- KPCDPHLMTCKJHG-UHFFFAOYSA-N C(CCC)NCCC1CCN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)CNCCCCC)C=CC1 Chemical compound C(CCC)NCCC1CCN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)CNCCCCC)C=CC1 KPCDPHLMTCKJHG-UHFFFAOYSA-N 0.000 claims 1
- FTNAEWJPIYDXOH-UHFFFAOYSA-N C(CCCCCCCCCCC)NC1CCN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O.C(CCC)NC1CCN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O Chemical compound C(CCCCCCCCCCC)NC1CCN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O.C(CCC)NC1CCN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O FTNAEWJPIYDXOH-UHFFFAOYSA-N 0.000 claims 1
- KPSXKPCPLCJJTO-UHFFFAOYSA-N C(CCCCCCCCCCC)NC1CN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O.C(CCC)NC1CN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O Chemical compound C(CCCCCCCCCCC)NC1CN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O.C(CCC)NC1CN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O KPSXKPCPLCJJTO-UHFFFAOYSA-N 0.000 claims 1
- XDZFSTANHRHTNF-UHFFFAOYSA-N C1(CCCCC1)CCNC1CCN(CCC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O.C(CCCCCCCCCCC)NC1CCN(CCC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O Chemical compound C1(CCCCC1)CCNC1CCN(CCC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O.C(CCCCCCCCCCC)NC1CCN(CCC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O XDZFSTANHRHTNF-UHFFFAOYSA-N 0.000 claims 1
- TXKUYCQAMIHGTH-UHFFFAOYSA-N C1(CCCCC1)CNC1CCN(CCC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CCC2)NCCOCCC)C=CC1 Chemical compound C1(CCCCC1)CNC1CCN(CCC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CCC2)NCCOCCC)C=CC1 TXKUYCQAMIHGTH-UHFFFAOYSA-N 0.000 claims 1
- MTJSBUNJOGUNFV-UHFFFAOYSA-N C1(CCCCC1)CNC1CN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CC(CC2)NCCOCCC)C=CC1 Chemical compound C1(CCCCC1)CNC1CN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CC(CC2)NCCOCCC)C=CC1 MTJSBUNJOGUNFV-UHFFFAOYSA-N 0.000 claims 1
- RBZWEWBNJGJGOE-UHFFFAOYSA-N C12(CC3CC(CC(C1)C3)C2)CNC2CCN(CC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC(=CC=C2)OC)=O.COC=2C=C(C(=O)NCC=3SC(=CC3)S(=O)(=O)N3CCC(CC3)NCCOCCC)C=CC2 Chemical compound C12(CC3CC(CC(C1)C3)C2)CNC2CCN(CC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC(=CC=C2)OC)=O.COC=2C=C(C(=O)NCC=3SC(=CC3)S(=O)(=O)N3CCC(CC3)NCCOCCC)C=CC2 RBZWEWBNJGJGOE-UHFFFAOYSA-N 0.000 claims 1
- VJRWERKXULJQBL-UHFFFAOYSA-N C12(CC3CC(CC(C1)C3)C2)CNC2CCN(CC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC=C(C=C2)Cl)=O.ClC2=CC=C(C(=O)NCC=3SC(=CC3)S(=O)(=O)N3CCC(CC3)NCCOCCC)C=C2 Chemical compound C12(CC3CC(CC(C1)C3)C2)CNC2CCN(CC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC=C(C=C2)Cl)=O.ClC2=CC=C(C(=O)NCC=3SC(=CC3)S(=O)(=O)N3CCC(CC3)NCCOCCC)C=C2 VJRWERKXULJQBL-UHFFFAOYSA-N 0.000 claims 1
- FWDUMNGFXOFGPP-ANQAEFHNSA-N C1C(NCCCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1.C1C(NCCCCCC)C[C@@H](C(=O)OC)N1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 Chemical compound C1C(NCCCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1.C1C(NCCCCCC)C[C@@H](C(=O)OC)N1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 FWDUMNGFXOFGPP-ANQAEFHNSA-N 0.000 claims 1
- JQVGRJITXWFCGI-UHFFFAOYSA-N COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC(C)C2=CC=CC=C2)C=CC1.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC2=CC=CC3=CC=CC=C23)C=CC1 Chemical compound COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC(C)C2=CC=CC=C2)C=CC1.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC2=CC=CC3=CC=CC=C23)C=CC1 JQVGRJITXWFCGI-UHFFFAOYSA-N 0.000 claims 1
- FAKDGTHTOWXSQR-UHFFFAOYSA-N COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC2=CC=C(C=C2)C(F)(F)F)C=CC1.ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCCCCCC)C=C1 Chemical compound COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC2=CC=C(C=C2)C(F)(F)F)C=CC1.ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCCCCCC)C=C1 FAKDGTHTOWXSQR-UHFFFAOYSA-N 0.000 claims 1
- PXAHICKLCKFUCB-UHFFFAOYSA-N COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC2=CC=C(C=C2)CCC)C=CC1.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC2=CC(=CC=C2)C)C=CC1 Chemical compound COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC2=CC=C(C=C2)CCC)C=CC1.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC2=CC(=CC=C2)C)C=CC1 PXAHICKLCKFUCB-UHFFFAOYSA-N 0.000 claims 1
- YIYFDCRUODICCL-UHFFFAOYSA-N COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC2=CC=NC=C2)C=CC1.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC2=CC=C(C=C2)OC)C=CC1 Chemical compound COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC2=CC=NC=C2)C=CC1.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC2=CC=C(C=C2)OC)C=CC1 YIYFDCRUODICCL-UHFFFAOYSA-N 0.000 claims 1
- NVHFJMHKOOLLKM-UHFFFAOYSA-N COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC=2C=NC=CC2)C=CC1.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC2=NC=CC=C2)C=CC1 Chemical compound COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC=2C=NC=CC2)C=CC1.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC2=NC=CC=C2)C=CC1 NVHFJMHKOOLLKM-UHFFFAOYSA-N 0.000 claims 1
- JVQYWAHDGUOFBY-UHFFFAOYSA-N COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCCCCC)C=CC1.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCCCCCCCC)C=CC1 Chemical compound COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCCCCC)C=CC1.COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCCCCCCCC)C=CC1 JVQYWAHDGUOFBY-UHFFFAOYSA-N 0.000 claims 1
- QHZVVQRKRBYLSB-UHFFFAOYSA-N COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCCCCCCCCC)C=CC1.OCCNC1CCN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O Chemical compound COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCCCCCCCCC)C=CC1.OCCNC1CCN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O QHZVVQRKRBYLSB-UHFFFAOYSA-N 0.000 claims 1
- VOQKHRIWSVHWHA-UHFFFAOYSA-N COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CCC2)NCCCCCCCC)C=CC1.C(CCCCCC)NC1CCN(CCC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O Chemical compound COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CCC2)NCCCCCCCC)C=CC1.C(CCCCCC)NC1CCN(CCC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O VOQKHRIWSVHWHA-UHFFFAOYSA-N 0.000 claims 1
- PVPNQAFQDUSQLR-UHFFFAOYSA-N COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CCC2)NCCCN2CCOCC2)C=CC1.C12(CC3CC(CC(C1)C3)C2)CNC2CCN(CCC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC(=CC=C2)OC)=O Chemical compound COC=1C=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CCC2)NCCCN2CCOCC2)C=CC1.C12(CC3CC(CC(C1)C3)C2)CNC2CCN(CCC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC(=CC=C2)OC)=O PVPNQAFQDUSQLR-UHFFFAOYSA-N 0.000 claims 1
- IWYPKSWRHZSURS-UHFFFAOYSA-N ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CC(CC2)NCC(CCCC)CC)C=C1.ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CC(CC2)NCCN2CCCCC2)C=C1 Chemical compound ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CC(CC2)NCC(CCCC)CC)C=C1.ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CC(CC2)NCCN2CCCCC2)C=C1 IWYPKSWRHZSURS-UHFFFAOYSA-N 0.000 claims 1
- DIXVLBAXLRZGER-UHFFFAOYSA-N ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CC(CC2)NCCCCC)C=C1.ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CC(CC2)NCCCCCC)C=C1 Chemical compound ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CC(CC2)NCCCCC)C=C1.ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CC(CC2)NCCCCCC)C=C1 DIXVLBAXLRZGER-UHFFFAOYSA-N 0.000 claims 1
- KBHIPXRXDQMZTG-UHFFFAOYSA-N ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CC(CC2)NCCCCCCC)C=C1.C(CCCCC)NC1CN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O Chemical compound ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CC(CC2)NCCCCCCC)C=C1.C(CCCCC)NC1CN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O KBHIPXRXDQMZTG-UHFFFAOYSA-N 0.000 claims 1
- RGLBGVQSFFSJBM-UHFFFAOYSA-N ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CC(CCC2)CNCCCCCC)C=C1.ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CC(CCC2)NCC2=CC=C(C=C2)C(F)(F)F)C=C1 Chemical compound ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CC(CCC2)CNCCCCCC)C=C1.ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CC(CCC2)NCC2=CC=C(C=C2)C(F)(F)F)C=C1 RGLBGVQSFFSJBM-UHFFFAOYSA-N 0.000 claims 1
- QPCFRJZLWDHXTN-UHFFFAOYSA-N ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC2=CC=C(C=C2)OC2=CC=CC=C2)C=C1.C(C)(C)(C)C1=CC=C(CNC2CCN(CC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC=C(C=C2)Cl)=O)C=C1 Chemical compound ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC2=CC=C(C=C2)OC2=CC=CC=C2)C=C1.C(C)(C)(C)C1=CC=C(CNC2CCN(CC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC=C(C=C2)Cl)=O)C=C1 QPCFRJZLWDHXTN-UHFFFAOYSA-N 0.000 claims 1
- PNCOAQYUDNWYPY-UHFFFAOYSA-N ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCCCCCCC)C=C1.ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NC=2SC=CN2)C=C1 Chemical compound ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCCCCCCC)C=C1.ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NC=2SC=CN2)C=C1 PNCOAQYUDNWYPY-UHFFFAOYSA-N 0.000 claims 1
- HXXNUSXZTYZSON-UHFFFAOYSA-N ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCCN2CCCCC2)C=C1.ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCCC2=NC=CC=C2)C=C1 Chemical compound ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCCN2CCCCC2)C=C1.ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCCC2=NC=CC=C2)C=C1 HXXNUSXZTYZSON-UHFFFAOYSA-N 0.000 claims 1
- FWPNECYTHSNNCH-UHFFFAOYSA-N ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CCC2)NCCC2CCCCC2)C=C1.ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CCC2)NCCCCCCCCCCCC)C=C1 Chemical compound ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CCC2)NCCC2CCCCC2)C=C1.ClC1=CC=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CCC2)NCCCCCCCCCCCC)C=C1 FWPNECYTHSNNCH-UHFFFAOYSA-N 0.000 claims 1
- PSCVTLBOTZELNK-UHFFFAOYSA-N ClC1=CC=C(CNC2CCN(CC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC(=CC=C2)OC)=O)C=C1.C1(=C(C(=CC(=C1)C)C)CNC1CCN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O)C Chemical compound ClC1=CC=C(CNC2CCN(CC2)S(=O)(=O)C2=CC=C(S2)CNC(C2=CC(=CC=C2)OC)=O)C=C1.C1(=C(C(=CC(=C1)C)C)CNC1CCN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O)C PSCVTLBOTZELNK-UHFFFAOYSA-N 0.000 claims 1
- NARYVODOJDLSSH-UHFFFAOYSA-N N-[[5-[3-(2-cyclohexylethylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C(C1=CC=CC=C1)(=O)NCC=1SC(=CC=1)S(=O)(=O)N1CC(CC1)NCCC1CCCCC1 NARYVODOJDLSSH-UHFFFAOYSA-N 0.000 claims 1
- IBWBEKHRKFFQBP-UHFFFAOYSA-N N-[[5-[4-(hexylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-2-hydroxybenzamide 2-hydroxy-N-[[5-[4-[[4-(trifluoromethyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound OC1=C(C(=O)NCC=2SC(=CC2)S(=O)(=O)N2CCC(CC2)NCC2=CC=C(C=C2)C(F)(F)F)C=CC=C1.C(CCCCC)NC1CCN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=C(C=CC=C1)O)=O IBWBEKHRKFFQBP-UHFFFAOYSA-N 0.000 claims 1
- YZZDNLPXRLBIIV-UHFFFAOYSA-N N-[[5-[4-(hexylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide N-[[5-[4-(3-imidazol-1-ylpropylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C(CCCCC)NC1CCN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O.N1(C=NC=C1)CCCNC1CCN(CC1)S(=O)(=O)C1=CC=C(S1)CNC(C1=CC(=CC=C1)OC)=O YZZDNLPXRLBIIV-UHFFFAOYSA-N 0.000 claims 1
- 208000006011 Stroke Diseases 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 1
- QFCPRUXYKVLAQK-UHFFFAOYSA-N n-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1CNC1CCNCC1 QFCPRUXYKVLAQK-UHFFFAOYSA-N 0.000 claims 1
- HVEKJUAYPMGFDD-UHFFFAOYSA-N n-[[4-(trifluoromethyl)phenyl]methyl]ethanamine Chemical compound CCNCC1=CC=C(C(F)(F)F)C=C1 HVEKJUAYPMGFDD-UHFFFAOYSA-N 0.000 claims 1
- DURIDXXKDRXNAX-UHFFFAOYSA-N n-[[5-[4-(2-ethylhexylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide;n-[[5-[4-(3-imidazol-1-ylpropylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(NCC(CC)CCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1.COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CCC2)NCCCN2C=NC=C2)=C1 DURIDXXKDRXNAX-UHFFFAOYSA-N 0.000 claims 1
- 229960003966 nicotinamide Drugs 0.000 claims 1
- 239000011570 nicotinamide Substances 0.000 claims 1
- 210000001672 ovary Anatomy 0.000 claims 1
- 201000002528 pancreatic cancer Diseases 0.000 claims 1
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 114
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
- 239000000243 solution Substances 0.000 description 58
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 50
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 44
- 210000004027 cell Anatomy 0.000 description 44
- 238000000034 method Methods 0.000 description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
- 238000006243 chemical reaction Methods 0.000 description 30
- 239000011541 reaction mixture Substances 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 27
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- 230000004913 activation Effects 0.000 description 24
- 235000019439 ethyl acetate Nutrition 0.000 description 24
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 22
- 235000019341 magnesium sulphate Nutrition 0.000 description 22
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 22
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 241000894007 species Species 0.000 description 20
- 239000007787 solid Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 230000005764 inhibitory process Effects 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 239000012267 brine Substances 0.000 description 16
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 101001050288 Homo sapiens Transcription factor Jun Proteins 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 102000000588 Interleukin-2 Human genes 0.000 description 14
- 108010002350 Interleukin-2 Proteins 0.000 description 14
- 102000043136 MAP kinase family Human genes 0.000 description 14
- 108091054455 MAP kinase family Proteins 0.000 description 14
- 102100023132 Transcription factor Jun Human genes 0.000 description 14
- 210000002569 neuron Anatomy 0.000 description 14
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 13
- 238000004458 analytical method Methods 0.000 description 13
- 125000006239 protecting group Chemical group 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 239000002158 endotoxin Substances 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 102000004127 Cytokines Human genes 0.000 description 11
- 108090000695 Cytokines Proteins 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 150000001266 acyl halides Chemical class 0.000 description 11
- 238000013459 approach Methods 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 229920006008 lipopolysaccharide Polymers 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 108091023040 Transcription factor Proteins 0.000 description 10
- 102000040945 Transcription factor Human genes 0.000 description 10
- 230000026731 phosphorylation Effects 0.000 description 10
- 238000006366 phosphorylation reaction Methods 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 9
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 150000002576 ketones Chemical class 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- 239000008194 pharmaceutical composition Substances 0.000 description 9
- GDKHKGCITPNDCG-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(hexylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 GDKHKGCITPNDCG-UHFFFAOYSA-N 0.000 description 8
- 108010068304 MAP Kinase Kinase 4 Proteins 0.000 description 8
- 230000006907 apoptotic process Effects 0.000 description 8
- 150000003857 carboxamides Chemical class 0.000 description 8
- 230000030833 cell death Effects 0.000 description 8
- 238000010790 dilution Methods 0.000 description 8
- 239000012895 dilution Substances 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 7
- 239000012825 JNK inhibitor Substances 0.000 description 7
- 108060001084 Luciferase Proteins 0.000 description 7
- 239000005089 Luciferase Substances 0.000 description 7
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 7
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 7
- 102100023482 Mitogen-activated protein kinase 14 Human genes 0.000 description 7
- 235000011089 carbon dioxide Nutrition 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 239000001963 growth medium Substances 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 239000002953 phosphate buffered saline Substances 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 7
- 230000011664 signaling Effects 0.000 description 7
- 238000010561 standard procedure Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 6
- YLHTUKZXHAJUID-UHFFFAOYSA-N 4-chloro-n-[[5-[3-(pentylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1C(NCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 YLHTUKZXHAJUID-UHFFFAOYSA-N 0.000 description 6
- 102100023995 Beta-nerve growth factor Human genes 0.000 description 6
- 102100023274 Dual specificity mitogen-activated protein kinase kinase 4 Human genes 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- 108010025020 Nerve Growth Factor Proteins 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 210000001744 T-lymphocyte Anatomy 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 239000013058 crude material Substances 0.000 description 6
- PZNLFFXOENCJNZ-UHFFFAOYSA-N ethyl 2-[4-(hexylamino)piperidin-1-yl]sulfonyl-5-[[(3-methoxybenzoyl)amino]methyl]thiophene-3-carboxylate Chemical compound C1CC(NCCCCCC)CCN1S(=O)(=O)C1=C(C(=O)OCC)C=C(CNC(=O)C=2C=C(OC)C=CC=2)S1 PZNLFFXOENCJNZ-UHFFFAOYSA-N 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 210000000987 immune system Anatomy 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- 210000000653 nervous system Anatomy 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 210000002222 superior cervical ganglion Anatomy 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 229930192474 thiophene Natural products 0.000 description 6
- 238000010626 work up procedure Methods 0.000 description 6
- CRHGHCURUYSQTN-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[(pentylamino)methyl]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(CNCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 CRHGHCURUYSQTN-UHFFFAOYSA-N 0.000 description 5
- 241000699694 Gerbillinae Species 0.000 description 5
- 102000001291 MAP Kinase Kinase Kinase Human genes 0.000 description 5
- 108060006687 MAP kinase kinase kinase Proteins 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 235000011054 acetic acid Nutrition 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 239000006285 cell suspension Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 210000001320 hippocampus Anatomy 0.000 description 5
- 230000002757 inflammatory effect Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 230000010410 reperfusion Effects 0.000 description 5
- 230000019491 signal transduction Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 230000035882 stress Effects 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 4
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 description 4
- RBGDLYUEXLWQBZ-UHFFFAOYSA-N 2-chlorobenzamide Chemical compound NC(=O)C1=CC=CC=C1Cl RBGDLYUEXLWQBZ-UHFFFAOYSA-N 0.000 description 4
- JJZPDCGJRLWDQI-UHFFFAOYSA-N 2-oxo-n-[[5-(4-oxopiperidin-1-yl)sulfonylthiophen-2-yl]methyl]-1h-pyridine-3-carboxamide Chemical compound C=1C=CNC(=O)C=1C(=O)NCC(S1)=CC=C1S(=O)(=O)N1CCC(=O)CC1 JJZPDCGJRLWDQI-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- KOXQQQLFMXRMEB-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[hexyl(pyridin-2-ylmethyl)amino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CCC1N(CCCCCC)CC1=CC=CC=N1 KOXQQQLFMXRMEB-UHFFFAOYSA-N 0.000 description 4
- HWAXMFYECKQLDX-UHFFFAOYSA-N 5-[[(4-chlorobenzoyl)amino]methyl]thiophene-2-sulfonyl chloride Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(Cl)(=O)=O)S1 HWAXMFYECKQLDX-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 101710105206 C-Jun-amino-terminal kinase-interacting protein 1 Proteins 0.000 description 4
- 102100022291 C-Jun-amino-terminal kinase-interacting protein 1 Human genes 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- 102100039556 Galectin-4 Human genes 0.000 description 4
- 101000608765 Homo sapiens Galectin-4 Proteins 0.000 description 4
- 101000950695 Homo sapiens Mitogen-activated protein kinase 8 Proteins 0.000 description 4
- 101710166851 JNK-interacting protein 1 Proteins 0.000 description 4
- 102100037808 Mitogen-activated protein kinase 8 Human genes 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- 241000242739 Renilla Species 0.000 description 4
- 150000003863 ammonium salts Chemical class 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 150000007942 carboxylates Chemical class 0.000 description 4
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 4
- 229960004132 diethyl ether Drugs 0.000 description 4
- 230000004069 differentiation Effects 0.000 description 4
- 239000012636 effector Substances 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 239000003102 growth factor Substances 0.000 description 4
- 150000003840 hydrochlorides Chemical class 0.000 description 4
- 230000028709 inflammatory response Effects 0.000 description 4
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- JIJTXGSBFBOTAP-UHFFFAOYSA-N n-[[5-[4-(heptylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(NCCCCCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 JIJTXGSBFBOTAP-UHFFFAOYSA-N 0.000 description 4
- 150000003053 piperidines Chemical class 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 3
- CWLUFVAFWWNXJZ-UHFFFAOYSA-N 1-hydroxypyrrolidine Chemical compound ON1CCCC1 CWLUFVAFWWNXJZ-UHFFFAOYSA-N 0.000 description 3
- BEOBZEOPTQQELP-UHFFFAOYSA-N 4-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC=C(C=O)C=C1 BEOBZEOPTQQELP-UHFFFAOYSA-N 0.000 description 3
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 3
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 208000032382 Ischaemic stroke Diseases 0.000 description 3
- 102000002569 MAP Kinase Kinase 4 Human genes 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 102100033115 Mitogen-activated protein kinase kinase kinase 1 Human genes 0.000 description 3
- 101710164423 Mitogen-activated protein kinase kinase kinase 1 Proteins 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- 108010029485 Protein Isoforms Proteins 0.000 description 3
- 102000001708 Protein Isoforms Human genes 0.000 description 3
- 102000001253 Protein Kinase Human genes 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000001640 apoptogenic effect Effects 0.000 description 3
- 230000001363 autoimmune Effects 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- MAMQLSRUHZSUEV-UHFFFAOYSA-N ethyl 5-[[(3-methoxybenzoyl)amino]methyl]-2-(4-oxopiperidin-1-yl)sulfonylthiophene-3-carboxylate Chemical compound S1C(S(=O)(=O)N2CCC(=O)CC2)=C(C(=O)OCC)C=C1CNC(=O)C1=CC=CC(OC)=C1 MAMQLSRUHZSUEV-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000012894 fetal calf serum Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 238000004020 luminiscence type Methods 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000004770 neurodegeneration Effects 0.000 description 3
- 208000015122 neurodegenerative disease Diseases 0.000 description 3
- 230000016273 neuron death Effects 0.000 description 3
- 230000009223 neuronal apoptosis Effects 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108060006633 protein kinase Proteins 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 238000006277 sulfonation reaction Methods 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 230000002889 sympathetic effect Effects 0.000 description 3
- FKKJJPMGAWGYPN-UHFFFAOYSA-N thiophen-2-ylmethanamine Chemical compound NCC1=CC=CS1 FKKJJPMGAWGYPN-UHFFFAOYSA-N 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- 238000011144 upstream manufacturing Methods 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- KPKNTUUIEVXMOH-UHFFFAOYSA-N 1,4-dioxa-8-azaspiro[4.5]decane Chemical compound O1CCOC11CCNCC1 KPKNTUUIEVXMOH-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 2
- SCMQZCDHXKMJJQ-UHFFFAOYSA-N 3-[[(3-methoxybenzoyl)amino]methyl]thiophene-2-sulfonyl chloride Chemical compound COC1=CC=CC(C(=O)NCC2=C(SC=C2)S(Cl)(=O)=O)=C1 SCMQZCDHXKMJJQ-UHFFFAOYSA-N 0.000 description 2
- GDZMSRFBYYKGIN-UHFFFAOYSA-N 3-methoxy-n-[[5-(4-oxoazepan-1-yl)sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(=O)CCC2)=C1 GDZMSRFBYYKGIN-UHFFFAOYSA-N 0.000 description 2
- RUQIUASLAXJZIE-UHFFFAOYSA-N 3-methoxybenzoyl chloride Chemical compound COC1=CC=CC(C(Cl)=O)=C1 RUQIUASLAXJZIE-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- OPXTXCLTXQNTQH-UHFFFAOYSA-N 4-chloro-n-(thiophen-2-ylmethyl)benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=CS1 OPXTXCLTXQNTQH-UHFFFAOYSA-N 0.000 description 2
- YXYZWXRBHIBALW-UHFFFAOYSA-N 4-chloro-n-[[5-(4-oxopiperidin-1-yl)sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CCC(=O)CC2)S1 YXYZWXRBHIBALW-UHFFFAOYSA-N 0.000 description 2
- XHGDOYAFJXNKQC-CYBMUJFWSA-N 4-chloro-n-[[5-[(3r)-3-hydroxypyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1[C@H](O)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 XHGDOYAFJXNKQC-CYBMUJFWSA-N 0.000 description 2
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 2
- WDGGZSSZDYAHCF-UHFFFAOYSA-M 5-[[(3-methoxybenzoyl)amino]methyl]thiophene-2-sulfonate;tetrabutylazanium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC.COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S([O-])(=O)=O)=C1 WDGGZSSZDYAHCF-UHFFFAOYSA-M 0.000 description 2
- RTSXKBQXXIFLKN-UHFFFAOYSA-N 5-[[bis(prop-2-enyl)amino]methyl]thiophene-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(CN(CC=C)CC=C)S1 RTSXKBQXXIFLKN-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 102100023332 Dual specificity mitogen-activated protein kinase kinase 7 Human genes 0.000 description 2
- 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 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 208000016988 Hemorrhagic Stroke Diseases 0.000 description 2
- 101000974934 Homo sapiens Cyclic AMP-dependent transcription factor ATF-2 Proteins 0.000 description 2
- 101000624594 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 7 Proteins 0.000 description 2
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 2
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 102000005741 Metalloproteases Human genes 0.000 description 2
- 108010006035 Metalloproteases Proteins 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 108091008874 T cell receptors Proteins 0.000 description 2
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 2
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 2
- 210000004241 Th2 cell Anatomy 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 229920004890 Triton X-100 Polymers 0.000 description 2
- 239000013504 Triton X-100 Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 150000001409 amidines Chemical class 0.000 description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 210000000612 antigen-presenting cell Anatomy 0.000 description 2
- 230000007503 antigenic stimulation Effects 0.000 description 2
- 238000003782 apoptosis assay Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000001743 benzylic group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 150000001728 carbonyl compounds Chemical class 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- 239000013553 cell monolayer Substances 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 229910052681 coesite Inorganic materials 0.000 description 2
- 229910052906 cristobalite Inorganic materials 0.000 description 2
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- ZWWWLCMDTZFSOO-UHFFFAOYSA-N diethoxyphosphorylformonitrile Chemical compound CCOP(=O)(C#N)OCC ZWWWLCMDTZFSOO-UHFFFAOYSA-N 0.000 description 2
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 230000003828 downregulation Effects 0.000 description 2
- 238000010864 dual luciferase reporter gene assay Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- PPNWPZYLTRSUMN-UHFFFAOYSA-N ethyl 2-(1,4-dioxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-5-[[(3-methoxybenzoyl)amino]methyl]thiophene-3-carboxylate Chemical compound S1C(S(=O)(=O)N2CCC3(CC2)OCCO3)=C(C(=O)OCC)C=C1CNC(=O)C1=CC=CC(OC)=C1 PPNWPZYLTRSUMN-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 230000003492 excitotoxic effect Effects 0.000 description 2
- 231100000063 excitotoxicity Toxicity 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 235000019264 food flavour enhancer Nutrition 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 150000002374 hemiaminals Chemical class 0.000 description 2
- JARKCYVAAOWBJS-UHFFFAOYSA-N hexanal Chemical compound CCCCCC=O JARKCYVAAOWBJS-UHFFFAOYSA-N 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- PGHMRUGBZOYCAA-ADZNBVRBSA-N ionomycin Chemical compound O1[C@H](C[C@H](O)[C@H](C)[C@H](O)[C@H](C)/C=C/C[C@@H](C)C[C@@H](C)C(/O)=C/C(=O)[C@@H](C)C[C@@H](C)C[C@@H](CCC(O)=O)C)CC[C@@]1(C)[C@@H]1O[C@](C)([C@@H](C)O)CC1 PGHMRUGBZOYCAA-ADZNBVRBSA-N 0.000 description 2
- PGHMRUGBZOYCAA-UHFFFAOYSA-N ionomycin Natural products O1C(CC(O)C(C)C(O)C(C)C=CCC(C)CC(C)C(O)=CC(=O)C(C)CC(C)CC(CCC(O)=O)C)CCC1(C)C1OC(C)(C(C)O)CC1 PGHMRUGBZOYCAA-UHFFFAOYSA-N 0.000 description 2
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- WPWFBRXWLVRKRG-UHFFFAOYSA-N n-[[5-[4-[[amino-[4-(trifluoromethyl)phenyl]methylidene]amino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-4-chlorobenzamide Chemical compound C1=CC(C(F)(F)F)=CC=C1C(=N)NC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CC1 WPWFBRXWLVRKRG-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 231100000590 oncogenic Toxicity 0.000 description 2
- 230000002246 oncogenic effect Effects 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- LWMPFIOTEAXAGV-UHFFFAOYSA-N piperidin-1-amine Chemical compound NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 description 2
- FLKRMXAWABTWSH-UHFFFAOYSA-N piperidine-1-sulfonamide Chemical class NS(=O)(=O)N1CCCCC1 FLKRMXAWABTWSH-UHFFFAOYSA-N 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 230000005522 programmed cell death Effects 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 208000037803 restenosis Diseases 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 229910052682 stishovite Inorganic materials 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- 150000003871 sulfonates Chemical class 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 2
- 229910052905 tridymite Inorganic materials 0.000 description 2
- 230000001960 triggered effect Effects 0.000 description 2
- 125000004953 trihalomethyl group Chemical group 0.000 description 2
- 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 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 229910052727 yttrium Inorganic materials 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- VXLPFTSOFKGDHB-IJHRGXPZSA-N (2s)-1-[5-[[(4-chlorobenzoyl)amino]methyl]thiophen-2-yl]sulfonyl-4-(hexylamino)pyrrolidine-2-carboxylic acid Chemical compound C1C(NCCCCCC)C[C@@H](C(O)=O)N1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 VXLPFTSOFKGDHB-IJHRGXPZSA-N 0.000 description 1
- GRRNUXAQVGOGFE-XKIAHZFYSA-N (2s,3'r,3as,4s,4's,5'r,6r,6'r,7s,7as)-4-[(1r,2s,3r,5s,6r)-3-amino-2,6-dihydroxy-5-(methylamino)cyclohexyl]oxy-6'-[(1r)-1-amino-2-hydroxyethyl]-6-(hydroxymethyl)spiro[4,6,7,7a-tetrahydro-3ah-[1,3]dioxolo[4,5-c]pyran-2,2'-oxane]-3',4',5',7-tetrol Chemical compound O[C@@H]1[C@@H](NC)C[C@@H](N)[C@H](O)[C@H]1O[C@H]1[C@H]2O[C@]3([C@@H]([C@@H](O)[C@@H](O)[C@@H]([C@H](N)CO)O3)O)O[C@H]2[C@@H](O)[C@@H](CO)O1 GRRNUXAQVGOGFE-XKIAHZFYSA-N 0.000 description 1
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000004529 1,2,3-triazinyl group Chemical group N1=NN=C(C=C1)* 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- VVSASNKOFCZVES-UHFFFAOYSA-N 1,3-dimethyl-1,3-diazinane-2,4,6-trione Chemical compound CN1C(=O)CC(=O)N(C)C1=O VVSASNKOFCZVES-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- PYHXGXCGESYPCW-UHFFFAOYSA-M 2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(C(=O)[O-])C1=CC=CC=C1 PYHXGXCGESYPCW-UHFFFAOYSA-M 0.000 description 1
- MXIUWSYTQJLIKE-UHFFFAOYSA-N 2-(trifluoromethyl)benzoyl chloride Chemical compound FC(F)(F)C1=CC=CC=C1C(Cl)=O MXIUWSYTQJLIKE-UHFFFAOYSA-N 0.000 description 1
- UEYQJQVBUVAELZ-UHFFFAOYSA-N 2-Hydroxynicotinic acid Chemical compound OC(=O)C1=CC=CN=C1O UEYQJQVBUVAELZ-UHFFFAOYSA-N 0.000 description 1
- KISWVXRQTGLFGD-UHFFFAOYSA-N 2-[[2-[[6-amino-2-[[2-[[2-[[5-amino-2-[[2-[[1-[2-[[6-amino-2-[(2,5-diamino-5-oxopentanoyl)amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)p Chemical compound C1CCN(C(=O)C(CCCN=C(N)N)NC(=O)C(CCCCN)NC(=O)C(N)CCC(N)=O)C1C(=O)NC(CO)C(=O)NC(CCC(N)=O)C(=O)NC(CCCN=C(N)N)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 KISWVXRQTGLFGD-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- PXQTZKZWTYRZQL-UHFFFAOYSA-N 2-hydroxy-n-[[5-[4-[[4-(trifluoromethyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound OC1=CC=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CCC(CC2)NCC=2C=CC(=CC=2)C(F)(F)F)S1 PXQTZKZWTYRZQL-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 125000000094 2-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
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- YFPMKTSZVUDZDO-UHFFFAOYSA-N 2-propoxyacetaldehyde Chemical compound CCCOCC=O YFPMKTSZVUDZDO-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- XPYOORHZRLSTSG-UHFFFAOYSA-N 2-sulfonylpiperidine Chemical class O=S(=O)=C1CCCCN1 XPYOORHZRLSTSG-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- RCPZMRMSIOJNEK-UHFFFAOYSA-N 3-methoxy-n-(thiophen-2-ylmethyl)benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC=CC=2)=C1 RCPZMRMSIOJNEK-UHFFFAOYSA-N 0.000 description 1
- MAHSHMCCJZUSIB-UHFFFAOYSA-N 3-methoxy-n-[[5-[3-(2-piperidin-1-ylethylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CC(CC2)NCCN2CCCCC2)=C1 MAHSHMCCJZUSIB-UHFFFAOYSA-N 0.000 description 1
- DLHZIDXNHZXNCG-UHFFFAOYSA-N 3-methoxy-n-[[5-[3-(2-propoxyethylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1C(NCCOCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 DLHZIDXNHZXNCG-UHFFFAOYSA-N 0.000 description 1
- FQWANLJPEMLYKA-UHFFFAOYSA-N 3-methoxy-n-[[5-[3-(octylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1C(NCCCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 FQWANLJPEMLYKA-UHFFFAOYSA-N 0.000 description 1
- WBWRBQJQTXJQEH-UHFFFAOYSA-N 3-methoxy-n-[[5-[3-(pentylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1C(NCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 WBWRBQJQTXJQEH-UHFFFAOYSA-N 0.000 description 1
- BQOPCSNIKARECX-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(2-phenylpropylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC(C)C=2C=CC=CC=2)=C1 BQOPCSNIKARECX-UHFFFAOYSA-N 0.000 description 1
- KITQPGQJYRKLSF-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(2-piperidin-1-ylethylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CCC2)NCCN2CCCCC2)=C1 KITQPGQJYRKLSF-UHFFFAOYSA-N 0.000 description 1
- GFJRJIKLSAEMNY-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(2-piperidin-1-ylethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCCN2CCCCC2)=C1 GFJRJIKLSAEMNY-UHFFFAOYSA-N 0.000 description 1
- KZSNDEFQVGXPMZ-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(2-propoxyethylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCOCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 KZSNDEFQVGXPMZ-UHFFFAOYSA-N 0.000 description 1
- WCEKCURXOZTGDS-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(2-propoxyethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCOCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 WCEKCURXOZTGDS-UHFFFAOYSA-N 0.000 description 1
- YSUDSBJJPCPFPT-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(2-thiophen-2-ylethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCCC=2SC=CC=2)=C1 YSUDSBJJPCPFPT-UHFFFAOYSA-N 0.000 description 1
- VJNFCXZOALNNPM-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(3-morpholin-4-ylpropylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CCC2)NCCCN2CCOCC2)=C1 VJNFCXZOALNNPM-UHFFFAOYSA-N 0.000 description 1
- RNZCQBIJDLAFHR-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(3-phenylpropylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCCCC=2C=CC=CC=2)=C1 RNZCQBIJDLAFHR-UHFFFAOYSA-N 0.000 description 1
- QHMAVLYJDMGCEA-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(naphthalen-1-ylmethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C3=CC=CC=C3C=CC=2)=C1 QHMAVLYJDMGCEA-UHFFFAOYSA-N 0.000 description 1
- JDDCXMNNTRBYBN-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(nonylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCCCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 JDDCXMNNTRBYBN-UHFFFAOYSA-N 0.000 description 1
- YDCCBDNEFUXAFX-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(octylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCCCCCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 YDCCBDNEFUXAFX-UHFFFAOYSA-N 0.000 description 1
- SRVHDHVRVFJPEC-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(octylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 SRVHDHVRVFJPEC-UHFFFAOYSA-N 0.000 description 1
- YWQNBWKSGSHTSA-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(pentylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 YWQNBWKSGSHTSA-UHFFFAOYSA-N 0.000 description 1
- GJDJWHWZYXRUFL-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(pentylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 GJDJWHWZYXRUFL-UHFFFAOYSA-N 0.000 description 1
- VKHNIKHUZIDBIF-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(pyridin-2-ylmethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2N=CC=CC=2)=C1 VKHNIKHUZIDBIF-UHFFFAOYSA-N 0.000 description 1
- KNBKWCCNNOOXPL-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(pyridin-3-ylmethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=NC=CC=2)=C1 KNBKWCCNNOOXPL-UHFFFAOYSA-N 0.000 description 1
- WMJNMYNGCZXGIA-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(pyridin-4-ylmethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=CN=CC=2)=C1 WMJNMYNGCZXGIA-UHFFFAOYSA-N 0.000 description 1
- DOBMKOAVENARPA-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-(quinolin-4-ylmethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C3=CC=CC=C3N=CC=2)=C1 DOBMKOAVENARPA-UHFFFAOYSA-N 0.000 description 1
- IMQRFPBEONZCPF-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[(2,4,6-trimethylphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C(=CC(C)=CC=2C)C)=C1 IMQRFPBEONZCPF-UHFFFAOYSA-N 0.000 description 1
- MNVLEGMIVINXKM-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[(3-methylphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=C(C)C=CC=2)=C1 MNVLEGMIVINXKM-UHFFFAOYSA-N 0.000 description 1
- BLJVWTGKRFCVBZ-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[(3-phenylphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=C(C=CC=2)C=2C=CC=CC=2)=C1 BLJVWTGKRFCVBZ-UHFFFAOYSA-N 0.000 description 1
- SZBHMBJTXNIGQH-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[(4-methoxyphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(OC)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=C(OC)C=CC=3)=CC=2)CC1 SZBHMBJTXNIGQH-UHFFFAOYSA-N 0.000 description 1
- XNKMZWSHDVMLSI-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[(4-pentylphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(CCCCC)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=C(OC)C=CC=3)=CC=2)CC1 XNKMZWSHDVMLSI-UHFFFAOYSA-N 0.000 description 1
- CHWPJAXADOPKIO-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[(4-phenylmethoxyphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=CC(OCC=3C=CC=CC=3)=CC=2)=C1 CHWPJAXADOPKIO-UHFFFAOYSA-N 0.000 description 1
- AZGRWGCJEDGBIZ-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[(4-phenylphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=CC(=CC=2)C=2C=CC=CC=2)=C1 AZGRWGCJEDGBIZ-UHFFFAOYSA-N 0.000 description 1
- GYBHJPHJSXIXCZ-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[(4-propan-2-ylphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=CC(=CC=2)C(C)C)=C1 GYBHJPHJSXIXCZ-UHFFFAOYSA-N 0.000 description 1
- SVSUWZYJFOYRFK-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[(4-propylphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(CCC)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=C(OC)C=CC=3)=CC=2)CC1 SVSUWZYJFOYRFK-UHFFFAOYSA-N 0.000 description 1
- OTQSQGVTQLVRQH-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[2-(4-phenylphenyl)ethylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCCC=2C=CC(=CC=2)C=2C=CC=CC=2)=C1 OTQSQGVTQLVRQH-UHFFFAOYSA-N 0.000 description 1
- ZXRIHWPEXPLNNC-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[2-[3-(trifluoromethyl)phenyl]ethylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCCC=2C=C(C=CC=2)C(F)(F)F)=C1 ZXRIHWPEXPLNNC-UHFFFAOYSA-N 0.000 description 1
- NONOZHXFYAEZEL-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[2-[4-(trifluoromethyl)phenyl]propan-2-ylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NC(C)(C)C=2C=CC(=CC=2)C(F)(F)F)=C1 NONOZHXFYAEZEL-UHFFFAOYSA-N 0.000 description 1
- MEJQSJZFHPABOL-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[[4-(2-methylpropyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=CC(CC(C)C)=CC=2)=C1 MEJQSJZFHPABOL-UHFFFAOYSA-N 0.000 description 1
- NLFQFVHCCRNBQW-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[[4-(trifluoromethoxy)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=CC(OC(F)(F)F)=CC=2)=C1 NLFQFVHCCRNBQW-UHFFFAOYSA-N 0.000 description 1
- SUKHVBVIZFJHOI-UHFFFAOYSA-N 3-methoxy-n-[[5-[4-[[4-(trifluoromethylsulfonyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=CC(=CC=2)S(=O)(=O)C(F)(F)F)=C1 SUKHVBVIZFJHOI-UHFFFAOYSA-N 0.000 description 1
- VKPLPDIMEREJJF-UHFFFAOYSA-N 3-methoxybenzamide Chemical compound COC1=CC=CC(C(N)=O)=C1 VKPLPDIMEREJJF-UHFFFAOYSA-N 0.000 description 1
- DRNJIKRLQJRKMM-UHFFFAOYSA-N 4-(trifluoromethyl)benzonitrile Chemical compound FC(F)(F)C1=CC=C(C#N)C=C1 DRNJIKRLQJRKMM-UHFFFAOYSA-N 0.000 description 1
- YMMNSNFRGFKVMR-UHFFFAOYSA-N 4-chloro-n-[[5-(3-oxopyrrolidin-1-yl)sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CC(=O)CC2)S1 YMMNSNFRGFKVMR-UHFFFAOYSA-N 0.000 description 1
- BUVCQNQBGZLGAH-UHFFFAOYSA-N 4-chloro-n-[[5-[3-(2-cyclohexylethylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CC(CC2)NCCC2CCCCC2)S1 BUVCQNQBGZLGAH-UHFFFAOYSA-N 0.000 description 1
- RWDUGBMWCMDUHQ-UHFFFAOYSA-N 4-chloro-n-[[5-[3-(2-ethylhexylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1C(NCC(CC)CCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 RWDUGBMWCMDUHQ-UHFFFAOYSA-N 0.000 description 1
- BRWJFVYFRSUCHH-UHFFFAOYSA-N 4-chloro-n-[[5-[3-(2-piperidin-1-ylethylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CC(CC2)NCCN2CCCCC2)S1 BRWJFVYFRSUCHH-UHFFFAOYSA-N 0.000 description 1
- TWGRXZOAOXCLGZ-UHFFFAOYSA-N 4-chloro-n-[[5-[3-(3-morpholin-4-ylpropylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CC(CC2)NCCCN2CCOCC2)S1 TWGRXZOAOXCLGZ-UHFFFAOYSA-N 0.000 description 1
- HCRATRDKMYDJDC-UHFFFAOYSA-N 4-chloro-n-[[5-[3-(heptylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1C(NCCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 HCRATRDKMYDJDC-UHFFFAOYSA-N 0.000 description 1
- XGIHWZNNOKUWDJ-UHFFFAOYSA-N 4-chloro-n-[[5-[3-(hexylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1C(NCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 XGIHWZNNOKUWDJ-UHFFFAOYSA-N 0.000 description 1
- RCVFSEZGFQCOBD-UHFFFAOYSA-N 4-chloro-n-[[5-[3-(octylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1C(NCCCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 RCVFSEZGFQCOBD-UHFFFAOYSA-N 0.000 description 1
- RQYKEGAQMFXVJP-UHFFFAOYSA-N 4-chloro-n-[[5-[3-[(hexylamino)methyl]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1C(CNCCCCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 RQYKEGAQMFXVJP-UHFFFAOYSA-N 0.000 description 1
- KWYJOFXOFWATEF-UHFFFAOYSA-N 4-chloro-n-[[5-[3-[[4-(trifluoromethyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC1CN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CCC1 KWYJOFXOFWATEF-UHFFFAOYSA-N 0.000 description 1
- GVHIWUGNPXBCTB-UHFFFAOYSA-N 4-chloro-n-[[5-[3-[[4-(trifluoromethyl)phenyl]methylamino]pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC1CN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CC1 GVHIWUGNPXBCTB-UHFFFAOYSA-N 0.000 description 1
- GDBCHABFFBVTAC-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(1,3-thiazol-2-ylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CCC(CC2)NC=2SC=CN=2)S1 GDBCHABFFBVTAC-UHFFFAOYSA-N 0.000 description 1
- CIIIXBGYIXZJBT-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(2-cyclohexylethylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CCC(CCC2)NCCC2CCCCC2)S1 CIIIXBGYIXZJBT-UHFFFAOYSA-N 0.000 description 1
- SDEYCKRAIPMKHJ-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(2-cyclohexylethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CCC(CC2)NCCC2CCCCC2)S1 SDEYCKRAIPMKHJ-UHFFFAOYSA-N 0.000 description 1
- ZEQTWQWSSSUDKV-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(2-ethylhexylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCC(CC)CCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 ZEQTWQWSSSUDKV-UHFFFAOYSA-N 0.000 description 1
- JHKPLVAAQGLEPX-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(2-ethylhexylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCC(CC)CCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 JHKPLVAAQGLEPX-UHFFFAOYSA-N 0.000 description 1
- TVJRQTSPMZXFGB-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(2-piperidin-1-ylethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CCC(CC2)NCCN2CCCCC2)S1 TVJRQTSPMZXFGB-UHFFFAOYSA-N 0.000 description 1
- LUMJMSMVXOTWCT-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(2-propoxyethylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCOCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 LUMJMSMVXOTWCT-UHFFFAOYSA-N 0.000 description 1
- CYPFWIUNFVXBTR-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(2-propoxyethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCOCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 CYPFWIUNFVXBTR-UHFFFAOYSA-N 0.000 description 1
- RGPOBKHHKYZHGO-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(2-pyridin-2-ylethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CCC(CC2)NCCC=2N=CC=CC=2)S1 RGPOBKHHKYZHGO-UHFFFAOYSA-N 0.000 description 1
- BOKQMLSFAHQVJD-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(3-imidazol-1-ylpropylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CCC(CC2)NCCCN2C=NC=C2)S1 BOKQMLSFAHQVJD-UHFFFAOYSA-N 0.000 description 1
- FRIAPOLWMNLJOE-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(cyclohexylmethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CCC(CC2)NCC2CCCCC2)S1 FRIAPOLWMNLJOE-UHFFFAOYSA-N 0.000 description 1
- PILHIILMXFXEGP-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(dodecylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCCCCCCCCCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 PILHIILMXFXEGP-UHFFFAOYSA-N 0.000 description 1
- FWXPQNAYNFBQIC-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(dodecylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCCCCCCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 FWXPQNAYNFBQIC-UHFFFAOYSA-N 0.000 description 1
- BRLVCXYGWOZEPV-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(heptylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCCCCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 BRLVCXYGWOZEPV-UHFFFAOYSA-N 0.000 description 1
- GQGVRCYFYVRTED-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(heptylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 GQGVRCYFYVRTED-UHFFFAOYSA-N 0.000 description 1
- RVLKWOOHJIBGHR-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(hexylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCCCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 RVLKWOOHJIBGHR-UHFFFAOYSA-N 0.000 description 1
- OPYRLNCUCPAIPQ-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(octylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCCCCCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 OPYRLNCUCPAIPQ-UHFFFAOYSA-N 0.000 description 1
- OHDMVTBELZFHAK-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(octylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 OHDMVTBELZFHAK-UHFFFAOYSA-N 0.000 description 1
- DMSSOIOIUWCVDY-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(pentylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 DMSSOIOIUWCVDY-UHFFFAOYSA-N 0.000 description 1
- FVIMGKFAIXLCRU-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(pentylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 FVIMGKFAIXLCRU-UHFFFAOYSA-N 0.000 description 1
- ZVUVHRYRAGSAOI-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(propylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 ZVUVHRYRAGSAOI-UHFFFAOYSA-N 0.000 description 1
- GETINMRFKPZTMI-UHFFFAOYSA-N 4-chloro-n-[[5-[4-(quinolin-4-ylmethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CCC(CC2)NCC=2C3=CC=CC=C3N=CC=2)S1 GETINMRFKPZTMI-UHFFFAOYSA-N 0.000 description 1
- MDIOJCXOEWWVOD-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[(3,4-dihydroxyphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=C(O)C(O)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CC1 MDIOJCXOEWWVOD-UHFFFAOYSA-N 0.000 description 1
- ZZIHVCCGSDQAAC-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[(3-chlorophenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CCC(CC2)NCC=2C=C(Cl)C=CC=2)S1 ZZIHVCCGSDQAAC-UHFFFAOYSA-N 0.000 description 1
- AVYCTEZUZHQYLR-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[(4-phenoxyphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CCC(CC2)NCC=2C=CC(OC=3C=CC=CC=3)=CC=2)S1 AVYCTEZUZHQYLR-UHFFFAOYSA-N 0.000 description 1
- FFTMEKVATSLZAW-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[(4-propoxyphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(OCCC)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CC1 FFTMEKVATSLZAW-UHFFFAOYSA-N 0.000 description 1
- QSHNSFUKEJXNCG-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[2-(trifluoromethylsulfonylamino)ethylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(NCCNS(=O)(=O)C(F)(F)F)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 QSHNSFUKEJXNCG-UHFFFAOYSA-N 0.000 description 1
- SCPWZCWDIIFELZ-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[[4-(difluoromethoxy)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(OC(F)F)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CC1 SCPWZCWDIIFELZ-UHFFFAOYSA-N 0.000 description 1
- RHDAZTUTKLAUNI-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[[4-(trifluoromethylsulfonyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1=CC(S(=O)(=O)C(F)(F)F)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CC1 RHDAZTUTKLAUNI-UHFFFAOYSA-N 0.000 description 1
- RKWXQGKEUVKRGE-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[cyclohexylmethyl(hexyl)amino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CCC1N(CCCCCC)CC1CCCCC1 RKWXQGKEUVKRGE-UHFFFAOYSA-N 0.000 description 1
- DYSCUYNFHSVFSU-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[hexyl(2-phenylethyl)amino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CCC1N(CCCCCC)CCC1=CC=CC=C1 DYSCUYNFHSVFSU-UHFFFAOYSA-N 0.000 description 1
- OCTZCSIXSFPNEQ-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[hexyl(methyl)amino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CC(N(C)CCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 OCTZCSIXSFPNEQ-UHFFFAOYSA-N 0.000 description 1
- QDOJFSKGVDWIHV-UHFFFAOYSA-N 4-chloro-n-[[5-[4-[hexyl(pyridin-3-ylmethyl)amino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]benzamide Chemical compound C1CN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CCC1N(CCCCCC)CC1=CC=CN=C1 QDOJFSKGVDWIHV-UHFFFAOYSA-N 0.000 description 1
- DBMFYTQPPBBKHI-UHFFFAOYSA-N 4-cyanobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(C#N)C=C1 DBMFYTQPPBBKHI-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- CZKLEJHVLCMVQR-UHFFFAOYSA-N 4-fluorobenzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C=C1 CZKLEJHVLCMVQR-UHFFFAOYSA-N 0.000 description 1
- SMISIQMCBPTDKU-UHFFFAOYSA-N 5-[[(3-methoxybenzoyl)amino]methyl]thiophene-2-sulfonyl chloride Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(Cl)(=O)=O)=C1 SMISIQMCBPTDKU-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- IRBAWVGZNJIROV-SFHVURJKSA-N 9-(2-cyclopropylethynyl)-2-[[(2s)-1,4-dioxan-2-yl]methoxy]-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one Chemical compound C1=C2C3=CC=C(C#CC4CC4)C=C3CCN2C(=O)N=C1OC[C@@H]1COCCO1 IRBAWVGZNJIROV-SFHVURJKSA-N 0.000 description 1
- 102100034540 Adenomatous polyposis coli protein Human genes 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000031104 Arterial Occlusive disease Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 230000003844 B-cell-activation Effects 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 101100026251 Caenorhabditis elegans atf-2 gene Proteins 0.000 description 1
- 101100513486 Caenorhabditis elegans mkk-4 gene Proteins 0.000 description 1
- 101100476202 Caenorhabditis elegans mog-2 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 206010048964 Carotid artery occlusion Diseases 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 101710150820 Cellular tumor antigen p53 Proteins 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108010077544 Chromatin Proteins 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
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 102100023033 Cyclic AMP-dependent transcription factor ATF-2 Human genes 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- 102000010170 Death domains Human genes 0.000 description 1
- 108050001718 Death domains Proteins 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 239000004097 EU approved flavor enhancer Substances 0.000 description 1
- 206010014824 Endotoxic shock Diseases 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 101000924577 Homo sapiens Adenomatous polyposis coli protein Proteins 0.000 description 1
- 101001115395 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 4 Proteins 0.000 description 1
- 101000997829 Homo sapiens Glial cell line-derived neurotrophic factor Proteins 0.000 description 1
- 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102100037850 Interferon gamma Human genes 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 102000003777 Interleukin-1 beta Human genes 0.000 description 1
- 108090000193 Interleukin-1 beta Proteins 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 108090000176 Interleukin-13 Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 102000004083 Lymphotoxin-alpha Human genes 0.000 description 1
- 108090000542 Lymphotoxin-alpha Proteins 0.000 description 1
- 108010075654 MAP Kinase Kinase Kinase 1 Proteins 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 102000047918 Myelin Basic Human genes 0.000 description 1
- 101710107068 Myelin basic protein Proteins 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 1
- 206010056677 Nerve degeneration Diseases 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 108010020346 Polyglutamic Acid Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102100027584 Protein c-Fos Human genes 0.000 description 1
- 108010018070 Proto-Oncogene Proteins c-ets Proteins 0.000 description 1
- 102000004053 Proto-Oncogene Proteins c-ets Human genes 0.000 description 1
- 108010071563 Proto-Oncogene Proteins c-fos Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 229910006024 SO2Cl2 Inorganic materials 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 208000000389 T-cell leukemia Diseases 0.000 description 1
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 description 1
- 230000029662 T-helper 1 type immune response Effects 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 210000000447 Th1 cell Anatomy 0.000 description 1
- YGZWVPBHYABGLT-KJEVXHAQSA-N Thr-Pro-Tyr Chemical group C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 YGZWVPBHYABGLT-KJEVXHAQSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- PRDBLLIPPDOICK-UHFFFAOYSA-N [4-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=C(C(F)(F)F)C=C1 PRDBLLIPPDOICK-UHFFFAOYSA-N 0.000 description 1
- ZHAFUINZIZIXFC-UHFFFAOYSA-N [9-(dimethylamino)-10-methylbenzo[a]phenoxazin-5-ylidene]azanium;chloride Chemical compound [Cl-].O1C2=CC(=[NH2+])C3=CC=CC=C3C2=NC2=C1C=C(N(C)C)C(C)=C2 ZHAFUINZIZIXFC-UHFFFAOYSA-N 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- VLSMHEGGTFMBBZ-UHFFFAOYSA-N alpha-Kainic acid Natural products CC(=C)C1CNC(C(O)=O)C1CC(O)=O VLSMHEGGTFMBBZ-UHFFFAOYSA-N 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000007854 aminals Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 208000021328 arterial occlusion Diseases 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 230000000923 atherogenic effect Effects 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- GMHPWGYTSXHHPI-UHFFFAOYSA-N azepan-4-one Chemical compound O=C1CCCNCC1 GMHPWGYTSXHHPI-UHFFFAOYSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- 229940054066 benzamide antipsychotics Drugs 0.000 description 1
- 150000003936 benzamides Chemical class 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 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
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000005978 brain dysfunction Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000006369 cell cycle progression Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 230000010307 cell transformation Effects 0.000 description 1
- 230000004637 cellular stress Effects 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 239000013626 chemical specie Substances 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000005957 chlorosulfonylation reaction Methods 0.000 description 1
- 210000003483 chromatin Anatomy 0.000 description 1
- JOPOVCBBYLSVDA-UHFFFAOYSA-N chromium(6+) Chemical class [Cr+6] JOPOVCBBYLSVDA-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N cinnamic acid Chemical compound OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 230000004940 costimulation Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- AFABGHUZZDYHJO-UHFFFAOYSA-N dimethyl butane Natural products CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000001037 epileptic effect Effects 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- OMOQNWFNWBKNDA-UHFFFAOYSA-N ethyl 5-[[(3-methoxybenzoyl)amino]methyl]-2-[4-[[4-(trifluoromethyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophene-3-carboxylate Chemical compound S1C(S(=O)(=O)N2CCC(CC2)NCC=2C=CC(=CC=2)C(F)(F)F)=C(C(=O)OCC)C=C1CNC(=O)C1=CC=CC(OC)=C1 OMOQNWFNWBKNDA-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 230000006355 external stress Effects 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- JFSPBVWPKOEZCB-UHFFFAOYSA-N fenfuram Chemical compound O1C=CC(C(=O)NC=2C=CC=CC=2)=C1C JFSPBVWPKOEZCB-UHFFFAOYSA-N 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- CATSNJVOTSVZJV-UHFFFAOYSA-N heptan-2-one Chemical compound CCCCCC(C)=O CATSNJVOTSVZJV-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- SXWRTZOXMUOJER-UHFFFAOYSA-N hydron;piperidin-4-one;chloride;hydrate Chemical compound O.Cl.O=C1CCNCC1 SXWRTZOXMUOJER-UHFFFAOYSA-N 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- DOUHZFSGSXMPIE-UHFFFAOYSA-N hydroxidooxidosulfur(.) Chemical compound [O]SO DOUHZFSGSXMPIE-UHFFFAOYSA-N 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 229940097277 hygromycin b Drugs 0.000 description 1
- 125000005946 imidazo[1,2-a]pyridyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 230000004073 interleukin-2 production Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000005990 isobenzothienyl group Chemical group 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
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- VLSMHEGGTFMBBZ-OOZYFLPDSA-N kainic acid Chemical compound CC(=C)[C@H]1CN[C@H](C(O)=O)[C@H]1CC(O)=O VLSMHEGGTFMBBZ-OOZYFLPDSA-N 0.000 description 1
- 229950006874 kainic acid Drugs 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 238000006263 metalation reaction Methods 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- MYMHRAOVLXQTBG-QWAKEFERSA-N methyl (2s)-1-[5-[[(4-chlorobenzoyl)amino]methyl]thiophen-2-yl]sulfonyl-4-(hexylamino)pyrrolidine-2-carboxylate Chemical compound C1C(NCCCCCC)C[C@@H](C(=O)OC)N1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 MYMHRAOVLXQTBG-QWAKEFERSA-N 0.000 description 1
- SAAUDOGTWMFFHD-UHFFFAOYSA-N methyl 2-[[1-[5-[[(4-chlorobenzoyl)amino]methyl]thiophen-2-yl]sulfonylpiperidin-4-yl]-hexylamino]acetate Chemical compound C1CC(N(CC(=O)OC)CCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 SAAUDOGTWMFFHD-UHFFFAOYSA-N 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000002297 mitogenic effect Effects 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- QKMJVIBQNUDLOS-UHFFFAOYSA-N n-[[5-(1,4-dioxa-8-azaspiro[4.5]decan-8-ylsulfonyl)thiophen-2-yl]methyl]-2-oxo-1h-pyridine-3-carboxamide Chemical compound C=1C=CNC(=O)C=1C(=O)NCC(S1)=CC=C1S(=O)(=O)N(CC1)CCC21OCCO2 QKMJVIBQNUDLOS-UHFFFAOYSA-N 0.000 description 1
- QTHHMMWIZXYCCX-UHFFFAOYSA-N n-[[5-[3-(2-ethylhexylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1C(NCC(CC)CCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 QTHHMMWIZXYCCX-UHFFFAOYSA-N 0.000 description 1
- YWVUEWMXOUVOQS-UHFFFAOYSA-N n-[[5-[3-(butylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1C(NCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 YWVUEWMXOUVOQS-UHFFFAOYSA-N 0.000 description 1
- SERLGPIXTTUKMR-UHFFFAOYSA-N n-[[5-[3-(cyclohexylmethylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CC(CC2)NCC2CCCCC2)=C1 SERLGPIXTTUKMR-UHFFFAOYSA-N 0.000 description 1
- XRTQWHAWFTWZQT-UHFFFAOYSA-N n-[[5-[3-(dodecylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1C(NCCCCCCCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 XRTQWHAWFTWZQT-UHFFFAOYSA-N 0.000 description 1
- GKEBJYVWVMHPNH-UHFFFAOYSA-N n-[[5-[3-(heptylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1C(NCCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 GKEBJYVWVMHPNH-UHFFFAOYSA-N 0.000 description 1
- NPRYDXVECUDIFH-UHFFFAOYSA-N n-[[5-[3-(hexylamino)pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1C(NCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 NPRYDXVECUDIFH-UHFFFAOYSA-N 0.000 description 1
- BZXQOWIECILVKG-JSTNZPBCSA-N n-[[5-[3-[[(1s,3r,4r)-3-bicyclo[2.2.1]heptanyl]amino]pyrrolidin-1-yl]sulfonylthiophen-2-yl]methyl]-4-chlorobenzamide Chemical compound N([C@H]1[C@]2([H])CC[C@@](C2)(C1)[H])C(C1)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 BZXQOWIECILVKG-JSTNZPBCSA-N 0.000 description 1
- XSGBYNKTCCNLKS-UHFFFAOYSA-N n-[[5-[4-(1-adamantylmethylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CCC2)NCC23CC4CC(CC(C4)C2)C3)=C1 XSGBYNKTCCNLKS-UHFFFAOYSA-N 0.000 description 1
- RKZRBDPUXPRQPW-UHFFFAOYSA-N n-[[5-[4-(1-adamantylmethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC23CC4CC(CC(C4)C2)C3)=C1 RKZRBDPUXPRQPW-UHFFFAOYSA-N 0.000 description 1
- ZYGCODOMBDMDLS-UHFFFAOYSA-N n-[[5-[4-(1-adamantylmethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-4-chlorobenzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(S(=O)(=O)N2CCC(CC2)NCC23CC4CC(CC(C4)C2)C3)S1 ZYGCODOMBDMDLS-UHFFFAOYSA-N 0.000 description 1
- REAKEZFLPJUGMX-UHFFFAOYSA-N n-[[5-[4-(2,3-dihydroxypropylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC(O)CO)=C1 REAKEZFLPJUGMX-UHFFFAOYSA-N 0.000 description 1
- ZBKMLQJTMYJAES-UHFFFAOYSA-N n-[[5-[4-(2-cyclohexylethylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CCC2)NCCC2CCCCC2)=C1 ZBKMLQJTMYJAES-UHFFFAOYSA-N 0.000 description 1
- BWZVXGXPQNCMNU-UHFFFAOYSA-N n-[[5-[4-(2-ethylhexylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(NCC(CC)CCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 BWZVXGXPQNCMNU-UHFFFAOYSA-N 0.000 description 1
- JYLIJHMCGACXOT-UHFFFAOYSA-N n-[[5-[4-(2-ethylhexylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(NCC(CC)CCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 JYLIJHMCGACXOT-UHFFFAOYSA-N 0.000 description 1
- XJUUHVHRPWRCQU-UHFFFAOYSA-N n-[[5-[4-(2-hydroxyethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCCO)=C1 XJUUHVHRPWRCQU-UHFFFAOYSA-N 0.000 description 1
- KNKWAANXGSZURL-UHFFFAOYSA-N n-[[5-[4-(3-imidazol-1-ylpropylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CCC2)NCCCN2C=NC=C2)=C1 KNKWAANXGSZURL-UHFFFAOYSA-N 0.000 description 1
- SQXCTJBQLYJXPH-UHFFFAOYSA-N n-[[5-[4-(3-imidazol-1-ylpropylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCCCN2C=NC=C2)=C1 SQXCTJBQLYJXPH-UHFFFAOYSA-N 0.000 description 1
- QDTNGIOBKJDZAT-UHFFFAOYSA-N n-[[5-[4-(butylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(NCCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 QDTNGIOBKJDZAT-UHFFFAOYSA-N 0.000 description 1
- PRRXFIRBCBVHNY-UHFFFAOYSA-N n-[[5-[4-(butylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]-4-chlorobenzamide Chemical compound C1CC(NCCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 PRRXFIRBCBVHNY-UHFFFAOYSA-N 0.000 description 1
- SWJFETHHKUJUKC-UHFFFAOYSA-N n-[[5-[4-(butylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(NCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 SWJFETHHKUJUKC-UHFFFAOYSA-N 0.000 description 1
- YFMLZVPBTJYRAE-UHFFFAOYSA-N n-[[5-[4-(butylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-4-chlorobenzamide Chemical compound C1CC(NCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 YFMLZVPBTJYRAE-UHFFFAOYSA-N 0.000 description 1
- VMUITQMEIFXYSI-UHFFFAOYSA-N n-[[5-[4-(cyclohexylmethylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CCC2)NCC2CCCCC2)=C1 VMUITQMEIFXYSI-UHFFFAOYSA-N 0.000 description 1
- ASNFRUWIAXUQCE-UHFFFAOYSA-N n-[[5-[4-(decylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(NCCCCCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 ASNFRUWIAXUQCE-UHFFFAOYSA-N 0.000 description 1
- AHHWHQBGQQEZBX-UHFFFAOYSA-N n-[[5-[4-(dodecylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(NCCCCCCCCCCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 AHHWHQBGQQEZBX-UHFFFAOYSA-N 0.000 description 1
- QHNZKMJXKUOTKJ-UHFFFAOYSA-N n-[[5-[4-(dodecylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(NCCCCCCCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 QHNZKMJXKUOTKJ-UHFFFAOYSA-N 0.000 description 1
- OPBMPAWOBNKSQI-UHFFFAOYSA-N n-[[5-[4-(ethylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(NCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 OPBMPAWOBNKSQI-UHFFFAOYSA-N 0.000 description 1
- ZCLGLTGKEPVHGJ-UHFFFAOYSA-N n-[[5-[4-(heptylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(NCCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 ZCLGLTGKEPVHGJ-UHFFFAOYSA-N 0.000 description 1
- MSEVCYYRWIFFMQ-UHFFFAOYSA-N n-[[5-[4-(hexylamino)azepan-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(NCCCCCC)CCCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 MSEVCYYRWIFFMQ-UHFFFAOYSA-N 0.000 description 1
- PMXPOABEASCNDB-UHFFFAOYSA-N n-[[5-[4-(hexylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-2-hydroxybenzamide Chemical compound C1CC(NCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC=C1O PMXPOABEASCNDB-UHFFFAOYSA-N 0.000 description 1
- VTKJUWWSYDUOTP-UHFFFAOYSA-N n-[[5-[4-(hexylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-2-oxo-1h-pyridine-3-carboxamide Chemical compound C1CC(NCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CNC1=O VTKJUWWSYDUOTP-UHFFFAOYSA-N 0.000 description 1
- RVLXBEJFSCUIDV-UHFFFAOYSA-N n-[[5-[4-(hexylamino)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(NCCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 RVLXBEJFSCUIDV-UHFFFAOYSA-N 0.000 description 1
- MGOOYKMCBKKAET-UHFFFAOYSA-N n-[[5-[4-(hydroxymethyl)piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CO)CC2)=C1 MGOOYKMCBKKAET-UHFFFAOYSA-N 0.000 description 1
- NMQOFBZKRUPPRK-UHFFFAOYSA-N n-[[5-[4-[(3-ethoxyphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound CCOC1=CC=CC(CNC2CCN(CC2)S(=O)(=O)C=2SC(CNC(=O)C=3C=C(OC)C=CC=3)=CC=2)=C1 NMQOFBZKRUPPRK-UHFFFAOYSA-N 0.000 description 1
- URIPWGBOHDBVGI-UHFFFAOYSA-N n-[[5-[4-[(4-butoxyphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1=CC(OCCCC)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=C(OC)C=CC=3)=CC=2)CC1 URIPWGBOHDBVGI-UHFFFAOYSA-N 0.000 description 1
- XRXPSQBFKULZLM-UHFFFAOYSA-N n-[[5-[4-[(4-butylanilino)methyl]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1=CC(CCCC)=CC=C1NCC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=C(OC)C=CC=3)=CC=2)CC1 XRXPSQBFKULZLM-UHFFFAOYSA-N 0.000 description 1
- GDFFDPMYMQCXSX-UHFFFAOYSA-N n-[[5-[4-[(4-butylphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1=CC(CCCC)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=C(OC)C=CC=3)=CC=2)CC1 GDFFDPMYMQCXSX-UHFFFAOYSA-N 0.000 description 1
- FOSRLIPIVDTNKW-UHFFFAOYSA-N n-[[5-[4-[(4-chlorophenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=CC(Cl)=CC=2)=C1 FOSRLIPIVDTNKW-UHFFFAOYSA-N 0.000 description 1
- IZGYKYJINBEEAT-UHFFFAOYSA-N n-[[5-[4-[(4-iodophenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=CC(I)=CC=2)=C1 IZGYKYJINBEEAT-UHFFFAOYSA-N 0.000 description 1
- UEHNWZFKDOMFGI-UHFFFAOYSA-N n-[[5-[4-[(4-tert-butylphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=CC(=CC=2)C(C)(C)C)=C1 UEHNWZFKDOMFGI-UHFFFAOYSA-N 0.000 description 1
- KYBJGRXKYJXTAN-UHFFFAOYSA-N n-[[5-[4-[(4-tert-butylphenyl)methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-4-chlorobenzamide Chemical compound C1=CC(C(C)(C)C)=CC=C1CNC1CCN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CC1 KYBJGRXKYJXTAN-UHFFFAOYSA-N 0.000 description 1
- XVDOZYUIWBXTIN-UHFFFAOYSA-N n-[[5-[4-[2-(butylamino)ethyl]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CC(CCNCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=CC(OC)=C1 XVDOZYUIWBXTIN-UHFFFAOYSA-N 0.000 description 1
- IMJDOYRGXAPQCN-UHFFFAOYSA-N n-[[5-[4-[[3,5-bis(trifluoromethyl)phenyl]methylamino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NCC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)=C1 IMJDOYRGXAPQCN-UHFFFAOYSA-N 0.000 description 1
- QEHDHRBPLGLGSO-UHFFFAOYSA-N n-[[5-[4-[benzyl(hexyl)amino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-4-chlorobenzamide Chemical compound C1CN(S(=O)(=O)C=2SC(CNC(=O)C=3C=CC(Cl)=CC=3)=CC=2)CCC1N(CCCCCC)CC1=CC=CC=C1 QEHDHRBPLGLGSO-UHFFFAOYSA-N 0.000 description 1
- JGKVXEHUGBMXGH-UHFFFAOYSA-N n-[[5-[4-[butyl(hexyl)amino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-4-chlorobenzamide Chemical compound C1CC(N(CCCC)CCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 JGKVXEHUGBMXGH-UHFFFAOYSA-N 0.000 description 1
- YZYLARBFCGWMJP-UHFFFAOYSA-N n-[[5-[4-[ethyl-[[4-(trifluoromethyl)phenyl]methyl]amino]piperidin-1-yl]sulfonylthiophen-2-yl]methyl]-3-methoxybenzamide Chemical compound C1CN(S(=O)(=O)C=2SC(CNC(=O)C=3C=C(OC)C=CC=3)=CC=2)CCC1N(CC)CC1=CC=C(C(F)(F)F)C=C1 YZYLARBFCGWMJP-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YNILDRGPFGMCDE-UHFFFAOYSA-N n-ethylfuran-2-amine Chemical compound CCNC1=CC=CO1 YNILDRGPFGMCDE-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- OJSDIMLQIDMVNL-UHFFFAOYSA-N n-methylfuran-2-amine Chemical compound CNC1=CC=CO1 OJSDIMLQIDMVNL-UHFFFAOYSA-N 0.000 description 1
- XJINZNWPEQMMBV-UHFFFAOYSA-N n-methylhexan-1-amine Chemical compound CCCCCCNC XJINZNWPEQMMBV-UHFFFAOYSA-N 0.000 description 1
- DYUWTXWIYMHBQS-UHFFFAOYSA-N n-prop-2-enylprop-2-en-1-amine Chemical compound C=CCNCC=C DYUWTXWIYMHBQS-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- BITOAPGZBZODKM-UHFFFAOYSA-N n-propylfuran-2-amine Chemical compound CCCNC1=CC=CO1 BITOAPGZBZODKM-UHFFFAOYSA-N 0.000 description 1
- 210000004897 n-terminal region Anatomy 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229960005010 orotic acid Drugs 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 229920005990 polystyrene resin Polymers 0.000 description 1
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 1
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- OCAAZRFBJBEVPS-UHFFFAOYSA-N prop-2-enyl carbamate Chemical group NC(=O)OCC=C OCAAZRFBJBEVPS-UHFFFAOYSA-N 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
- LPPOVVJDAVMOET-UHFFFAOYSA-N pyrrolidine-1-sulfonamide Chemical class NS(=O)(=O)N1CCCC1 LPPOVVJDAVMOET-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000011663 regulation of signaling Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000008672 reprogramming Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- SOGMBUSBLTXMKX-UHFFFAOYSA-N tert-butyl 2-[[1-[5-[[(4-chlorobenzoyl)amino]methyl]thiophen-2-yl]sulfonylpiperidin-4-yl]-hexylamino]acetate Chemical compound C1CC(N(CC(=O)OC(C)(C)C)CCCCCC)CCN1S(=O)(=O)C(S1)=CC=C1CNC(=O)C1=CC=C(Cl)C=C1 SOGMBUSBLTXMKX-UHFFFAOYSA-N 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
- SEYDWUDASGFNOX-UHFFFAOYSA-N tert-butyl n-[1-[5-[[(3-methoxybenzoyl)amino]methyl]thiophen-2-yl]sulfonylpiperidin-4-yl]carbamate Chemical compound COC1=CC=CC(C(=O)NCC=2SC(=CC=2)S(=O)(=O)N2CCC(CC2)NC(=O)OC(C)(C)C)=C1 SEYDWUDASGFNOX-UHFFFAOYSA-N 0.000 description 1
- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000002381 testicular Effects 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 150000003555 thioacetals Chemical class 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- YNVOMSDITJMNET-UHFFFAOYSA-M thiophene-3-carboxylate Chemical compound [O-]C(=O)C=1C=CSC=1 YNVOMSDITJMNET-UHFFFAOYSA-M 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 108091006106 transcriptional activators Proteins 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000006433 tumor necrosis factor production Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000029069 type 2 immune response Effects 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 210000005167 vascular cell Anatomy 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229940045860 white wax Drugs 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- 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
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
- C07D333/30—Hetero atoms other than halogen
- C07D333/34—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Description
Područje izuma
Izum je iz područja farmacije i genetike.
Ovaj izum odnosi se na sulfonamidske derivate koji imaju lipofilnu speciju i koji su suštinski topljivi. Navedeni sulfonamidski derivati namijenjeni su uporabi kao farmaceutski aktivni spojevi. Također, ovaj izum se odnosi na farmaceutske formulacije koje sadrže takve sulfonamidske derivate. Konkretno, ovaj izum se odnosi na sulfonamidske derivate koji su korisni u tretiranju i/ili prevenciji bolesti imunološkog i živčanog sustava. Specifično, sulfonamidski derivati ovog izuma pokazuju značajnu modulatorsku, odnosno inhibitorsku aktivnost JNK (jun-kinaza) funkcije, odnosno ciklusa.
Stanje tehnike
Apoptoza označuje složeno uvijanje stanične membrane i organela kada ona prolazi proces programirane stanične smrti. Tijekom navedenog procesa, stanica aktivira intrinzični program samouništenja i sistematski se uništava. Može se uočiti sljedeći niz događaja:
Stanična površina dobiva mjehuriće i vrši ekspresiju pro-fagocitnih signala. Cijela apoptozna stanica zatim se fragmentira u membranski-vezane vezikule koje se brzo odlažu fagocitozom, tako da postoji minimalno oštećenje okolnog tkiva.
Stanica se zatim odvaja od okoline.
Jezgra također prolazi kroz karakterističan ciklus morfoloških promjena kada podliježe genetskom samoubojstvu, kromatin se kondenzira i specifično cijepa u fragmente DNA.
Neuronska stanična smrt igra značajnu ulogu u osiguranju da se živčani sustav normalno razvija. Čini se da smrt neurona koji se razvijaju ovisi o veličini mete koju inerviraju: stanice s manje sinaptičkih partnera vjerojatnije umiru nego one koje imaju razvijene multiple sinapse. To može biti odraz procesa kojim se balansira relativni broj pre- prema post-sinaptičkim neuronima u razvoju živčanog sustava.
Premda se za neuronsku staničnu smrt pretpostavlja da je apoptotička, noviji je podatak da neuroni u razvijanju mozga glodavca podliježu apoptozi sukladno klasifikaciji pomoću morfologije i DNA fragmentiranja. Budući da stanična smrt tijekom razvoja vrlo jasno nije patološki proces, logično je da stanice stvarno prestaju postojati.
Do neuronske smrti dolazi bilo apototičkim ili nekrotičkim procesom nakon ozljede živca traumom ili tijekom neurodegenerativnih bolesti. Više komponenti je uključeno kao ključnih sudionika koje imaju ulogu u pokretanju neuronske programirane stanične smrti. Među komponentama koje vode neuronskoj apoptozi su članovi SAPK/JNK koji su subfamilija MAP kinaza (MAPK).
Stanice sisavaca odgovaraju na neke izvanstanične stimulanse aktiviranjem signalnih kaskada koje su upravljane različitim mitogen-aktiviranim protein kinazama (MAPK). Bez obzira na njihove razlike na stimulans u gornjem toku, MAP kinaza kaskade su organizirane na sličan način, koji se sastoji MAP kinaze kinaze kinaza (MAPKKK ili MEKK), MAP kinaze kinaza (MAPKK ili MKK) i MAP kinaza (MAPK). MAP kinaze su velika familija kinaza koja obuhvaća c-Jun N-terminalne kinaze (JNK), koje su također poznate kao "stresaktivirane proteinske kinaze " (SAPK), kao i izvanstaničnim signalom regulirane kinaze (ERK) te p38 MAP kinaze. Svaka subfamilija ovih triju MAP kinaza je uključena u bar tri paralelna ciklusa koji prenose informaciju koju je pokrenuo vanjski stimulans. JNK signalni ciklus je aktiviran izlaganjem stanica vanjskom stresu, kao što su kemijski toksini, zračenje, hipoksija i osmotski šok – kao i tretiranjem stanica čimbenicima rasta i proupalnim citokinima – kao što su tumorski nekrotizirajući čimbenik alfa (TNF-α) ili interleukin-1 beta (IL-1β).
Dvije MAP kinaza kinaze (poznate kao MKK ili MAPKK), tj. MKK4 (poznata također kao JNKK1) i MKK7 (poznata kao JNKK2), aktiviraju JNK dualnim fosforiliranjem specifičnog treonina i tirozinskih rezidua koje su smještene unutar Thr-Pro-Tyr motiva na aktivacijskoj petlji na enzimu, kao odgovor na citokine i stresne signale. U gornjem toku signalne kaskade, poznato je da je sam MKK4 aktiviran pomoću MAP kinaze kinaze kinaze, MEKK1 kroz fosforiliranje na serinskim i treoninskim reziduama.
Kada je jednom aktiviran, JNK se veže za N-terminalno područje ciljeva transkripcijskog čimbenika i fosforilira transkripcijsko aktiviranje domena što rezultira doreguliranjem ekspresije različitih genskih produkata, što može voditi apoptozi, upalnim odgovorima ili onkogenim procesima (1-5).
MAPK (mitogen-aktivirane protein kinaze) su serin/treonin kinaze koje su aktivirane dualnim fosforiliranjem na treoninskim i tirozinskim reziduama. U stanicama sisavaca, postoje bar tri odvojena ali paralelna ciklusa koji prenos einformaciju koju generira izvanstanični stimulator prema MAPK. Navedeni ciklus sastoji se od kinaza kaskada koje vode aktiviranju ERK (izvanstanično regulirane kinaze), JNK (c-Jun N-terminalne kinaze), te p38/CSBP kinazama. Premda su i JNK i p38 ciklusi uključeni u otpuštanje izvanmolekularnih signala stresnog tipa, ERK ciklus je primarno odgovoran za prenošenje mitogenih/diferencijacijskih signala prema staničnoj jezgri.
SAPK kaskade predstavljaju pod-familiju mitogen-aktivirajuće proteinske kinaza familije, koje su aktivirane različitim eksternim stimulatorima uključujući DNA oštećenje nakon UV ozračenja, TNF-α , IL-1β, keramid, stanični stres, te reaktivne kisikove specije te imaju različite supstratne specifičnosti. Prijenos signala putem MKK4/JNK od MKK3/p38 rezultira fosforiliranjem inducirajućih transkripcijskih čimbenika, c-Jun i ATF2, koji zatim djeluju bilo kao homodimeri ili kao heterodimeri da se započne transkripcija efektora niz tok.
c-Jun je protein koji stvara homodimere i heterodimere (npr. s c-Fos) da se dobije transaktivacijski kompleks AP koji je potreban za aktiviranje mnogih gena (npr. matričnih metaloproteaza) koji su uključeni u upalnom odgovoru. JNK su otkrivene kada je nađeno da nekoliko različitih stimulansa kao što u ultraljubičasto svjetlo i TNF-α stimulirano fosforiliranje c-Jun na specifičnim serinskim reziduama na N-terminalu proteina.
Identificirana su tri različita JNK enzima kao produkti gena JNK1, JNK2 i JNK3 te deset različitih izoformi JNK (3, 6, 7). JNK1 i -2 su sveprisutno ekspresirane u humanim tkivima, dok je ekspresija JNK3 selektivno vezana za mozak, srce i testise (7, 8, 9, 10). Svaka izoforma veže se za supstrate s različitim afinitetom što sugerira, in vivo, supstratno specifično reguliranje signalnih ciklusa pomoću različitih JNK izoformi.
U novijoj publikaciji Xie X et al, (Structure 1998, 6 (8); 983-991) sugerirano je da je aktiviranje stres-aktiviranih signalnih transdukcijskih ciklusa neophodno za apoptozu neurona koja je izazvana odsutnošću NGF u PC-12 i gornjim cervikalnim ganglijima (SCG) štakora simpatičkih živčanih stanica. Inhibiranje specifičnih kinaza, dotično MAP kinaze kinaze (MKK3) i MAP kinaze kinaze 4 (MKK4), ili c-Jun (dio MKK-4 kaskade) može biti dovoljno da se blokira apoptoza (vidi također Kumagae Y et al, u Brain Res Mol Brain Res, 1999, 67(1), 10-17 i Yang DD et al u Nature, 1997, 389 (6653); 865-870). Unutar nekoliko sati od gubitka NGF u SCG neuronima, c-Jun postaje jako fosforiliran i povećava se razina proteina. Slično, u PC-12 stanicama štakora koje su izgubile NGF, JNK i p38 su podvrgnuti podržanom aktiviranju dok su ERK inhibirani. Sukladno s ovom JNK3 KO miševi su otporni u odnosu na apoptozu koja je izazvana egzitoksičnošću u hipokampusu i što je značajnije, oni pokazuju jako smanjeni epileptički odgovor prema egzitoksičnosti u odnosu na normalne životinje (Nature 1997, 389, 865-870).
Nedavno, izviješćeno je da je JNK signalni ciklus uključen u staničnu proliferaciju i može imati značajnu ulogu u autoimunim bolestima (Immunity, 1998, 9, 575-585; Current Biology, 1999, 3, 116-125) koje su upravljane T-staničnim aktiviranjem i proliferacijom.
Naivne (prekursorske) CD4+ pomoćničke T (Th) stanice prepoznaju specifične MHC-peptidne komplekse antigen-prisutnih stanica (APC) putem T-staničnog receptorskog (TCR) kompleksa. Uz TCT-upravljani signal, postoji ko-stimulirajući signal bar djelomično povezivanjem CD28 koji je s ekspresijom na T-stanicama s B7 proteinima na APC. Kombiniranje ovih signala izaziva T-staničnu klonsku ekspresiju.
Nakon 4-5 dana proliferacije, prekursorske CD4+ T stanice diferenciraju se u naoružane efektorske T stanice koje upravljaju funkcijama imunološkog sustava. Tijekom procesa diferenciranja, dolazi do suštinskog reprogramiranja ekspresije gena.
Dva podskupa efektorskih Th stanica su definirana temeljem slike njihova različita citokinska izlučivanja i njihovih imuno-modulatorskih učinaka: Th1 stanice proizvode IFNγ i LT (TNF-β), što je potrebno za stanično-upravljane upalne reakcije; Th2 stanice izlučuju IL-4, IL-5, IL-6, IL-10 i IL-13, što upravlja B-staničnim aktiviranjem i diferenciranjem. Ove stanice imaju središnju ulogu u imunološkom odgovoru. JNK MAP ciklus kinaze induciran je u Th1 ali ne i u Th2 efektorskim stanicama nakon antigenskog stimuliranja. Štoviše, diferenciranje prekursorskih CD4+ T stanica u efektorske Th1 ali ne i Th2 stanice je onemogućeno u JNK2-deficijentnih miševa. Dakle, posljednjih godina je uočeno da ciklus JNK kinaze ima značajnu ulogu u balansu Th1 i Th2 imunološkog odgovora putem JNK2.
Za neke transkripcijske čimbenike se zna da su JNK supstrati Jun proteina (c-jun, Jun B i Jun D), srodnih transkripcijskih čimbenika ATF2 i ATFa, Ets transkripcijskih čimbenika kao što su Elk-1 i Sap-1, tumorskog supresora p53 i proteina domene stanične smrti (DENN).
Aktiviranje JNK ciklusa dokumentirano je za određen broj bolesti, tako da postoji objašnjenje za ciljanje na ovaj ciklus da bi se otkrio lijek. Nadalje, molekularni genetički pristupi su potvrdili patogenu ulogu ovog ciklusa u nekoliko bolesti.
Primjerice, autoimune i upalne bolesti izvedene su iz neodgovarajućeg aktiviranja imunološkog sustava. Aktivirane imunološke stanice vrše ekspresiju mnogih gena koji kodiraju upalne molekule, uključujući citokine, čimbenike rasta, stanične površinske receptore, stanične adhezijske molekule i degradirajuće enzime. Za mnoge od ovih gena je poznato da su regulirani KNK ciklusom, aktiviranjem transkripcijskih čimbenika c-Jun i ATF-2.
Inhibiranje JNK aktiviranja u bakterijskim liposaharid-stimuliranim makrofagima, učinkovito modulira proizvodnju ključnog pro-upalnog citokina, TNFα�(11).
Inhibiranje JNK aktiviranja smanjuje aktiviranje transkripcijskog čimbenika koji je odgovoran za inducirajuću ekspresiju matričnih metaloproteaza (MMP) (12), što je poznato kao ono što je odgovorno za napredovanje erozije kostiju i hrskavice u reumatoidnom artritisu te u općem uništenju tkiva u drugim autoimunim bolestima.
JNK kaskada je također aktivirana u T-stanicama pomoću antigenskog stimuliranja i CD28 receptorskog kostimuliranja (13) te regulira proizvodnju IL-2 promotora (14). Neodgovarajuće aktiviranje T-limfocita potiče i nastavlja mnoge autoimune bolesti, uključujući astmu, upalni trbušni sindrom i multiplu sklerozu.
U neurona koji su skloni oštećenju pri Alzheimerovoj bolesti i u CA1 neurona bolesnika s akutnom hipoksijom (15), JNK3 protein je visoke ekspresije. JNK3 gen je također nađen s ekspresijom u oštećenim područjima mozga Alzheimerovih bolesnika (16). Nadalje, neuroni JNK3 KO miševa su nađeni rezistentni prema neuronskoj apoptozi koja je izazvana kainskom kiselinom, u odnosu na neurone miševa divljeg tipa (8).
Temeljem ovih nalaza, JNK signalni ciklus i posebice onaj JNK2 i JNK3, pretpostavlja se da je uključen u apoptozno pokrenutim neurodegenerativnim bolestima, kao što je Alzheimerova bolet, Parkinsonova bolest, epilepsija i napadaj, Huntingtonova bolest, traumatske ozljede mozga kao i ishemijski i hemoragični udar.
Kardiovaskularne bolesti, kao što su ateroskleroza i restenoza, rezultat su manjkavog reguliranja rasta krvožilnih stijenki. JNK ciklus se aktivira pomoću aterogenog stimulatora i regulira lokalni citokin i proizvodnju čimbenika rasta u vaskularnim stanicama (17, 18) izazivajući pro-aterosklerotični gen (19).
Ishemija koja je sama ili koja je povezana s reperfuzijom u srcu, jetri, bubrezima ili mozgu, rezultira staničnom smrću i nastajanjem ožiljka, što u konačnici vodi kongestivnom otkazivanju srca, hepatičkim poremećajima, otkazivanju bubrega ili moždanoj disfunkciji. JNK ciklus je aktiviran ishemijom i reperfuzijom u srcu (20), što vodi aktiviranju JNK-responzivnih gena i leukocitno upravljanom oštećenju tkiva. JNK aktiviranje se također uočava u bubrezima (21) ili jetri (22) nakon ishemije i reperfuzije. Podreguliranje JNK je dokazano da poboljšava bubrežnu funkciju i dugotrajne posljedice tijekom nefritičnog ili ishemičnog otkazivanja bubrega (23).
Karcinom je karakteriziran nekontroliranim rastom, proliferacijom i migracijom stanica. U ranom karcinomu pluća, ekspresija c-jun je promijenjena i može upravljati signaliziranjem čimbenika rasta u “non-small cell” karcinomu pluća (24). Osim što regulira c-jun proizvodnju i aktivnost, JNK aktiviranje može regulirati fosforiliranje p53, pa tako može modulirati progresiju staničnog ciklusa (25). Štoviše, uloga JNK aktiviranja u HTLV-1 (humani T-stanični virus leukemije tipa 1) upravljanom tumorgenezom (26) sugerira potencijalnu upotrebu JNK inhibitora u tretiranju karcinoma (27). Selektivno inhibiranje JNK aktiviranja pomoću prirodnog JNK inhibitorskog proteina, nazvanog JNK-interakcijski-protein-1 (JIP1), blokira stanično transformiranje (28). Dakle, JNK inhibitori mogu blokirati transformiranje i rast tumorskih stanica.
S ciljem koji je inhibiranje JNK kinaza ciklusa, patent WO/9849188 definira uporabu humanog polipeptida, tj. JNK-interakcijskog proteina 1 (JIP-1), koji je biološki proizvod i koji je također analiziran u svezi poremećaja koji su povezani s apoptozom.
Premda je potvrđeno da takvi humani polipeptidi imaju inhibitorski učinak na ciklus JNK kinaze, s njihovom uporabompovezan je cijeli niz nedostataka:
- Aktivni bio-peptidi ili bio-proteini dobivaju se samo putem opsežne i skupe biosinteze što je razlog da je konačni produkt skup.
- Za peptide je poznato da pokazuju slabu sposobnost prodiranja i da ne mogu proći moždanu krvnu membranu,
- Principijelni nedostatak uporabe peptidnih inhibitora ili antagonista je problem slabe oralne raspoloživosti koja je rezultat intestinalne degradacije. Dakle, on se mora primijeniti parenteralno i najzad,
- peptidni inhibitori ili antagonisti se često od strane domaćina smatraju tuđom tvari koju treba izbaciti, tako da se isključuje autoimuni odgovor.
Osobit značaj JNK ciklusa u nekih raširenih bolesti pojačava potrebu da se razviju inhibitori, poželjno selektivni, za JNK.
Prema tome, cilj ovog izuma je da se dobiju molekule koje su pogodne za tretiranje različitih bolesti, konkretno poremećaja živčanog ili autoimunog sustava, karcinoma, ishemijskih stanja i kardivaskularnih bolesti.
Cilj ovog izuma je da se dobiju kemijski spojevi koji mogu modulirati, poželjno podregulirati ili inhibirati JNK (Jun kinaza) put što može biti korisna metoda u tretiranju bolesti koje uključuju JNK ciklus.
Nadalje, cilj ovog izuma je definiranje metoda za priređivanje navedenih kemijskih spojeva. Također je cilj ovog izuma da se definira nova kategorija kemijskih formulacija za tretiranje bolesti, posebice onih kojima upravlja JNK funkcija.
Konačno, cilj ovog izuma je definiranje metode za tretiranje i/ili prevenciju bolesti koje su izazvane poremećajima autoimunog i/ili živačnog sustava.
Opis izuma
Gore navedeni ciljevi su postignuti sukladno neovisnim patentnim zahtjevima. Poželjne realizacije su definirane unutar ovisnih patentnih zahtjeva koji su ovdje uključeni.
U sljedećim odlomcima nalaze se definicije različitih kemijskih vrsta od kojih se sastoje spojevi sukladno ovom izumu te se odnose na cijelu ovu specifikaciju i patentne zahtjeve, osim ako drukčije navedena definicija ne daje šire definiranje.
“C1-C6 -alkil” odnosi se na monovalentne alkilne skupine koje imaju od 1 do 6 atoma ugljika. Primjer za skupine obuhvaćene ovim pojmom su metil, etil, n-propil, izopropil, n-butil, izobutil, tert-butil, n-heksil i slično.
“Aril” odnosi se na nezasićene aromatske ugljikove prstenaste skupine sa od 6 do 14 atoma ugljika koje se sastoje od jednog prstena (npr. fenil) ili više kondenziranih prstena (npr. naftil). Poželjne arilne skupine obuhvaćaju fenil, naftil, fenantril i slično.
“C1-C6-alkil aril” odnosi se na C1-C6-alkil skupine koje imaju arilni supstituent, uključujući benzil, fenetil i slično.
“Heteroaril” odnosi se na monocikličke heteroaromate, ili na bicikličke ili tricikličke združene heteroaromatske skupine. Konkretni primjeri heteroaromatskih skupina uključuju proizvoljno supstituirani piridil, pirolil, furil, tienil, imidazolil, oksazolil, izoksazolil, tiazolil, izotiazolil, pyrazolil, 1,2,3-triazolil, 1,2,4-triazolil, 1,2,3-oksadiazolil, 1,2,4-oksadiazolil, 1,2,5-oksadiazolil, 1,3,4-oksadiazolil,1,3,4-triazinil, 1,2,3-triazinil, benzofuril, [2,3-dihidro]benzofuril, izobenzofuril, benzotienil, benzotriazolil, izobenzotienil, indolil, izoindolil, 3H-indolil, benzimidazolil, imidazo[1,2-a]piridil, benzotiazolil, benzoksazolil, kinolizinil, kinazolinil, fhalazinil, kinoksalinil, cinnolinil, nafhiridinil, pirido[3,4-b]piridil, pirido[3,2-b]piridil, pirido[4,3-b]piridil, kinolil, izokinolil, tetrazolil, 5,6,7,8-tetrahidrokinolil, 5,6,7,8-tetra-hidroizokinolil, purinil, pteridinil, karbazolil, ksantenil ili benzokinolil.
“C1-C6-alkil heteroaril” odnosi se na C1-C6-alkilne skupine koje imaju heteroarilni supstituent, uključujući 2-furiylmetil, 2-tienilmetil, 2-(1H-indol-3-il)etil i slično.
“Alkenil” odnosi se na alkenilne skupine koje poželjno imaju 2 do 6 atoma ugljika i imaju bar 1 do 2 mjesta alkenilnog nezasićenja. Poželjne alkenilne skupine uključuju etenil (-CH=CH2), n-2-propenil (alil, -CH2CH=CH2) i slično.
“Alkinil” odnosi se na alkinilne skupine koje poželjno imaju od 2 do 6 atoma ugljika i iaju bar 1-2 mjesta alkinilnog nezasićenja, a poželjne alkinilne skupine uključuju etinil (-C≡CH), propargil (-CH2C≡CH), i slično.
“Acil” odnosi se na skupinu –C(O)R gdje R uključuje “C1-C6-alkil”, “aril”, “heteroaril”, “C1-C6-alkil aril” ili “C1-C6-alkil heteroaril”.
“Aciloksi” odnosi se na skupinu –OC(O)R gdje R uključuje “C1-C6-alkil”, “aril”, “heteroaril”, “C1-C6-alkil aril” ili “C1-C6-alkil heteroaril”.
“Alkoksi” odnosi se na skupinu –O-R gdje R uključuje “C1-C6-alkil“ ili “aril” ili “hetero-aril” ili “C1-C6-alkil aril” ili “C1-C6-alkil heteroaril”. Poželjne alkoksi skupine uključuju, primjerice, metoksi, etoksi, fenoksi i slično.
“Alkoksikarbonil” odnosi se na skupinu –C(O)OR gdje R uključuje “C1-C6-alkil” ili “aril” ili “heteroaril” ili “C1-C6-alkil aril” ili “C1-C6-alkil heteroaril”.
“Aminokarbonil” odnosi se na skupinu –C(O)NRR’ gdje svaki R, R’ uključuje neovisno vodik ili C1-C6-alkil ili aril ili heteroaril ili “C1-C6-alkil aril” ili “C1-C6-alkil heteroaril”.
“Acilamino” odnosi se na skupinu –NR(CO)R’ gdje je svaki R, R’ neovisno vodik ili “C1-C6-alkil” ili “aril” ili “heteroaril” ili “C1-C6-alkil aril” ili “C1-C6-alkil heteroaril”.
“Halogen” se odnosi na atome fluora, klora, broma i joda.
“Sulfonil” odnosi se na skupinu “–SO2-R“ gdje R je odabran između H, “aril”, “heteroaril”, “C1-C6-alkil”, “C1-C6-alkil” supstituiranih s halogenima, npr.–SO2-CF3 skupine, “C1-C6-alkil aril” ili “C1-C6-alkil heteroaril”.
“Sulfoksi” odnosi se na skupinu “–S(O)-R” gdje R je odabran između H, “C1-C6-alkil”, “C1-C6-alkil” supstituiranih s halogenima, npr.–SO-CF3 skupine, “aril”, “heteroaril” , “C1-C6-alkil aril” ili “C1-C6-alkil heteroaril”.
“Tioalkoksi” odnosi se na skupinu –S-R gdje R uključuje “C1-C6-alkil“ ili “aril” ili “heteroaril” ili “C1-C6-alkil aril” ili “C1-C6-alkil heteroaril”. Poželjne tioalkoksi skupine uključuju tiometoksi, tioetoksi i slične.
“Supstituirani ili nesupstituirani”: Ako nije drukčije određeno definicijom pojedinih supstituenata, gore navedene skupine, poput “alkil“, “alkenil“, “alkinil“, “aril“ i “heteroaril“ itd. skupina mogu proizvoljno biti supstituirane s 1 do 5 supstituenata koji su odabrani iz skupa kojega sačinjavaju “C1-C6-alkil“, “C1-C6-alkil aril“, “C1-C6-alkil heteroaril“, “C2-C6-alkenil“, “C2-C6-alkinil“, primarne, sekundarne ili tercijarne aminoskupine ili kvarterne amonijeve specije, “acil“, “aciloksi“, “acilamino“, “aminokarbonil“, “alkoksikarbonil“, “aril“, “heteroaril“, karboksil, cijano, halogen, hidroksi, merkapto, nitro, sulfoksi, sulfonil, alkoksi, tioalkoksi, trihalogenmetil i slično. Alternativno, navedene supstitucije mogu također obuhvaćati situacije kada susjedni supstituenti podliježu zatvaranju prstena, odnosno kada su uključeni susjedni funkcionalni supstituenti, pa tako nastaju npr. laktami, laktoni, ciklički anhidridi, ali također i acetali, tioacetali, aminali koji nastaju zatvaranjem prstena, primjerice u pokušaju da se dobije zaštitna skupina.
Pojam “farmaceutski prihvatljive soli ili kompleksi” odnosi se na soli ili komplekse niže definiranih spojeva formule I koji zadržavaju željenu biološku aktivnost. Primjeri takvih soli uključuju, ali nisu ograničeni na kisele adicijske soli koje nastaju s anorganskim kiselinama (npr. klorovodičnom kiselinom, bromovodičnom kiselinom, sumpornom kiselinom, fosfornom kiselinom, dušičnom kiselinom i slično), soli koje nastaju s organskim kiselinama kao što su octena kiselina, oksalna kiselina, vinska kiselina, jantarna kiselina, jabučna kiselina, fumarna kiselina, maleinska kiselina, askorbinska kiselina, benzojeva kiselina, taninska kiselina, pamoična kiselina, alginska kiselina, poliglutaminska kiselina, naftalen sulfonska kiselina, naftalen disulfonska kiselina i poligalakturonska kiselina. Navedeni spojevi mogu se primijeniti kao farmaceutski aktivne kvarterne soli što je poznato onima koji poznaju ovo područje, što specifično uključuje kvarterne amonijeve soli formule–NR,R’,R” + Z-, gdje R, R’, R” su neovisno vodik, alkil ili benzil, a Z je protivion, uključujući klorid, bromid, jodid, -O-alkil, toluenesulfonat, metilsulfonat, sulfonat, fosfat ili karboksilat (kao što je benzoat, sukcinat, acetat, glikolat, maleat, malat, fumarat, citrat, tartrat, askorbat, cinamoat, mandeloat i difenilacetat).
“Farmaceutski aktivan derivat” odnosi se na bilo koji spoj koji nakon primjene primatelju može neposredno ili posredno djelovati aktivno.
“Ionizirajuća specija” odnosi sena funkcionalne skupine, gdje je karakteristična elektronska raspodjela odogovrna što se navedena specija može transformirati u ionsku ili ioniziranu skupinu, ili drugim riječima u sol. Poželjne ionizirajuće specije su bazične skupine kao što su amini koji protonirani daju sol.
“Suštinski topljiv” označuje spoj ovog izuma koji ima dobru topljivost u vodenim otapalima. Poželjan prag je oko 50 μg/mL otapala, poželjnije bar 100 μg/mL otapala.
“Lipofilni lanac” odnosi se na skupine koje imaju izraženu sklonost prema hidrofobnim skupinama, supstituentima ili spojevima, dotično prema lipidima ili specijama ili spojevima masnih kiselina. To obuhvaća proizvoljno supstituirane C4-C18-alkilne skupine ili supstituirane ili nesupstituirane alkil-arilne skupine.
“Hidrofilna skupina” odnosi se na funkcionalne skupine koje imaju izraženu sklonost prema hidrofilnim ili polarnim skupinama, supstituentima ili spojevima ili spojevima ili specijama masnih kiselina.
To konkretno obuhvaća karboksilate, hidrokside, sulfate ili sulfonate ili amine ili amonijeve soli.
“Enantiomerni suvišak” (ee) odnosi se na produkte koji se dobivaju praktički enantiomernom sintezom ili sintezom koja uključuje enantioselektivni stupanj, pri čemu se dobiva suvišak jednog enantiomera u odnosu na drugi za bar oko 52% ee. U odsutnosti enantiomerne sinteze, obično se dobivaju racemički produkti koji također posjeduju aktivnost ovog izuma kao JunK 2 i/ili 3 inhibitori.
Jedan aspekt ovog izuma sastoji se u sulfonamidskim derivatima sukladno formuli I:
[image] I
Ar1 i Ar2 su međusobno neovisno arilna ili heteroarilna skupina,
X je O ili S, poželjno O.
R1 je vodik ili C1-C6-alkilna skupina, poželjno H, ili R1 čini 5-6-člani zasićeni ili nezasićeni prsten s Ar1,
n je cijeli broj između 0 i 5, poželjno između 1 i 3, a najpoželjnije 1.
Y u formuli I je 4-12-člani zasićeni ciklički ili biciklički alkil koji sadrži dušik, koji čini vezu sa sulfonilnom skupinom formule I. Navedeni 4-12-člani zasićeni ciklički ili biciklički alkil je supstituiran s bar jednom ionizirajućom specijom koja nosi lipofilni lanac.
Gore navedena ionizirajuća specija u L1 donosi povećanu stabilnost molekula formule I, u odnosu na sulfonamidske spojeve koji nemaju takvu speciju.
Osobito jaki spojevi formule I u odnosu na inhibiranje JNK, a poglavito JNK 2 i/ili 3, su oni spojevi gdje L1 također sadrži lipofilnu speciju. Za takve lipofilne skupine se vjeruje da ulaze u šupljine enzima koji se inhibira.
Ovim izumom su također obuhvaćni geometrijski izomeri, optički aktivni oblici, enantiomeri, diastereomeri spojeva sukladno formuli I, ako i njihovi racemati i također farmaceutski prihvatljive soli te farmaceutski aktivni derivati sulfonamidnih derivata formule I.
Poželjni Ar1 i Ar2 u formuli I su oni koji su neovisno odabrani iz skupa kojega sačinjavaju ili koji se sastoji od skupina fenil, tienil, furanil, pirol, piridil, proizvoljno supstituirani sa supstituiranim ili nesupstituiranim C1-C6-alkil, kao trihalometil, supstituirani ili nesupstituirani C1-C6-alkoksi, supstituirani ili nesupstituirani C2-C6-alkenil, supstituirani ili nesupstituirani C2-C6-alkinil, amino, acilamino, aminokarbonil, C1-C6-alkoksikarbonil, aril, karboksil, cijano, halo, hidroksi, nitro, sulfonil, sulfoksi, aciloksi, C1-C6- tioalkoksi. Najpoželjniji Ar1 je supstituirani fenil uključujući halogenofenil (npr. 4-klorfenil), nitrofenil, hidroksifenil, alkoksi fenil, piridil, 3,4,-dihidroksifenil, tiokso-dihidropiridin ili njegove tautomere, pirazol dok je najpoželjniji Ar2 nesupstituirani ili supstituirani tienil ili furanilna skupina.
Poželjno, takvi supstituenti koji su vezani za navedenu tienilnu ili furanilnu skupinu su hidrofilne skupine što su molekule koje posjeduju bolju topljivost prema molekulama formule I. To obuhvaća karboksilne skupine, karboksilate, karboksamide, OH ili OH-alkilne skupine, hidrazido karbonilne skupine, sulfate ili sulfonate ili amine ili amonijeve soli. Hidrofilni supstituenti na Ar2 su od osobitog značaja da bi se dodatno povećala topljivost molekula formule I.
Kada je Ar1 4-klorfenil, nitrofenil, hidroksifenil, alkoksi fenil, piridil, 3,4,-dihidroksifenil, tiokso-dihidropiridin ili njihov tautomer, pirazolna skupina, X je poželjno O, R1 je vodik, n je 1 i Ar2 je tienil ili furanil.
Oosbito poželjna realizacija ovog izuma odnosi se na sulfonamidne derivate, gdje je Y pirolidin, azepan ili piperidinska specija dolje navedene formule.
[image] ili [image] ili [image]
U navedenim formulama, R6 je odabran iz skupa kojega sačinjavaju vodik, supstituirani ili nesupstituirani C1-C6-alkil, supstituirani ili nesupstituirani C1-C6-alkoksi, OH, halogen, nitro, cijano, sulfonil, okso (=O), sulfoksi, aciloksi, tioalkoksi i kada R6 nije vodik, n’ je cijeli broj od 0 do 4, poželjno 1 ili 2, pri čemu je bar jedan od L1 i/ili L2 ionizirajuća vrsta na koju je vezan lipofilni lanac.
U poželjnijoj realizaciji sulfonamidnih derivata sukladno formuli I, Y je pirolidin, azepan ili piperidinska vrsta kao što je prije opisano, gdje R6 je H, L2 je H, L1 je –NR3’R3; gdje bar jedan od R3’ i R3 nije vodik, već supstituent koji je odabran iz skupa kojega sačinjavaju lančasti ili razgranati C4-C18-alkil, aril-C1-C18-alkil, heteroaril-C2-C18-alkil, C1-C14-alkil supstituiran s C3-C12-cikloalkil ili -biciklo ili -tricikloalkil, pri čemu navedeni alkilni lanac može sadržavati 1-3 atoma kisika ili sumpora.
Poželjniji L1 je –NHR3; gdje je R3 lančasti ili razgranati C4-C12-alkil, poželjno C6-C12-alkil, proizvoljno supstituiran s cikloheksilnom skupinom ili je R3 benzilna specija.
Najpoželjniji sulfonamidni derivati sukladno ovom izumu su oni gdje je Y piperidinska skupina
[image]
i gdje L1 je –NHR3; pri čemu je R3 lančasti ili razgranati C6-C12-alkil, poželjno C8-C12-alkil, ili je R3 benzilna specija..
Specifični primjeri spojeva formule I uključuju sljedeće:
4-klor-N-[(5-{[4-(heksilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
3-Metoksi-N-{[5-({4-[(4-trifluormetilbenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-[(5-{[4-(1,3-tiazol-2-ilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-[(5-{[4-(heptilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-[(5-{[4-(pentilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-[(5-{[4-(butilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-[(5-{[4-(dodecilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-{[5-({4-[(2-cikloheksiletil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({4-[(cikloheksilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-({5-[(4-{[(1R)-1-cikloheksiletil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)benzamid
N-{[5-({4-[(1R,2R,4S)-biciklo[2.2.1]hept-2-ilamino]piperidin-1-il}sulfonil)tien-2-il]metil}-4-klorbenzamid
4-klor-N-{[5-({4-[(2-propoksietil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[(1-adamantilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-4-klorbenzamid
4-klor-N-{[5-({4-[(2-piridin-2-iletil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({4-[(2-piperidin-1-iletil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({4-[(2-etilheksil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-({5-[(4-{[3-(1H-imidazol-1-il)propil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)benzamid
4-klor-N-[(5-{[4-(oktilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
N-[(5-{[4-(heptilamino)piperidin-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
3-metoksi-N-[(5-{[4-(oktilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
3-metoksi-N-[(5-{[4-(pentilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
N-[(5-{[4-(butilamino)piperidin-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
N-[(5-{[4-(dodecilamino)piperidin-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
N-{[5-({4-[(2-cikloheksiletil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-({5-[(4-{[(1R)-1-cikloheksiletil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)-3-metoksibenzamid
N-{[5-({4-[(1R,2R,4S)-biciklo[2.2.1]hept-2-ilamino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(2-propoksietil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[(1-adamantilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-{[5-({4-[(3,3-dietoksipropil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(3-morfolin-4-ilpropil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(2-piridin-2-iletil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(2-piperidin-1-iletil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[(2-etilheksil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-({5-[(4-{[3-(1H-imidazol-1-il)propil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)-3-metoksibenzamid
N-[(5-{[4-(heksilamino)piperidin-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
N-[(5-{[4-(heptilamino)azepan-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
3-metoksi-N-[(5-{[4-(oktilamino)azepan-1-il]sulfonil}tien-2-il)metil]benzamid
3-metoksi-N-[(5-{[4-(pentilamino)azepan-1-il]sulfonil}tien-2-il)metil]benzamid
N-[(5-{[4-(butilamino)azepan-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
N-[(5-{[4-(dodecilamino)azepan-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
N-{[5-({4-[(2-cikloheksiletil)amino]azepan-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-({5-[(4-{[(1R)-1-cikloheksiletil]amino}azepan-1-il)sulfonil]tien-2-il}metil)-3-metoksibenzamid
N-{[5-({4-[(1R,2R,4S)-biciklo[2.2.1]hept-2-ilamino]azepan-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(2-propoksietil)amino]azepan-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[(cikloheksilmetil)amino]azepan-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-{[5-({4-[(1-adamantilmetil)amino]azepan-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(3-morfolin-4-ilpropil)amino]azepan-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(2-piridin-2-iletil)amino]azepan-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(2-piperidin-1-iletil)amino]azepan-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[(2-etilheksil)amino]azepan-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-({5-[(4-{[3-(1H-imidazol-1-il)propil]amino}azepan-1-il)sulfonil]tien-2-il}metil)-3-metoksibenzamid
4-klor-N-[(5-{[4-(heptilamino)azepan-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-[(5-{[4-(oktilamino)azepan-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-[(5-{[4-(pentilamino)azepan-1-il]sulfonil}tien-2-il)metil]benzamid
N-[(5-{[4-(butilamino)azepan-1-il]sulfonil}tien-2-il)metil]-4-klorbenzamid
4-klor-N-[(5-{[4-(dodecilamino)azepan-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-{[5-({4-[(2-cikloheksiletil)amino]azepan-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[(1R,2R,4S)-biciklo[2.2.1]hept-2-ilamino]azepan-1-il}sulfonil)tien-2-il]metil}-4-klorbenzamid
4-klor-N-{[5-({4-[(2-propoksietil)amino]azepan-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({4-[(2-etilheksil)amino]azepan-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-[(5-{[4-(heksilamino)azepan-1-il]sulfonil}tien-2-il)metil]benzamid
N-[(5-{[4-(heksilamino)azepan-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
3-metoksi-N-[(5-{[4-({2-[3-(trifluormetil)fenil]etil}amino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
3-metoksi-N-({5-[(4-{[2-(4-metilfenil)etil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)benzamid
3-metoksi-N-({5-[(4-{[(1S,2R)-2-fenilciklopropil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)benzamid
3-metoksi-N-{[5-({4-[(1-naphthylmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(2-fenilpropil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-({5-[(4-{[2-(4-hidroksifenil)etil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(3-fenilpropil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[(2,3-dihidroksipropil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-{[5-({4-[(2-hidroksietil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-[(5-{[4-(nonilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
3-metoksi-N-[(5-{[4-(decilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
3-metoksi-N-[(5-{[4-(etilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
N-{[5-({4-[(2-[1,1'-bifenil]-4-iletil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-{[5-({4-[([1,1'-bifenil]-3-ilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(2-tien-2-iletil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-[(5-{[4-({4-[(trifluormetil)sulfonil]benzil}amino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
3-metoksi-N-{[5-({4-[(kinolin-4-ilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[([1,1'-bifenil]-4-ilmetil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
4-klor-N-{[5-({4-[(2-{[(trifluormetil)sulfonil]amino}etil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}benzamid
4-klor-N-[(5-{[4-(propilamino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
4-klor-N-[(5-{[4-({4-[(trifluormetil)sulfonil]benzil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
4-klor-N-{[5-({4-[(3,4-dihidroksibenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}benzamid
metil [{1-[(5-{[(4-klorbenzoil)amino]metil}-2-tienil)sulfonil]-4-piperidinil}(heksil)amino]acetat
tert-butil [{1-[(5-{[(4-klorbenzoil)amino]metil}-2-tienil)sulfonil]-4-piperidinil}(heksil)amino]acetat
[{1-[(5-{[(4-klorbenzoil)amino]metil}-2-tienil)sulfonil]-4-piperidinil}(heksil)amino]octena kiselina
N-[(5-{[3-(heptilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
3-metoksi-N-[(5-{[3-(oktilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]benzamid
3-metoksi-N-[(5-{[3-(pentilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]benzamid
N-[(5-{[3-(butilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
N-[(5-{[3-(dodecilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
N-{[5-({3-[(2-cikloheksiletil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-({5-[(3-{[(1R)-1-cikloheksiletil]amino}pirolidin-1-il)sulfonil]tien-2-il}metil)-3-metoksibenzamid
N-{[5-({3-[(1R,2R,4S)-biciklo[2.2.1]hept-2-ilamino]pirolidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({3-[(2-propoksietil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({3-[(cikloheksilmetil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-{[5-({3-[(1-adamantilmetil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({3-[(3-morfolin-4-ilpropil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({3-[(2-piridin-2-iletil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({3-[(2-piperidin-1-iletil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({3-[(2-etilheksil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-[(5-{[3-(heksilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
4-klor-N-[(5-{[3-(heptilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-[(5-{[3-(heksilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-[(5-{[3-(pentilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]benzamid
N-[(5-{[3-(butilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]-4-klorbenzamid
4-klor-N-{[5-({3-[(2-cikloheksiletil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({3-[(1R,2R,4S)-biciklo[2.2.1]hept-2-ilamino]pirolidin-1-il}sulfonil)tien-2-il]metil}-4-klorbenzamid
4-klor-N-({5-[(3-{[(1-hidroksicikloheksil)metil]amino}pirolidin-1-il)sulfonil]tien-2-il}metil)benzamid
N-{[5-({3-[(1-adamantilmetil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}-4-klorbenzamid
4-klor-N-{[5-({3-[(3-morfolin-4-ilpropil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({3-[(2-piridin-2-iletil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({3-[(2-piperidin-1-iletil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({3-[(2-etilheksil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-[(5-{[3-(oktilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]benzamid
metil (2S)-1-[(5-{[(4-klorbenzoil)amino]metil}-2-tienil)sulfonil]-4-(heksilamino)-2-pirolidinekarboksilat
3-metoksi-N-{[5-({4-[(pentilamino)metil]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[2-(butilamino)etil]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-{[5-({4-[(4-butilanilino)metil]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
4-klor-N-{[5-({4-[heksil(metil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({4-[(cikloheksilmetil)(heksil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[benzil(heksil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-4-klorbenzamid
4-klor-N-{[5-({4-[heksil(piridin-3-ilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({4-[heksil(piridin-4-ilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({4-[heksil(piridin-2-ilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[butil(heksil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-4-klorbenzamid
4-klor-N-{[5-({4-[heksil(3-fenilpropil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({4-[heksil(2-feniletil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[[(5-bromo-2-furyl)metil](heksil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-4-klorbenzamid
3-metoksi-N-({5-[(4-{metil[4-(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)benzamid
4-klor-N-{[5-({4-[(3-klorbenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-({5-[(4-{[4-(trifluormetil)benzil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)benzamid
3-metoksi-N-{[5-({4-[(3-metilbenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(4-propilbenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-({5-[(4-{[3-(trifluormetil)benzil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)benzamid
3-metoksi-N-({5-[(4-{[4-(trifluormetoksi)benzil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)benzamid
N-({5-[(4-{[4-(difluormetoksi)benzil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(2,3,4,5,6-pentametilbenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(4-propoksibenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[(4-butoksibenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(4-metoksibenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(piridin-4-ilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(piridin-2-ilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(piridin-3-ilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[(4-tert-butilbenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-{[5-({4-[(3-etoksibenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(4-fenoksibenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-[(5-{[4-({4-[(trifluormetil)sulfanil]benzil}amino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
3-metoksi-N-({5-[(4-{[4-(metilsulfonil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)benzamid
N-({5-[(4-{[3,5-bis(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)-3-metoksibenzamid
N-({5-[(4-{[2,5-bis(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)-3-metoksibenzamid
N-({5-[(4-{[4-(etilsulfanil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)-3-metoksibenzamid
3-metoksi-N-[(5-{[4-({3-[(trifluormetil)sulfanil]benzil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
N-({5-[(4-{[(2,2-difluor-1,3-benzodioxol-5-il)metil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)-3-metoksibenzamid
N-{[5-({4-[(4-iodobenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
N-({5-[(4-{[4-(benziloksi)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)-3-metoksibenzamid
N-{[5-({4-[(mezitilmetil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
N-{[5-({4-[(4-klorbenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
N-{[5-({4-[(4-etilbenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(4-pentilbenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}benzamid
3-metoksi-N-[(5-{[4-({1-[4-(trifluormetil)fenil]etil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
3-metoksi-N-{[5-({4-[(4-metilbenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}benzamid
N-{[5-({4-[(4-butilbenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
N-{[5-({4-[(4-izopropilbenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
N-{[5-({4-[(4-izobutilbenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
N-({5-[(4-{[(1-hidroksi-1lambda~5~-piridin-4-il)metil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)-3-metoksibenzamid
N-{[5-({4-[(2,3-dihidro-1,4-benzodioksin-6-ilmetil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
N-{[5-({4-[(2,3-dihidro-1-benzofuran-5-ilmetil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
4-klor-N-{[5-({4-[(4-propilbenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}benzamid
4-klor-N-({5-[(4-{[4-(trifluormetoksi)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)benzamid
4-klor-N-({5-[(4-{[4-(difluormetoksi)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)benzamid
4-klor-N-{[5-({4-[(4-propoksibenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}benzamid
N-{[5-({4-[(4-butoksibenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-4-klorbenzamid
4-klor-N-{[5-({4-[(4-kinolinylmetil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}benzamid
N-{[5-({4-[(4-tert-butilbenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-4-klorbenzamid
4-klor-N-{[5-({4-[(4-fenoksibenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}benzamid
4-klor-N-[(5-{[4-({4-[(trifluormetil)sulfanil]benzil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
4-klor-N-({5-[(4-{[4-(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)benzamid
3-metoksi-N-({5-[(4-{[2-(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)benzamid
3-metoksi-N-[(5-{[4-({[6-(trifluormetil)-3-piridinil]metil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
N-[(5-{[4-(benzilamino)-1-piperidinil]sulfonil}-2-tienil)metil]-3-metoksibenzamid
3-metoksi-N-[(5-{[4-({1-[4-(trifluormetil)fenil]propil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
3-metoksi-N-[(5-{[4-({1-metil-1-[4-(trifluormetil)fenil]etil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
4-klor-N-[(5-{[4-({1-[4-(trifluormetil)fenil]etil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
4-klor-N-[(5-{[4-({1-metil-1-[4-(trifluormetil)fenil]etil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
4-klor-N-[(5-{[2-({[4-(trifluormetil)benzil]amino}metil)-1-pirolidinil]sulfonil}-2-tienil)metil]benzamid
4-klor-N-[(5-{[(3R)-3-({[4-(trifluormetil)benzil]amino}metil)pirolidinil]sulfonil}-2-tienil)metil]benzamid
4-klor-N-({5-[(3-{[4-(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)benzamid
4-klor-N-{[5-({3-[(heksilamino)metil]-1-piperidinil}sulfonil)-2-tienil]metil}benzamid
4-klor-N-({5-[(3-{[4-(trifluormetil)benzil]amino}-1-pirolidinil)sulfonil]-2-tienil}metil)benzamid
4-klor-N-{[5-({(3R)-3-[(heksilamino)metil]pirolidinil}sulfonil)-2-tienil]metil}benzamid
4-klor-N-[(5-{[3-({[4-(trifluormetil)benzil]amino}metil)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
2-okso-N-({5-[(4-{[4-(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)-1,2-dihidro-3-piridinkarboksamid
N-[(5-{[4-(heksilamino)-1-piperidinil]sulfonil}-2-tienil)metil]-2-okso-1,2-dihidro-3-piridinkarboksamid
N-[(5-{[4-(heksilamino)-1-piperidinil]sulfonil}-2-tienil)metil]-2-hidroksibenzamid
2-hidroksi-N-({5-[(4-{[4-(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)benzamid
N-[(5-{[4-(heksilamino)-1-piperidinil]sulfonil}-2-tienil)metil]-2-tiokso-1,2-dihidro-3-piridinkarboksamid
2-tiokso-N-({5-[(4-{[4-(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)-1,2-dihidro-3-piridinkarboksamid
N-[(5-{[4-(butilamino)-1-piperidinil]sulfonil}-2-tienil)metil]-2-okso-1,2-dihidro-3-piridinkarboksamid
N-({5-[(4-{etil[4-(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)-3-metoksibenzamid
4-klor-N-[(5-{[4-({imino[4-(trifluormetil)fenil]metil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
1-[(5-{[(4-klorbenzoil)amino]metil}-2-tienil)sulfonil]-4-(heksilamino)prolin
etil 2-{[4-(heksilamino)piperidin-1-il]sulfonil}-5-{[(3-metoksibenzoil)amino]metil}tiofen-3-karboksilat
N-{[5-{[4-(heksilamino)piperidin-1-il]sulfonil}-4-(trimetilsilil)tien-2-il]metil}-3-metoksibenzamid
N-({5-{[4-(heksilamino)piperidin-1-il]sulfonil}-4-[hidroksi(fenil)metil]tien-2-il}metil)-3-metoksibenzamid
5-[(3-Metoksi-benzoilamino)-metil]-2-[4-(4-trifluormetil-benzilamino)-piperidin-1-sulfonil]-tiofen-3-karboksilic acid etil ester
N-[(4-klor-5-{[4-(heksilamino)piperidin-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
Spojevi formule I pogodni su za tretiranje poremećaja imunološkog sustava i živčanog sustava sisavaca, poglavito ljudi. Takvi poremećaji živčanog sustava uključuju primjerice neurodegenerativne bolesti, npr. Alzheimerovu bolest, Huntingtonovu bolest, Parkinsonovu bolest, bolesti mrežnice, ozljede kralježnice, multiplu sklerozu, ozljede glave, epilpsiju i ataku, ishemički i hemoragijski moždani udar. Poremećaji imunološkog sustava uključuju primjerice astmu, odbacivanje transplantiranog organa, upalne procese kao što su upalna trbušna bolest (IBD), poremećaji povezani s oštećenjem hrskavice i kostiju, reumatoidni artritis, septični šok.
Spojevi sukladno formuli I su također pogodni za korištenje pri tretiranju karcinoma, kao što su karcinom dojke, debelog crijeva, gušterače, prostate, testisa, jajnika, pluća, jetre i bubrega.
U drugoj realizaciji, spojevi sukladno formuli I mogu se koristiti za tretiranje kardiovaskularnih bolesti uključujući aterosklerozu, restenozu, srčani udar, ishemiju, npr. cerebralnu ishemiju, infarkt miokarda.
U sljedećoj realizaciji, spojevi sukladno formuli I mogu se koristiti za tretiranje različitih ishemičkih stanja uključujući prestanak rada srca i bubrega, hepatičke poremećaje i moždane reperfuzijske ozljede.
Poželjno, spojevi prema formuli I, sami ili u obliku farmaceutskih smjesa, korisni su za moduliranje JNK ciklusa, specifičnije za tretiranje ili prevenciju poremećaja koji su povezani s ekspresijom ili aktivnošću JNK, dotično JNK2 ili -3. Navedeno moduliranje obično poželjno uključuje inhibiranje JNK ciklusa, dotično JNK2 i/ili -3. Takva nenormalna ekspresija ili aktivnost JNK može biti potaknuta različitim stimulansima (npr. stres, septični šok, oksidativni stres, citokini) i može izazvati cijeli lanac procesa koji vode prema, primjerice, nekontroliranoj apoptozi, upalnim odgovorima ili onkogenim procesima. Ovi fenomeni su često uključeni u različitim poremećajima što uključuje gore nabrojane poremećaje i bolesti. Dakle, spojevi sukladno ovom izumu mogu se koristiti za tretiranje poremećaja moduliranjem JNK funkcije ili signalnih ciklusa. Moduliranje JNK funkcije ili ciklusa može uključivati njegovo aktiviranje, ali poželjno uključuje podreguliranje do inhibiranja JNK ciklusa, dotično JNK1 i/ili -2 i/ili JNK3. Spojevi ovog izuma mogu se kroistiti sami ili u kombinaciji s drugim farmaceutskim sredstvima, npr. s drugim JNK modulatorom.
Sljedeći cilj ovog izuma je definiranje procesa za priređivanje novih sulfonamidskih derivata sukladno formuli I koja je navedena prije. Sulfonamidski derivati ovog izuma mogu se prirediti iz lako dostupnih polaznih tvari korištenjem sljedećih općih metoda i postupaka.
Valja naglasiti da tamo gdje su dani poželjni eksperimentalni uvjeti (npr. reakcijska temperatura, vrijeme, količina reagensa, otapala itd.), mogu se koristiti i drugi eksperimentalni uvjeti, ako nije drukčije navedeno. Optimalni reakcijski uvjeti mogu varirati ovisno o konkretnim reaktantim ili otapalima koji se koriste, ali takve uvjete može odrediti onaj tko poznaje ovo područje rutinskim postupcima optimiziranja.
Spojevi formule I mogu se dobiti bilo kojim pristupom koji su prikazani na shemama 1 ili 2:
Shema 1
[image]
Shema 2
[image]
Ovdje, Ar1, Ar2, R1, L i n su ko što je prije definirano, P je pogodna zaštitna skupina (R1 poželjno nije vodik, već je poželjno zaštitna skupina).
Sulfonil kloridi formule (V), kao oni koji se rabe u shemi 1, mogu se prirediti sukladno postupku koji je prikazan na shemi 3.
Shema 3 :
[image]
Ovdje, Ar1, Ar2, R1 i n su kao što je prije definirano.
Amini formule II su bilo poznati spojevi ili se mogu prirediti iz poznatih spojeva standardnim postupcima. Poželjni amini kao polazne tvari uključuju tien-2-il-metilamin, furan-2-il-metilamin, pirolil-2-il-metilamin, piridil-2-il-metilamin, tien-2-il-etilamin, furan-2-il-etilamin, piridil-2-il-etilamin, tien-2-il-propilamin, furan-2-il-propilamin, piridil-2-il-propilamin i slično.
Acil kloridi formule III su također komercijalno dostupni, kao i prethodno opisani spojevi. Poželjni acil kloridi uključuju halogenobenzoilkloride, npr. 4-klorbenzoil klorid, 4-fluorbenzoil klorid ili trifluormetilbenzoil klorid, alkoksibenzoilklorid, piridilkarbonilklorid i slično. Acil halogenidi (III) se mogu također prirediti reakcijom odgovarajuće karboksilne kiseline s anorganskim kiselim halogenidom, kao što je tionil klorid, fosforni triklorid ili oksalil klorid u standardnim uvjetima. Općenito, takva reakcija s evrši korištenjem 1 do 5 molarnih ekvivalenata acil halogenida ili oksalil klorida, bilo u čistom obliku ili u inertnom otapalu, kao što je ugljik tetraklorid, u temperaturnom rasponu od oko 0°C do oko 80°C tijekom 1do 48 sati. U ovoj reakciji može se koristiti katalizator, kao što je N,N-dimetilformamid.
Kada se koristi acil halogenid (III) u reakciji vezanja koja je prikazana na shemi 3, tipično reagira s aminom (II) u prisutnosti odgovarajuće baze da se ukloni kiselina koja nastaje tijekom reakcije. Odgovarajuće baze obuhvaćaju, primjerice, trietilamin, diizopropiletilamin, N-metilmorfolin i slično. Alternativno, može se koristiti suvišak amina II za uklanjanje kiseline koja nastaje tijekom reakcije.
Alternativno, karboksilna kiselina spoja (III) može se koristiti u reakciji vezanja. Karboksilne kiseline i derivati (III) su obično komercijalno raspoloživi reagensi ili se mogu prirediti standardnim postupcima.
Reakcija vezanja karbokilne kiseline formule (III) (npr. acil klorid) s aminom (II) tipično se vrši uz korištenje nekog standardnog vezujućeg reagensa kao što su, na primjer, karbodiimidi kao što su dicikloheksilkarbodiimid, N-(3-dimetilaminopropil)-N’-etilkarbodiimid i drugi promotorski reagensi, kao što je N,N-karbonil-diimidazol ili PyBOP. Ova reakcija može se provesti sa ili bez uporabe dobro poznatih dodataka kao što su N-hidroksisukcinimid, 1-hidroksibenzotriazol, itd. za koje je poznato da olakšavaju vezanje karboksilnih kiselina i amina.
Reakcija vezanja korištenjem bilo acil halogenida (III) ili njegove karboksilne kiseline poželjno se vrši pri temperaturi od oko 0°C do oko 6°C tijekom 1 do oko 24 sati. Tipično, reakcija se provodi u inertnom neprotonskom polarnom otapalu kao što je N,N-dimetilformamid, diklormetan, klorform, acetonitril, tetrahidrofuran i slično, korištenjem oko 1 do oko 5 molarnih ekvivalenata amina temeljem karboksilne kiseline ili kiselinskog hlogenida. Nakon završetka reakcije, karboksamid (IV) se sakuplja standardnim metodama uključujući tloženje, kromatografiju, filtriranje, destilaciju i slično.
Sulfonil kloridi formule V koji su neophodni za priređivanje konačnog produkta formule I, dakle oni koji su sulfonilpiperidini ili –pirolidini ili –azepani, priređuju se standardnim metodama sulfoniranja koje se primijenjuju na karboksamide (IV):
[image]
Poželjan sulfonirajući reagens za uporabu u ovoj reakciji (kao što je navedeno u shemi 3) je klorsulfonska kiselina (HSO3-Cl). Tipično, reakcija sulfoniranja vrši se tretiranjem karboksamida formule (IV) sa oko 5 do oko 10 molarnih ekvivalenata sulfonirajućeg reagensa u inertnom otapalu, kao što je diklormetan, pri temperaturi u rasponu od oko–70°C do oko 50°C. Poželjno, dodatak klorsulfonske kiseline dešava se na–70°C te vodi nastajanju intermedijera sulfonske kiseline. Povišenje temperature na oko 20°C omogućuje nastajanje sulfonil klorida formule V. Spojevi formule I s X = S dostupni su iz odgovarajućih arilamida (s X = O), npr. benzamidi, putem standardnih metoda prevođenja funkcionalnih skupina koje su dobro poznate onima koji poznaju ovo područje, npr. tretiranjem s Lawessonovim reagensom ili drugim (Pedersen, B. S. et al.; Bull. Soc. Chim. Belg. 1978, 87, 223).
Alternativni pristup za priređivanje spojeva formule I je prikazan na shemi 2 gore i uključuje sljedeće stupnjeve:
- Zaštita aminske funkcionalne skupine spojeva formule II;
- Klorsulfoniliranje aromatske skupine (Ar2 u spojevima VI), tako da se dobiju spojevi formule VII;
- Nastajanje sulfonamidne funkcionalne skupine (nastajanje spojeva IX);
- Uklanjanje zaštitne skupine P u spojevima IX;
- Aciliranje gore nastalog slobodnog amina da se dobiju spojevi (I);
Na taj način, sulfonil kloridni prekursor (VII) može se prirediti pomoću sljedećih stupnjeva:
Shema 4
[image]
Amini formule II zaštićeni su pogodnom zaštitnom skupinom za aminsku speciju da se dobije intermedijer formule VI gdje P označuje zaštitnu skupinu. Brojne zaštitne skupine P aminske funkcionalne skupine, kao i njihovo uvođenje i uklanjanje, opisane su u T.W. Greene i G.M. Wuts, Protecting groups u Organic Synthesis, Third Edition, Wiley, New York, 1998, te u referencama koje su tamo citirane. Poželjne su zaštitine skupine koje su stabilne u odnosu na kiseline i baze i mogu se naknadno ukloniti korištenjem kompleksa prijelaznih metala kao što su paladijevi kompleksi, primjerice alilkarbamatna skupina (Alloc) ili N,N’-bisalilna skupina. Druga poželjna zaštitna skupina je maleimidna skupina koja je postojana u širokom rasponu eksperimentalnih uvjeta.
Uvođenje navedene skupine može se izvršiti reakcijom odgovarajućeg bisalilkarbonat anhidrida ili alilbromida ili anhidrida maleinske kiseline u prisutnosti baze kao što je trietilamin, diizopropiletilamin, N-metilmorfolin i slično u neprotonskom otapalu kao što je N,N-dimetilformamid, diklormetan, klorform, acetonitril, tetrahidrofuran i slično pri temperaturi u rasponu od oko 0°C do oko 80°C.
Spojevi formule VI u shemi 4 zatim se sulfoniraju pomoću standardnih, vrlo blagih postupaka sulfoniranja što omogućuje dobivanje sulfonil klorida formule VII. Tipično, zaštićeni amini VI are obrađuju se bazom kao što je n-butillitij ili tert-butil-litij u inertnoj atmosferi, u polarnom neprotonskom otapalu kao što je tetrahidrofuran, eter ili dioksan pri temperaturi u rasponu od -70°C do 0°C tijekom vremena u rasponu od 15 minuta do 4 sata. Tako nastali anion je zatim tretiran s SO2Cl2 ili najpoželjnije SO2 propuštanjem mjehurića plina kroz reakcijsku smjesu pri temperaturi od -70°C do 20°C tijekom vremena u rasponu od 5 minuta do 1 zas. Dobiveni sulfinat se zatim transformira “in situ” do sulfonil klorida formule VII kontaktiranjem s N-klorsukcinimidom ili drugim pogodnim sredstvom za kloriranje uključujući POCl3, SO2Cl2, COCl2, pri temperaturi od u rasponu od 0°C do 70°C.
Slijedeći bilo koju shemu između 1 i 2, sulfonamidski derivati formule I mogu se dobiti reakcijom sulfonil klorida V ili VII s cikličkim ili bicikličkim aminom (VIII), tj. alkilom koji sadrži dušik sukladno gore navedenoj definiciji. Poželjni ciklički amini (VIII) uključuju pirolidin ili azepan ili piperidinske derivate opće formule (VIII’’) ili (VIII’) ili (VIII’’’).
[image] VIII’’ ili [image] VIII’
ili [image] VIII’’’
gdje (R6)n, L1 i L2 su kao što je gore definirano.
Amini formule VIII’’’ ili VIII’’ ili VIII’ su bilo komercijalno dostupni spojevi ili spojevi koji se mogu prirediti poznatim postupcima.
Reakcija vezanja sulfonil klorida (V) i (VII) s aminima VIII da se dobiju sulfonamidi formule I vrši se kontaktiranjem sulfonil klorida s aminom formule VIII u prisutnosti odgovarajuće baze da se ukloni kiselina koja nastaje tijekom reakcije. odgovarajuće baze uključuju, kao primjer, trietilamin, diizopropiletilamin, N-metilmorfolin i slično. Reakcija se poželjno vrši u otapalu kao što je N,N-dimetilformamid, dimetilsulfokside, N-metil-pirolidon, etanol, acetonitril tipično pri temperaturi od oko 0° do oko 100°C.
Sukladno poželjnoj realizaciji, sulfonamidski derivati formule I priređeni su reakcijom sulfonil klorida V ili VII, s piperidinom formule VIII’’’.
Piperidini formule VIII’’’ su bilo komercijalno dostupni ili se mogu prirediti poznatim postupcima. Takve standardne metode poznate su onima koji poznaju ovo područje i opisane su primjerice u J. Pharm. Sci. 1972, 61, 1316; J. Heterocyclic. Chem., 1986, 23, 73; Tetrahedron Lett., 1996, 37, 1297, US 5106983, WO/9113872 i WO/9606609.
Piperidino sulfonamidi formule I mogu se prirediti kontaktiranjem sulfonil klorida (V) i/ili (VII) s piperidinom formule VIII’’’ u prisutnosti odgovarajuće baze da se ukloni kiselina koja nastaje tijekom reakcije. Pogodne baze uključuju, kao primjer, trietilamin, diizopropiletilamin, N-metilmorfolin i slično. Reakcija se poželjno vrši u otapalima kao što su N,N-dimetilformamid, dimetilsulfoksid, N-metilpirolidon, etanol, acetonitril pri temperaturi od oko 0° do oko 100°C.
Specifični sulfonamidi formule XIV – gdje je R1 vodik – lako se priređuju iz zaštićenih sulfonilklorida VII, kontaktom navedenih sulfonil klorida VII s aminom formule VIII u prisutnosti odgovarajuće baze da se ukloni kiselina koja nastaje tijekom reakcije. Pogodne baze uključuju, kao primjer, trietilamin, diizopropiletilamin, N-metilmorfolin i slično. Reakcija se poželjno vrši u otapalima kao što su N,N-dimetilformamid, dimetilsulfoksid, N-metilpirolidon, etanol, acetonitril pri temperaturi od oko 0° do oko 100°C. Uporaba sulfonil klorida tipa VII vodi aminima s kojih treba ukloniti zaštitu pomoću dobro poznatih metoda što je poznato onima koji znaju ovo područje, da se dobije amin opće formule XIV
[image] XIV
gdje R1, Ar2, Y i n su kao što je prije definirano.
Derivati tipa XIV su zatim acilirani sukladno opisanim metodama za priređivanje amida kondenziranjem amina s kiselinskim kloridima ili karboksilnim kiselinama u poželjnim uvjetima koji su prije opisani što vodi spojevima opće formule I.
Specifičan pristup za priređivanje piperidino sulfonamida formule I (Y je piperidin VIII’’’), gdje je L1 specija –NHR3, uključuje bilo
- reakciju amino-piperidina (VIIIa) s aldehidom (Xa), ili
- reakciju piperidin-4-ona (VIIIb) s aminom (Xb);
te je specificiran u shemi 5.
Shema 5
[image]
R3, R3’, R6 su kao što je prije definirano, R’ je H ili alkilna skupina, R je aril, poželjno fenilna skupina i P je zaštitna skupina. Aminirani piperidini (VIIIc) i (VIIId) mogu zatim reagirati sa sulfonil kloridima V ili VII da se dobiju sulfonamidi formule I, odnosno formule IX.
Karbonilni spojevi (Xa) su komercijalno dostupni i obuhvaćaju nesupstituirane ili supstituirane benzaldehide (kao što su npr. benzaldehid ili 4-trifluormetilbenzaldehid, itd.), nesupstituirane ili supstituirane ketone (kao što su npr. acetofenon ili 4-trifluoracetofenon, itd.), nesupstituirane ili supstituirane alifatske ladehide ili ketone (kao što su npr. heksanal, 2-propoksiacetaldehid ili heptane-2-on, itd.)
Amini (Xb) su komercijalno dostupni i obuhvaćaju nesupstituirane ili supstituirane primarne alkilamine (kao što su npr. heksilamin, 2-piridin-2-etilamin itd.), kao i nesupstituirane ili supstituirane sekundarne alkilamine (poput npr. N-metilheksilamina, itd.).
4-okso-piperidin i azepan-4-on su komercijalno raspoloživi.
Poželjniji pristup za priređivanje sulfonamida formule I gdje je Y piperidinska specija (VIIIc) i (VIIId) dobije se slijedom shema 6 i 7.
Shema 6
[image]
Shema 7
[image]
Specifičan pristup za priređivanje pirolidin sulfonamida formule I (tj. gdje je Y pirolidin VIII’’), gdje je L1 specija –NHR3, uključuje sljedeće stupnjeve:
- dobivanje hidroksipirolidina (VIIIf);
- podvrgavanje navedenog hidroksipirolidina (VIIIf) oksidaciji da se dobije odgovarajući keton (VIIIg) i
- da se reduktivno aminira keton (VIIIg) da se dobije sulfonamid (Ic).
Navedeni pristup prikazan je na shemi 8.
Shema 8 :
[image]
Oksidacijski stupanj može se izvršiti pomoću oksidacijskog sredstva kao što su C2O2Cl2/DMSO ili derivati kroma(VI) ili perjodni derivati kao što su opisali Dess i Martin (40).
Specifičan pristup u priređivanju sulfonamida formule I gdje je Ar2 supstituiran s R6 uključuje sljedeće stupnjeve:
- dobivanje sulfonil klorida (VII) sa zaštitnom skupinom P;
- reakcija sulfonil klorida (VII) s aminom (VIII), npr. zaštićenim piperidin-4-onom tako da se dobije sulfonamid (IX)
- podvrgavanje navedenog sulfonamida (IX) metaliranju Ar2 (npr. pomoću BuLi) da se dobije odgovarajući supstituirani sulfonamid (IXa), gdje je R6 karboksilna skupina, karboksilat, karboksamid, OH ili OH-noseća alkilna skupina, hidrazido karbonilna skupina, sulfat ili sulfonat ili amin ili amonijeva sol,
- uklanjanje zaštitne skupine P navedenog sulfonamida (IXa) i aciliranje sulfonamida da se dobije spoj formule (IXb),
- uklanjanje zaštite s navedenog sulfonamida (IXb) te reduktivno aminiranje odgovarajućeg ketona da se dobije spoj formule I.
Navedeni pristup prikazan je na shemi 9.
Shema 9:
[image]
Ako u gore navedenom prikazu opće sintetske metode nisu primjenjive za dobivanje spojeva formule I, treba koristiti pogodne metode pripravljanja koje su poznate osobi koja poznaje ovo područje. Primjerice, kada je Ar2 fenil, treba početi s komercijalno dostupnim 4-cijanofenil sulfonil kloridom i primijeniti standardne metode koje su poznate osobi koja poznaje ovo područje da se dobiju sulfonamidski derivati formule I.
Sljedeći aspekt ovog izuma odnosi se na sulfonamidske spojeve (XIX)
[image]
konkretno na uporabu intermedijernih spojeva za priređivanje sulfonamida formule (I).
gdje Ar1 i Ar2 su međusobno neovisno aril ili heteroaril,
X is O ili S;
R1 je vodik ili C1-C6-alkilna skupina,
n je cijeli broj od 0 do 5, i
Y je pirolidin-3-on, a piperidin-4-on, pirolidin-3-amin ili piperidin-4-amin, ili njihova amonijeva sol.
[image]
Konačni aspekt ovog izuma odnosi se na uporabu spojeva sukladno formuli I za moduliranje JNK funkcije, ili signalnih ciklusa, uporabu navedenih spojeva za priređivanje farmaceutskih smjesa za moduliranje JNK ciklusa kao i formulacija koje sadrže aktivan spoj sukladno formuli I. Navedeno moduliranje JNH ciklusa smatra se odgovarjućim pristupom za tretiranje različitih poremećaja. Kada se koriste kao farmaceutski pripravci, sulfonamidski derivati ovog izuma tipično se primjenjuju u obliku farmaceutske smjese. Prema tome, farmaceutske smjese koje sadrže spoj formule I i farmaceutski prihvatljivi nosač, razrjeđivač ili ekscipijent, također su unutar dosega ovog izuma. Osoba koja poznaje ovo područje zna da postoji cijeli niz takvih nosača, razrjeđivača ili ekscipijentskih spojeva koji su pogodni za formuliranje farmaceutske smjese. Također, ovim izumom dobivaju se spojevi koji se mogu koristiti kao medikament. KOnkretno, izumom se dobivaju spojevi formule I koji se mogu koristiti kao JNK inhibitor, dotično za JNK 2 i/ili 3, za tretiranje poremećaja imunološkog te živčanog sustava sisavaca, dotično ljudi, bilo sami ili u kombinaciji s drugim medikamentima.
Spojevi ovog izuma, zajedno sa standardno korištenim adjuvantima, nosačima, razrjeđivačima ili ekscipijentima mogu se staviti u farmaceutske smjese i njihove jedinične dozirajuće oblike, pa se u tom obliku mogu koristiti kao krutine, kao što su tablete ili napunjene kapsule, ili tekućine kao što su otopine, suspenzije, emulzije, eliksiri ili kapsule napunjene istim, sve za oralnu uporabu, ili u obliku sterilnih otopina za injiciranje za parenteralnu (uključivo supkutanu) uporabu. Takve farmaceutske smjese i njihovi jedinični dozirajući oblici mogu sadržavati ingredijente u standardnim proporcijama, sa ili bez dodatnih aktivnih spojeva ili načela, te takvi jedinični dozirajući oblici mogu sadržavti bilo koju odgovarajuću učinkovitu količinu aktivnog sastojka koja je sukladna planiranom dnevnom dozirajućem rasponu.
Kada se rabe kao farmaceutski pripravci, sulfonamidski derivati ovog izuma se tipično primijenjuju u obliku farmaceutske smjese. Takve smjese mogu se prirediti na način koji je dobro poznat u farmaceutskoj tehnici i u njima se nalazi bar jedan aktivan spoj. Općenito, spojevi ovog izuma primjenjuju se u farmaceutski učinkovitoj količini. Količinu spoja koja će se stvarno primijeniti odredit će liječnik, uzveši u obzir relevantne okolnosti, uključujući stanje koje se tretira, odabrani put primjene, realni spoj koji se primjenjuje, starost, težinu, odgovor pojedinačnog bolesnika, opseg simptoma bolesnika i slično.
Farmaceutske smjese ovog izuma mogu se primijeniti na različite načine uključujući oralni, rektalni, transdermalni, supkutani, intravenski, intramuskularni i intranazalni. Ovisno o predviđenom putu unošenja, spojevi se poželjno formuliraju bilo kao smjese za injiciranje ili oralne smjese. Smjese za oralnu primjenu mogu biti u obliku ishodnih tekućih otopina ili suspenzija, ili ishodnih prašaka. Češće, međutim, smjese se pojavljuju u obliku jediničnih dozirajućih oblika da se olakša točno doziranje. Pojam “jedinični dozirajući oblici” odnosi se na fizički diskretne jedinice koje su pogodne kao jedinično doziranje za ljude ili druge sisavce, pri čemu svaka jedinica sadrži unaprijed određenu količinu aktivne tvari koja je izračunata da bi se postigao željeni terapijski učinak, u sprezi s pogodnim farmaceutskim ekscipijentom. Tipični jedinični dozirajući oblici obuhvaćaju prethodno napunjene, unaprijed odmejrene ampulče ili štrcaljke tekućeg sadržaja ili pilule, tablete, kapsule i slično u slučaju čvrstih smjesa. U takvim smjesama, sulfonamidski spoje je obično manje zastupljena komponenta (od oko 0,1 do oko 50% težinski ili poželjno od oko 1 do oko 40% težinski), dok su ostatak nosači i pomoćna sredstva koja pomažu oblikovanju željenog dozirajućeg oblika.
Tekući oblici koji su pogodni za oralnu primjenu mogu sadržavati pogodne vodene ili nevodene nosače s puferima, sredstvima za suspendiranje i raspršenje, boje, sredstva za poboljšanje okusa i slično. Čvrsti oblici mogu sadržavati, primjerice, bilo koji od sljedećih sastojaka ili spojeve slične prirode: vezivo kao što je mikrokristalna celuloza, guma tragakant ili želatina; ekscipijent kao što je škrob ili laktoza, sredstvo za razgrađivanje kao što je alginska kiselina, Primogel ili kukuruzni škrob; lubrikant kao što je magnezijev stearat; glidant kao što je koloidni silicijev dioksid; sladilo kao što je saharoza ili saharin; ili sredstvo za poboljšanje okusa kao što je pepermint, metil salicilat ili okus naranče.
Smjese za injiciranje se tišično zasnivaju na sterilnoj fiziološkoj otopini za injiciranje ili na fosfatno puferiranoj fiziološkoj otopini ili drugim nosačima za injiciranje koji su poznati u tehnici. kao što je prije navedeno, sulfonamidski spoj formule I u takvim smjesama je tipično manje zastupljena komponenta, često u rasponu između 0,05 do 10% težinski, pri čemu je ostatak nosač za injiciranje i slično.
Gore opisane komponente za oralnu primjenu ili smjese za injiciranje su samo uzorak. Daljnji materijali kao i tehnike obrade i slično mogu s enaći u 8. dijelu Remington’s Pharmaceutical Sciences, 17th Edition, 1985, Marck Publishing Company, Easton, Pennsylvania, što je ovdje uključeno u cijelosti kao referenca. Spojevi ovog izuma mogu se primijeniti u oblicima s produženim otpuštanjem ili u sustavu za unošenje lijeka s produženim otpuštanjem. Opis reprezentativnih materijala s prduženim otpuštanjem može se također naći u navedenim materijalima u priručniku Remington’s Pharmaceutical Sciences.
U nastavku, ovaj izum bit će ilustriran nekim primjerima koji nisu namijenjeni ograničenju dosega izuma. Podaci za HPLC, NMR i MS koji su navedeni u primjerima su eksperimentalno dobiveni. U popratnim primjerima korištene su sljedeće kratice: min (minuta), h (sat), g (gram), mmol (milimol), t.t. (talište), ekv (ekvivalent), mL (mililitar), μL (mikrolitar), ACN (acetonitrile), Boc (butoksikarbonil), CDCl3 (deuterirani klorform), cHex (cikloheksan), DCM (diklormethane), DECP (dietilcijanofosfonat), DIEA (diizopropiletilamin), DIC (Diizopropil karbodiimid), DMAP (4- dimetilaminopiridin) DMF (dimetilformamid), DMSO (dimetilsulfoksid), DMSO-d6 (deuterirani dimetilsulfoksid), EDC (1-(3-dimetil-amino-propil)-3-etilkarbodiimid), EtOAc (etilacetat), Et2O (dietileter), Fmoc (9-fluorenilmetoksikarbonil), HOBt (1-hidroksibenzotriazol), K2CO3 (kalijev karbonat), NaH (natrijev hidrid), NaHCO3 (natrijev bikarbonat), nBuLi (n-butillitij), TBTU (O-benzotriazolil-N,N,N’,N’-tetrametiluronij-tetrafluorborat), TEA (trietilamin), TFA (trifluoroctena kiselina), THF (tetrahidrofuran), TMOF (trimetilortoformat), MgSO4 (magnezijev sulfat), PetEther (petroleter), rt (sobna temperatura).
Primjeri
Primjer 1 (Protokol E; vidi sheme 1, 3 & 6)
Priređivanje 3-metoksi-N-{[5-({4-[(4-trifluormetilbenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamida (1)
{[(3-metoksibenzoil)amino]metil}tiofen-2-sulfonil klorid (1a)
Otopini 2-aminometiltiofena (10,6 ml, 103 mmol) i piridina (9,1 ml, 104 mmol) u 100 ml klorforma je dodana na 0°C otopina 3-metoksibenzoil-klorida (19,2 g, 103 mmol) u CH2Cl2. Reakcijska smjesa je ostavljena da se ugrije na sobnu temperaturu tijekom 1 sat i miješana je daljnjih 3 sata. Dodana je voda te se staložio 3-metoksi-N-(tien-2-ilmetil)benzamid, (1b) (10,1g). Krutina je filtrirana i isprana vodom. Preostali organski sloj je ispran slanom otopinom, osušen iznad MgSO4 i uparen do suhog da se dobije daljnjih (1b) (15,2 g). Ukupni prinos bio je 25,3 g (99,9%). (1b) je korišten za sljedeći stupanj bez daljnjeg pročišćavanja.
Klorsulfonska kiselina (5,62 ml, 84 mmol) otopljena je u 20 ml CH2Cl2 i dodana otopini (1b) (11,0 g, 42 mmol) u 100 ml CH2Cl2 uz snažno miješanje. Nastala je gumasta krutina i reakcijska smjesa je miješana 3 sata. Reakcija je zaustavljena dodatkom leda, pa je dodana ledohladna otopina NaHCO3 da se dostigne pH 8,5. Vodeni sloj je ispran dva puta s CH2Cl2. Vodenom sloju je dodan tetrabutilamonijev hidroksid (40% u vodi) (32 ml, 50 mmol), pri čemu je nastala krutina. Talog je ekstrahiran u CH2Cl2 i vodeni sloj je ispran 3× sh CH2Cl2. Sjedinjeni organski slojevi su osušeni iznad MgSO4 i upareni do suhog da se dobije slabo obojena pjena tetrabutilamonijeva 5-{[(3-metoksibenzoil)-amino]metil}tiofen-2-sulfonata (1c) (24 g, 97%). NMR spektar je indicirao čisti spoj, koji je korišten za sljedeći stupanj kloriranja.
Otopini (1c) (2,0 g, 3,4 mmol) u 50 ml CH2Cl2 dodan je trifosgen (800 mg, 2,7 mmol, 2,3 ekv.), otopljen u 10 ml CH2Cl2. Reakcijskoj smjesi je dodan DMF (0,1 ml, 1,4 mmol) dokapavanjem tijekom 10’, pri čemu je uočeno razvijanje plina. Plinovi su zadržani na izlazu iz reakcijske posude u 2N otopini NaOH. Reakcijska smjesa je miješana tijekom 3h, te je sirova tvar izravno filtrirana kroz silika-gel pomoću smjese EtOAc/heksan 1:2 kao eluensa. Naranasta krutina je izdvojena koja je rekristalizirala iz smjese cikloheksan/CH2Cl2. (1a) (730 mg, 60%) dobiven je kao bezbojne iglice. 1H NMR (CDCl3) δ 8.83 (t, J = 1.5 Hz, 1H), 8.35 (t, J = 7.5Hz, 1H), 7.76 (t, J = 4.1 Hz, 1H), 7.70-7.58 (m, 3H), 7.52-7.40 (m, 2H), 7.05 (t, J = 3.8 Hz, 1H).
1-[(5-{[(3-metoksibenzoil)amino]metil}tien-2-il)sulfonil]piperidin-4-amonijev trifluoracetat (1d)
Otopini 5-({[1-(3-Metoksibenzoil]-amino}-metil)-tiofen-2-sulfonil klorida (1a) (8g, 23 mmol) i DIEA (8,7 ml, 50,9 mmol) u 100 ml CH2Cl2 dodana je otopina 4-Boc-amino-piperidina (5,5 g, 27,7 mmol) u 50 ml CH2Cl2. Reakcijska smjesa je miješana tijekom 4 h. Suvišk amina je uklonjen ekstrahiranjem s HCl (1N). Organski sloj je uparen do suhog. Rekristaliziranjem je dobiveno 8,3 g (71%) čistog tert-butil 1-[(5-{[(3-metoksibenzoil)amino]metil}tien-2-il)sulfonil]piperidin-4-ilkarbamata, (1e). 1H NMR je pokazao da se radi o čistom produktu, kojemu je uklonjena zaštita standardnim postupkom korištenjem TFA. Sirovi produkt kojemu je uklonjena zaštita staložen je s dietileterom da se dobije 8,43 g (82%) (1d): H1 NMR (DMSO-d6) δ 9.29 (t, J = 5.8 Hz, 1H), 7.88 (m, 3H), 7.48-7.36 (m, 4H), 7.17 (d, J = 3.7 Hz, 1H), 7.11 (d, J = 6.8 Hz, 1H), 4.66 (d, J = 5.6 Hz, 2H), 3.79 (s, 3H), 3.61 (d, J = 11.7 Hz, 2H), 3.09 (m, 1H), 2.43 (t, J = 11.1 Hz, 2H), 1.96 (d, J = 11.1 Hz, 2H), 1.54 (dd, J = 11.9, 3.7 Hz, 2H), M/Z APCI: 410.1 (M+1), 408.2 (M-1).
3-metoksi-N-{[5-({4-[(4-trifluormetilbenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid (1)
(1d) (50 mg, 0,1 mmol) otopljen je u 2 ml DCM i neutraliziran s DIEA (18 μl, 0,1 mmol) do pH 7. Ovoj otopini dodan je 4-trifluormetilbenzaldehid (18 mg, 0,11 mmol), te je reakcijska smjesa miješana 30’, nakon čega je dodana octena kiselina (6 μl, 0,1 mmol) i natrijev triacetoksiborhidrid (28 mg, 0,14 mmol). Reakcijska smjesa je miješana na sobnoj temperaturi tijekom 4 h, razrijeđena je etileterom i reakcija je zaustavljena dodatkom NaOH (1N) da se dosegne pH 9. Organski loj je ispran slanom otopinom, osušen iznad MgSO4 i uparen do suhog. Sirovi produkt je pročišćen “flash” kromatografijom da se dobije 51 mg čistog (1) (91%) u obliku bezbojne krutine: talište HCl soli: 235-236°C, H1 NMR (DMSO-d6) δ 9.29 (t, J = 5.8Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.65-7.40 (m, 6H), 7.19 (d, J = 3.8 Hz, 1H), 7.15 (dd, J = 7.9, 1.5 Hz, 1H), 4.70 (d, J = 5.6 Hz, 2H), 3.83 (s, 3H), 3.77 (d, b, 2H), 3.41 (d, b, 2H), 2.61-2.40 (m, 3H), 1.93 (m, 2H), 1.42 (m, 2H), M/Z APCI: 568.6 (M+1), 566.6 (M-1).
Alternativno, 1 se može sintetizirati paralelno u tekućoj fazi:
(1d) (50 mg, 0,1 mmol) suspendiran je u 2 ml DCE pomoću paralelnog sintetizatora Quest®210. Suspenzija je neutralizirana s DIEA (18 μl, 0,1 mmol) do pH 7, pri čemu je otopljen (1c). Ovoj otopini je dodan 4-trifluormetilbenzaldehid u 100 μl DMF (18 mg, 0,11 mmol), te je reakcijska smjesa miješana 30’ pod Ar, nakon čega je dodana octena kiselina (6 μl, 0,1 mmol) i natrijev triacetoksiborhidrid (28 mg, 0,14 mmol). Reakcijska smjesa je miješana na sobnoj temperaturi preko noći, razrijeđena je s DCE i reakcija je zaustavljena dodatkom NaHCO3 (zas.) da se postigne pH 9. Organski sloj je ispran slanom otopinom, osušen iznad MgSO4 i filtriran i scintilcijske posudice. Dodano je 50 mg polimerno vezanog benzaldehida i 20 mg aminometil Merryfield smole, te je mućkano preko noći. Otopina je otfiltrirana, polimeri su dva puta isprani otapalom i sjedinjeni organski lojevi su upareni do suhog pri temperaturi medija tijekom 1 h korištenjem Savant Speed Vac® Plus vakuumske centrifuge.
Postupak je paralelno dao čisti (1), u obliku bezbojnog praha, koji je nakon tretiranja s HCl i dieteileterom transformiran u odgovarajuću HCl sol.
Dolje navedeni spojevi (označeni brojem primjera) su priređeni na sličan način sukladno gore navedenom protokolu te polazeći od odgovarajućih polaznih spojeva (HPLC uvjeti: C8 simetrija a: MeCN, 0,09% TFA, 0 do 100% (10 min), b: MeCN, 0,09% TFA, 0 do 100% (8 min); spektar masa APCI).
[image] [image] [image] [image]
Primjer 63 (Protokol A; vidi sheme 1, 3 & 7:
Priređivanje 4-klor-N-[(5-{[4-(heksilamino)piperidin-1-il]sulfonil}-tien-2-il)metil]benzamid
4-klor-N-tiofen-2-ilmetil-benzamid (63a)
Otopini 4-klorbenzoil klorida (0,114 mol) u 50 ml suhog CH2Cl2 dodana je tijekom 30 min uz miješanje otopina 2-aminometil-tiofena (0,137 mol) i iPr2NEt (0,25 mol) u CH2Cl2 (200 ml) na 0°C. Nastala je bijela krutina i reakcijska smjesa je ostavljena da se ugrije do sobne temperature tijekom 1 h. Smjesa je razrijeđena s 200 ml CH2Cl2, isprana je dva puta vodenom otopinom HCl (0,1 N) i osušena iznad MgSO4. Uparavanje otapala dalo je 28 g (98%) naslovnog benzamida u obliku bijele krutin: t.t. 153-54°C, 1H NMR (CDCl3) δ�� 7.9 (d, J = 8.67 Hz, 2H), 7.58 (d, J = 8.67 Hz, 2H), 7.44 �(d, J = 3.77, 1.13 Hz, 1H), 7.22 (d, J = 5.27 Hz, 1H), 7.16 �(d, ��J = 3.39, 5.27 Hz, 1H), 6.62 �br d, 1H), 4.98 (d, J = 5.65 Hz, 2H).
5-({[1-(4-klor-fenil)-methanoyl]-amino}-metil)-tiofen-2-sulfonil klorid (63b)
Klorsulfonska kiselina (20,1 ml, 198 mmol) u CH2Cl2 (80 ml) dodana je dokapavanjem otopini (63a) (10 g, 40 mmol) u CH2Cl2 (500 ml) na -80°C. Smjesa je ostavljena da dosegne sobnu temperaturu tijekom 5 h. Reakcijska smjesa je stavljena na led i brzo ekstrahirana s CH2Cl2. Organski sloj je osušen iznad MgSO4 i otapalo je upareno do suhoga što je dalo 8,8 g (63%) željenog sulfonil klorida (63b); talište 133-35°C, 1H NMR (DMSO-d6) δ������ �t��J = 6.4 Hz, 1H), 7.87 �d��J = 8.67 Hz, 2H), 7.53 �d��J = 8.67 Hz, 2H), 6.91 �d��J = 3.39 Hz, 1H), 6.77 �d��J = 3.39 Hz, 1H), 4.53 �d��J = 3.77 Hz, 2H).
4-klor-N-({5-[(4-oksopiperidin-1-il)sulfonil]tien-2-il}metil)benzamid (63c)
Otopini 5-({[1-(4-klor-fenil)-metanoil]-amino}-metil)-tiofen-2-sulfonil klorida (1b) (5,0 g, 14 mmol) u 100 ml klorforma i otopina 4-piperidinon hidroklorid monohidrata (4,3 g, 28 mmol) u 21 ml NaOH (2N) miješane su snažno tijekom 15 h. Reakcija je zaustavljena s HCl (2 N) i organski sloj je ekstrahiran dva puta s HCl (2 N) i dva puta slanom otopinom. Osušena organska faza dala je nakon uparavnja kloroforma 5,8 g (99,5%) (63c) u obliku bezbojne krutine: 1H NMR (CDCl3) δ 7.67 (d, J = 8.7 Hz, 2H), 7.42-7.38 (m, 3H), 6.99 (d, J = 3.8 Hz, 1H), 6.53 (t, J = 5.3 Hz, 1H), 4.74 (d, J = 6.0 Hz, 2H), 3.37 (d, J = 6.2 Hz, 4H), 2.50 (d, J = 6.2 Hz, 4H).
4-klor-N-[(5-{[4-(heksilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid (63)
Smjesa N-sulfonil piperidona (63c) (3,01 g, 7,28 mmol), n-heksilamina (1,06 ml, 8,01 mmol), svježe usitnjenog NaBH(OAc)3 (3,1 g, 14,6 mmol), bezvodnog 1,2-dikloretana (150 ml), i THF (100 ml) miješana je tijekom 80 min na 23 ̊C. Smjesa je koncentrirana na rotacijskom uparivaču (Tkupelj = 57 ̊C), otopljena u EtOAc (500 ml), isprana (slana otopina:K2CO3 zas., 4:1; 250 ml) i uparena da se dobije 4,1 g sirovog materijala. Rezidue su otopljene u 50 ml vrućeg acetona, adsorbirane na silika-gelu, uparene, nanesene na kromatografsku kolonu (silika-gel, promjer = 5,5 cm), te eluirane (MeOH:CH2Cl2 7:150). Kromatografija je ponovljena da se dobije 2,95 g (81%) naslovnog sekundarnog amina u obliku bijele krutine: 1H NMR (DMSO-d6) 9.37 (t, J = 5.8 Hz, 1H), 7.90 (dt, J = 8.7, 2.2 Hz, 2H), 7.51 (dt, J = 8.5, 2.2 Hz, 2H), 7.16 (d, J = 3.8 Hz, 1H), 4.65 (d, J = 5.8 Hz, 2H), 3.39 (dm, J = 11.9 Hz, 2H), 3.60–3.00 (br. s, 1H), 2.49 (ddd, J = 11.5, 9.8, 1.7 Hz, 2H), 2.43 (t, J = 6.9 Hz, 2H), 2.44–2.38 (buried m, 1H), 1.82 (dm, J = 10.0 Hz, 2H), 1.38–1.14 (m, 10H), 0.83 (t, J = 6.7 Hz). 13C NMR (DMSO-d6) 165.33 (C=O), 150.46 (tiofen, C2), 136.41 (klorbenzamid, C1), 133.86 (tiofen, C5), 132.42 (tiofen, C3), 132.37 (klorbenzamid, C4, 129.22 (klorbenzamid, C2 & C6), 128.52 (klorbenzamid, C3 & C5), 126.27 (tiofen, C4), 52.53 (piperidin, C4), 46.07 (heksil), 44.41 (piperidin, C2 & C6), 38.09 (tienil-CH2), 31.21 (piperidin, C3 & C5), 30.66 (heksil), 29.49 (heksil), 26.48 (heksil), 22.06 (heksil), 13.91 (heksil). ). M/Z APCI : 498 (M+1), 496 (M–1). Anal. HPLC: Retencijsko vrijeme = 5,00 min (metoda a).C23H32ClN3O3S2 Izračunato: C: 55,46%. H: 6,48%. N: 8,44%. Nađeno: C: 54,19%, H: 6,52%, N: 8,22%.
Alternativno, spoj (63) može se paralelno sintetizirati u tekućoj fazi:
(63c) (20 mg, 0,05 mmol) otopljen je u 2 ml THF pomoću paralelnog sintetizatora Quest®210. Ovoj otopini je dodan N-heksilamin u DCE (5,6 mg, 0,06 mmol), te je reakcijska smjesa miješana 30’ pod Ar, nakon čega je dodana octena kiselina (6 μl, 0,1 mmol) i natrijev triacetoksiborhidrid (28 mg, 0,14 mmol). Reakcijska smjesa je miješana na sobnoj temperaturi 4 h, razrijeđena s DCE i reakcija je zaustavljena dodatkom NaHCO3 (zas.) da se dosegne pH 8,5. Organski sloj je ispran slanom otopinom, osušen iznad MgSO4 i filtriran u scintilacijske posudice. U svaku posudicu je dodan MP-TsOH (3 ekv.) i mućkano je preko noći. Otopina je filtrirana i polimer je ispran detaljno s DCE. Polimeru je zatim dodano 3 puta po 1 ml NH3 u EtOH i svaki put je mućkano 10 min. Polimer je ispran i etanolne otopine su sjedinjene te uparene do suhoga pri temperaturi medija tijekom 1 h korištenjem Savant Speed Vac® Plus vakuumske centrifuge.
Postupak koji je paralelno proveden dao je čisti (63), u obliku bezbojne krutine, koji je nakon tretiranja s HCl u dietileteru transformiran u HCl sol.
Dolje navedeni spojevi (označeni brojem primjera) su priređeni na sličan način sukladno gore navedenom protokolu te polazeći od odgovarajućih polaznih spojeva:
[image] [image] [image]
Primjer 122 (Protokol L; vidi sheme 2 & 7):
Priređivanje Etil 2-{[4-(heksilamino)piperidin-1-il]sulfonil}-5-{[(3-metoksi-benzoil)amino]metil}tiofen-3-karboksilat (122)
Dialil-tiofen-2-ilmetilamin (122a)
Otopina 2-aminometil-tiofena (51,4 g, 956 mmol) i i-Pr2NEt (140 g, 1081 mmol) u CH2Cl2 (1 l) stavljena je u bocu od 3 litre koja je opremljena kondenzorom i djelotvornim magnetskim mješačem. Dodan je alil bromide (115,7 g, 454 mmol), nakon čega je umjereno egzotermna reakcija spontano dosegla temperaturu refluksa nakon 2 h. Smjesa je miješana preko noći (16 h), isprana (NaHCO3 zas.; slana otopina), osušena (MgSO4), te koncentrirana. Dobiveno ulje filtrirano je preko silika-gela (EtOAc:heksan 1:4). Filtrat je koncentriran i filtriranje je ponovljeno da se dobije 70,3 g (80%) naslovnog dialilamina kao smeđe-žutog ulja, koje je čisto prema NMR: 1H NMR (CDCl3) δ 7.25 (br. d, J = 5.9 Hz, 1H), 6.98 (br. dd, J = 5.1, 2.8 Hz, 1H), 6.94–6.92 (m, 1H), 5.99–5.86 (m, 2H), 5.29–5.18 (m, 4H), 3.85 (s, 2H), 3.16 (dd, J = 6.3, 0.9 Hz, 4H).
5-Dialilaminometil-tiofen-2-sulfonil klorid (122b)
Otopina alil-zaštićenog tiofena (122a) (6,2 g, 32,1 mmol) u Et2O ohlađena je na – 70°C u kupelji aceton/suhi led. Otopina t-BuLi u pentanu (21,38 ml, 1,5 M, 32,1 mmol) dodana je tijekom 2 min nakon čega je unutrašnja temperatura trenutačno narasla na–50°C i smjesa je postala naranšaste boje. Nakon 10 min., SO2 je propušten kroz otopinu tijekom 2 min, što je uzrokovalo trenutačno nastajanje obilnog taloga. Reakcijska smjesa je ostavljena da dosegne 0°C, pa je dodana suspenzija NCS (4,63 g, 32,1 mmol) u THF (20 ml), nakon čega je kaša postala purpurna. Nakon 45 min na sobnoj temperaturi, smjesa je filtrirana preko SiO2, eluiranjem s EtOAc. Uparavanje, razrjeđenje s EtOAc:heksan 1:5 i filtriranje preko SiO2 dalo je 5,0 g (53%) naslovnog sulfonil klorida (122b) u obliku blijedosmeđeg ulja što je korišteno bez daljnjeg pročišćavanja.
N,N-Dialil-N-{[5-(1,4-dioksa-8-azaspiro[4.5]dec-8-ilsulfonil)tien-2-il]metil}amin (122c)
Postupak A (iz izdvojenog sulfonil klorida (122b)). Otopina (122b) (5,84 g, 20 mmol) u CHCl3 ohlađena je na 0 ̊C, pa tretirana s 1,4-dioksa-8-azaspiro[4,5]dekanom (2,8 ml, 22 mmol) i Et3N (4,2 ml, 30 mmol), pa grijana na 23 ̊C tijekom 10 min. Razrjeđivanje s EtOAc (100 ml), standardno dorađivanje (NaHCO3 zas.; slana otopina; MgSO4) te kromatografija (EtOAc:cikloheksan 1:2) dala je 7,57 g (95%) naslovnog sulfonamida u obliku bezbojnog ulja.
Postupak B (od (122a), bez izdvajanja sulfonil klorida (122b). Otopina alil-zaštićenog tiofena (1a) (29,1 g, 150 mmol) u Et2O (440 g, 617 ml) stavljena je u 1-l tikvicu s tri grla (termometar; argon; septum ili SO2 ulaz) te ohlađena na – 74°C pomoću kupelji aceton/suhi led. otopina t-BuLi u pentanu (100 ml, 1,5 M, 150 mmol) dodavana je tijekom 5 min nakon čega je unutrašnja temperatura trenutačno porasla na–64°C i smjesa je postala ružičasta. Nakon 20 min., SO2 (20 g, 312 mmol) je propušten kroz otopinu 15 min. Potrošnja SO2 se može najbolje pratiti stavljanjem SO2 boce na vagu tijekom reakcije. Reakcijska smjesa, koja se pretvorila u gusti, bijeli vosak, ostavljena je da se ugrije na sobnu temperaturu tijekom 2 h. Dodana je suspenzija NCS (30 g, 226 mmol), pa je nastavljeno miješanjem preko noći, nakon čega je kaša postala purpurna. Smjesa je filtrirana (sinter), te je talog pažljivo ispran s CH2Cl2 (2×300 ml). Sjedinjeni organski slojevi su ohlađeni na 0 ̊C pod Ar, pa su tretirani otopinom 1,4-dioksa-8-azaspiro[4,5]dekana (27,8 g, 194 mmol) i trietilamina (19,7 g, 194 mmol) u CH2Cl2 (200 ml). Nakon 1 h, smjesa je isprana (NaHCO3 zas.; slana otopina), osušena (MgSO4) i koncentrirana da se dobije 53 g (83%) naslovnog sulfonamida u obliku žutog ulja: 1H NMR (CDCl3) δ 7.36 (d, J = 3.8 Hz, 1H), 6.90 (br. d, J = 3.4 Hz, 1H), 5.92–5.79 (m, 2H), 5.33–5.16 (m, 4H), 3.93 (s, 4H), 3.78 (s, 2H), 3.21 (t, 5.7 Hz, 4H), 3.13 (d, 6.2 Hz, 4H), 1.81 (t, 5.7 Hz, 4H).
Etil 5-[(dialilamino)metil]-2-(1,4-dioksa-8-azaspiro[4.5]dec-8-ilsulfonil)tiofen-3-karboksilat (122d)
Otopina sulfonamida (122c) (3,36 g, 8,43 mmol) u THF (120 ml) ohlađena je na –78 ̊C i tretirana s t-BuLi (7,0 ml, 1,5 M u heksanu, 10,5 ml). Nakon 5 min, smjesa je kanulom unesena u ohlađenu (–100 ̊C; aceton/tekući N2) otopinu etil klorformata (6,45 ml, 67,5 mmol) u THF (60 ml). Reakcijska smjesa je ostavljena da se ugrije na–30 ̊C tijekom 2 h, pa zatim na 23 ̊C preko noći. Smjesa je koncentrirana na rotacijskom uparivaču i razrijeđena s EtOAc (250 ml). Standardna dorada (H2O; slana otopina; MgSO4) i dva kromatografiranja (EtOAc:cikloheksan 1:4) dala su 1,48 (37%) naslovnog etil estera: 1H NMR (DMSO-d6) δ 7.36 (d, 1H), 5.98–5.82 (m, 2H), 5.32–5.17 (m, 4H), 4.33 (q, J = 7.1 Hz, 2H), 3.92 (s, 4H), 3.85 (s, 2H), 3.32 (dd, J ≈ 6.0, 5.0 Hz, 4H), 3.17 (d, J = 6.0 Hz, 4H), 1.74 dd, J ≈ 6.0, 5.0 Hz, 4H), 1.33 (t, J = 7.2 Hz, 3H).
Etil 2-(1,4-dioksa-8-azaspiro[4.5]dec-8-ilsulfonil)-5-{[(3-metoksibenzoil)amino]-metil}tiofen-3-karboksilat (122e)
Otopina etil estera (122d) (1,47 g, 3,12 mmol) i NDMBA (1,07 g, 6,87 mmol) u CH2Cl2 (30 ml) je oslobođena plina propuštanjem argona i soniciranjem. Zatim je dodan Pd(PPh3)4 (216 mg, 0,187 mmol) i smjesa je miješana na 23 ̊C. Nakon 2h, smjesa je ohlađena na–50 ̊C, tretirana s Et3N (525 μl, 3,76 mmol) i 3-(metoksi)-benzoil kloridom (300 μl, 2,13 mmol), pa zagrijana na sobnu temperaturu tijekom 30 min. Razrjeđivanje s EtOAc, standardno dorađivanje (H2O; NaHCO3 zas.; slana otopina; MgSO4) i kromatografija (EtOAc:cikloheksan 1:1) dali su 1,0 g (61%) naslovnog 3-metoksibenzamida: 1H NMR (DMSO-d6) 9.29 (t, J = 5.8 Hz, 1H), 7.49–7.34 (m, 4H), 7.12 (ddd, J = 7.9, 2.6, 1.0 Hz, 1H), 4.66 (d, J = 5.7 Hz, 2H), 4.27 (q, J = 7.2 Hz, 2H), 3.84 (s, 4H), 3.80 (s, 3H), 3.24 (dd, J ≈ 6.0, 5.0 Hz, 4H), 1.67 (dd, J ≈ 6.0, 5.0 Hz, 4H), 1.26 (t, J = 7.0 Hz, 3H). M/Z APCI: 525 (M + 1), 523 (M–1).
Etil 5-{[(3-metoksibenzoil)amino]metil}-2-[(4-oksopiperidin-1-il)sulfonil]-tiofen-3-karboksilat (122f)
Otopina spiroketala (122e) (500 mg, 0,953 mmol) u acetonu (5 ml) tretirana je s HCl 1N (2,5 ml) tijekom 18 h na 48 ̊C. Razrjeđivanje s EtOAc i standardno dorađivanje (H2O; NaHCO3 zas.; slana otopina; MgSO4) dali su 425 mg 9:1 smjese željenog naslovnog ketona (83%) te neizreagirane tvari (9%) (jedna mrlja s TLC). 1H NMR (CDCl3) 7.37–7.35 (m, 1H), 7.33–7.29 (m, 3H), 7.05 (ddd, J = 7.7, 2.6, 1.7 Hz, 1H), 6.81 (t, J = 5.8 Hz, 1H), 4.74 (d, J = 6.1 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 3.70 (t, J = 6.1 Hz, 4H), 2.52 (t, J = 6.2 Hz, 4H), 1.34 (t, J = 7.1 Hz, 3H). M/Z APCI: 481 (M + 1), 479 (M–1).
Etil 5-{[(3-metoksibenzoil)amino]metil}-2-{[4-(heksilamino)piperidin-1-il]-sulfonil}tiofen-3-karboksilat (122)
Otopina ketona (122f) (86 mg, 0,18 mmol), n-heksilamina (26 μl, 0,20 mmol) i NaBH(OAc)3 (75 mg, 0,36 mmol) u 1,2-dikloretanu (3 ml) miješana je 3 h na sobnoj temperaturi. razrjeđivanje s EtOAc, standardno dorađivanje (NaHCO3 zas.; slana otopina; MgSO4) dali su 85 mg (84%) željenog spoja 122 u obliku bijele pjene.
Dolje navedeni spojevi (označeni brojem primjera) su priređeni na sličan način sukladno gore navedenom protokolu te polazeći od odgovarajućih polaznih spojeva:
[image]
Primjer 127 (Protokol N; vidi sheme 1 & 7)
Priređivanje N-[(5-{[4-(heptilamino)azepan-1-il]sulfonil}tien-2-il)metil]-3-metoksi-benzamida (127)
Odgovarajući 3-metoksi-N-({5-[(4-oksoazepan-1-il)sulfonil]tien-2-il}metil)-benzamid (127a), priređen je sukladno primjeru 63 i može se izdvojiti kao bezbojni prašak s kvantitativnim prinosom (693 mg). M/Z APCI: 423,5 (M+1), 421 (M–1). ). Anal. HPLC: Retencijsko vrijeme = 4,97 min (metoda a).
(127) je priređen sukladno primjeru protokola 63 i izdvojen je kao bezbojna krutina s prinosom 47% (12 mg). 1H NMR (DMSO-d6) 9.25 (t, J = 5.8 Hz, 1H), 7.46-7.35 (m, 4H), 7.10 (m, 2H), 4.65 (d, J = 6.0 Hz, 2H), 3.79 (s, 3H), 3.29–3.20 (m, 2H), 3.12 (m, 2H), 2.58 (m, 1H), 2.49 (m, 2H), 1.75 (m, 2H), 1.44-1.22 (m, 14H), 0.85 (t, J = 6.9 Hz, 3H). M/Z APCI: 522.5 (M+1), 520 (M–1). ).
Alternativno, (127) može se sintetizirati paralelno sukladno sintezi koja je opisana za (63).
Sljedeći spojevi (označeni brojem primjera) priređeni su na paralelni način sukladno gore navedenom protokolu.
[image]
Primjer 154 (Protokol D)
Priređivanje 4-klor-N-{[5-({4-[heksil(piridin-2-ilmetil)amino]-piperidin-1-il}sulfonil)tien-2-il]metil}benzamida (154)
Otopina 63 (19,6 mg, 0,039 mmol) i piridin 2-karbaldehida (20 μl, 0,210 mmol) u THF (2,5 ml) tretirana je s NaBH(OAc)3 (90 mg, 0,425 mmol) pod argonom uz refluks tijekom 16 h. Smjesa je ohlađena na sobnu temperaturu i uklonjen je suvišak aminometilne polistirenske smole (160 mg, 0,308 mmol, pre-suspendirano u 4 ml CH2Cl2) tijekom 10 min na 23 ̊C. Razrjeđivanje s CH2Cl2 (10 ml), filtriranje preko pamučne vune i standardno dorađivanje (H2O; slana otopina; MgSO4) dali su 17,8 mg (77%) naslovnog tercijarnog amina u obliku blijedožutog ulja.). M/Z APCI : 589 (M+1), 587 (M–1). Anal. HPLC: Retencijsko vrijeme = 5,00 min (metoda a, 96% optička čistoća (254 nM)).
U ovom protokolu, piridin-2-karbaldehid može se zamijeniti s drugim aldehidima, što uključuje (ali nije ograničeno na): piridin-3-karbaldehid, piridin-4-karbaldehid, benzaldehid, cikloheksankarbaldehid.
Dolje navedeni spojevi (označeni brojem primjera) su priređeni na sličan način sukladno gore navedenom protokolu te polazeći od odgovarajućih polaznih spojeva (HPLC uvjeti: C8 simetrija a: MeCN, 0,09% TFA, 0 do 100% (10 min), b: MeCN, 0,09% TFA, 0 do 100% (8 min); spektar masa APCI).
[image]
Primjer 164 (Protokol B; vidi sheme 1 & 8)
Priređivanje 4-klor-N-[(5-{[3-(pentilamino)pirolidin-1-il]-sulfonil}tien-2-il)metil]benzamida (164)
4-klor-N-[(5-{[(3R)-3-hidroksipirolidin-1-il]sulfonil}tien-2-il)metil]benzamid, (164a)
Suspenziji R-3-pirolidinol hidroklorida (530 mg, 4,29 mmol) i DIEA (0,75 ml, 14,3 mmol) u CH2Cl2/DMF 1:1 dodana je otopina 5-({[1-(4-klor-fenil)-metanoil]-amino}-metil)-tiofen-2-sulfonil klorida (63b) (1,0 g, 2,86 mmol). Pri kraju dodavanja, suspenzija je nestala. Reakcijska smjesa je miješana preko noći. Dodano je 100 ml EtOAc i suvišak amina estrahiran je s HCl (1 N), nakon čega je izvršeno ispiranje sa slanom otopinom. Organski sloj je osušen iznad MgSO4 i uparen do suhog da se dobije (164a) (1,14 g, 99,9%) u obliku bezbojne pjene: H1 NMR (DMSO d6) δ 9.34 (t, J = 5.8 Hz, 1H), 7.89 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 3.8 Hz, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.13 (d, J = 3.8 Hz, 1H), 4.95 (d, J = 3.4 Hz, 1H), 4.65 (d, J = 5.6 Hz, 2H), 4.16 (m, 1H), 3.40-3.20 (m, 5H), 3.00 (m, 1H), 3.35-3.23 (m, 3H), 1.80-1.60 (m, 2H), M/Z APCI: 401.2 (M+1), 398.9 (M-1).
4-klor-N-({5-[(3-oksopirolidin-1-il)sulfonil]tien-2-il}metil)benzamid, (164b)
Na –80°C oksalilklorid (36 mg, 0,28 mmol) otopljen je u suhom CH2Cl2, te je polako dodan DMSO (50 μl, 0,6 mmol). otopina je miješana pod Ar tijekom 15minuta. (164a) (100 mg, 0,25 mmol) otopljen je u 2 ml CH2Cl2, pa je ova otopina dodavana dokapavanjem na gore navedenu reakcijsku smjesu na–80°C. Reakcijska smjesa je miješana 15’ pri niskoj temperaturi, prijennego je dodan DIEA (0,21 ml, 1,25 mmol). Reakcijska smjesa je miješana na–80°C tijekom 30 minuta i ostavljena je da se grije na sobnoj temperaturi tijekom 2 h. Nastala je bijela krutina, reakcija je zaustavljena vodom i reakcijska smjesa je ekstrahirana s CH2Cl2 nekoliko puta. Sjedinjeni organski slojevi osušeni su iznad MgSO4 i upareni do suhog. Sirova tvar je pročišćena “flash” kromatografijom na silika-gelu korištenjem smjese EtOAc/cikloheksan 2:1 kao eluens. (164b) (80 mg, 80%) dobiven je u obliku bezbojne krutine: H1 NMR (CDCl3) δ 7.72 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 3.8 Hz, 1H), 7.42 (d, J = 8.7 Hz, 2H), 7.08 (d, J = 3.8 Hz, 1H), 6.59 (t, J = 5.8, 1H), 4.80 (d, J = 6.0 Hz, 2H), 3.58 (t, J = 7.5 Hz, 2H), 3.50 (s, 3H), 2.54 (t, J = 7.5, 2H), 3.35-3.23 (m, 3H), 2.95 (m, 2H), 1.94 (m, 2H), 1.86 (m, 2H), 1.70-1.50 (m, 5H), 1.30-1.20 (m, 8H), 0.87 (t, J = 6.8, 3H), M/Z APCI 399.0 (M+1), 397.2 (M-1)
4-klor-N-[(5-{[3-(pentilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]benzamid (164)
(164b) priređen je sukladno primjeru i izdvojen je kao bezbojna krutina s prinosom 84% (15 mg). M/Z APCI: 522.5 (M+1), 520 (M–1). ). Anal. HPLC: Retencijsko vrijeme = 4,62 min (metoda a).
Alternativno, (164) može se sintetizirati paralelno pristupom sukladno sintezi koja je opisana za spoj (63).
Dolje navedeni spojevi (označeni brojem primjera) su priređeni na sličan način sukladno gore navedenom protokolu te polazeći od odgovarajućih polaznih spojeva (HPLC uvjeti: C8 simetrija a: MeCN, 0,09% TFA, 0 do 100% (10 min), b: MeCN, 0,09% TFA, 0 do 100% (8 min); spektar masa APCI).
[image] [image]
Primjer 195 (Protokol C; vidi sheme 1 & 2)
Priređivanje 3-metoksi-N-{[5-({4-[(pentilamino)metil]piperidin-1-il}sulfonil)-tien-2-il]metil}benzamida (195)
N-[(5-{[4-(hidroksimetil)piperidin-1-il]sulfonil}tien-2-il)metil]-3-metoksi-benzamid, (195a)
Otopini 4-hidroksimetil-piperidina (499 mg, 4,33 mmol) i DIEA (1,5 ml, 8,67 mmol) u 15 ml CH2Cl2 polako je dodana otopina 5-({[1-(3-metoksi-fenil)-metanoil]-amino}-metil)-tiofen-2-sulfonil klorida (1,0 g, 2,89 mmol) u CH2Cl2/DMF. reakcijska smjesa je miješana preko noći. Dodano je 100 ml EtOAc i suvišak amina je uklonjen ekstrahiranjem s HCl (1 N). Osušen organski sloj je uparen do suhog da se dobije 1,25 g (99,9%) čistog spoja (135a) u obliku bezbojne pjene: H1 NMR (DMSO d6) δ 9.26 (t, J = 5.8 Hz, 1H), 7.55-7.25 (m, 4H), 7.16 (d, J = 3.8 Hz, 1H), 7.11 (d, J = 9.4 Hz, 1H), 4.66 (d, J = 6.0 Hz, 2H), 4.48 (m, 1H), 3.80 (s, 3H), 3.59 (d, J = 11.7, 2H), 3.31 (b, m, 1H), 3.20 (d, J = 6.0 Hz, 2H), 2.27 (t, J = 11.0 Hz, 2H), 1.72 (d, J = 11.0 Hz, m, 2H), 1.40-1.0 (m, 4H), M/Z APCI: 425.3 (M+1).
3-metoksi-N-{[5-({4-[(pentilamino)metil]piperidin-1-il}sulfonil)tien-2-il]-metil}benzamid, (195)
(195a) (200 mg, 0,47 mmol) i trifenilfosfin (247 mg, 0,94 mmol) otopljeni su u suhom DMF. Ovoj otopini je dodan na 0°C u malenim obrocima N-bromo-sukcinimid (167 mg, 0,94 mmol) kao krutina. Svaki obrok je dodan nakon što je žuta boja otopina iščezla. Na kraju dodavanja se žuta boja otopine zadržala i reakcijska smjesa je grijana na 50°C tijekom 90’. Vruća reakcijska smjesa je stavljena u bočicu i nakon toga je dodan amilamin (410 mg, 4,7 mmol). Bočica je zatvorena i grijana na 65°C preko noći. Reakcijska smjesa je uparena do suhog i sirova tvar je pročišćena “flash” kromatografijom na silika-gelu korištenjem smjese EtOAc/metanol 10:1 da se dobije 180 mg (78%) spoja (196) u obliku bezbojnog ulja. H1 NMR (CDCl3) δ 7.43-7.25 (m, 4H), 7.05 (m, 2H), 6.75 (m, 1H), 4.82 (d, J = 6.0 Hz, 2H), 3.76 (s, 3H), 3.77 (d, J = 11.7, 2H), 2.63 (d, J = 7.3 Hz, 2H), 2.54 (d, J = 6.8 Hz, 2H), 2.35 (t, J = 11.1, 2H), 1.85 (d, J = 11.1 Hz, m, 2H), 1.70-1.50 (m, 4H), 1.30-1.20 (m, 6H), 0.89 (t, J = 6.8, 3H), M/Z APCI: 494.2 (M+1).
Dolje navedeni spojevi (označeni brojem primjera) su priređeni na sličan način sukladno gore navedenom protokolu te polazeći od odgovarajućih polaznih spojeva (HPLC uvjeti: C8 simetrija a: MeCN, 0,09% TFA, 0 do 100% (10 min), b: MeCN, 0,09% TFA, 0 do 100% (8 min); spektar masa APCI).
[image]
Primjer 198 (Protokol F; vidi sheme 2 & 7) :
Priređivanje 2-okso-N-({5-[(4-{[4-(trifluormetil)benzil]amino}-1-piperidinil)-sulfonil]-2-tienil}metil)-1,2-dihidro-3-piridinkarboksamida (198)
N-{[5-(1,4-Dioksa-8-azaspiro[4.5]dec-8-ilsulfonil)-2-tienil]metil}-2-okso-1,2-dihidro-3-piridinkarboksamid 198a
Bisalilamin 122c (22,9 g, 57,5 mmol, 1,0 ekv.), N,N’-dimetilbarbiturna kiselina (NDMBA, 17,9 g, 156,1 mmol, 2,0 ekv.) i Pd(PPh3)4 (3,32 g, 2,87 mmol, 0,05 ekv.) otopljeni su u CH2Cl2 (250 ml). Otopina je oslobođena plina propuštanjem argona na sobnoj temperaturi tijekom 15 h. Provjera pomoću TLC (EtOAc:cikloheksan 1:1) je pokazala da je početna tvar u potpunosti potrošena. Smjesa je uparena te ponovo otopljena u DMF (150 ml). Zatim su dodani 2-hidroksinikotinska kiselina (9,59 g, 69,0 mmol, 1,2 ekv.), HOBt (9,32 g, 69,0 mmol, 1,8 ekv.) i EDC (16,5 g, 86,1 mmol, 1,5 ekv.).
Nakon miješanja na sobnoj temperaturi preko noći je smjesa koncentrirana, razrijeđena s EtOAc (500 ml), pa isprana vodom (100 ml). Vodena faza je dva puta ponovo ekstrahirana s etil-acetatom. Sjedinjene organske faze su koncentrirane, pa je sirova tvar ponovo otopljena u CH2Cl2 (500 ml), prije ispiranja s NaHCO3. Sirova tvar je koncentrirana da se dobije približno 31 g tvari, koja je otopljena u 80 ml smjese CHCl3:aceton 2:1. Nakon stajanja 1 sat na sobnoj temperaturi, pojavio se talog koji je filtriran i ispran (EtOAc:cikloheksan 1:2) da se dobije dodatni produkt (6,1 g, 24%). Ostatak je kromatografiran na biotage Flash75 (kratka kolona, CHCl3:aceton 2:1) da se dobije još produkta (3,6 g, 14%). Dakle, tri produkta (precipitat 1, precipitat 2, te kromatografirani produkt) su sjedinjeni da se dobije ukupno 17,9 g (70%) željenog piridona u obliku bijele krutine.
1H NMR (DMSO-d6) δ 12.51–12.61 (br. s, 1H), 10.29 (t, J = 6.0 Hz, 1H), 8.36 (dd, J = 7.2, 2.2 Hz, 1H), 7.70–7.75 (br. d, J ≈ 4.0 Hz, 1H), 7.47 (d, J = 3.7 Hz, 1H), 7.17 (d, J = 3.7 Hz, 1H), 6.49 (dd, J ≈ 7,6 Hz, 1H), 4.53 (d, J = 6.0 Hz, 2H), 3.82 (s, 4H), 3.00 (t, J = 5.7 Hz, 4H), 1.67 (t, J = 5.7 Hz, 4H).
2-okso-N-({5-[(4-okso-1-piperidinil)sulfonil]-2-tienil}metil)-1,2-dihidro-3-piridinkarboksamid (198b)
Otopina ketala 198a (6,0 g, 13,7 mmol) u acetonu (60 ml), vodena otopina HCl 1 N (30 ml) i konc. vodena otopina formaldehida (8 ml) grijani su na 48 ̊C tijekom 15 h. Smjesa je koncentrirana do ukupne težine 46 g, nakon čega je narančasto ulje odijeljeno, te je dodan CH2Cl2 (200 ml). Narančasto ulje otišlo je u organsku fazu, dok je voda (27 ml) odijeljena i uklonjena. Sloj CH2Cl2 ispran je s malenim količinama vode (20 ml), osušen (MgSO4) i koncentriran što je dalo sirovi keton kao hemiaminal (5,1 g, 88%).
Otopina hemiaminala (5,1 g, 12 mmol) u acetonu (8 ml) i 1 N vodena otopina HCl (4 ml) su grijani na 49 ̊C tijekom 15 h. Smjesa je stavljena u lijevak za odjeljivanje koji sadrži 200 ml EtOAc, pa je uklonjen vodeni spoj. Sušenje (MgSO4) i koncentriranje je dalo 286 mg sirovog piridinona 198b (81%) u obliku bijele krutine koja je sukladno NMR vrlo čista. 1H NMR (DMSO-d6) δ 12.57 (s, 1H), 10.27 (t, J = 6.1 Hz, 1H), 8.36 (dd, J = 7.1, 2.2 Hz, 1H), 7.73 (dd, J = 6.3, 2.1 Hz, 1H), 7.52 (d, J = 3.8 Hz, 1H), 7.16 (d, J = 3.7 Hz, 1H), 6.49 (dd, J = 7.1, 6.4 Hz, 1H), 4.72 (d, J = 6.0 Hz, 2H), 3.32 (q, J = 6.2 Hz, 4H), 2.43 (q, J = 6.2 Hz, 4H).
2-okso-N-({5-[(4-{[4-(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)-1,2-dihidro-3-piridinkarboksamid (198)
Suspenzija ketona 198b (2,33 g, 5,89 mmol, 1,0 ekv.), 4-(trifluormetil)benzilamina (0,98 g, 5,59 mmol, 0,95 ekv.) i NaBH(OAc)3 (1,62 g, 7,66 mmol, 1,3 ekv.) u 1,2-diklorethanu (70 ml) miješana je na sobnoj temperaturi. Nakon 3 dana, stavljena je u CH2Cl2 (600 ml), isprana sa zasićenom vodenom otopinom NaHCO3 (100 ml), osušena (MgSO4), te koncentrirana. Sirovo bezbojno ulje otopljeno je u MeOH (100 ml) i tretirano s 2 ml dimeće HCl (pre-razrijeđeno s 20 ml MeOH). Nakon 30 sekundi, počeo se pojavljivati bijeli talog. On je sakupljen nakon 10 minuta filtriranjem što je dalo željeni produkt u obliku HCl soli, odlične čistoće (1,6 g, 47% prinos). Koncentriranje filtrata na 10 ml dalo je još taloga (0,6 g, 17% prinos).
T.t. = 288–289 ̊C, 1H NMR (DMSO-d6) δ 12.5 (s, 1H), 10.38 (t, J = 6.0 Hz, 1H), 9.90–9.70 (br.s, 1.5H), 8.37 (dd, J = 7.2 & 2.1 Hz, 1H), 7.85–7.70 (m, 5H), 7.48 (d, J = 3.7 Hz, 1H), 7.16 (d, J = 3.8 Hz, 1H), 6.49 (t, J = 6.8 Hz, 1H), 4.73 (d, J = 5.8 Hz, 2H), 4.24–4.16 (br s, 2H), 3.66 (d, J = 11.7 Hz, 2H), 3.20–3.05 (br. m, 1H), 2.39 (t, J = 11.3 Hz, 2H), 2.19 (d, J = 10.7 Hz, 2H), 1.76 (qd, J = 11.5, 3.2 Hz, 2H).19F NMR (DMSO-d6) –61.64.
Sljedeći spoj je priređen na sličan način sukladno protokolu primjera 198 što je prije opisano:
[image]
Primjer 205 (Protokol G)
Priređivanje 3-Metoksi-N-({5-[(4-{metil[4-(trifluormetil)benzil]amino}-1-piperidinil)-sulfonil]-2-tienil}metil)benzamida (205)
Otopina hidrokloridne soli 1 (50 mg, 0,08 mmol), DIEA (12 μl, 0,08 mmol), formaldehidna vodena otopina 37% (32 μl, 0,4 mmol) i natrijev cijanoborhidrid (10 mg, 0,16 mmol) u THF su grijani pod refluksom 15 h, nakon čega je završeno alkiliranje. Reakcijska smjesa je razrijeđena s DCM i anorganske soli su ekstrahirane vodom. Sirova tvar je osušena iznad MgSO4, te je otopina uparena do suhog. Uljasta rezidua je pokupljena s THF, pa je polako dodana 1N HCl u eteru, nakon čega su nastali bezbojni kristali spoja 205 (prinos: 51 mg, 97%). Anal. HPLC: Retencijsko vrijeme = 4,39 min (metoda b). M/Z APCI: 582.1 (M+1), 580.4 (M–1).
Sljedeći spoj je priređen na sličan način sukladno primjeru 205 što je prije opisano.
[image]
Primjer 207: (Protokol H; vidi shemu 6)
Priređivanje 4-klor-N-[(5-{[4-({imino[4-(trifluormetil)fenil]-metil}-amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamida 207
Odgovarajući 1-[(5-{[(4-klorbenzoil)amino]metil}tien-2-il)sulfonil]-piperidin-4-amonijev trifluoracetat 208a priređen je sukladno sintezi 1d. Spoj 202a je prije upotrebe neutraliziran. 50 mg (0,12 mmol) spoja 208a otopljeno je u 2 ml DCE. Dodana je otopina trimetilaluminija u toluenu (2M, 86 μl, 0,16 mmol) na 0°C pod argonom. Reakcijska smjesa je miješana 15 min. na 0°C, a zatim 3 sata na sobnoj temperaturi. Polako je dodana otopina 4-trifluormetilbenzonitrila (41 mg, 0,24 mmol) u DCE u gore navedenu reakcijsku smjesu. Reakcijska smjesa je zatvorena i grijana na 70°C u atmosferi argona 15 h. Reakcijska posuda je ohlađena i otopina je razrijeđena s DCE, pa je zatim izvršeno ekstrahiranje sa slanom otopinom. Orgnaski sloj je osušen iznad MgSO4. Polazna aminska tvar je razgrađena pomoću polimerno vezanog izocijanata (3 ekv.). Preostala otopina je tretirana s polimerno vezanim tozilatom da bi se uhvatio bazični amidin. Ispiranjem smole uklonjen je kvantitativno polazni nitril. Tozilatna smola je konačno tretirana s NH3 u MeOH da se otpusti slobodni amidin 208. On je otopljen u THF, a nakon toga je izvršeno tretiranje s 1N HCl u eteru što je dalo hidrokloridnu sol spoja 207 u čistom obliku (35 mg, 48%). Anal. HPLC: Retencijsko vrijeme = 3,67 min (metoda b). M/Z APCI: 585.1 (M+1), 583 (M–1).
Primjer 208:
Priređivanje farmaceutske formulacije
Sljedeći primjeri formulacija ilustriraju reprezentativne farmaceutske smjese sukladno ovom izumu, ali bez ograničenja.
Formulacija 1 – Tablete
Sulfonamidski spoj formule I pomiješan je kao suhi prah sa suhim želatinskim vezivom u približnom težinskom odnosu 1:2. Dodana je manja količina magnezijeva sterata kao lubrikanta. Smjesa je oblikovana u tablete 240-270 mg (80-90 mg aktivnog sulfonamidskog spoja po tableti) u stroju za prešanje tableta.
Formulacija 2 – Kapsule
Sulfonamidski spoj formule I pomiješan je kao suhi prah sa škrobnim razrjeđivačem u približnom težinkom odnosu 1:1. Smjesom su napunjene 250 mg kapsule (125 mg aktivnog sulfonamidskog spoja po kapsuli).
Formulacija 3 – Tekućina
Sulfonamidski spoj formule I (1250 mg), saharoza (1,75 g) i ksantanska guma (4 mg) su pomiješani, propušteni 10 mesh U.S. sieve sito, te pomiješani s prethodno priređenom otopinom mikrokristalne celuloze i natrijeve karboksimetilceluloze (11:89, 50 mg) u vodi. Natrijev benzoat (10 mg), tvari za okus i boju su razrijeđene vodom i dodane uz miješanje. Zatim je dodano dovoljno vode da se dobije ukupni volumen 5 mL.
Formulacija 4 – Tablete
Sulfonamidski spoj formule I pomiješan je kao suhi prah sa suhim želatinskim vezivom u približnom težinskom odnosu 1:2. Kao lubrikant dodana je manja količina magnezijeva stearata. Smjesa je oblikovana u tablete 450-900 mg (150-300 mg aktivnog sulfonamidskog spoja) u stroju za prešanje tableta.
Formulacija 5 – Injekcija
Sulfonamidski spoj formule I otopljen je u puferiranoj sterilnog fiziološkoj otopini do koncentracije približno 5 mg/ ml.
Primjer 209 :
Biološke analize
Biološki rezultati
Biološke aktivnosti spojeva sukladno formuli I mogu se procijeniti sukladno sljedećim in vitro i in vivo analizama.
JNK2 i -3 u vitro analize:
Fosforiliranje c-jun pomoću JNK2 ili JNK3 može se pratiti praćenjem ugradnje 33P u c-jun sukladno dolje navedenom protokolu. Inhibitorska aktivnost spojeva sukladno formuli I, u odnosu na c-jun fosforiliranje kroz JNK, određeno je izračunavanje aktivnosti fosforiliranja JNK u prisutnosti i odsutnosti testnih spojeva sukladno formuli I.
JNK3 i/ili -2 analize izvršene su u MTT pločama s 96 jažica: inkubiranje 0,5 μg rekombinantnog, preaktiviranog GST-JNK3 ili GST-JNK2 s 1 μg rekombinantnog, biotiniranog GST-c-Jun i 2 μM 33γ-ATP (2 nCi/μl), u prisutnosti ili odsutnosti spojeva sukladno formuli I i u reakcijskom volumenu od 50 μl koji sadrži 50 mM Tris-HCl, pH 8,0; 10 mM MgCl2; 1 mM ditiotheitola, te 100 μM NaVO4. Inkubiranje je izvršeno tijekom 120 min. na sobnoj temperaturi i zaustavljeno dodatkom 200 μl otopine koja sadrži 250 μg streptavidin-prevučenih SPA kuglica (Amersham, Inc.)*, 5 mM EDTA, 0,1% Triton X-100 i 50 μM ATP, u fosfatno puferiranoj fiziološkoj otopini.
Nakon inkubiranja tijekom 60 minuta na sobnoj temperaturi, kuglice su sedimentirane centrifugiranjem na 1500g tijekom 5 minuta, resuspendirane u 200 μl PBS koji sadrži 5 mM EDTA, 0,1% Triton X-100 i 50 μM ATP pa je radioaktivnost izmjerena scintilacijskim β-brojačem, nakon čega su kuglice staložene kao što je prije opisano. zamjenom biotinirane GST-c Jun s biotiniranim GST-1ATF2 ili biotiniranim mijelinskim bazičnim proteinom, ova analiza može se također koristiti za mjerenje inhibiranja pre-aktiviranog p38 i ERK MAP kinaza.
[image]
Vrijednosti koje se odnose na JNK2 i 3 odnose se na IC50 (µM), tj. na količinu tvari koja je potrebna da se postigne 50% inhibiranje JNK3 i JNK2.
Ispitani spojevi sukladno formuli I pokazuju inhibiranje (IC50) u odnosu na JNK3 manje od 0,4 µM, poželjnije, jednako ili manje od 0,2 µM.
Ispitani spojevi sukladno formuli I pokazuju inhibiranje (IC50) u odnosu na JNK2 manje od 0,2 µM, poželjnije, jednako ili manje od 0,02 µM.
Spojevi primjera 1, 63, 86, 198 pokazuju inhibiranje (IC50) u odnosu na JNK1 između 0,1-0,7 µM.
Kultura simpatičkih neurona i analiza preživljavanja
Sposobnost spojeva ovog izuma formule I da poveća brzinu preživljavanja živčanih stanica koje su primorane na staničnu smrt je procijenjena sljedećim protokolom.
Simpatički neuroni iz gornjih cervikalnih ganglija (SCG) novorođenih štakora (p4) su raščlanjeni, naneseni na ploču s gustoćom 104 stanica/cm2 u 48 jažica MTT ploča koje su prevučene s kolagenom repa štakora, te su uzgajani u Leibowitz mediju koji sadrži 5% seruma štakora, 0,75 μg/mL NGF 7S (Boehringer Mannheim Corp., Indianapolis, IN.) i arabinozin 105M. Stanična smrt je izazvana četvrtog dana izlaganjem kulture mediju koji sadrži 10 μg/mL anti NGF antitijela (Boehringer Mannheim Corp., Indianapolis, IN.) bez NGF ili arabinozina, u prisutnosti ili odsutnosti sulfonamidskih inhibitora. 24 sata nakon što je izazvana stanična smrt, određena je stanična vijabilnost inkubiranjem kulture tijekom 1 sat, na 37°C u 0,5 mg/mL 3-(4,5-dimetiltiazol-2-il)-2,5-difenil tetrazolijeva bromida (MTT). Nakon inkubiranja u MTT stanice su resuspendirane u DMSO, prenesene na 96 MTT ploču i stanična vijabilnost je procijenjena mjerenjem optičke gustoće na 590 nm.
Rezultati ove analize s različitim ispitanim spojevima pokazuju da spojevi formule I spašavaju neurone od stanične smrti (% neurona koji preživljavaju je između 10 i 80).
Gore navedena analiza sa testnim spojem (63) pokazuje brzinu preživljavanja SCG stanica od 35% sa 3 μM.
Analiza otpuštanja IL-2:
Sposobnost spojeva sukladno formuli I da moduliraju upalni odgovor inhibiranjem otpuštanja IL-2 procijenjena je pomoću sljedećeg protokola.
JNK ciklus aktiviranja započinje produkciju upalnih citokina kao što su IL-2. JNK se može aktivirati vanjskim stimulansom kao što je PMA i ionomicin te se IL-2 proizvodnja može izmjeriti putem IL-2 ELISA testa. Komparativna mjerenja sa i bez spojeva ovog izuma sukladno sljedećem protokolu mjere aposobnost spojeva da spriječe otpuštanje IL-2 koje je izazvano stresom.
Jurkat stanice, humana T-stanična linije leukemije (American Type Culture Collection # TIB 152) su uzgojene u RPMI 1640 mediju (Gibco, BRL) kojemu je dodano 10% toplinski aktiviranog fetalnog telećeg seruma (FCS), glutamin i Penstrep. Stanična suspenzija u mediju je razrijeđena da se dobije 2×106 stanica/mL. Stanice su nanesene na ploču (2×10� stanica/jažica) na ploču s 96 jažica koja sadrže različite koncentracije spoja sukladno formuli I (konačne koncentracije spojeva, 10, 3, 1, 0,3 i 0,1 µM). Ova smjesa je inkubirana 30 minuta na 37oC u vlažnoj CO2 atmosferi. Stanice su zatim tretirane s 10 µl PMA (forbolmiristat-13 acetat-12) + ionomicin (0,1 µM i 1 µM konačna koncentracija) u svim jažicama osim u negativnoj kontroli. U jažicama bez spoja, dodano je 10 µl RPMI 2% DMSO (=0,1% konačnog). Stanice su inkubirane 24 sata na 37oC i zatim je sakupljen supernatant (zamrznut na –20oC ako se ne koristi istog dana) prije izvršenja IL-2 ELISA testa u supernatantu.
ELISA Analiza IL-2:
IL-2 otpuštanje u medij pomoću (PMA + iononomicin)-stimuliranih Jurkat stanica, u prisutnosti i odsutnosti testnih spojeva, može se analizirati ELISA tehnikom. Treba slijediti postupak koji je dolje opisan.
Korištena su monoklonska anti-humana IL-2 antitijela (MAB602) (hvatanje), biotinirano anti-humano IL-2 antitijelo (BAF202) (detektiranje) i recombinantni humani IL-2 (202-IL-010) (standard) of From R&D Systems.
Priređivanje ploče
100 µl antitijelo za hvatanje koje je razrijeđeno u PBS na 5 µg/mL (PBS-Tween 0,05%) prenseno je na ELISA ploču s 96 jažica i inkubirano je preko noći na sobnoj temperaturi.
Svaka jažica je aspirirana i isprana 3 puta s puferom za ispiranje (PBS-Tween 0,05%). Nakon zadnjeg ispiranja, ploča je prigušena.
Postupak analize
1. Dodano je 100 µl uzorka ili standarda (2000, 1000, 500, 250, 125, 62,5, 31,25 pg/mL) i inkubirano je 2 sata na sobnoj temperaturi.
2. 3 puta ispiranje
3. 100 µl biotiniliranog anti-humanog IL-2 na 12,5 ng/mL je dodano i inkubirano 2 sata na sobnoj temperaturi.
4. 3-time-wash
5. 100 µl streptavidin-HRP (Zymed #43-4323) na 1:10’000 je dodano i inkubirano 30 minuta na sobnoj temperaturi.
6. 3 puta ispiranje
7. 100 µl supstratne otopine (limunska kiselina/ Na2HPO4 (1:1) + H2O2 1:2000 + OPD) je dodano i inkubirano 20-30 minuta na sobnoj temperaturi.
8. 50 µl “stop” otopine (H2SO4 20%) dodano je u svaku jažicu.
9. Izmjerena je optička gustoća pomoću čitača mikrotitarske ploče koji je postavljen na 450 nm s korekcijom na 570 nm.
Rezultat ove analize pokazuju da rzličiti ispitivani spojevi smanjuju rpoizvodnju IL-2 za više od 30% pri μM.
Primjerice, spojevi (1), (64) i (68) pokazuju vrijednost IC50 manju od 800 nM u ovoj analizi.
Analiza C-Jun reportera
Fosforiliranje transkripcijskog čimbenika, c-jun, pomoću JNK u MAP kinaza ciklus prenošenja signala može se pratiti putem trans-reporterskog sustava kao što je komercijalno raspoloživi PathDetect ® (32).
Može se procijeniti inhibiranje spojeva pomoću spojeva sukladno formuli I.
Trans-reporterski sustav omogućuje da se prati, putem aktivnosti Luciferaze, status aktiviranja fuzijskog trans-aktivatorskog proteina. Trans-aktivatorski protein sastoji s eod aktivacijske domene transkripcijskog čimbenika od interesa (c-jun) koji je sjedinjen s kvaščevim transkripcijskim aktivatorom, GAL4 DNA vezujuće domene (dbd). GAL4 dbd ima tu prednost što nema poznatih transkripcijskih čimbenika sisavaca koji se vežu za njega pa je prema tome osnovni šum pri ovoj analizi vrlo nizak.
U ovom slučaju, korištena je Hela luciferaza reporter-c-Jun (HLR-c-Jun) stanična linija koja kontitutivno vrši ekspresiju GAL4-cJun.
Ubačen je MEKK-1 gen. MEKK-1 je MAPKKK koji starta aktiviranje JNK. Ekspresija divljeg tipa MEKK-1 dovoljna je za JNK aktiviranje (33).
Kada je jednom JNKaktivirana, ona može izazvati fosforiliranje c-jun domene fuzijkog trans-aktivatorskog proteina (GAL4dbd -cJun) koji stvara dimer. Dimer zatim može vezati GAL4 uz tok aktivirajuće sekvencije (GAL4 UAS) reportera koji aktivira ekspresiju Luciferaze.
Ekspresija Luciferaze detektirana je pomoću luminescencije korištenjem jednostavne analize kao što je sustav “Dual-Luciferase ® Reporter Assay” (34) u kojem se koristi Renilla kao "kontrolni reporter".
Inhibiranje JNK je uočeno kao smanjenje ekspresije Luciferaze i detektirano je smanjenjem luminescencije.
Stanična kultura
HLR-c-Jun stanice su uzgojene u DMEM High Glc kojemu je dodano 10% FCS (Sigma), 2 mM glutamina (Gibco), P/S, Hygromycin b 100 µg/mL i G418 250 µg/mL.
Priređivanje stanične kulture
Banke stanica
Stanice su pohranjene zamrznute u epruvetama za zamrzavanje, kao 1,8 mL volumen stanične suspenzije u mediju kulture koji sadrži 10% dimetil sulfoksida.
Odmrzavanje stanične kulture
Kada je to potrebno, stanice su brzo odmrznute na 37°C u vodenoj kupelji blagim potresivanjem dok odrzavanje nije bilo napola završeno. Zatim je staničnoj suspenziji dodano 10 mL medija kulture i izvršeno je centrifugiranje 5 minuta na 1200 rpm. Supernatant je uklonjen i stanični grumen je rekonstituiran u mediju. Tikvice su inkubirane na 37°C u atmosferi 5% CO2.
Prolaz stanica
Stanice su serijski sub-kulturirane (propuštene) kada su dobiveni 80% konfluentni monoslojevi.
Uklonjen je medij iz svake tikvice i monosloj je ispran s 10-15 mL fosfatno puferirane otopine (PBS).
Tripsin-EDTA otopina je dodana staničnom monosloju, inkubirana na 37°C i povremeno blago potresena da se izbace stanice. Potpuno odvajanje i disagregiranje staničnog sloja je potvrđeno mikroskopskim ispitivanjem. Stanice su zatim resuspendirane u 10 mL kompletnog medija i centrifugirane 5 minuta na 1200 rpm.
Supernatanti su odbačeni, a stanice su resuspendirane u mediju kulture te razrijeđene 1/5 u 175 cm2 tikvicama.
Dan 0, jutro
Priređivanje stanica za transfekciju
Stanice gotovo sjedinjenih kultura su odvojene i disagregirane tretiranjem s tripsinom kao što je prije opisano.
Stanice su resuspendirane u mediju kulture i ponovo izbrojane.
Stanične suspenzije su razrijeđene medijem da se dobije oko 3,5×106 stanica/mL i 1mL µl stanične suspenzije je stavljen na dvije 10 cm posudice za kulture koje sadrže 9 mL medija kulture.
Ploče su inkubirane na 37°C u vlažnoj atmosferi 5% CO2 u zraku.
Dan 0, uveče
Transfekcije
Kontrola : 0,2 µg pTK Renilla, 5,8 µg pBluescript KS, 500 µl OPTIMEM (GIBCO), 18µl Fugene 6.
Inducirani : 0,1 µg pMEKK1, 0,2 µg pTK Renilla, 5,7 µg pBluescript KS, 500 µl OPTIMEM (GIBCO), 18 µl Fugene 6 30‘ RT.
Smjesa za transfekciju je dodana stanicama na ploči. Ploče su inkubirane preko noći na 37°C u vlažnoj atmosferi 5% CO2 u zraku.
Dan 1
Priređena je ploča s 96 jažica (100 µl medija kulture po jažici).
Negativna kontrola (nosač): 2 µl DMSO dodano je u 100 µl (u triplikatu).
2 µl spoja prema formuli I “stock” razrjeđenja (3, 1 i 0,1 mM u 100% DMSO) dodano je u 100 µl (u triplikatu).
Transficirane stanice su tripsinizirane i resuspendirane u 12 mL medija kulture.
100 µl razrjeđenja dodano je u svaku jažicu ploče s 96 jažica.
Ploča je inkubirana preko noći na 37°C u vlažnoj atmosferi 5% CO2 u zraku.
Dan 2
Postupak ispitivanja: sustav analize reporterske Dual-Luciferase ® (34).
Medij je uklonjen s ploča i stanice su isprane dva puta s 100 µl PBS. Lizni reagens je primijenjen (paisni luzni pufer, PLB). U svaku jažicu kulture stavljeno je 5 µl 1X PLB. Ploče s kulturom su stavljene na ploču za potresivanje ili u orbitalni potresivač s blagim potresivanjem/treskanjem da se postigne potpuno prekrivanje staničnog monosloja s 1X PLB. Ploče kulture su potresivane na sobnoj temperaturi tijekom 15 minuta. 20 µl
lizata prenseno je u bijelu neprozirnu ploču s 96 jažica. Zabilježeno je očitanje na lumonometru.
- 50 µl regensa II za analizu luciferaze je injicirano i zabilježena su očitanja na 5 i 10 min.
50µl Stop&Glo ® reagensa je injicirano i očitanja su zabilježena za 5 i 10 min.
Zatim je izmjerena relativna luminiscencija: RLU luciferaza/RLU renila.
Rezultat ove analize pokazuje da različitini testni spojevi inhibiraju više od 20% aktivnosti JNK za 10 μM.
Primjerice, spojevi (1), (10), (11) ili (117) pokazuju u ovoj analizi IC50 vrijednost koja je manja od 0,7 μM.
LPS-izazvani endotoksični šok u miševa
Sposobnost JNK inhibitora koji su opisani formulom I da značajno smanje rezinu upalnih citokina koji su izazvani LPS podražajem procijenjena je pomoću sljedećeg protokola:
Endotoksini su lipopolisaharidi (LPS) koji grade vanjsku membranu Gram-negativnih bakterija. Pokazalo se da LPS odgovor uključuje aktiviranje različitih staničnih populacija i da vodi ekspresiji vazličitih upalnih citokina što obuhvaća tumorski nekrotizirajući čimbenik alfa (TNFα) i interferon gama (IFN-γ).
Budući da je poznato da LPS stimulira aktiviranje MAP kinaza ciklusa, uključujući JNK (35), sposobnost JNK inhibitora može se ispitati nakon uključivanja JNK signalnog ciklusa pomoću LPS podražaja.
Aktivnost spojeva formule I kao JNK inhibitora može se procijeniti nakon LPS podražaja pomoću sljedećeg protokola:
LPS (S. abortus-Galanos Lab.-) je injiciran (200 μg/kg, i.v.) mužjacima C57BL/6 miševa da se izazove endotoksinski šok. Spojevi sukladno formuli I (0,1, 1, 10 mg/kg) ili NaCl (200 μM) su intravenski injicirani (10 mL/kg) 15 min prije LPS podražaja. Heparinizirana krv je dobivena iz orbitalnog sinusa u različitim vremenskim točkama nakon LPS podražaja, pa je krv centrifugirana na 9 000 rpm tijekom 10 min na 40C da se sakupi supernatant.
Mjerenje proizvodnje citokina kao što su TNFα i IFNγ u miševa izvršena je ELISA priborom kao što je Duoset ® DY410 za TNFα i DY 485 za IFN γ. Mogu se rabiti druge ELISA analize kao što su one opisane u (36).
Prema tome, spoj primjera (63) pokazuje inhibiranje proizvodnje IFN γ od 65% za 1 mg/kg i 40 % inhibiranje proizvodnje TNFα� za 10 mg/kg.
Globalna ishemija u gerbilima
Sposobnost JNK inhibitora koji su opisani formulom I da se spriječi stanična smrt tijekom udara procijenjena je sljedećim protokolom:
Okluzija gerbilne bilateralne karotide je dobro poznati životinjski model akutnog ishemijskog udara i uključuje relativno jednostavne kirurške tehnike.
Degeneracija živaca u hipokampusu razvija se tijekom nekoliko dana i često se naziva “odgođena živčana smrt”. Nadalje, degeneracija živaca koja se uočava histološki je očigledna i lako se kvantificira (37). Nadalje, histopatologija koja se uočava u gerbilu je slična onoj koja se uočava u CA1 području hipokampusa nakon srčanog zastoja. Uočena svojstva, kao što su testovi pamćenja, mogu se čak provesti u slučaju gerbila. Ova vrsta testova za utvrđivanje stupnja oporavka je laka za realizaciju u drugim modelima kao što je štakorski, gdje su sposobnosti učenja mnogo slabije (38).
Neuroprotektivni učinak spojeva formule I može se procijeniti pomoći modela globalne gerbilne ishemije i ovog protokola:
-1- Metoda
* Kirurugija
- Anesteziranje s izofluranom (0,5-4%).
- Glavne karotidne arterije (lijeva i desna) su oslobođene tkiva.
- Okluzija arterija pomoću Bulldog mikroštipaljki tijekom 5 min.
- Uklanjanje štipaljki (reperfuzija).
- Stavljanje životinja pod graijaću svjetiljku do buđenja.
- Stavljanje životinja u pojedinačne kaveze.
* Žrtvovanje životinja
- 7 dana nakon ishemije (usmrćivanje ili predoziranje pentobarbitalom)
- uzorkovanje mozga.
* Histološki paramteri
- Zamrzavanje mozga u izopentanu (-20°C)
- Rezanje slojeva hipokapmusa pomoću krio-mikrotoma (20 µm).
- Bojenje s krezil-violetnom metodom
- Procjena ozljede (u CA1/CA2 podpoljima hipokampusa) pomoću Gerhard&Boast indeksa (39).
-2- Tretiranje
- Primjena spoja sukladno formuli I ili nosača: 15 min, 24 sata ili 48 sati nakon reperfuzije (5-10 min nakon oporavka od anestezije).
- Standardni postupak
50 životinja : 5 skupina po 8 (skupina A : kontrole, skupine B-D: testni uzorak po 3 doze i skupina E : referentni spoj (orotična kiselina 3×300 mg/kg, ip).
Dakle, spoj primjera (68) pokazao je inhibiranje globalne ishemije od 64% (% inhibiranja ukupne lezije) za 80 mg/kg.
Topljivost spojeva formule (I)
Procijenjena je topljivost spojeva u vodi, pri pH 7,4 na sobnoj temperaturi. Općenito, topljivost spojeva formule (I) je u rasponu od bar 50 μg/mL otapala, poželjnije bar 100 μg/mL otapala. Primjerice, spojevi (63), (163), (198) pokazuju topljivost u vodi od bar 200 μg/mL otapala.
Reference
Davis, Roger J., Signal Transduction by the JNK Group of MAP Kinases. Cell, 2000, 103: 239-252.
Chen, Yi-Rong and Tan, Tse-Hua. The c-Jun N-terminal kinase pathway and apoptotic signaling. International Journal of Oncology, 2000 , 16: 651-662
Ip, YT. and Davis RJ, Signal transduction by the c-Jun N-terminal kinase (JNK) from c-Jun N-terminal kinase (JNK) from inflammation to development Curr Opin Cell Biol 1998,10:205-219.
Leppä, S. and Bohmann D., Diverse functions of JNK signalling and c-Jun u stress response and apoptosis, Oncogene 1999, 18(45):6158-6162.
Minden, A. and Karin M.. Regulation and function if the JNK subgroup of MAP kinases. Biochim Biophys Acta 1997,1333:F85-F104.
Whitmarsh, A.J., and Davis. R.J. Transcription factor AP-1: regulation by mitogen activated protein kinases signal transduction pathways. J. Mol, Med. 1996, 77, 2360-2371.
Gupta, S. et al., Selective interaction of JNK protein kinase isoforms with transcription factors. The EMBO Journal, 1996, 158(11): 2760-2770.
Derek D. et al., Absence of excitotoxicity- induced apoptosis u the hippocampus of mice lacking the Jnk3 gene. Nature 1997, 389:865-876.
Martin, Loel H. et al., Developmental expression u the mouse nervous system of the p493F12 SAP kinase. Molecular Brain Research, 1996, 35: 47-57.
Kumagae, Y. et al., Human c-Jun N-terminal kinase expression and activation u the nervous system, Molecular Brain Research 1999, 67: 10-17
Dumitru, Calin D. et al.. TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 2000, 103: 1071-1083.
Han, Z. et al., C-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction u inflammatory arthritis. The Journal of Clinical Investigation 2001, 108 (1):73-81.
Nishina, H., et al.. Impaired CD28-mediated interleukin 2 production and proliferation u stress kinase SAPK/ERK1 kinase (SEK1)/mitogen-activated protein kinase kinase 4 (MKK4)-deficient T lymphocytes. Journal of Experimental Medicine 1997, 186(6): 941-953.
Kempiak, Stephan J. et al.. The Jun Kinase Cascade is responsible for activating the CD28 Response element of the IL-2 Promoter: proof of cross-talk with the I�B Kinase Cascade, The Journal of Immunology, 1999, 162: 3176-3187.
De la Monte, S. M. et al., Oksigen free radical injury is sufficient to cause some Alzheimer-type molecular abnormalities u human CNS neuronal cells. J. Alzheimer's Dis. 2000, 2(3-4): 261-281.
Zhu,X, Activation and redistribution of c-Jun N-terminal kinase/stress activated protein kinase u degenerating neurons u Alzheimer's disease. Journal of Neurochemistry 2001, 76: 435-441
Force, T. et al., Stress-Activated Protein Kinases u cardiovascular Disease. Circulation Research. 1996, 78:947-953.
Kim, S. et al., Angiotensin blockade inhibits activation of mitogen-activated Protein Kinases u Rat balloon-injured artery. Circulation 1998, 97:1731-1737.
Xu, Q. et al., Acute Hypertension Activates Mitogen-activated Protein Kinases u Arterial Wall. The Journal of Clinical Investigation 1996, 97 (2):508-514 .
Bogoyevitch, M.A. et al., Stimulation of the stress-activated mitogen-activated protein kinase subfamilies u perfused heart. Circulation Research. 1996, 79:162-173.
Pombo, CM. et al., The stress-activated protein kinases are major c-Jun amino-terminal kinases activated by ischemia and reperfusion, J. Biol. Chem. 1994, 269 (42): 26546-26551.
Onishi, I. et al., Activation of c-Jun N-terminal kinase during ischemia and reperfusion u mouse liver , FEBS Letters 1997, 420: 201-204
Safirstein, R., Renal stress response and acute renal failure Adv. Ren. Replace Ther. 1997, 4 (2 Suppl 1): 38-42.
Butterfield, L. et al., C-Jun NH2-terminal kinase regulation of the apoptotic response of small cell lung cancer cells to ultraviolet. The Journal of Biological Chemitry 1997, 272 (15) : 10110-10116.
Hu, M. et al., JNK1, JNK2 and JNK3 are p53 N-terminal serine 34 kinases, Oncogene 1997, 15: 2277-2287.
Xu, X. et al., Constitutively activated JNK is associated with HTLV-1 mediated tumorigenesis, Oncogene 1996, 13: 135-142.
Chen YR and Tan TH, The c-Jun N-terminal kinase pathway and apoptotic signaling, Int. J. Oncol. 2000, 16(4):651-62.
Harding, T.C. et al, Inhibition of JNK by overexpression of the JNK binding domain of JIP-1 prevents apoptosis u sympathetic neurons, The Journal Of Biological Chemistry 2001, 276(7):4531-4534.
Gennaro, A.R. et al., Remington’s Pharmaceutical Sciences. 18th ed. Easton: The Mack Publishing Company, 1995.
Green TW and Wuts PG, 1999, 3rd Edition, Wiley Ed.
Abdel-Magid AF et al., Reductive amination of aldehvdes and ketones with sodium triacetoksiborohydride. Studies on direct and indirect reductive amination procedures, Journal of Organic Chemistry 1996, 61, 3849-62.
Xu, L. et al., Assess the in-vivo activation of signal transduction pathways with Pathdetect ® reporting systems, Strategies 2001, 14 (1): 17-19.
Xu, S. et al., Cloning of rat MEK kinase 1 cDNA reveals an endogenous membrane-associated 195-kDa protein with a large regulatory domain, Proc. Natl. Acad. Sci. USA 1996, 93:5291-5295.
Patent Number US 5,744,320; Promega Corporation; April 28, 1998
Guha, M. and Mackman, N., LPs induction of gene expression u human monocytes, Cellular Signalling 2001, 13: 85 -94 .
Fomsgaard, A. et al., Quantification and biological activities of native tumour necrosis factor from LPS-stimulated human monocytes, APMIS 1990, 98(6): 529-34.
Hunter J.L. et al., Animal models of acute ischaemic stroke: can they predict clinically successful neuroprotective drugs? TIPS 1995, 16:123-128.
Block, F., Global Ischemia And Behavioural Deficits, Progress u Neurobiology 1999, 58: 279-295.
Gerhard SC and Boast CA, Behavioral Neuroscience 1988, 102: 301-303.
40. Dess, D.B.; Martin, J.C. J. Org. Soc., 1983, 48, 4155.
Claims (19)
1. Sulfonamidski derivati prema formuli I
[image]
I
sa svojim geometrijskim izomerima, u optički aktivnom obliku kao enantiomeri, diastereomeri, kao i u obliku racemata, te njihovih farmaceutski prihvatljivih soli, naznačeni time što
Ar1 i Ar2 su međusobno neovisno aril ili heteroaril,
X je O ili S;
R1 je vodik ili C1-C6-alkilna skupina, ili R1 čini 5-6-člani zasićeni ili nezasićeni prsten s Ar1;
n je cijeli broj od 0 do 5;
Y je 4-12-člani zasićeni ciklički ili biciklički alkil koji sadrži dušik, koji čini vezu sa sulfonilnom skupinom formule I, pri čemu je navedeni 4-12-člani zasićeni ciklički ili biciklički alkil supstituiran sbar jednom ionizirajućom specijom na koju je vezan lipofilni lanac.
2. Sulfonamidski derivat prema bilo kojem prethodnom zahtjevu, naznačen time što su Ar1 i Ar2 neovisno odabrani iz skupa kojega sačinjavaju fenil, tienil, furil, pirolo, piridil, proizvoljno supstituirani s C1-C6-alkil, C1-C6-alkoksi, C2-C6-alkenil, C2-C6-alkinil, amino, acilamino, aminokarbonil, C1-C6-alkoksikarbonil, aril, karboksil, cijano, halogen, hidroksi, nitro, sulfonil, C1-C6-tioalkoksi.
3. Sulfonamidski derivat prema zahtjevu 2, naznačen time što je Ar1 fenil.
4. Sulfonamidski derivat prema bilo kojem prethodnom zahtjevu, naznačen time što je Ar2 tienilna ili furanilna skupina.
5. Sulfonamidski derivat prema bilo kojem prethodnom zahtjevu, naznačen time što je Ar1 odabran iz skupa kojega sačinjavaju halogenofenil, nitrofenil, hidroksifenil, alkoksifenil, piridil, 3,4,-dihidroksifenil, tiokso-dihidropiridin ili njegov tautomer, pirazol i X je O, R1 je vodik, n je 1, Ar2 je tienil ili furanil.
6. Sulfonamidski derivat prema zahtjevu 5, naznačen time što je Y pirolidin, azepan ili piperidinska specija dolje navedene formule
[image]
ili
[image]
ili
[image]
gdje je R6 odabran iz skup kojega sačinjavaju vodik, C1-C6-alkil, C1-C6-alkoksi, OH, halogen, nitro, cijano, sulfonil, okso (=O), sulfoksi, aciloksi, tioalkoksi i gdje R6 nije vodik, n’ je cijeli broj od 0 do 4, poželjno 1 ili 2, gdje je bar jedno od L1 i/ili L2 ionizirajući entitet za kojega je vezan lipofilni lanac.
7. Sulfonamidski derivat prema zahtjevu 6, naznačen time što R6 je H, L2 je H, L1 je -NR3’R3; gdje bar jedan od R3’ i R3 nije vodik, već supstituent koji je odabran iz skupa kojega sačinjavaju ravni ili razgranati C4-C18-alkil, aril-C1-C18-alkil, heteroaril-C2-C18-alkil, C1-C14-alkil supstituiran s C3-C12-cikloalkil ili -biciklo ili -tricikloalkil, pri čemu navedeni alkilni lanac može imati 1-3 atoma kisika ili sumpora.
8. Sulfonamidski derivat prema zahtjevu 7, naznačen time što L1 je -NHR3; gdje R3 je ravni ili razgranati C4-C12-alkil, poželjno C6-C12-alkil, proizvoljno supstituiran sa cikloheksilnom skupinom ili benzilnom skupinom.
9. Sulfonamidski derivati prema zahtjevu 8, naznačen time što je Y piperidinska skupina
[image]
L1 je –NHR3; gdje je R3 ravni ili razgranati C6-C12-alkil, poželjno C8-C12-alkil, ili benzilna skupina.
10. Sulfonamidski derivat prema bilo kojem prethodnom zahtjevu, naznačen time što je odabran iz skupa kojega sačinjavaju:
4-klor-N-[(5-{[4-(heksilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
3-Metoksi-N-{[5-({4-[(4-trifluormetilbenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-[(5-{[4-(1,3-tiazol-2-ilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-[(5-{[4-(heptilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-[(5-{[4-(pentilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-[(5-{[4-(butilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-[(5-{[4-(dodecilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-{[5-({4-[(2-cikloheksiletil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({4-[(cikloheksilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-({5-[(4-{[(1R)-1-cikloheksiletil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)benzamid
N-{[5-({4-[(1R,2R,4S)-biciklo[2.2.1]hept-2-ilamino]piperidin-1-il}sulfonil)tien-2-il]metil}-4-klorbenzamid
4-klor-N-{[5-({4-[(2-propoksietil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[(1-adamantilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-4-klorbenzamid
4-klor-N-{[5-({4-[(2-piridin-2-iletil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({4-[(2-piperidin-1-iletil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({4-[(2-etilheksil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-({5-[(4-{[3-(1H-imidazol-1-il)propil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)benzamid
4-klor-N-[(5-{[4-(oktilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
N-[(5-{[4-(heptilamino)piperidin-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
3-metoksi-N-[(5-{[4-(oktilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
3-metoksi-N-[(5-{[4-(pentilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
N-[(5-{[4-(butilamino)piperidin-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
N-[(5-{[4-(dodecilamino)piperidin-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
N-{[5-({4-[(2-cikloheksiletil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-({5-[(4-{[(1R)-1-cikloheksiletil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)-3-metoksibenzamid
N-{[5-({4-[(1R,2R,4S)-biciklo[2.2.1]hept-2-ilamino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(2-propoksietil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[(1-adamantilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-{[5-({4-[(3,3-dietoksipropil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(3-morfolin-4-ilpropil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(2-piridin-2-iletil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(2-piperidin-1-iletil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[(2-etilheksil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-({5-[(4-{[3-(1H-imidazol-1-il)propil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)-3-metoksibenzamid
N-[(5-{[4-(heksilamino)piperidin-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
N-[(5-{[4-(heptilamino)azepan-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
3-metoksi-N-[(5-{[4-(oktilamino)azepan-1-il]sulfonil}tien-2-il)metil]benzamid
3-metoksi-N-[(5-{[4-(pentilamino)azepan-1-il]sulfonil}tien-2-il)metil]benzamid
N-[(5-{[4-(butilamino)azepan-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
N-[(5-{[4-(dodecilamino)azepan-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
N-{[5-({4-[(2-cikloheksiletil)amino]azepan-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-({5-[(4-{[(1R)-1-cikloheksiletil]amino}azepan-1-il)sulfonil]tien-2-il}metil)-3-metoksibenzamid
N-{[5-({4-[(1R,2R,4S)-biciklo[2.2.1]hept-2-ilamino]azepan-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(2-propoksietil)amino]azepan-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[(cikloheksilmetil)amino]azepan-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-{[5-({4-[(1-adamantilmetil)amino]azepan-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(3-morfolin-4-ilpropil)amino]azepan-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(2-piridin-2-iletil)amino]azepan-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(2-piperidin-1-iletil)amino]azepan-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[(2-etilheksil)amino]azepan-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-({5-[(4-{[3-(1H-imidazol-1-il)propil]amino}azepan-1-il)sulfonil]tien-2-il}metil)-3-metoksibenzamid
4-klor-N-[(5-{[4-(heptilamino)azepan-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-[(5-{[4-(oktilamino)azepan-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-[(5-{[4-(pentilamino)azepan-1-il]sulfonil}tien-2-il)metil]benzamid
N-[(5-{[4-(butilamino)azepan-1-il]sulfonil}tien-2-il)metil]-4-klorbenzamid
4-klor-N-[(5-{[4-(dodecilamino)azepan-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-{[5-({4-[(2-cikloheksiletil)amino]azepan-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[(1R,2R,4S)-biciklo[2.2.1]hept-2-ilamino]azepan-1-il}sulfonil)tien-2-il]metil}-4-klorbenzamid
4-klor-N-{[5-({4-[(2-propoksietil)amino]azepan-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({4-[(2-etilheksil)amino]azepan-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-[(5-{[4-(heksilamino)azepan-1-il]sulfonil}tien-2-il)metil]benzamid
N-[(5-{[4-(heksilamino)azepan-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
3-metoksi-N-[(5-{[4-({2-[3-(trifluormetil)fenil]etil}amino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
3-metoksi-N-({5-[(4-{[2-(4-metilfenil)etil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)benzamid
3-metoksi-N-({5-[(4-{[(1S,2R)-2-fenilciklopropil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)benzamid
3-metoksi-N-{[5-({4-[(1-naphthylmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(2-fenilpropil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-({5-[(4-{[2-(4-hidroksifenil)etil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(3-fenilpropil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[(2,3-dihidroksipropil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-{[5-({4-[(2-hidroksietil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-[(5-{[4-(nonilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
3-metoksi-N-[(5-{[4-(decilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
3-metoksi-N-[(5-{[4-(etilamino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
N-{[5-({4-[(2-[1,1'-bifenil]-4-iletil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-{[5-({4-[([1,1'-bifenil]-3-ilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(2-tien-2-iletil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-[(5-{[4-({4-[(trifluormetil)sulfonil]benzil}amino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
3-metoksi-N-{[5-({4-[(kinolin-4-ilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[([1,1'-bifenil]-4-ilmetil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
4-klor-N-{[5-({4-[(2-{[(trifluormetil)sulfonil]amino}etil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}benzamid
4-klor-N-[(5-{[4-(propilamino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
4-klor-N-[(5-{[4-({4-[(trifluormetil)sulfonil]benzil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
4-klor-N-{[5-({4-[(3,4-dihidroksibenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}benzamid
metil [{1-[(5-{[(4-klorbenzoil)amino]metil}-2-tienil)sulfonil]-4-piperidinil}(heksil)amino]acetat
tert-butil [{1-[(5-{[(4-klorbenzoil)amino]metil}-2-tienil)sulfonil]-4-piperidinil}(heksil)amino]acetat
[{1-[(5-{[(4-klorbenzoil)amino]metil}-2-tienil)sulfonil]-4-piperidinil}(heksil)amino]octena kiselina
N-[(5-{[3-(heptilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
3-metoksi-N-[(5-{[3-(oktilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]benzamid
3-metoksi-N-[(5-{[3-(pentilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]benzamid
N-[(5-{[3-(butilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
N-[(5-{[3-(dodecilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
N-{[5-({3-[(2-cikloheksiletil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-({5-[(3-{[(1R)-1-cikloheksiletil]amino}pirolidin-1-il)sulfonil]tien-2-il}metil)-3-metoksibenzamid
N-{[5-({3-[(1R,2R,4S)-biciklo[2.2.1]hept-2-ilamino]pirolidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({3-[(2-propoksietil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({3-[(cikloheksilmetil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-{[5-({3-[(1-adamantilmetil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({3-[(3-morfolin-4-ilpropil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({3-[(2-piridin-2-iletil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({3-[(2-piperidin-1-iletil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({3-[(2-etilheksil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-[(5-{[3-(heksilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
4-klor-N-[(5-{[3-(heptilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-[(5-{[3-(heksilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]benzamid
4-klor-N-[(5-{[3-(pentilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]benzamid
N-[(5-{[3-(butilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]-4-klorbenzamid
4-klor-N-{[5-({3-[(2-cikloheksiletil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({3-[(1R,2R,4S)-biciklo[2.2.1]hept-2-ilamino]pirolidin-1-il}sulfonil)tien-2-il]metil}-4-klorbenzamid
4-klor-N-({5-[(3-{[(1-hidroksicikloheksil)metil]amino}pirolidin-1-il)sulfonil]tien-2-il}metil)benzamid
N-{[5-({3-[(1-adamantilmetil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}-4-klorbenzamid
4-klor-N-{[5-({3-[(3-morfolin-4-ilpropil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({3-[(2-piridin-2-iletil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({3-[(2-piperidin-1-iletil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({3-[(2-etilheksil)amino]pirolidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-[(5-{[3-(oktilamino)pirolidin-1-il]sulfonil}tien-2-il)metil]benzamid
metil (2S)-1-[(5-{[(4-klorbenzoil)amino]metil}-2-tienil)sulfonil]-4-(heksilamino)-2-pirolidinekarboksilat
3-metoksi-N-{[5-({4-[(pentilamino)metil]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[2-(butilamino)etil]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-{[5-({4-[(4-butilanilino)metil]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
4-klor-N-{[5-({4-[heksil(metil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({4-[(cikloheksilmetil)(heksil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[benzil(heksil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-4-klorbenzamid
4-klor-N-{[5-({4-[heksil(piridin-3-ilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({4-[heksil(piridin-4-ilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({4-[heksil(piridin-2-ilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[butil(heksil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-4-klorbenzamid
4-klor-N-{[5-({4-[heksil(3-fenilpropil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
4-klor-N-{[5-({4-[heksil(2-feniletil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[[(5-bromo-2-furyl)metil](heksil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-4-klorbenzamid
3-metoksi-N-({5-[(4-{metil[4-(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)benzamid
4-klor-N-{[5-({4-[(3-klorbenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-({5-[(4-{[4-(trifluormetil)benzil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)benzamid
3-metoksi-N-{[5-({4-[(3-metilbenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(4-propilbenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-({5-[(4-{[3-(trifluormetil)benzil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)benzamid
3-metoksi-N-({5-[(4-{[4-(trifluormetoksi)benzil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)benzamid
N-({5-[(4-{[4-(difluormetoksi)benzil]amino}piperidin-1-il)sulfonil]tien-2-il}metil)-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(2,3,4,5,6-pentametilbenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(4-propoksibenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[(4-butoksibenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(4-metoksibenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(piridin-4-ilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(piridin-2-ilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-{[5-({4-[(piridin-3-ilmetil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
N-{[5-({4-[(4-tert-butilbenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
N-{[5-({4-[(3-etoksibenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(4-fenoksibenzil)amino]piperidin-1-il}sulfonil)tien-2-il]metil}benzamid
3-metoksi-N-[(5-{[4-({4-[(trifluormetil)sulfanil]benzil}amino)piperidin-1-il]sulfonil}tien-2-il)metil]benzamid
3-metoksi-N-({5-[(4-{[4-(metilsulfonil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)benzamid
N-({5-[(4-{[3,5-bis(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)-3-metoksibenzamid
N-({5-[(4-{[2,5-bis(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)-3-metoksibenzamid
N-({5-[(4-{[4-(etilsulfanil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)-3-metoksibenzamid
3-metoksi-N-[(5-{[4-({3-[(trifluormetil)sulfanil]benzil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
N-({5-[(4-{[(2,2-difluor-1,3-benzodioxol-5-il)metil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)-3-metoksibenzamid
N-{[5-({4-[(4-iodobenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
N-({5-[(4-{[4-(benziloksi)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)-3-metoksibenzamid
N-{[5-({4-[(mezitilmetil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
N-{[5-({4-[(4-klorbenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
N-{[5-({4-[(4-etilbenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
3-metoksi-N-{[5-({4-[(4-pentilbenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}benzamid
3-metoksi-N-[(5-{[4-({1-[4-(trifluormetil)fenil]etil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
3-metoksi-N-{[5-({4-[(4-metilbenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}benzamid
N-{[5-({4-[(4-butilbenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
N-{[5-({4-[(4-izopropilbenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
N-{[5-({4-[(4-izobutilbenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
N-({5-[(4-{[(1-hidroksi-1lambda~5~-piridin-4-il)metil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)-3-metoksibenzamid
N-{[5-({4-[(2,3-dihidro-1,4-benzodioksin-6-ilmetil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
N-{[5-({4-[(2,3-dihidro-1-benzofuran-5-ilmetil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-3-metoksibenzamid
4-klor-N-{[5-({4-[(4-propilbenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}benzamid
4-klor-N-({5-[(4-{[4-(trifluormetoksi)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)benzamid
4-klor-N-({5-[(4-{[4-(difluormetoksi)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)benzamid
4-klor-N-{[5-({4-[(4-propoksibenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}benzamid
N-{[5-({4-[(4-butoksibenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-4-klorbenzamid
4-klor-N-{[5-({4-[(4-kinolinylmetil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}benzamid
N-{[5-({4-[(4-tert-butilbenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}-4-klorbenzamid
4-klor-N-{[5-({4-[(4-fenoksibenzil)amino]-1-piperidinil}sulfonil)-2-tienil]metil}benzamid
4-klor-N-[(5-{[4-({4-[(trifluormetil)sulfanil]benzil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
4-klor-N-({5-[(4-{[4-(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)benzamid
3-metoksi-N-({5-[(4-{[2-(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)benzamid
3-metoksi-N-[(5-{[4-({[6-(trifluormetil)-3-piridinil]metil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
N-[(5-{[4-(benzilamino)-1-piperidinil]sulfonil}-2-tienil)metil]-3-metoksibenzamid
3-metoksi-N-[(5-{[4-({1-[4-(trifluormetil)fenil]propil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
3-metoksi-N-[(5-{[4-({1-metil-1-[4-(trifluormetil)fenil]etil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
4-klor-N-[(5-{[4-({1-[4-(trifluormetil)fenil]etil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
4-klor-N-[(5-{[4-({1-metil-1-[4-(trifluormetil)fenil]etil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
4-klor-N-[(5-{[2-({[4-(trifluormetil)benzil]amino}metil)-1-pirolidinil]sulfonil}-2-tienil)metil]benzamid
4-klor-N-[(5-{[(3R)-3-({[4-(trifluormetil)benzil]amino}metil)pirolidinil]sulfonil}-2-tienil)metil]benzamid
4-klor-N-({5-[(3-{[4-(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)benzamid
4-klor-N-{[5-({3-[(heksilamino)metil]-1-piperidinil}sulfonil)-2-tienil]metil}benzamid
4-klor-N-({5-[(3-{[4-(trifluormetil)benzil]amino}-1-pirolidinil)sulfonil]-2-tienil}metil)benzamid
4-klor-N-{[5-({(3R)-3-[(heksilamino)metil]pirolidinil}sulfonil)-2-tienil]metil}benzamid
4-klor-N-[(5-{[3-({[4-(trifluormetil)benzil]amino}metil)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
2-okso-N-({5-[(4-{[4-(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)-1,2-dihidro-3-piridinkarboksamid
N-[(5-{[4-(heksilamino)-1-piperidinil]sulfonil}-2-tienil)metil]-2-okso-1,2-dihidro-3-piridinkarboksamid
N-[(5-{[4-(heksilamino)-1-piperidinil]sulfonil}-2-tienil)metil]-2-hidroksibenzamid
2-hidroksi-N-({5-[(4-{[4-(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)benzamid
N-[(5-{[4-(heksilamino)-1-piperidinil]sulfonil}-2-tienil)metil]-2-tiokso-1,2-dihidro-3-piridinkarboksamid
2-tiokso-N-({5-[(4-{[4-(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)-1,2-dihidro-3-piridinkarboksamid
N-[(5-{[4-(butilamino)-1-piperidinil]sulfonil}-2-tienil)metil]-2-okso-1,2-dihidro-3-piridinkarboksamid
N-({5-[(4-{etil[4-(trifluormetil)benzil]amino}-1-piperidinil)sulfonil]-2-tienil}metil)-3-metoksibenzamid
4-klor-N-[(5-{[4-({imino[4-(trifluormetil)fenil]metil}amino)-1-piperidinil]sulfonil}-2-tienil)metil]benzamid
1-[(5-{[(4-klorbenzoil)amino]metil}-2-tienil)sulfonil]-4-(heksilamino)prolin
etil 2-{[4-(heksilamino)piperidin-1-il]sulfonil}-5-{[(3-metoksibenzoil)amino]metil}tiofen-3-karboksilat
N-{[5-{[4-(heksilamino)piperidin-1-il]sulfonil}-4-(trimetilsilil)tien-2-il]metil}-3-metoksibenzamid
N-({5-{[4-(heksilamino)piperidin-1-il]sulfonil}-4-[hidroksi(fenil)metil]tien-2-il}metil)-3-metoksibenzamid
Ester 5-[(3-Metoksi-benzoilamino)-metil]-2-[4-(4-trifluormetil-benzilamino)-piperidin-1-sulfonil]-tiofen-3-karboksilne kiseline
N-[(4-klor-5-{[4-(heksilamino)piperidin-1-il]sulfonil}tien-2-il)metil]-3-metoksibenzamid
11. Sulfonamidski derivat prema bilo kojem prethodnom zahtjevu, naznačen time što se koristi kao medikament.
12. Uporaba sulfonamidskog derivata prema bilo kojem zahtjevu 1-10, naznačena time što se odnosi na priređivanje medikamenta za tretiranje živčanih poremećaja koji su odabrani iz skupa kojega sačinjavaju epilepsija, Alzheimerova bolest, Huntingtonova bolest, Parkinsonova bolest, bolest mrežnice, ozljeda kralježnice, multipla skleroza, ozljeda glave i ishemija, autoimuna bolest koja je odabrana iz skupa kojega sačinjavaju upalna trbušna bolest (IBD), reumatoidni artritis, astma, septični šok, odbacivnaje transplantiranog organa, karcinoma koji su odabrani iz skupa kojega sačinjavaju karcinom dojke, debelog crijeva, gušterače, jajnika, prostate, testisa, jetre, bubrega, pluća, kardiovaskularnih bolesti uključujući udar, aterosklerozu, infarkt miokarda, reperfuzijske ozljeda srca i ishemijsko stanje koje uključuje srce, bubrege, reperfuzijske ozljede bubrega i mozga, otkazivanje bubrega.
13. Sulfonamidski derivat prema zahtjevu 12, naznačen time što se koristi za moduliranje JNK puta.
14. Uporaba prema zahtjevu 13, naznačena time što se odnosi na tretiranje ili prevenciju bolesti koje su povezane s nenormalnom ekspresijom ili aktivnošću JNK.
15. Uporaba prema zahtjevu 14, naznačena time što se odnosi na tretiranje ili prevenciju bolesti koje su povezane s nenormalnom ekspresijom ili aktivnošću JNK2 i/ili JNK3.
16. Farmaceutska smjesa, naznačena time što sadrži bar jedan sulfonamidski derivat prema bilo kojem zahtjevu 1 do 10 i farmaceutski prihvatljivi nosač, razrjeđivač ili ekscipijent.
17. Postupak priređivanja sulfonamidskog derivata prema bilo kojem zahtjevu 1 do 10, naznačen time što je sulfonamid formule (XIX)
[image]
gdje Ar1, Ar2, X, R1, R2 i n su kao što je prije definirano, Y je pirolidin-3-on ili piperidin 4-on, podvrgnut reduktivnom aminiranju korištenjem amina H2N-R3 pri čemu je R3 kao što je prije definirano.
18. Postupak priređivanja sulfonamidskog derivat prema bilo kojem zahtjevu 1 do 10, naznačen time što je sulfonamid formule (XIX)
[image]
gdje Ar1, Ar2, X, R1, R2 i n su kao što je gore definirano i Y je pirolidin-3-amin ili piperidin-4-amin, te reagira s aldehidom R3-CHO formule (Xa) pri čemu je R3 kao što je prije definirano.
19. Sulfonamidni spojevi formule (XIX),
[image]
naznačeni time što
Ar1 id Ar2 su međusobno neovisno aril ili heteroaril,
X je O ili S;
R1 je vodik ili C1-C6-alkilna skupin,
n je cijeli broj od 0 do 5, i
Y je pirolidin-3-on, piperidin-4-on, pirolidin-3-amin ili piperidin-4-amin.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00810887A EP1193268A1 (en) | 2000-09-27 | 2000-09-27 | Pharmaceutically active sulfonamide derivatives bearing both lipophilic and ionisable moieties as inhibitors of protein Junkinases |
PCT/IB2001/001772 WO2002026733A2 (en) | 2000-09-27 | 2001-09-27 | sHARMACEUTICALLY ACTIVE SULFONAMIDE DERIVATIVES BEARING BOTH LIPOPHILIC AND IONISABLE MOIETIES AS INHIBITORS OF PROTEIN JUNKINASES |
Publications (1)
Publication Number | Publication Date |
---|---|
HRP20030214A2 true HRP20030214A2 (en) | 2005-02-28 |
Family
ID=8174937
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
HR20030214A HRP20030214A2 (en) | 2000-09-27 | 2003-03-20 | Pharmaceutically active sulfonamide derivatives bearing both lipohilic and ionisable moieties as inhibitors of protein junkinases |
Country Status (27)
Country | Link |
---|---|
US (1) | US7544700B2 (hr) |
EP (2) | EP1193268A1 (hr) |
JP (1) | JP4927304B2 (hr) |
KR (1) | KR20030057532A (hr) |
CN (1) | CN1288150C (hr) |
AR (1) | AR033999A1 (hr) |
AU (2) | AU2001287991B2 (hr) |
BG (1) | BG107633A (hr) |
BR (1) | BR0114223A (hr) |
CA (1) | CA2421209A1 (hr) |
CZ (1) | CZ2003884A3 (hr) |
EA (1) | EA005819B1 (hr) |
EE (1) | EE200300119A (hr) |
ES (1) | ES2438185T3 (hr) |
HK (1) | HK1072768A1 (hr) |
HR (1) | HRP20030214A2 (hr) |
HU (1) | HUP0302980A3 (hr) |
IL (1) | IL154965A0 (hr) |
MX (1) | MXPA03002568A (hr) |
NO (1) | NO20031375L (hr) |
NZ (1) | NZ524542A (hr) |
PL (1) | PL361687A1 (hr) |
SK (1) | SK3662003A3 (hr) |
UA (1) | UA75891C2 (hr) |
WO (1) | WO2002026733A2 (hr) |
YU (1) | YU21803A (hr) |
ZA (1) | ZA200301746B (hr) |
Families Citing this family (48)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1193256A1 (en) * | 2000-09-27 | 2002-04-03 | Applied Research Systems ARS Holding N.V. | Pharmaceutically active benzsulfonamide derivatives as inhibitors of JNK proteins |
EP1193267A1 (en) * | 2000-09-27 | 2002-04-03 | Applied Research Systems ARS Holding N.V. | Pharmaceutically active hydrophilic sulfonamide derivatives as inhibitors of protein JunKinases |
EP1193268A1 (en) | 2000-09-27 | 2002-04-03 | Applied Research Systems ARS Holding N.V. | Pharmaceutically active sulfonamide derivatives bearing both lipophilic and ionisable moieties as inhibitors of protein Junkinases |
US7683078B2 (en) * | 2001-07-23 | 2010-03-23 | Laboratoires Serono S.A. | Arylsulfonamide derivatives as C-Jun-N-Terminal Kinases (JNK's) inhibitors |
US7705052B2 (en) | 2003-09-12 | 2010-04-27 | Merck Serono Sa | Sulfonamide derivatives for the treatment of diabetes |
PL1701940T3 (pl) * | 2003-12-23 | 2008-11-28 | H Lundbeck As | Pochodne 2-(1H-indolilosulfanylo)benzyloaminy jako SSRI |
AR052308A1 (es) * | 2004-07-16 | 2007-03-14 | Lundbeck & Co As H | Derivados de 2-(1h-indolilsulfanil)-arilamina y una composicion farmaceutica que contiene al compuesto |
AR054393A1 (es) * | 2005-06-17 | 2007-06-20 | Lundbeck & Co As H | Derivados de benzo(b)furano y benzo(b)tiofeno, composiciones farmaceuticas que los contienen y su uso en la fabricacion de un medicamento para el tratamiento de enfermedades mediadas por la inhibicion de la reabsorcion de neurotransmisores de amina biogenicos. |
US7629473B2 (en) * | 2005-06-17 | 2009-12-08 | H. Lundbeck A/S | 2-(1H-indolylsulfanyl)-aryl amine derivatives |
KR20080044836A (ko) | 2005-07-15 | 2008-05-21 | 라보라뚜와르 세로노 에스. 에이. | 자궁내막증 치료용 jnk 억제제 |
AU2011265521B8 (en) * | 2005-07-15 | 2014-05-22 | Merck Serono Sa | JNK inhibitors for the treatment of endometreosis |
BRPI0613042A2 (pt) | 2005-07-15 | 2010-12-14 | Serono Lab | inibidores de jnk para o tratamento de endometriose |
JP2009538882A (ja) * | 2006-06-02 | 2009-11-12 | メルク セローノ ソシエテ アノニム | 皮膚疾患の治療のためのjnk阻害物質 |
EP2361242B1 (en) | 2008-10-17 | 2018-08-01 | Oryzon Genomics, S.A. | Oxidase inhibitors and their use |
WO2010084160A1 (en) | 2009-01-21 | 2010-07-29 | Oryzon Genomics S.A. | Phenylcyclopropylamine derivatives and their medical use |
MX338041B (es) | 2009-09-25 | 2016-03-30 | Oryzon Genomics Sa | Inhibidores de demetilasa-1 especificos de lisina y su uso. |
EP2486002B1 (en) | 2009-10-09 | 2019-03-27 | Oryzon Genomics, S.A. | Substituted heteroaryl- and aryl- cyclopropylamine acetamides and their use |
US9616058B2 (en) | 2010-02-24 | 2017-04-11 | Oryzon Genomics, S.A. | Potent selective LSD1 inhibitors and dual LSD1/MAO-B inhibitors for antiviral use |
US9186337B2 (en) | 2010-02-24 | 2015-11-17 | Oryzon Genomics S.A. | Lysine demethylase inhibitors for diseases and disorders associated with Hepadnaviridae |
KR101794020B1 (ko) | 2010-04-19 | 2017-11-06 | 오리존 지노믹스 에스.에이. | 라이신 특이적 디메틸라아제-1 억제제 및 이의 용도 |
WO2012013727A1 (en) | 2010-07-29 | 2012-02-02 | Oryzon Genomics S.A. | Cyclopropylamine derivatives useful as lsd1 inhibitors |
US9181198B2 (en) | 2010-07-29 | 2015-11-10 | Oryzon Genomics S.A. | Arylcyclopropylamine based demethylase inhibitors of LSD1 and their medical use |
WO2012045883A1 (en) | 2010-10-08 | 2012-04-12 | Oryzon Genomics S.A. | Cyclopropylamine inhibitors of oxidases |
WO2012072713A2 (en) | 2010-11-30 | 2012-06-07 | Oryzon Genomics, S.A. | Lysine demethylase inhibitors for diseases and disorders associated with flaviviridae |
EP2712315B1 (en) | 2011-02-08 | 2021-11-24 | Oryzon Genomics, S.A. | Lysine demethylase inhibitors for myeloproliferative disorders |
WO2012156531A2 (en) * | 2011-05-19 | 2012-11-22 | Oryzon Genomics, S.A. | Lysine demethylase inhibitors for inflammatory diseases or conditions |
WO2012156537A2 (en) * | 2011-05-19 | 2012-11-22 | Oryzon Genomics, S.A. | Lysine demethylase inhibitors for thrombosis and cardiovascular diseases |
RS58475B1 (sr) | 2011-10-20 | 2019-04-30 | Oryzon Genomics Sa | Jedinjenja (hetero)aril ciklopropilamina kao lsd1 inhibitori |
CN107266345B (zh) | 2011-10-20 | 2021-08-17 | 奥瑞泽恩基因组学股份有限公司 | 作为lsd1抑制剂的(杂)芳基环丙胺化合物 |
TWI622578B (zh) | 2011-12-21 | 2018-05-01 | 諾維拉治療公司 | B型肝炎抗病毒劑 |
BR112015004192B1 (pt) | 2012-08-28 | 2021-02-09 | Janssen Sciences Ireland Uc | sulfamoíl-arilamidas, composição farmacêutica que os compreende e uso das mesmas no tratamento da hepatite b |
WO2014131847A1 (en) | 2013-02-28 | 2014-09-04 | Janssen R&D Ireland | Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis b |
BR112015025052A2 (pt) | 2013-04-03 | 2021-07-06 | Janssen Sciences Ireland Uc | derivados de n-fenil-carboxamida e o seu uso como medicamentos para o tratamento da hepatite b |
JO3603B1 (ar) | 2013-05-17 | 2020-07-05 | Janssen Sciences Ireland Uc | مشتقات سلفامويل بيرولاميد واستخدامها كادوية لمعالجة التهاب الكبد نوع بي |
EA035500B1 (ru) | 2013-05-17 | 2020-06-25 | Янссен Сайенсиз Айрлэнд Юси | Производные сульфамоилтиофенамида и их применение в качестве медикаментов для лечения гепатита b |
EP3357906B1 (en) | 2013-07-25 | 2019-12-04 | Janssen Sciences Ireland Unlimited Company | Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b |
MX368158B (es) | 2013-10-23 | 2019-09-20 | Janssen Sciences Ireland Uc | Derivados de carboxamida y su uso como medicamentos para el tratamiento de la hepatitis b. |
US10392349B2 (en) | 2014-01-16 | 2019-08-27 | Novira Therapeutics, Inc. | Azepane derivatives and methods of treating hepatitis B infections |
US9169212B2 (en) | 2014-01-16 | 2015-10-27 | Novira Therapeutics, Inc. | Azepane derivatives and methods of treating hepatitis B infections |
WO2015120178A1 (en) | 2014-02-05 | 2015-08-13 | Novira Therapeutics, Inc. | Combination therapy for treatment of hbv infections |
CN105980378B (zh) | 2014-02-06 | 2019-09-27 | 爱尔兰詹森科学公司 | 氨磺酰基吡咯酰胺衍生物及其作为药物用于治疗乙型肝炎的用途 |
CN107847762A (zh) | 2015-03-19 | 2018-03-27 | 诺维拉治疗公司 | 氮杂环辛烷和氮杂环壬烷衍生物以及治疗乙型肝炎感染的方法 |
US10875876B2 (en) | 2015-07-02 | 2020-12-29 | Janssen Sciences Ireland Uc | Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
EP3356328A1 (en) | 2015-09-29 | 2018-08-08 | Novira Therapeutics, Inc. | Crystalline forms of a hepatitis b antiviral agent |
SG11201808949SA (en) | 2016-04-15 | 2018-11-29 | Novira Therapeutics Inc | Combinations and methods comprising a capsid assembly inhibitor |
AU2019235522A1 (en) | 2018-03-14 | 2020-09-03 | Janssen Sciences Ireland Unlimited Company | Capsid assembly modulator dosing regimen |
MA55020A (fr) | 2019-02-22 | 2021-12-29 | Janssen Sciences Ireland Unlimited Co | Dérivés d'amide utiles dans le traitement d'une infection par le virus de l'hépatite b ou de maladies induites par le virus de l'hépatite b |
AR119732A1 (es) | 2019-05-06 | 2022-01-05 | Janssen Sciences Ireland Unlimited Co | Derivados de amida útiles en el tratamiento de la infección por vhb o de enfermedades inducidas por vhb |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2553414B1 (fr) * | 1983-10-18 | 1986-08-14 | Choay Sa | Nouveaux benzenesulfonamides n-cyclises, leur procede de preparation et leur utilisation comme substance active de compositions pharmaceutiques |
US5238950A (en) * | 1991-12-17 | 1993-08-24 | Schering Corporation | Inhibitors of platelet-derived growth factor |
US5744320A (en) * | 1995-06-07 | 1998-04-28 | Promega Corporation | Quenching reagents and assays for enzyme-mediated luminescence |
WO1997045403A1 (en) * | 1996-05-31 | 1997-12-04 | Pharmacia & Upjohn Company | Aryl substituted cyclic amines as selective dopamine d3 ligands |
US6043083A (en) | 1997-04-28 | 2000-03-28 | Davis; Roger J. | Inhibitors of the JNK signal transduction pathway and methods of use |
JP2002512625A (ja) * | 1997-05-29 | 2002-04-23 | メルク エンド カンパニー インコーポレーテッド | 細胞接着阻害薬としての複素環アミド化合物 |
DE19743435A1 (de) * | 1997-10-01 | 1999-04-08 | Merck Patent Gmbh | Benzamidinderivate |
AR019322A1 (es) * | 1998-06-18 | 2002-02-13 | Smithkline Beecham Corp | Derivados de sulfonilo sustituido por heterociclo-etanodionanilina sustituida por heterociclo, composicion farmaceutica que los contiene y su uso para lamanufactura de un medicamento |
CA2336807C (en) * | 1998-07-08 | 2010-04-13 | Aventis Pharma Deutschland Gmbh | Sulfur substituted sulfonylaminocarboxylic acid n-arylamides, their preparation, their use and pharmaceutical preparations comprising them |
EP1088821A1 (en) * | 1999-09-28 | 2001-04-04 | Applied Research Systems ARS Holding N.V. | Pharmaceutically active sulfonamide derivatives |
EP1193268A1 (en) | 2000-09-27 | 2002-04-03 | Applied Research Systems ARS Holding N.V. | Pharmaceutically active sulfonamide derivatives bearing both lipophilic and ionisable moieties as inhibitors of protein Junkinases |
EP1193256A1 (en) * | 2000-09-27 | 2002-04-03 | Applied Research Systems ARS Holding N.V. | Pharmaceutically active benzsulfonamide derivatives as inhibitors of JNK proteins |
EP1193267A1 (en) * | 2000-09-27 | 2002-04-03 | Applied Research Systems ARS Holding N.V. | Pharmaceutically active hydrophilic sulfonamide derivatives as inhibitors of protein JunKinases |
-
2000
- 2000-09-27 EP EP00810887A patent/EP1193268A1/en not_active Withdrawn
-
2001
- 2001-09-27 WO PCT/IB2001/001772 patent/WO2002026733A2/en active IP Right Grant
- 2001-09-27 EE EEP200300119A patent/EE200300119A/xx unknown
- 2001-09-27 KR KR10-2003-7004265A patent/KR20030057532A/ko not_active Application Discontinuation
- 2001-09-27 JP JP2002531117A patent/JP4927304B2/ja not_active Expired - Fee Related
- 2001-09-27 PL PL36168701A patent/PL361687A1/xx not_active Application Discontinuation
- 2001-09-27 EP EP01967622.0A patent/EP1322642B1/en not_active Expired - Lifetime
- 2001-09-27 HU HU0302980A patent/HUP0302980A3/hu unknown
- 2001-09-27 EA EA200300412A patent/EA005819B1/ru not_active IP Right Cessation
- 2001-09-27 SK SK366-2003A patent/SK3662003A3/sk not_active Application Discontinuation
- 2001-09-27 CN CNB01819141XA patent/CN1288150C/zh not_active Expired - Fee Related
- 2001-09-27 IL IL15496501A patent/IL154965A0/xx unknown
- 2001-09-27 YU YU21803A patent/YU21803A/sh unknown
- 2001-09-27 ES ES01967622.0T patent/ES2438185T3/es not_active Expired - Lifetime
- 2001-09-27 NZ NZ524542A patent/NZ524542A/en unknown
- 2001-09-27 BR BR0114223-2A patent/BR0114223A/pt not_active IP Right Cessation
- 2001-09-27 MX MXPA03002568A patent/MXPA03002568A/es not_active Application Discontinuation
- 2001-09-27 CZ CZ2003884A patent/CZ2003884A3/cs unknown
- 2001-09-27 CA CA002421209A patent/CA2421209A1/en not_active Abandoned
- 2001-09-27 ZA ZA200301746A patent/ZA200301746B/en unknown
- 2001-09-27 US US10/381,665 patent/US7544700B2/en not_active Expired - Fee Related
- 2001-09-27 AU AU2001287991A patent/AU2001287991B2/en not_active Ceased
- 2001-09-27 UA UA2003032606A patent/UA75891C2/uk unknown
- 2001-09-27 AU AU8799101A patent/AU8799101A/xx active Pending
- 2001-09-27 AR ARP010104565A patent/AR033999A1/es unknown
-
2003
- 2003-03-13 BG BG107633A patent/BG107633A/bg unknown
- 2003-03-20 HR HR20030214A patent/HRP20030214A2/hr not_active Application Discontinuation
- 2003-03-26 NO NO20031375A patent/NO20031375L/no not_active Application Discontinuation
-
2005
- 2005-04-29 HK HK05103676A patent/HK1072768A1/xx not_active IP Right Cessation
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2438185T3 (es) | Derivados de sulfonamida farmacéuticamente activos portadores de restos lipófilos e ionizables como inhibidores de proteína quinasas Jun | |
US8008341B2 (en) | Pharmaceutically active benzsulfonamide derivatives as inhibitors of protein junkinases | |
JP5015397B2 (ja) | 医薬として活性なスルホンアミド誘導体 | |
AU2001287991A1 (en) | Pharmaceutically active sulfonamide derivatives bearing both lipophilic and ionisable moieties as inhibitors of protein junkinases | |
AU2001287992A1 (en) | Pharmaceutically active benzsulfonamide derivatives as inhibitors of protein junkinases | |
JP4927306B2 (ja) | タンパク質Jun−キナーゼのインヒビターとしての医薬的活性親水性スルホンアミド誘導体 | |
AU2001287990A1 (en) | Pharmaceutically active hydrophilic sulfonamide derivatives as inhibitors of protein junkinases |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A1OB | Publication of a patent application | ||
ARAI | Request for the grant of a patent on the basis of the submitted results of a substantive examination of a patent application | ||
PPPP | Transfer of rights |
Owner name: LABORATOIRES SERONO SA, CH |
|
OBST | Application withdrawn |