HRP20020328A2 - Heteroalkylamino-substited bicyclic nitrogen heterocycles as inhibitors of p38 protein kinase - Google Patents

Info

Publication number

HRP20020328A2

HRP20020328A2 HR20020328A HRP20020328A HRP20020328A2 HR P20020328 A2 HRP20020328 A2 HR P20020328A2 HR 20020328 A HR20020328 A HR 20020328A HR P20020328 A HRP20020328 A HR P20020328A HR P20020328 A2 HRP20020328 A2 HR P20020328A2

Authority

HR

Croatia

Prior art keywords

optionally substituted

dihydropyrimido

chlorophenyl

mmol

pyrimidin

Prior art date

1999-10-21

Links

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• 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 title description 22
• 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 title description 22
• 229910052757 nitrogen Inorganic materials 0.000 title description 17
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title description 12
• 239000003112 inhibitor Substances 0.000 title 1
• -1 amino, monosubstituted amino Chemical group 0.000 claims description 273
• 150000001875 compounds Chemical class 0.000 claims description 259
• 239000000203 mixture Substances 0.000 claims description 138
• 125000000217 alkyl group Chemical group 0.000 claims description 85
• 239000001257 hydrogen Substances 0.000 claims description 60
• 229910052739 hydrogen Inorganic materials 0.000 claims description 60
• 150000003839 salts Chemical class 0.000 claims description 57
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 42
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 39
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 37
• 125000000623 heterocyclic group Chemical group 0.000 claims description 37
• 125000001188 haloalkyl group Chemical group 0.000 claims description 34
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
• 238000000034 method Methods 0.000 claims description 31
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 30
• 238000011282 treatment Methods 0.000 claims description 30
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 22
• 125000001072 heteroaryl group Chemical group 0.000 claims description 22
• 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 21
• 125000003107 substituted aryl group Chemical group 0.000 claims description 20
• 125000004475 heteroaralkyl group Chemical group 0.000 claims description 19
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
• 125000003545 alkoxy group Chemical group 0.000 claims description 16
• 150000001412 amines Chemical class 0.000 claims description 15
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 15
• 125000003118 aryl group Chemical group 0.000 claims description 10
• 239000003814 drug Substances 0.000 claims description 10
• 125000001475 halogen functional group Chemical group 0.000 claims description 8
• 229940079593 drug Drugs 0.000 claims description 7
• 239000000825 pharmaceutical preparation Substances 0.000 claims description 7
• 125000002252 acyl group Chemical group 0.000 claims description 6
• 206010003246 arthritis Diseases 0.000 claims description 6
• 125000004966 cyanoalkyl group Chemical group 0.000 claims description 6
• 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 5
• 208000024827 Alzheimer disease Diseases 0.000 claims description 5
• 208000011231 Crohn disease Diseases 0.000 claims description 5
• 208000001132 Osteoporosis Diseases 0.000 claims description 5
• 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 5
• 125000005356 cycloalkylalkenyl group Chemical group 0.000 claims description 5
• 125000005357 cycloalkylalkynyl group Chemical group 0.000 claims description 5
• 239000000543 intermediate Substances 0.000 claims description 5
• FDBVYXJFOHVTSQ-UHFFFAOYSA-N 3-(2-chlorophenyl)-1-methyl-7-[(4-oxocyclohexyl)amino]-4h-pyrimido[4,5-d]pyrimidin-2-one Chemical compound N1=C2N(C)C(=O)N(C=3C(=CC=CC=3)Cl)CC2=CN=C1NC1CCC(=O)CC1 FDBVYXJFOHVTSQ-UHFFFAOYSA-N 0.000 claims description 4
• XFBDYRNRMRJJBD-UHFFFAOYSA-N 6-(2-chlorophenyl)-2-(oxan-4-ylamino)-5,8-dihydropyrimido[4,5-d]pyrimidin-7-one Chemical compound ClC1=CC=CC=C1N1C(=O)NC2=NC(NC3CCOCC3)=NC=C2C1 XFBDYRNRMRJJBD-UHFFFAOYSA-N 0.000 claims description 4
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 4
• 230000002452 interceptive effect Effects 0.000 claims description 4
• 208000002551 irritable bowel syndrome Diseases 0.000 claims description 4
• 239000007800 oxidant agent Substances 0.000 claims description 4
• 230000008569 process Effects 0.000 claims description 4
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
• HQHXVEZJBBPLII-UHFFFAOYSA-N 7-[[1-(2-hydroxyethyl)piperidin-4-yl]amino]-1-methyl-3-(2-methylphenyl)-4h-pyrimido[4,5-d]pyrimidin-2-one Chemical compound N1=C2N(C)C(=O)N(C=3C(=CC=CC=3)C)CC2=CN=C1NC1CCN(CCO)CC1 HQHXVEZJBBPLII-UHFFFAOYSA-N 0.000 claims description 3
• IPDRIFQWRUIZSL-KOMQPUFPSA-N C1C[C@@H](OC)CC[C@@H]1CNC1=NC=C(CN(C(=O)N2C)C=3C(=CC=CC=3)Cl)C2=N1 Chemical compound C1C[C@@H](OC)CC[C@@H]1CNC1=NC=C(CN(C(=O)N2C)C=3C(=CC=CC=3)Cl)C2=N1 IPDRIFQWRUIZSL-KOMQPUFPSA-N 0.000 claims description 3
• NSHBSERFNQQOCC-JOCQHMNTSA-N chembl1235713 Chemical compound C1C[C@@H](O)CC[C@@H]1NC1=NC=C(CN(C(=O)N2)C=3C(=CC=CC=3)Cl)C2=N1 NSHBSERFNQQOCC-JOCQHMNTSA-N 0.000 claims description 3
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 3
• SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 3
• 229920002554 vinyl polymer Polymers 0.000 claims description 3
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
• 239000007795 chemical reaction product Substances 0.000 claims description 2
• 125000005350 hydroxycycloalkyl group Chemical group 0.000 claims description 2
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
• 238000010511 deprotection reaction Methods 0.000 claims 1
• 238000009472 formulation Methods 0.000 claims 1
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 408
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 385
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 360
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 195
• 238000002360 preparation method Methods 0.000 description 153
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 146
• 235000019439 ethyl acetate Nutrition 0.000 description 128
• 229940093499 ethyl acetate Drugs 0.000 description 128
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 120
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 110
• 239000000243 solution Substances 0.000 description 109
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 95
• 239000007787 solid Substances 0.000 description 87
• 238000006243 chemical reaction Methods 0.000 description 83
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 81
• 239000003480 eluent Substances 0.000 description 77
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 72
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 71
• 239000000047 product Substances 0.000 description 71
• 239000011541 reaction mixture Substances 0.000 description 63
• 239000000741 silica gel Substances 0.000 description 63
• 229910002027 silica gel Inorganic materials 0.000 description 63
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 58
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 57
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 54
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 54
• 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 50
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 47
• 230000002829 reductive effect Effects 0.000 description 46
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 45
• 150000003457 sulfones Chemical class 0.000 description 43
• 238000004440 column chromatography Methods 0.000 description 41
• 239000000725 suspension Substances 0.000 description 40
• 239000002244 precipitate Substances 0.000 description 36
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 33
• 235000011121 sodium hydroxide Nutrition 0.000 description 31
• HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 30
• 150000002431 hydrogen Chemical group 0.000 description 30
• 239000010410 layer Substances 0.000 description 27
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 27
• 235000019341 magnesium sulphate Nutrition 0.000 description 27
• 239000002904 solvent Substances 0.000 description 27
• 239000003921 oil Substances 0.000 description 26
• 235000019198 oils Nutrition 0.000 description 26
• 102100040247 Tumor necrosis factor Human genes 0.000 description 25
• 239000000706 filtrate Substances 0.000 description 24
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
• 238000003756 stirring Methods 0.000 description 21
• 238000003818 flash chromatography Methods 0.000 description 20
• 239000012044 organic layer Substances 0.000 description 20
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 19
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 19
• 239000006260 foam Substances 0.000 description 18
• 229920006395 saturated elastomer Polymers 0.000 description 18
• 125000001424 substituent group Chemical group 0.000 description 18
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 17
• IMLXLGZJLAOKJN-UHFFFAOYSA-N 4-aminocyclohexan-1-ol Chemical compound NC1CCC(O)CC1 IMLXLGZJLAOKJN-UHFFFAOYSA-N 0.000 description 16
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
• UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 16
• 239000007864 aqueous solution Substances 0.000 description 16
• 201000010099 disease Diseases 0.000 description 16
• 208000035475 disorder Diseases 0.000 description 16
• 125000005843 halogen group Chemical group 0.000 description 16
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
• 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 16
• 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 15
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
• 238000004587 chromatography analysis Methods 0.000 description 14
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 14
• 238000000746 purification Methods 0.000 description 14
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 13
• YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 12
• 125000004432 carbon atom Chemical group C* 0.000 description 12
• 239000000843 powder Substances 0.000 description 12
• 238000010992 reflux Methods 0.000 description 12
• 108060008682 Tumor Necrosis Factor Proteins 0.000 description 11
• 239000000284 extract Substances 0.000 description 11
• 239000012458 free base Substances 0.000 description 11
• 239000012280 lithium aluminium hydride Substances 0.000 description 11
• 238000004519 manufacturing process Methods 0.000 description 11
• 150000003254 radicals Chemical class 0.000 description 11
• 229910052938 sodium sulfate Inorganic materials 0.000 description 11
• 235000011152 sodium sulphate Nutrition 0.000 description 11
• 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 10
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 10
• 239000004215 Carbon black (E152) Substances 0.000 description 10
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
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• 150000004945 aromatic hydrocarbons Chemical class 0.000 description 10
• FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 10
• SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 10
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• 239000012071 phase Substances 0.000 description 10
• 235000017557 sodium bicarbonate Nutrition 0.000 description 10
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
• VUAMWPCYRCKDTP-UHFFFAOYSA-N 1-methyl-3-(2-methylphenyl)-7-(piperidin-4-ylamino)-4h-pyrimido[4,5-d]pyrimidin-2-one Chemical compound N1=C2N(C)C(=O)N(C=3C(=CC=CC=3)C)CC2=CN=C1NC1CCNCC1 VUAMWPCYRCKDTP-UHFFFAOYSA-N 0.000 description 9
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 9
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 9
• 239000000908 ammonium hydroxide Substances 0.000 description 9
• 150000004292 cyclic ethers Chemical class 0.000 description 9
• 239000012299 nitrogen atmosphere Substances 0.000 description 9
• 230000003647 oxidation Effects 0.000 description 9
• 238000007254 oxidation reaction Methods 0.000 description 9
• 238000007363 ring formation reaction Methods 0.000 description 9
• 239000012312 sodium hydride Substances 0.000 description 9
• 229910000104 sodium hydride Inorganic materials 0.000 description 9
• 102000004127 Cytokines Human genes 0.000 description 8
• 108090000695 Cytokines Proteins 0.000 description 8
• 229960001701 chloroform Drugs 0.000 description 8
• 230000002349 favourable effect Effects 0.000 description 8
• 229910000027 potassium carbonate Inorganic materials 0.000 description 8
• 229910052705 radium Inorganic materials 0.000 description 8
• 229910052701 rubidium Inorganic materials 0.000 description 8
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
• NSHBSERFNQQOCC-UHFFFAOYSA-N 6-(2-chlorophenyl)-2-[(4-hydroxycyclohexyl)amino]-5,8-dihydropyrimido[4,5-d]pyrimidin-7-one Chemical compound C1CC(O)CCC1NC1=NC=C(CN(C(=O)N2)C=3C(=CC=CC=3)Cl)C2=N1 NSHBSERFNQQOCC-UHFFFAOYSA-N 0.000 description 7
• WQNNRWPTJYOMJI-UHFFFAOYSA-N 6-(2-chlorophenyl)-2-methylsulfanyl-5,8-dihydropyrimido[4,5-d]pyrimidin-7-one Chemical compound O=C1NC2=NC(SC)=NC=C2CN1C1=CC=CC=C1Cl WQNNRWPTJYOMJI-UHFFFAOYSA-N 0.000 description 7
• 108091003079 Bovine Serum Albumin Proteins 0.000 description 7
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 7
• 108010002352 Interleukin-1 Proteins 0.000 description 7
• 102000000589 Interleukin-1 Human genes 0.000 description 7
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• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 7
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• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 6
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• 230000029936 alkylation Effects 0.000 description 6
• 238000005804 alkylation reaction Methods 0.000 description 6
• 125000004429 atom Chemical group 0.000 description 6
• 229940098773 bovine serum albumin Drugs 0.000 description 6
• 150000001721 carbon Chemical group 0.000 description 6
• 229910052799 carbon Inorganic materials 0.000 description 6
• 239000000969 carrier Substances 0.000 description 6
• 210000004027 cell Anatomy 0.000 description 6
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• NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 6
• 230000001404 mediated effect Effects 0.000 description 6
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• 125000004433 nitrogen atom Chemical group N* 0.000 description 6
• 239000000651 prodrug Substances 0.000 description 6
• 229940002612 prodrug Drugs 0.000 description 6
• 125000006413 ring segment Chemical group 0.000 description 6
• GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
• 239000007858 starting material Substances 0.000 description 6
• 238000012360 testing method Methods 0.000 description 6
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