CN1246858A - 取代的嘧啶化合物和它们的应用 - Google Patents

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Publication number

CN1246858A

CN1246858A CN97181563A CN97181563A CN1246858A CN 1246858 A CN1246858 A CN 1246858A CN 97181563 A CN97181563 A CN 97181563A CN 97181563 A CN97181563 A CN 97181563A CN 1246858 A CN1246858 A CN 1246858A

Authority

CN

China

Prior art keywords

amino

group

alkyl

pyridyl

phenyl

Prior art date

1996-12-05

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Pending

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• 150000003230 pyrimidines Chemical class 0.000 title description 65
• 150000001875 compounds Chemical class 0.000 claims abstract description 129
• 238000000034 method Methods 0.000 claims abstract description 87
• 150000003839 salts Chemical class 0.000 claims abstract description 24
• 108090001007 Interleukin-8 Proteins 0.000 claims abstract description 18
• 108090001005 Interleukin-6 Proteins 0.000 claims abstract description 14
• 206010061218 Inflammation Diseases 0.000 claims abstract description 9
• 230000004054 inflammatory process Effects 0.000 claims abstract description 9
• 238000011282 treatment Methods 0.000 claims abstract description 9
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
• -1 heterocyclic radical Chemical class 0.000 claims description 1299
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 754
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 272
• 229910052736 halogen Inorganic materials 0.000 claims description 271
• 150000002367 halogens Chemical class 0.000 claims description 271
• 125000001072 heteroaryl group Chemical group 0.000 claims description 200
• 125000003118 aryl group Chemical group 0.000 claims description 133
• 125000000217 alkyl group Chemical group 0.000 claims description 127
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 110
• 125000003368 amide group Chemical group 0.000 claims description 108
• 125000001188 haloalkyl group Chemical group 0.000 claims description 101
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 97
• 239000001257 hydrogen Substances 0.000 claims description 93
• 229910052739 hydrogen Inorganic materials 0.000 claims description 93
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 91
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 85
• 238000006243 chemical reaction Methods 0.000 claims description 82
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 78
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 78
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 76
• 125000004760 (C1-C4) alkylsulfonylamino group Chemical group 0.000 claims description 70
• 239000000203 mixture Substances 0.000 claims description 63
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 59
• 125000004414 alkyl thio group Chemical group 0.000 claims description 57
• 125000003545 alkoxy group Chemical group 0.000 claims description 49
• ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 claims description 46
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 44
• 125000003282 alkyl amino group Chemical group 0.000 claims description 43
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 41
• 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 35
• 125000002905 alkanoylamido group Chemical group 0.000 claims description 34
• 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 30
• 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 30
• 125000005418 aryl aryl group Chemical group 0.000 claims description 27
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 27
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 26
• 108010002352 Interleukin-1 Proteins 0.000 claims description 25
• 125000000623 heterocyclic group Chemical group 0.000 claims description 25
• RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 22
• 229910052757 nitrogen Inorganic materials 0.000 claims description 21
• 239000000126 substance Substances 0.000 claims description 21
• 229910052760 oxygen Inorganic materials 0.000 claims description 18
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 17
• 230000000694 effects Effects 0.000 claims description 16
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 15
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 15
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 13
• 239000001301 oxygen Substances 0.000 claims description 13
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
• GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 11
• 239000005864 Sulphur Substances 0.000 claims description 10
• 239000000460 chlorine Substances 0.000 claims description 10
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
• 125000001624 naphthyl group Chemical group 0.000 claims description 10
• 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 9
• 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 9
• 125000004429 atom Chemical group 0.000 claims description 9
• 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 claims description 9
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
• 230000002829 reductive effect Effects 0.000 claims description 9
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
• 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 8
• 206010040070 Septic Shock Diseases 0.000 claims description 8
• 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 8
• 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 8
• 125000003342 alkenyl group Chemical group 0.000 claims description 8
• 125000000304 alkynyl group Chemical group 0.000 claims description 8
• 150000002431 hydrogen Chemical class 0.000 claims description 8
• 150000003254 radicals Chemical group 0.000 claims description 8
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 7
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 7
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
• 206010006895 Cachexia Diseases 0.000 claims description 6
• 241000701022 Cytomegalovirus Species 0.000 claims description 6
• 230000002490 cerebral effect Effects 0.000 claims description 6
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 6
• 230000006866 deterioration Effects 0.000 claims description 6
• 125000004475 heteroaralkyl group Chemical group 0.000 claims description 6
• 208000014674 injury Diseases 0.000 claims description 6
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 6
• 210000003205 muscle Anatomy 0.000 claims description 6
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• 229920006395 saturated elastomer Polymers 0.000 claims description 6
• 230000008733 trauma Effects 0.000 claims description 6
• 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 claims description 5
• 208000004232 Enteritis Diseases 0.000 claims description 5
• 102000051325 Glucagon Human genes 0.000 claims description 5
• 108060003199 Glucagon Proteins 0.000 claims description 5
• 201000004681 Psoriasis Diseases 0.000 claims description 5
• 206010063837 Reperfusion injury Diseases 0.000 claims description 5
• 229910052801 chlorine Inorganic materials 0.000 claims description 5
• 208000026500 emaciation Diseases 0.000 claims description 5
• MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 claims description 5
• 229960004666 glucagon Drugs 0.000 claims description 5
• 125000005842 heteroatom Chemical group 0.000 claims description 5
• 229910052717 sulfur Inorganic materials 0.000 claims description 5
• 125000006730 (C2-C5) alkynyl group Chemical group 0.000 claims description 4
• 201000001320 Atherosclerosis Diseases 0.000 claims description 4
• 206010009900 Colitis ulcerative Diseases 0.000 claims description 4
• 208000011231 Crohn disease Diseases 0.000 claims description 4
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
• 208000031886 HIV Infections Diseases 0.000 claims description 4
• 206010020164 HIV infection CDC Group III Diseases 0.000 claims description 4
• 241000713772 Human immunodeficiency virus 1 Species 0.000 claims description 4
• 241000713340 Human immunodeficiency virus 2 Species 0.000 claims description 4
• 206010031252 Osteomyelitis Diseases 0.000 claims description 4
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• 208000033464 Reiter syndrome Diseases 0.000 claims description 4
• 206010040047 Sepsis Diseases 0.000 claims description 4
• 206010044248 Toxic shock syndrome Diseases 0.000 claims description 4
• 231100000650 Toxic shock syndrome Toxicity 0.000 claims description 4
• 201000006704 Ulcerative Colitis Diseases 0.000 claims description 4
• 230000001154 acute effect Effects 0.000 claims description 4
• 208000006673 asthma Diseases 0.000 claims description 4
• 208000019664 bone resorption disease Diseases 0.000 claims description 4
• 239000011737 fluorine Substances 0.000 claims description 4
• 229910052731 fluorine Inorganic materials 0.000 claims description 4
• 201000006417 multiple sclerosis Diseases 0.000 claims description 4
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
• 208000002574 reactive arthritis Diseases 0.000 claims description 4
• 230000036303 septic shock Effects 0.000 claims description 4
• 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 3
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• 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 3
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• 206010012442 Dermatitis contact Diseases 0.000 claims description 3
• 208000007514 Herpes zoster Diseases 0.000 claims description 3
• 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 3
• 208000034578 Multiple myelomas Diseases 0.000 claims description 3
• 208000000112 Myalgia Diseases 0.000 claims description 3
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• 125000003107 substituted aryl group Chemical group 0.000 claims description 3
• 125000004149 thio group Chemical group *S* 0.000 claims description 3
• 241000701161 unidentified adenovirus Species 0.000 claims description 3
• 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 2
• 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 2
• HJHGQAVUFBUUKT-UHFFFAOYSA-N 2-(2-anilinoethylsulfanyl)-5-(4-fluorophenyl)-6-pyridin-4-yl-1h-pyrimidin-4-one Chemical compound C1=CC(F)=CC=C1C(C(N1)=O)=C(C=2C=CN=CC=2)N=C1SCCNC1=CC=CC=C1 HJHGQAVUFBUUKT-UHFFFAOYSA-N 0.000 claims description 2
• KCCJWVIEGXBNAL-UHFFFAOYSA-N 4-[2-[[5-(4-fluorophenyl)-4-pyridin-4-ylpyrimidin-2-yl]amino]ethyl]phenol Chemical compound C1=CC(O)=CC=C1CCNC(N=C1C=2C=CN=CC=2)=NC=C1C1=CC=C(F)C=C1 KCCJWVIEGXBNAL-UHFFFAOYSA-N 0.000 claims description 2
• DTNJCGSDISUMCI-UHFFFAOYSA-N 4-[5-(4-fluorophenyl)-4-pyridin-4-ylpyrimidin-2-yl]-2-methyl-1,3-thiazole Chemical compound S1C(C)=NC(C=2N=C(C(C=3C=CC(F)=CC=3)=CN=2)C=2C=CN=CC=2)=C1 DTNJCGSDISUMCI-UHFFFAOYSA-N 0.000 claims description 2
• KPABRDGBGDVPCC-UHFFFAOYSA-N 4-[5-(4-fluorophenyl)-4-pyridin-4-ylpyrimidin-2-yl]morpholine Chemical compound C1=CC(F)=CC=C1C1=CN=C(N2CCOCC2)N=C1C1=CC=NC=C1 KPABRDGBGDVPCC-UHFFFAOYSA-N 0.000 claims description 2
• BRYBZPBPVDEMJR-UHFFFAOYSA-N 5-(4-fluorophenyl)-2-(4-phenylbutan-2-ylamino)-6-pyridin-4-yl-1h-pyrimidin-4-one Chemical compound N=1C(C=2C=CN=CC=2)=C(C=2C=CC(F)=CC=2)C(=O)NC=1NC(C)CCC1=CC=CC=C1 BRYBZPBPVDEMJR-UHFFFAOYSA-N 0.000 claims description 2
• RGIZQHDYGJLOHC-UHFFFAOYSA-N 5-(4-fluorophenyl)-2-piperazin-1-yl-4-pyridin-4-ylpyrimidine Chemical compound C1=CC(F)=CC=C1C1=CN=C(N2CCNCC2)N=C1C1=CC=NC=C1 RGIZQHDYGJLOHC-UHFFFAOYSA-N 0.000 claims description 2
• NGPPAWIEXQPCQA-UHFFFAOYSA-N 5-(4-fluorophenyl)-4-pyridin-4-yl-2-pyrrolidin-1-ylpyrimidine Chemical compound C1=CC(F)=CC=C1C1=CN=C(N2CCCC2)N=C1C1=CC=NC=C1 NGPPAWIEXQPCQA-UHFFFAOYSA-N 0.000 claims description 2
• HOPCLZFUVJYHMS-UHFFFAOYSA-N 5-(4-fluorophenyl)-4-pyridin-4-yl-2-thiophen-2-ylpyrimidine Chemical compound C1=CC(F)=CC=C1C1=CN=C(C=2SC=CC=2)N=C1C1=CC=NC=C1 HOPCLZFUVJYHMS-UHFFFAOYSA-N 0.000 claims description 2
• ORAZGTXCRHKNBR-UHFFFAOYSA-N 5-(4-fluorophenyl)-4-pyridin-4-yl-n-(2-pyrrolidin-1-ylethyl)pyrimidin-2-amine Chemical compound C1=CC(F)=CC=C1C(C(=N1)C=2C=CN=CC=2)=CN=C1NCCN1CCCC1 ORAZGTXCRHKNBR-UHFFFAOYSA-N 0.000 claims description 2
• HYLBZJAJPJJGPF-UHFFFAOYSA-N 5-(4-fluorophenyl)-n-(2-morpholin-4-ylethyl)-4-pyridin-4-ylpyrimidin-2-amine Chemical compound C1=CC(F)=CC=C1C(C(=N1)C=2C=CN=CC=2)=CN=C1NCCN1CCOCC1 HYLBZJAJPJJGPF-UHFFFAOYSA-N 0.000 claims description 2
• WAUSKYGFULPCPY-UHFFFAOYSA-N 5-(4-fluorophenyl)-n-(2-phenylethyl)-4-pyridin-4-ylpyrimidin-2-amine Chemical compound C1=CC(F)=CC=C1C(C(=N1)C=2C=CN=CC=2)=CN=C1NCCC1=CC=CC=C1 WAUSKYGFULPCPY-UHFFFAOYSA-N 0.000 claims description 2
• USYITSDDXIKXSG-UHFFFAOYSA-N 5-(4-fluorophenyl)-n-(4-phenylbutan-2-yl)-4-pyridin-4-ylpyrimidin-2-amine Chemical compound N=1C=C(C=2C=CC(F)=CC=2)C(C=2C=CN=CC=2)=NC=1NC(C)CCC1=CC=CC=C1 USYITSDDXIKXSG-UHFFFAOYSA-N 0.000 claims description 2
• MVXWNCISMXKKFT-UHFFFAOYSA-N 5-(4-fluorophenyl)-n-(4-phenylbutyl)-4-pyridin-4-ylpyrimidin-2-amine Chemical compound C1=CC(F)=CC=C1C(C(=N1)C=2C=CN=CC=2)=CN=C1NCCCCC1=CC=CC=C1 MVXWNCISMXKKFT-UHFFFAOYSA-N 0.000 claims description 2
• BGUNEQJBAXZMFT-UHFFFAOYSA-N 5-(4-fluorophenyl)-n-[2-(2-fluorophenyl)ethyl]-4-pyridin-4-ylpyrimidin-2-amine Chemical compound C1=CC(F)=CC=C1C(C(=N1)C=2C=CN=CC=2)=CN=C1NCCC1=CC=CC=C1F BGUNEQJBAXZMFT-UHFFFAOYSA-N 0.000 claims description 2
• MVEFUUAXUGCKDO-UHFFFAOYSA-N 5-(4-fluorophenyl)-n-[2-(4-fluorophenyl)ethyl]-4-pyridin-4-ylpyrimidin-2-amine Chemical compound C1=CC(F)=CC=C1CCNC(N=C1C=2C=CN=CC=2)=NC=C1C1=CC=C(F)C=C1 MVEFUUAXUGCKDO-UHFFFAOYSA-N 0.000 claims description 2
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
• 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 2
• AEIYIQXHUVFPDN-UHFFFAOYSA-N n'-[5-(4-fluorophenyl)-4-pyridin-4-ylpyrimidin-2-yl]-n-phenylethane-1,2-diamine Chemical compound C1=CC(F)=CC=C1C(C(=N1)C=2C=CN=CC=2)=CN=C1NCCNC1=CC=CC=C1 AEIYIQXHUVFPDN-UHFFFAOYSA-N 0.000 claims description 2
• IANQVURMLZDWCH-UHFFFAOYSA-N n,5-bis(4-fluorophenyl)-4-pyridin-4-ylpyrimidin-2-amine Chemical compound C1=CC(F)=CC=C1NC(N=C1C=2C=CN=CC=2)=NC=C1C1=CC=C(F)C=C1 IANQVURMLZDWCH-UHFFFAOYSA-N 0.000 claims description 2
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• CEPNYRGGEXJJAW-NRFANRHFSA-N (2s)-1-n-[5-(1-benzothiophen-2-yl)-4-pyridin-4-ylpyrimidin-2-yl]-3-phenylpropane-1,2-diamine Chemical compound C([C@@H](N)CC=1C=CC=CC=1)NC(N=1)=NC=C(C=2SC3=CC=CC=C3C=2)C=1C1=CC=NC=C1 CEPNYRGGEXJJAW-NRFANRHFSA-N 0.000 claims 1
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