CA2420286A1 - 7 oxo pyridopyrimidines comme inhibiteurs d'une proliferation cellulaire - Google Patents

7 oxo pyridopyrimidines comme inhibiteurs d'une proliferation cellulaire Download PDF

Info

Publication number: CA2420286A1
Authority: CA; Canada
Prior art keywords: compound; mmol; stirred; alkyl; added
Prior art date: 2000-08-31
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.): Abandoned

Application number

CA002420286A

Other languages

English (en)

Inventor

Jian Jeffrey Chen

James Patrick Dunn

David Michael Goldstein

Julie Anne Lim

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

F Hoffmann La Roche AG

Original Assignee

Individual

Priority date (The priority date 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 date listed.)

2000-08-31

Filing date

2001-08-22

Publication date

2002-03-07

2001-08-22 Application filed by Individual filed Critical Individual

2002-03-07 Publication of CA2420286A1 publication Critical patent/CA2420286A1/fr

Status Abandoned legal-status Critical Current

Links

239000003112 inhibitor Substances 0.000 title description 3
UWABAWGNHPXGBQ-UHFFFAOYSA-N 6h-pyrido[3,2-d]pyrimidin-7-one Chemical class C1=NC=NC2=CC(=O)CN=C21 UWABAWGNHPXGBQ-UHFFFAOYSA-N 0.000 title description 2
230000004663 cell proliferation Effects 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims abstract description 226
-1 monoalkylamino Chemical group 0.000 claims abstract description 188
125000000217 alkyl group Chemical group 0.000 claims abstract description 78
239000001257 hydrogen Substances 0.000 claims abstract description 68
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 68
125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 56
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 37
125000000623 heterocyclic group Chemical group 0.000 claims abstract description 32
125000003118 aryl group Chemical group 0.000 claims abstract description 26
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 26
125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 25
238000011282 treatment Methods 0.000 claims abstract description 25
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 23
125000003545 alkoxy group Chemical group 0.000 claims abstract description 22
125000004404 heteroalkyl group Chemical group 0.000 claims abstract description 22
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 22
125000001188 haloalkyl group Chemical group 0.000 claims abstract description 19
125000004442 acylamino group Chemical group 0.000 claims abstract description 11
125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 11
125000002252 acyl group Chemical group 0.000 claims abstract description 10
125000004966 cyanoalkyl group Chemical group 0.000 claims abstract description 7
125000005346 substituted cycloalkyl group Chemical group 0.000 claims abstract description 7
208000024827 Alzheimer disease Diseases 0.000 claims abstract description 4
206010001052 Acute respiratory distress syndrome Diseases 0.000 claims abstract description 3
208000011231 Crohn disease Diseases 0.000 claims abstract description 3
208000013616 Respiratory Distress Syndrome Diseases 0.000 claims abstract description 3
208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims abstract description 3
201000000028 adult respiratory distress syndrome Diseases 0.000 claims abstract description 3
206010003246 arthritis Diseases 0.000 claims abstract description 3
208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract 2
208000002551 irritable bowel syndrome Diseases 0.000 claims abstract 2
239000000203 mixture Substances 0.000 claims description 164
150000001412 amines Chemical class 0.000 claims description 49
238000002360 preparation method Methods 0.000 claims description 45
238000000034 method Methods 0.000 claims description 29
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 24
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 claims description 24
108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 claims description 24
238000004519 manufacturing process Methods 0.000 claims description 16
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
230000001404 mediated effect Effects 0.000 claims description 11
239000000651 prodrug Substances 0.000 claims description 11
229940002612 prodrug Drugs 0.000 claims description 11
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 7
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
239000003814 drug Substances 0.000 claims description 7
239000000546 pharmaceutical excipient Substances 0.000 claims description 6
125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 claims description 5
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
125000003386 piperidinyl group Chemical group 0.000 claims description 5
125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 4
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 4
125000000113 cyclohexyl group Chemical class [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
125000001475 halogen functional group Chemical group 0.000 claims description 4
125000004487 4-tetrahydropyranyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
230000008569 process Effects 0.000 claims description 3
125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 2
125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
239000013543 active substance Substances 0.000 claims description 2
125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 2
125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims 1
125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 20
208000035475 disorder Diseases 0.000 abstract description 9
125000004367 cycloalkylaryl group Chemical group 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 496
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 421
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 372
239000000243 solution Substances 0.000 description 182
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 173
235000019439 ethyl acetate Nutrition 0.000 description 170
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 167
229940093499 ethyl acetate Drugs 0.000 description 156
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 152
SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 132
239000000047 product Substances 0.000 description 127
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 122
239000007787 solid Substances 0.000 description 110
150000003839 salts Chemical class 0.000 description 109
239000011541 reaction mixture Substances 0.000 description 102
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 95
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 78
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 72
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 70
239000012267 brine Substances 0.000 description 67
238000004949 mass spectrometry Methods 0.000 description 65
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 64
230000002829 reductive effect Effects 0.000 description 62
238000006243 chemical reaction Methods 0.000 description 61
239000012044 organic layer Substances 0.000 description 60
150000003457 sulfones Chemical class 0.000 description 57
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
239000000741 silica gel Substances 0.000 description 54
229910002027 silica gel Inorganic materials 0.000 description 54
229910052943 magnesium sulfate Inorganic materials 0.000 description 50
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 48
238000004440 column chromatography Methods 0.000 description 47
239000000725 suspension Substances 0.000 description 47
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
239000002904 solvent Substances 0.000 description 43
235000019341 magnesium sulphate Nutrition 0.000 description 39
239000000843 powder Substances 0.000 description 37
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 33
150000002431 hydrogen Chemical group 0.000 description 30
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 30
238000003818 flash chromatography Methods 0.000 description 28
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
238000000746 purification Methods 0.000 description 27
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 26
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 26
102100040247 Tumor necrosis factor Human genes 0.000 description 25
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
201000010099 disease Diseases 0.000 description 24
239000006260 foam Substances 0.000 description 23
239000012043 crude product Substances 0.000 description 22
239000000706 filtrate Substances 0.000 description 22
UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 21
239000010410 layer Substances 0.000 description 21
239000002585 base Substances 0.000 description 20
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
238000003756 stirring Methods 0.000 description 20
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
229910052938 sodium sulfate Inorganic materials 0.000 description 18
235000011152 sodium sulphate Nutrition 0.000 description 18
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 17
239000002253 acid Substances 0.000 description 17
239000000908 ammonium hydroxide Substances 0.000 description 17
239000012458 free base Substances 0.000 description 17
239000003921 oil Substances 0.000 description 17
235000019198 oils Nutrition 0.000 description 17
239000002244 precipitate Substances 0.000 description 16
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 15
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
150000003840 hydrochlorides Chemical class 0.000 description 15
229910052757 nitrogen Inorganic materials 0.000 description 15
239000002002 slurry Substances 0.000 description 15
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
238000012746 preparative thin layer chromatography Methods 0.000 description 14
238000010992 reflux Methods 0.000 description 14
229910000104 sodium hydride Inorganic materials 0.000 description 14
125000001424 substituent group Chemical group 0.000 description 14
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 13
229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
229910000029 sodium carbonate Inorganic materials 0.000 description 13
239000012312 sodium hydride Substances 0.000 description 13
150000003462 sulfoxides Chemical class 0.000 description 13
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
229910000027 potassium carbonate Inorganic materials 0.000 description 12
235000017557 sodium bicarbonate Nutrition 0.000 description 12
108060008682 Tumor Necrosis Factor Proteins 0.000 description 11
239000000463 material Substances 0.000 description 11
230000003647 oxidation Effects 0.000 description 11
238000007254 oxidation reaction Methods 0.000 description 11
150000003254 radicals Chemical class 0.000 description 11
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 10
239000012467 final product Substances 0.000 description 10
125000005843 halogen group Chemical group 0.000 description 10
238000002844 melting Methods 0.000 description 10
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235000011181 potassium carbonates Nutrition 0.000 description 10
229920006395 saturated elastomer Polymers 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 9
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
239000000284 extract Substances 0.000 description 9
AHVQYHFYQWKUKB-UHFFFAOYSA-N oxan-4-amine Chemical compound NC1CCOCC1 AHVQYHFYQWKUKB-UHFFFAOYSA-N 0.000 description 9
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 8
238000001035 drying Methods 0.000 description 8
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 8
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 7
108091003079 Bovine Serum Albumin Proteins 0.000 description 7
108010002352 Interleukin-1 Proteins 0.000 description 7
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238000001914 filtration Methods 0.000 description 7
230000005764 inhibitory process Effects 0.000 description 7
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 7
239000007788 liquid Substances 0.000 description 7
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
239000011734 sodium Substances 0.000 description 7
238000004809 thin layer chromatography Methods 0.000 description 7
150000003568 thioethers Chemical class 0.000 description 7
QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 6
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
102000004127 Cytokines Human genes 0.000 description 6
108090000695 Cytokines Proteins 0.000 description 6
WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
241000124008 Mammalia Species 0.000 description 6
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
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RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
239000012280 lithium aluminium hydride Substances 0.000 description 6
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FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
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SNNHLSHDDGJVDM-UHFFFAOYSA-N ethyl 4-chloro-2-methylsulfanylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(SC)N=C1Cl SNNHLSHDDGJVDM-UHFFFAOYSA-N 0.000 description 5
239000007789 gas Substances 0.000 description 5
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125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 5
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RPIXOLUIHUFDOY-UHFFFAOYSA-N thian-4-amine Chemical compound NC1CCSCC1 RPIXOLUIHUFDOY-UHFFFAOYSA-N 0.000 description 5
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229920002223 polystyrene Polymers 0.000 description 1
229920000166 polytrimethylene carbonate Polymers 0.000 description 1
GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 1
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
150000003141 primary amines Chemical class 0.000 description 1
MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
229960004919 procaine Drugs 0.000 description 1
238000011321 prophylaxis Methods 0.000 description 1
235000019260 propionic acid Nutrition 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
108060006633 protein kinase Proteins 0.000 description 1
208000009305 pseudorabies Diseases 0.000 description 1
230000002685 pulmonary effect Effects 0.000 description 1
201000003651 pulmonary sarcoidosis Diseases 0.000 description 1
239000013014 purified material Substances 0.000 description 1
ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical class [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
159000000018 pyrido[2,3-d]pyrimidines Chemical class 0.000 description 1
125000001422 pyrrolinyl group Chemical group 0.000 description 1
229940107700 pyruvic acid Drugs 0.000 description 1
238000010791 quenching Methods 0.000 description 1
230000000171 quenching effect Effects 0.000 description 1
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
230000009257 reactivity Effects 0.000 description 1
230000010410 reperfusion Effects 0.000 description 1
WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 description 1
229960004889 salicylic acid Drugs 0.000 description 1
239000012047 saturated solution Substances 0.000 description 1
231100000241 scar Toxicity 0.000 description 1
229940116351 sebacate Drugs 0.000 description 1
CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
239000012056 semi-solid material Substances 0.000 description 1
238000013207 serial dilution Methods 0.000 description 1
229910001961 silver nitrate Inorganic materials 0.000 description 1
229910001923 silver oxide Inorganic materials 0.000 description 1
235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
239000011780 sodium chloride Substances 0.000 description 1
235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
CMZUMMUJMWNLFH-UHFFFAOYSA-N sodium metavanadate Chemical compound [Na+].[O-][V](=O)=O CMZUMMUJMWNLFH-UHFFFAOYSA-N 0.000 description 1
239000012265 solid product Substances 0.000 description 1
201000005671 spondyloarthropathy Diseases 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
150000003431 steroids Chemical class 0.000 description 1
239000011550 stock solution Substances 0.000 description 1
230000035882 stress Effects 0.000 description 1
TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
239000006228 supernatant Substances 0.000 description 1
239000003765 sweetening agent Substances 0.000 description 1
230000002194 synthesizing effect Effects 0.000 description 1
230000009885 systemic effect Effects 0.000 description 1
201000000596 systemic lupus erythematosus Diseases 0.000 description 1
239000000454 talc Substances 0.000 description 1
229910052623 talc Inorganic materials 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
CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 1
239000012085 test solution Substances 0.000 description 1
OVRJVKCZJCNSOW-UHFFFAOYSA-N thian-4-one Chemical compound O=C1CCSCC1 OVRJVKCZJCNSOW-UHFFFAOYSA-N 0.000 description 1
125000003396 thiol group Chemical group [H]S* 0.000 description 1
210000001519 tissue Anatomy 0.000 description 1
230000009772 tissue formation Effects 0.000 description 1
238000012546 transfer Methods 0.000 description 1
238000002054 transplantation Methods 0.000 description 1
ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
229960000281 trometamol Drugs 0.000 description 1
230000006433 tumor necrosis factor production Effects 0.000 description 1
241000712461 unidentified influenza virus Species 0.000 description 1
235000015112 vegetable and seed oil Nutrition 0.000 description 1
239000008158 vegetable oil Substances 0.000 description 1
230000009385 viral infection Effects 0.000 description 1
230000003612 virological effect Effects 0.000 description 1
238000005303 weighing Methods 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1
229910000166 zirconium phosphate Inorganic materials 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
- 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
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
- 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

Landscapes

Health & Medical Sciences (AREA)
Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
General Chemical & Material Sciences (AREA)
Public Health (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Pharmacology & Pharmacy (AREA)
Veterinary Medicine (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Rheumatology (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Virology (AREA)
Communicable Diseases (AREA)
Oncology (AREA)
Hospice & Palliative Care (AREA)
Pain & Pain Management (AREA)
AIDS & HIV (AREA)
Tropical Medicine & Parasitology (AREA)
Molecular Biology (AREA)
Psychiatry (AREA)
Immunology (AREA)
Orthopedic Medicine & Surgery (AREA)
Physical Education & Sports Medicine (AREA)
Pulmonology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)

CA002420286A 2000-08-31 2001-08-22 7 oxo pyridopyrimidines comme inhibiteurs d'une proliferation cellulaire Abandoned CA2420286A1 (fr)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US22958400P	2000-08-31	2000-08-31
US60/229,584		2000-08-31
PCT/EP2001/009689 WO2002018380A1 (fr)	2000-08-31	2001-08-22	7 oxo pyridopyrimidines comme inhibiteurs d'une proliferation cellulaire

Publications (1)

Publication Number	Publication Date
CA2420286A1 true CA2420286A1 (fr)	2002-03-07

Family

ID=22861859

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002420286A Abandoned CA2420286A1 (fr)	2000-08-31	2001-08-22	7 oxo pyridopyrimidines comme inhibiteurs d'une proliferation cellulaire

Country Status (15)

Country	Link
EP (1)	EP1315726A1 (fr)
JP (1)	JP4141830B2 (fr)
KR (1)	KR100571339B1 (fr)
CN (1)	CN1275964C (fr)
AR (1)	AR033681A1 (fr)
AU (2)	AU9378401A (fr)
BR (1)	BR0113628A (fr)
CA (1)	CA2420286A1 (fr)
GT (1)	GT200100191A (fr)
MX (1)	MXPA03001821A (fr)
PA (1)	PA8527301A1 (fr)
PE (1)	PE20020406A1 (fr)
UY (1)	UY26918A1 (fr)
WO (1)	WO2002018380A1 (fr)
ZA (1)	ZA200301079B (fr)

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PL374544A1 (en) *	2002-04-03	2005-10-31	F.Hoffmann-La Roche Ag	Imidazo fused compounds
PL373339A1 (en) *	2002-04-19	2005-08-22	Smithkline Beecham Corporation	Novel compounds
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UY27939A1 (es)	2002-08-21	2004-03-31	Glaxo Group Ltd	Compuestos
US7129351B2 (en)	2002-11-04	2006-10-31	Hoffmann-La Roche Inc.	Pyrimido compounds having antiproliferative activity
DE60327097D1 (de) *	2002-11-18	2009-05-20	Hoffmann La Roche	Diazinopyrimidine und ihre verwendung als proteinkinaseinhibitoren
US7098332B2 (en)	2002-12-20	2006-08-29	Hoffmann-La Roche Inc.	5,8-Dihydro-6H-pyrido[2,3-d]pyrimidin-7-ones
KR100864393B1 (ko)	2003-04-10	2008-10-20	에프. 호프만-라 로슈 아게	피리미도 화합물
ATE451115T1 (de) *	2003-07-07	2009-12-15	Van Andel Res Inst	Hemmung der tumor-angiogenese durch eine kombination von thrombospondin-1 und hemmern des vaskulären endothel-wachstumsfaktors
SI1685131T1 (sl) *	2003-11-13	2007-06-30	Hoffmann La Roche	Hidroksialkil-substituirani pirido-7-pirimidin-7-oni
WO2005105097A2 (fr) *	2004-04-28	2005-11-10	Gpc Biotech Ag	Derives de pyridopyrimidine
US20070054916A1 (en) *	2004-10-01	2007-03-08	Amgen Inc.	Aryl nitrogen-containing bicyclic compounds and methods of use
WO2006056863A1 (fr) *	2004-11-23	2006-06-01	Ranbaxy Laboratories Limited	Pyrido'2, 3-d!pyrimidines utilisees comme agents anti-inflammatoires
EP1846403A1 (fr) *	2005-02-02	2007-10-24	Ranbaxy Laboratories Limited	Derives azabicyclo utilises comme agents anti-inflammatoires
US20090221600A1 (en) *	2005-09-28	2009-09-03	Ashwani Kumar Verma	Pyrido-pyridimidine derivatives useful as antiinflammatory agents
DE602007001952D1 (de)	2006-01-31	2009-09-24	Hoffmann La Roche	7h-pyridoä3,4-düpyrimidin-8-one, ihre herstellung und ihre verwendung als proteinkinaseinhibitoren
KR100661523B1 (ko) *	2006-06-09	2006-12-26	주식회사 청용산기	포장박스 제조장치에 장착되는 개선된 비틀림 교정 장치
EP1914234A1 (fr)	2006-10-16	2008-04-23	GPC Biotech Inc.	Pyrido[2,3-d]pyrimidines et leur utilisation comme inhibiteurs de kinases
CN101535308A (zh)	2006-11-09	2009-09-16	霍夫曼-拉罗奇有限公司	作为激酶抑制剂的取代的6-苯基-吡啶并[2，3-d]嘧啶-7-酮衍生物及其使用方法
WO2008078249A1 (fr) *	2006-12-21	2008-07-03	Ranbaxy Laboratories Limited	Agents anti-inflammatoires
EP2112150B1 (fr)	2008-04-22	2013-10-16	Forma Therapeutics, Inc.	Inhibiteurs Raf améliorés
KR101106162B1 (ko) *	2010-04-20	2012-01-20	주식회사 청용산기	포장박스 제조장치용 스티칭 장치에 있어서의 하역가이드 지지유닛
ES2694223T3 (es) *	2012-03-22	2018-12-19	Oscotec, Inc.	Compuestos de piridopirimidina y su uso como inhibidores de FLT3
CN111793068A (zh)	2013-03-15	2020-10-20	西建卡尔有限责任公司	杂芳基化合物和其用途
KR102350704B1 (ko)	2013-03-15	2022-01-13	셀젠 카르 엘엘씨	헤테로아릴 화합물 및 이의 용도
TWI647220B (zh)	2013-03-15	2019-01-11	美商西建卡爾有限責任公司	雜芳基化合物及其用途
KR20170054408A (ko)	2014-09-12	2017-05-17	바이오랩 세너스 팔마씨우티카 엘티디에이.	신규한 피리도피리미딘 유도체 화합물
EP3692144A1 (fr)	2017-10-05	2020-08-12	Fulcrum Therapeutics, Inc.	Utilisation d'inhibiteurs de p38 pour réduire l'expression de dux4
US10342786B2 (en)	2017-10-05	2019-07-09	Fulcrum Therapeutics, Inc.	P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
TWI831829B (zh)	2018-09-12	2024-02-11	美商建南德克公司	苯氧基-吡啶基-嘧啶化合物及使用方法
US12077534B2 (en)	2018-12-27	2024-09-03	Les Laboratoires Servier	Aza-heterobicyclic inhibitors of MAT2A and methods of use for treating cancer
EP3941919B1 (fr)	2019-01-03	2025-12-24	Genentech, Inc.	Composés de pyrido-pyrimidinone et de ptéridinone utilisés en tant qu'inhibiteurs de l'enzyme nécessitant l'inositol i (ire i alpha) à activité endoribonucléase pour le traitement de maladies cancéreuses
MA56050A (fr) *	2019-05-31	2022-04-06	Servier Lab	Inhibiteurs hétérobicycliques de mat2a et procédés d'utilisation pour le traitement du cancer
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2001
- 2001-08-22 JP JP2002523895A patent/JP4141830B2/ja not_active Expired - Fee Related
- 2001-08-22 MX MXPA03001821A patent/MXPA03001821A/es active IP Right Grant
- 2001-08-22 KR KR1020037002936A patent/KR100571339B1/ko not_active Expired - Fee Related
- 2001-08-22 CA CA002420286A patent/CA2420286A1/fr not_active Abandoned
- 2001-08-22 AU AU9378401A patent/AU9378401A/xx active Pending
- 2001-08-22 AU AU2001293784A patent/AU2001293784B2/en not_active Ceased
- 2001-08-22 WO PCT/EP2001/009689 patent/WO2002018380A1/fr not_active Ceased
- 2001-08-22 EP EP01974206A patent/EP1315726A1/fr not_active Withdrawn
- 2001-08-22 BR BR0113628-3A patent/BR0113628A/pt not_active Application Discontinuation
- 2001-08-22 CN CNB018150306A patent/CN1275964C/zh not_active Expired - Fee Related
- 2001-08-28 PE PE2001000860A patent/PE20020406A1/es not_active Application Discontinuation
- 2001-08-28 PA PA20018527301A patent/PA8527301A1/es unknown
- 2001-08-30 UY UY26918A patent/UY26918A1/es not_active Application Discontinuation
- 2001-08-30 AR ARP010104132A patent/AR033681A1/es unknown
- 2001-09-18 GT GT200100191A patent/GT200100191A/es unknown
2003
- 2003-02-07 ZA ZA200301079A patent/ZA200301079B/en unknown

Also Published As

Publication number	Publication date
CN1451005A (zh)	2003-10-22
AU9378401A (en)	2002-03-13
KR20030022422A (ko)	2003-03-15
JP4141830B2 (ja)	2008-08-27
GT200100191A (es)	2002-05-16
CN1275964C (zh)	2006-09-20
JP2004507541A (ja)	2004-03-11
EP1315726A1 (fr)	2003-06-04
AR033681A1 (es)	2004-01-07
PA8527301A1 (es)	2002-07-30
WO2002018380A1 (fr)	2002-03-07
MXPA03001821A (es)	2003-06-04
PE20020406A1 (es)	2002-05-17
BR0113628A (pt)	2003-07-01
AU2001293784B2 (en)	2007-08-30
UY26918A1 (es)	2002-02-28
KR100571339B1 (ko)	2006-04-17
ZA200301079B (en)	2004-05-07

Publication	Publication Date	Title
AU2001293784B2 (en)	2007-08-30	7-OXO pyridopyrimidines as inhibitors of a cellular proliferation
AU2001293784A1 (en)	2002-06-06	7-OXO pyridopyrimidines as inhibitors of a cellular proliferation
EP1539755B1 (fr)	2007-09-26	6-alcoxy-pyrido-pyrimidines utilisees comme inhibiteurs de la map kinase p-38
US7449581B2 (en)	2008-11-11	6-Substituted pyrido-pyrimidines
CA2388142C (fr)	2008-12-09	Heterocyles d'azote bicycliques substitue par heteroalkylamino en tant qu'inhibiteurs de la proteine kinase p38
US20080119497A1 (en)	2008-05-22	Hydroxyalkyl substituted pyrido-7-pyrimidin-7-ones
US6506749B2 (en)	2003-01-14	7-oxo-pyridopyrimidines (I)
EP1315727B1 (fr)	2005-06-29	7-oxo pyridopyrimidines
AU2002212147A1 (en)	2002-06-06	7-OXO pyridopyrimidines
US6753427B2 (en)	2004-06-22	7-oxo-pyridopyrimidines (II)

Legal Events

Date	Code	Title	Description
2003-12-09	EEER	Examination request
2010-08-23	FZDE	Dead