JP2005535570A - 新規ピリミドン誘導体 - Google Patents
新規ピリミドン誘導体 Download PDFInfo
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- JP2005535570A JP2005535570A JP2003582135A JP2003582135A JP2005535570A JP 2005535570 A JP2005535570 A JP 2005535570A JP 2003582135 A JP2003582135 A JP 2003582135A JP 2003582135 A JP2003582135 A JP 2003582135A JP 2005535570 A JP2005535570 A JP 2005535570A
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- aryl
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- 150000008318 pyrimidones Chemical class 0.000 title claims abstract description 25
- 239000000203 mixture Substances 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 239000012453 solvate Substances 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 118
- -1 amino, hydroxylamino Chemical group 0.000 claims description 88
- 125000000217 alkyl group Chemical group 0.000 claims description 56
- 125000003118 aryl group Chemical group 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 40
- 150000002431 hydrogen Chemical group 0.000 claims description 37
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- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 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 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 25
- 125000002252 acyl group Chemical group 0.000 claims description 22
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 20
- 125000004442 acylamino group Chemical group 0.000 claims description 19
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- KWEDUNSJJZVRKR-UHFFFAOYSA-N carbononitridic azide Chemical compound [N-]=[N+]=NC#N KWEDUNSJJZVRKR-UHFFFAOYSA-N 0.000 claims description 15
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- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 13
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- 125000004104 aryloxy group Chemical group 0.000 claims description 13
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- 230000006378 damage Effects 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
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- 239000000243 solution Substances 0.000 claims description 8
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
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- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
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- 208000034578 Multiple myelomas Diseases 0.000 claims description 6
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 6
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- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 125000000033 alkoxyamino group Chemical group 0.000 claims description 5
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
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- 230000036303 septic shock Effects 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- SWQQRSLRSSNPEI-UHFFFAOYSA-N 4-methylsulfanyl-1-(4-methylsulfanylphenyl)-6-oxo-2-phenylpyrimidine-5-carbonitrile Chemical compound C1=CC(SC)=CC=C1N1C(=O)C(C#N)=C(SC)N=C1C1=CC=CC=C1 SWQQRSLRSSNPEI-UHFFFAOYSA-N 0.000 claims description 4
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- 208000000112 Myalgia Diseases 0.000 claims description 4
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- 230000002378 acidificating effect Effects 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
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- 231100000135 cytotoxicity Toxicity 0.000 claims description 4
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- 125000002541 furyl group Chemical group 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 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 claims description 3
- ZPKBCCNUXWFKDC-UHFFFAOYSA-N 1-(4-fluorophenyl)-4-methylsulfanyl-2-(4-methylsulfanylphenyl)-6-oxopyrimidine-5-carbonitrile Chemical compound C1=CC(SC)=CC=C1C1=NC(SC)=C(C#N)C(=O)N1C1=CC=C(F)C=C1 ZPKBCCNUXWFKDC-UHFFFAOYSA-N 0.000 claims description 3
- TWQIUCYXICDLFR-UHFFFAOYSA-N 1-(4-methylphenyl)-4-methylsulfanyl-2-(4-methylsulfanylphenyl)-6-oxopyrimidine-5-carbonitrile Chemical compound C1=CC(SC)=CC=C1C1=NC(SC)=C(C#N)C(=O)N1C1=CC=C(C)C=C1 TWQIUCYXICDLFR-UHFFFAOYSA-N 0.000 claims description 3
- KEMVKFWEZZYNJV-UHFFFAOYSA-N 1-(4-methylphenyl)-4-methylsulfanyl-2-(4-methylsulfonylphenyl)-6-oxopyrimidine-5-carbonitrile Chemical compound C=1C=C(C)C=CC=1N1C(=O)C(C#N)=C(SC)N=C1C1=CC=C(S(C)(=O)=O)C=C1 KEMVKFWEZZYNJV-UHFFFAOYSA-N 0.000 claims description 3
- UCILWYHXLAUHCY-UHFFFAOYSA-N 2-(4-fluorophenyl)-4-methylsulfanyl-1-(4-methylsulfanylphenyl)-6-oxopyrimidine-5-carbonitrile Chemical compound C1=CC(SC)=CC=C1N1C(=O)C(C#N)=C(SC)N=C1C1=CC=C(F)C=C1 UCILWYHXLAUHCY-UHFFFAOYSA-N 0.000 claims description 3
- XDVZLXYEFQTQNW-UHFFFAOYSA-N 4-methylsulfanyl-1-(4-methylsulfanylphenyl)-6-oxo-2-[4-(trifluoromethyl)phenyl]pyrimidine-5-carbonitrile Chemical compound C1=CC(SC)=CC=C1N1C(=O)C(C#N)=C(SC)N=C1C1=CC=C(C(F)(F)F)C=C1 XDVZLXYEFQTQNW-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
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- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000005874 benzothiadiazolyl group Chemical group 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
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- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
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- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
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- 125000004076 pyridyl group Chemical group 0.000 claims description 3
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- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
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- SETLRKGMLZNJNW-UHFFFAOYSA-N 1-(4-fluorophenyl)-4-methylsulfanyl-2-(4-methylsulfonylphenyl)-6-oxopyrimidine-5-carbonitrile Chemical compound C=1C=C(F)C=CC=1N1C(=O)C(C#N)=C(SC)N=C1C1=CC=C(S(C)(=O)=O)C=C1 SETLRKGMLZNJNW-UHFFFAOYSA-N 0.000 claims description 2
- ZAFGUJZCHZCCGI-UHFFFAOYSA-N 1-(4-methylphenyl)-2-(4-methylsulfanylphenyl)-4-methylsulfonyl-6-oxopyrimidine-5-carbonitrile Chemical compound C1=CC(SC)=CC=C1C1=NC(S(C)(=O)=O)=C(C#N)C(=O)N1C1=CC=C(C)C=C1 ZAFGUJZCHZCCGI-UHFFFAOYSA-N 0.000 claims description 2
- ILDSTHMNWFCADL-UHFFFAOYSA-N 1-(4-methylphenyl)-4-methylsulfanyl-2-(4-methylsulfonylphenyl)-6-oxopyrimidine-5-carboxylic acid Chemical compound C=1C=C(C)C=CC=1N1C(=O)C(C(O)=O)=C(SC)N=C1C1=CC=C(S(C)(=O)=O)C=C1 ILDSTHMNWFCADL-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
【化1】
Description
i)US特許No.5,726,124および5,300,477は式(IIa)の新規除草剤化合物について開示している:
これら化合物の例は式(IIb)で示される:
これら化合物の例は式(IId)で示される:
これら化合物の例は式(IIf)で示される:
これら化合物の例は式(IIh)で示される:
これら化合物の例は式(IIj)で示される:
これら化合物の例は式(IIl)で示される:
5‐シアノ‐4‐メチルチオ‐1‐(4‐メチルチオフェニル)‐2‐フェニル‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐4‐メチルチオ‐1‐(4‐メチルチオフェニル)‐2‐(4‐トリフルオロメチルフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐1‐(4‐フルオロフェニル)‐4‐メチルチオ‐2‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐1‐(4‐メチルフェニル)‐2‐(4‐メチルスルホニルフェニル)‐4‐メチルチオ‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐1‐(4‐フルオロフェニル)‐2‐(4‐メチルスルホニルフェニル)‐4‐メチルチオ‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐1‐(4‐メチルフェニル)‐4‐メチルスルホニル‐2‐(4‐メチルスルホニルフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐1‐(4‐メチルフェニル)‐4‐メチルスルホニル‐2‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐1‐(4‐メチルフェニル)‐4‐メチルチオ‐2‐(4‐スルファモイルフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐2‐(4‐フルオロフェニル)‐1‐(4‐メチルチオフェニル)‐4‐メチルチオ‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐2‐(4‐フルオロフェニル)‐1‐(4‐メチルスルホニルフェニル)‐4‐メチルチオ‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐2‐(4‐フルオロフェニル)‐4‐メチルチオ‐1‐(4‐スルファモイルフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐2‐(4‐クロロフェニル)‐4‐メチルチオ‐1‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐1‐(4‐メチルフェニル)‐4‐メチルチオ‐2‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
2‐(4‐メタンスルホニルフェニル)‐4‐メチルスルファニル‐6‐オキソ‐1‐(4‐メチルフェニル)‐1,6‐ジヒドロピリミジン‐5‐カルボン酸;
2‐(4‐メタンスルファニルフェニル)‐4‐メチルスルファニル‐6‐オキソ‐1‐(4‐メチルフェニル)‐1,6‐ジヒドロピリミジン‐5‐カルボン酸;
2‐(4‐フルオロフェニル)‐4‐メチルスルファニル‐6‐オキソ‐1‐(4‐メチルフェニル)‐1,6‐ジヒドロピリミジン‐5‐カルボン酸;
5‐カルボキシ‐4‐メチルチオ‐1‐(4‐メチルチオフェニル)‐2‐フェニル‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐カルバモイル‐2‐(4‐フルオロフェニル)‐4‐メチルチオ‐1‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐クロロ‐2‐(4‐クロロフェニル)‐4‐メチルチオ‐1‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
2‐(4‐クロロフェニル)‐4‐メチルチオ‐1‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
2‐(4‐クロロフェニル)‐1‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
1‐(4‐メチルフェニル)‐4‐メチルチオ‐2‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
1‐(4‐メチルフェニル)‐2‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
4‐(5‐シアノ‐4‐メチルチオ‐6‐オキソ‐2‐フェニル‐6H‐ピリミジン‐1‐イル)ベンゼンスルホンアミド;
4‐(5‐シアノ‐4‐メチルチオ‐6‐オキソ‐2‐(4‐メチルフェニル)‐6H‐ピリミジン‐1‐イル)ベンゼンスルホンアミド;および
4‐(5‐カルボキシ‐4‐メチルチオ‐6‐オキソ‐2‐フェニル‐6H‐ピリミジン‐1‐イル)ベンゼンスルホンアミド
N‐(4‐メチルチオフェニル)‐4‐クロロベンズアミジンの合成
N‐(4‐メチルチオフェニル)‐4‐フルオロベンズアミジンの合成
N‐(4‐メチルチオフェニル)ベンズアミジンの合成
N‐(4‐メチルチオフェニル)‐4‐トリフルオロメチルベンズアミジンの合成
N‐(4‐フルオロフェニル)‐4‐メチルチオベンズアミジンの合成
N‐(4‐メチルフェニル)‐4‐メチルチオベンズアミジンの合成
4‐メチルスルホニルベンゾニトリルの合成
N‐(4‐メチルフェニル)‐4‐メチルスルホニルベンズアミジンの合成
5‐シアノ‐2‐(4‐クロロフェニル)‐4‐メチルチオ‐1‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オンの合成
5‐シアノ‐2‐(4‐フルオロフェニル)‐4‐メチルチオ‐1‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オンの合成
5‐シアノ‐4‐メチルチオ‐1‐(4‐メチルチオフェニル)‐2‐フェニル‐1,6‐ジヒドロピリミジン‐6‐オンの合成
5‐シアノ‐4‐メチルチオ‐1‐(4‐メチルチオフェニル)‐2‐(4‐トリフルオロメチルフェニル)‐1,6‐ジヒドロピリミジン‐6‐オンの合成
5‐シアノ‐1‐(4‐フルオロフェニル)‐4‐メチルチオ‐2‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オンの合成
5‐シアノ‐1‐(4‐メチルフェニル)‐4‐メチルチオ‐2‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オンの合成
5‐シアノ‐1‐(4‐メチルフェニル)‐2‐(4‐メチルスルホニルフェニル)‐4‐メチルチオ‐1,6‐ジヒドロピリミジン‐6‐オンの合成
5‐カルボキシ‐1‐(4‐メチルフェニル)‐4‐メチルチオ‐2‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オンの合成
カラゲナン足蹠浮腫試験をWinter et al(Proc.Soc.Exp.Biol.Me.,111,544,1962)で記載されたように行った。雄性Wistarラットを選択し、体重を各群で同等にした。ラットを18時間絶食させたが、水へは自由に近づけるようにした。ラットに0.5%メチルセルロース含有ビヒクルに懸濁された試験化合物を経口投与した。コントロールラットへはビヒクル単独で投与した。1時間後、ラットの右後足蹠の足裏下表面に0.9%塩水中1%カラゲナン溶液0.1mlを注射した。0時間目、2および3時間後に、ノギスを用いて足蹠厚さを測定した。薬物処理動物における足腫脹の平均をコントロール動物のものと比較した。抗炎症活性は、コントロール群と比較した浮腫の抑制率として表示した〔Arzneim-Forsch/Drug Res.,43(I),1,44-50,1993;Otterness and Bliven,Laboratory Models for Testing NSAIDs,In Non-Steroidal Anti-Inflammatory Drugs,(J.Lombardino,ed.1985)〕。本発明で選択された化合物のデータは表Iでまとめられている。潰瘍形成に際するそれらの役割を評価するために、動物を頸部脱臼で犠牲にし、胃を摘出し、1%ホルマリン(10ml)で洗い流した。胃を大弯に沿い開いた。出血点および溝を肉眼で確認した。胃病変の存在または不在を評点した。潰瘍の発生率を、少くとも1つの胃潰瘍または出血性びらんを示したラットの数から計算した。
本発明の化合物はCOX‐2のインビトロ阻害を示した。例中で記載された化合物のCOX‐2阻害活性を下記方法で調べた。
ヒト全血は、選択COX‐2インヒビターのような抗炎症化合物の生化学効力の試験に適した、タンパク質および細胞に富む環境を提供する。リポ多糖(LPS)含有のヒト血液は、血中でCOX‐2産生を誘導する。
鮮血を男性ボランティアから血管穿刺によりEDTAカリウム含有管へ集めた。被験者は、見掛け上炎症症状を有してはならず、採血前に少くとも7日間はNSAIDの投与を受けてはならない。COX‐1を不活性化するためにインビトロでアスピリン(ゼロ時に10μg/ml)、次いで試験剤またはビヒクルと一緒にLPS(10μg/ml)で、血液を処理した。血液を37℃で24時間インキュベートし、次いで管を遠心し、血漿を分離させ、−80℃で貯蔵した(J.Pharmacol.Exp.Ther.,271,1705,1994;Proc.Natl.Acad.Sci.USA,96,7563,1999)。製造業者(Cayman Chemicals,Ann Arbor,USA)により示された操作に従い、Cayman ELISAキットを用いて、PGE2について血漿を試験した。製造業者(Cayman Chemicals,Ann Arbor,USA)の操作に従い、適切なヒトELISAキットを用いて、TNF‐α、IL‐1βおよびIL‐6についても血漿を試験した。COX‐2阻害の代表的結果が表IIで示されている。
このアッセイでは、ヒト単球からTNF‐αの産生に関して、試験化合物の効果を調べる。活性化単球でTNF‐αの産生を負調節しうる能力について、化合物を試験した。試験化合物をヒト単球と一緒に3、6および24時間インキュベートした。単球を刺激するためにリポ多糖を用いた。TNF‐αのレベルを、96ウェルフォーマットで酵素結合免疫吸着剤アッセイを用いて定量した。TNF‐α阻害の代表的結果が表IIIで示されている。
このアッセイでは、ヒト単球からIL‐6の産生に関して、試験化合物の効果を調べる。活性化単球でIL‐6の産生を負調節しうる能力について、化合物を試験する。試験化合物をヒト単球と一緒に3、6および24時間インキュベートした。単球を刺激するためにリポ多糖を用いた。インターロイキン‐6のレベルを、96ウェルフォーマットで酵素結合免疫吸着剤アッセイを用いて定量した。IL‐6阻害の代表的結果が表IVで示されている。
化合物を、Theisen-Popp et al.,(Agents Actions,42,50-55,1994)に従い、ラットアジュバント誘導性関節炎でそれらの活性についてアッセイした。6〜7週齢Wistarラットを体重測定し、印を付け、各群に割り当てた〔関節炎が誘導されなかった陰性コントロール群(非アジュバントコントロール)、ビヒクル処理関節炎コントロール群、試験物質処理関節炎群〕。右後足蹠の足裏下領域への、液体パラフィンに懸濁されたMycobacterium butyricum(Difco)の注射により、アジュバント誘導性関節炎を誘導した(J.Pharmacol.Exp.Ther.,284,714,1998)。体重、中側面足蹠容積をすべての群で様々な日(0、4、14、21日目)に測定した。試験化合物またはビヒクルをアジュバントの注射後から経口投与し始め、21日間続けた。21日目に、体重および左右両後足蹠の容積、脾臓および胸腺重量を測定した。加えて、両後足蹠のX線写真をとり、脛‐足根骨関節の完全性を評価した。膝関節下の後肢を摘出し、1%ホルマリン塩水で固定した。実験の最後に、血漿サンプルをサイトカイン、インターロイキンおよびプロスタグランジンについて分析した。胃で病変の存在または不在も観察した。
‘時間’で反復測定しながら、2要因(‘処理’および‘時間’)分散分析を体重および足容積の変化%に適用した。事後ダネット検定を行い、ビヒクルに対する処理の効果を比較した。一元分散分析を胸腺および脾臓重量に適用し、次いでダネット検定により、ビヒクルに対する処理の効果を比較した。4、14および21日目における足容積の抑制%に関する用量‐応答曲線を、非直線最小二乗回帰法を用いて、4パラメーターロジスティック関数により当てはめた。ID50はビヒクルから50%減少に相当する用量として定義され、適用4パラメーター式から補間により求めた。
本発明の化合物を抗癌活性についても試験した。各試験化合物を8臓器から得られた一連の60種ヒト細胞系に対してスクリーニングした。細胞懸濁物を具体的細胞タイプに応じて希釈し、標的細胞をある密度(細胞増殖特性に基づき5000〜40,000細胞/ウェル)で96ウェルマイクロタイタープレート中へ加えた。接種後、安定化のため37℃で24時間プレインキュベートした。所定試験濃度の希釈液を、2回にわけて、ゼロ時にマイクロタイタープレートウェルへ100μLずつ加えた。通常、試験化合物を5回の10倍希釈で評価した。試験に用いられた最高ウェル濃度は10−4Mである。次いで、細胞を5%CO2雰囲気および100%湿度中試験化合物の存在下で更に48時間インキュベートした。インキュベート終了後、付着細胞をトリクロロ酢酸によりプレートへ固定させた。3〜5回の洗浄後、細胞層をタンパク質色素Sulforhodamine Bで処理した。次いで、タンパク質質量に比例する光学濃度を、515nmの波長で分光光度計プレートリーダーにより読み取った。抗癌活性は図1〜4で示されている。
Claims (36)
- 式(I)の新規ピリミドン誘導体:
- AおよびBで表わされる環系が、フェニル、ナフチル、ピロリジニル、モルホリニル、チオモルホリニル、ピペリジニル、ピペラジニル、ピリジル、チエニル、フリル、ピロリル、オキサゾリル、チアゾリル、イミダゾリル、ピラゾリル、オキサジアゾリル、チアジアゾリル、テトラゾリル、ピリミジニル、ベンゾピラニル、ベンゾフラニル、ベンゾイミダゾリル、ベンゾオキサゾリル、ベンゾチアゾリル、ベンゾピロリル、ベンゾオキサジアゾリル、ベンゾチアジアゾリル、キノリニル、イソキノリニル、ベンゾチエニル、ベンゾフラニル、インドリルから選択される、請求項1に記載の式(I)の新規ピリミドン誘導体。
- 5‐シアノ‐4‐メチルチオ‐1‐(4‐メチルチオフェニル)‐2‐フェニル‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐4‐メチルチオ‐1‐(4‐メチルチオフェニル)‐2‐(4‐トリフルオロメチルフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐1‐(4‐フルオロフェニル)‐4‐メチルチオ‐2‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐1‐(4‐メチルフェニル)‐2‐(4‐メチルスルホニルフェニル)‐4‐メチルチオ‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐1‐(4‐フルオロフェニル)‐2‐(4‐メチルスルホニルフェニル)‐4‐メチルチオ‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐1‐(4‐メチルフェニル)‐4‐メチルスルホニル‐2‐(4‐メチルスルホニルフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐1‐(4‐メチルフェニル)‐4‐メチルスルホニル‐2‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐1‐(4‐メチルフェニル)‐4‐メチルチオ‐2‐(4‐スルファモイルフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐2‐(4‐フルオロフェニル)‐1‐(4‐メチルチオフェニル)‐4‐メチルチオ‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐2‐(4‐フルオロフェニル)‐1‐(4‐メチルスルホニルフェニル)‐4‐メチルチオ‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐2‐(4‐フルオロフェニル)‐4‐メチルチオ‐1‐(4‐スルファモイルフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐2‐(4‐クロロフェニル)‐4‐メチルチオ‐1‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐シアノ‐1‐(4‐メチルフェニル)‐4‐メチルチオ‐2‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
2‐(4‐メタンスルホニルフェニル)‐4‐メチルスルファニル‐6‐オキソ‐1‐(4‐メチルフェニル)‐1,6‐ジヒドロピリミジン‐5‐カルボン酸;
2‐(4‐メタンスルファニルフェニル)‐4‐メチルスルファニル‐6‐オキソ‐1‐(4‐メチルフェニル)‐1,6‐ジヒドロピリミジン‐5‐カルボン酸;
2‐(4‐フルオロフェニル)‐4‐メチルスルファニル‐6‐オキソ‐1‐(4‐メチルフェニル)‐1,6‐ジヒドロピリミジン‐5‐カルボン酸;
5‐カルボキシ‐4‐メチルチオ‐1‐(4‐メチルチオフェニル)‐2‐フェニル‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐カルバモイル‐2‐(4‐フルオロフェニル)‐4‐メチルチオ‐1‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
5‐クロロ‐2‐(4‐クロロフェニル)‐4‐メチルチオ‐1‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
2‐(4‐クロロフェニル)‐4‐メチルチオ‐1‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
2‐(4‐クロロフェニル)‐1‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
1‐(4‐メチルフェニル)‐4‐メチルチオ‐2‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
1‐(4‐メチルフェニル)‐2‐(4‐メチルチオフェニル)‐1,6‐ジヒドロピリミジン‐6‐オン;
4‐(5‐シアノ‐4‐メチルチオ‐6‐オキソ‐2‐フェニル‐6H‐ピリミジン‐1‐イル)ベンゼンスルホンアミド;
4‐(5‐シアノ‐4‐メチルチオ‐6‐オキソ‐2‐(4‐メチルフェニル)‐6H‐ピリミジン‐1‐イル)ベンゼンスルホンアミド;および
4‐(5‐カルボキシ‐4‐メチルチオ‐6‐オキソ‐2‐フェニル‐6H‐ピリミジン‐1‐イル)ベンゼンスルホンアミド
から選択される、請求項1に記載の式(I)の新規ピリミドン誘導体。 - 式(I)の新規ピリミドン誘導体:
酸性条件下で適切な溶媒を用いて、式(I)の化合物を製造するために、下記式(Ia)の化合物:
- 式(I)の新規ピリミドン誘導体:
酸性条件下で適切な溶媒を用いて、式(I)の化合物を製造するために、下記式(Ic)の化合物:
- 式(Ib)の化合物:
- 式(Id)の化合物:
- 錠剤、カプセル、粉末、シロップ、溶液または懸濁液の形態をとる、請求項14に記載の医薬組成物。
- 請求項3に記載された化合物および製薬上許容されるキャリア、希釈物、賦形剤または溶媒和物を含んでなる、医薬組成物。
- 錠剤、カプセル、粉末、シロップ、溶液または懸濁液の形態をとる、請求項16に記載の医薬組成物。
- リウマチ様関節炎;骨粗鬆症;多発性骨髄腫;ブドウ膜炎;急性および慢性骨髄性白血病;虚血性心疾患;アテローム性動脈硬化症;癌;虚血誘導性細胞障害;膵臓β細胞破壊;骨関節炎;リウマチ様脊椎炎;痛風性関節炎;炎症性腸疾患;成人呼吸窮迫症候群(ARDS);乾癬;クローン病;アレルギー性鼻炎;潰瘍性大腸炎;アナフィラキシー;接触皮膚炎;喘息;筋肉変性;悪液質;I型およびII型糖尿病;骨吸収疾患;虚血再灌流傷害;アテローム性動脈硬化症;脳外傷;多発性硬化症;大脳マラリア;敗血症;敗血症性ショック;毒ショック症候群;感染による発熱および筋肉痛;HIV‐1、HIV‐2、HIV‐3、サイトメガロウイルス(CMV)、インフルエンザ、アデノウイルス、ヘルペスウイルス(HSV‐1、HSV‐2を含む)および帯状疱疹ウイルス感染の予防または治療のための、請求項1に記載された式(I)の化合物の使用。
- リウマチ様関節炎;骨粗鬆症;多発性骨髄腫;ブドウ膜炎;急性および慢性骨髄性白血病;虚血性心疾患;アテローム性動脈硬化症;癌;虚血誘導性細胞障害;膵臓β細胞破壊;骨関節炎;リウマチ様脊椎炎;痛風性関節炎;炎症性腸疾患;成人呼吸窮迫症候群(ARDS);乾癬;クローン病;アレルギー性鼻炎;潰瘍性大腸炎;アナフィラキシー;接触皮膚炎;喘息;筋肉変性;悪液質;I型およびII型糖尿病;骨吸収疾患;虚血再灌流傷害;アテローム性動脈硬化症;脳外傷;多発性硬化症;大脳マラリア;敗血症;敗血症性ショック;毒ショック症候群;感染による発熱および筋肉痛;HIV‐1、HIV‐2、HIV‐3、サイトメガロウイルス(CMV)、インフルエンザ、アデノウイルス、ヘルペスウイルス(HSV‐1、HSV‐2を含む)および帯状疱疹ウイルス感染の予防または治療のための、請求項3に記載された化合物の使用。
- リウマチ様関節炎、パジェット病、骨粗鬆症、多発性骨髄腫、ブドウ膜炎、急性または慢性骨髄性白血病、膵臓β細胞破壊、骨関節炎、リウマチ様脊椎炎、痛風性関節炎、炎症性腸疾患、成人呼吸窮迫症候群(ARDS)、乾癬、クローン病、アレルギー性鼻炎、潰瘍性大腸炎、アナフィラキシー、接触皮膚炎、喘息、筋肉変性、悪液質、ライター症候群、I型糖尿病、II型糖尿病、骨吸収疾患、移植片対宿主反応、アルツハイマー病、発作、心筋梗塞、虚血再灌流傷害、アテローム性動脈硬化症、脳外傷、多発性硬化症、大脳マラリア、敗血症、敗血症性ショック、毒ショック症候群、HIV‐1、HIV‐2、HIV‐3、サイトメガロウイルス(CMV)、インフルエンザ、アデノウイルス、ヘルペスウイルスまたは帯状疱疹ウイルス感染による発熱、筋肉痛の予防または治療のための、請求項14に記載された組成物の使用。
- TNF‐αおよびIL‐1の一方または双方の血漿濃度を低下させるための、請求項1に記載された式(I)の化合物の使用。
- TNF‐αおよびIL‐1の一方または双方の血漿濃度を低下させるための、請求項3に記載された化合物の使用。
- TNF‐αおよびIL‐1の一方または双方の血漿濃度を低下させるための、請求項14に記載された組成物の使用。
- IL‐6およびIL‐8の一方または双方の血漿濃度を低下させるための、請求項1に記載された式(I)の化合物の使用。
- IL‐6およびIL‐8の一方または双方の血漿濃度を低下させるための、請求項3に記載された化合物の使用。
- IL‐6およびIL‐8の一方または双方の血漿濃度を低下させるための、請求項14に記載された組成物の使用。
- 痛み障害の予防または治療のための、請求項1に記載された式(I)の化合物の使用。
- 痛み障害の予防または治療のための、請求項3に記載された化合物の使用。
- 痛み障害の予防または治療のための、請求項14に記載された組成物の使用。
- プロスタグランジン産生を減少させるための、請求項1に記載された式(I)の化合物の使用。
- プロスタグランジン産生を減少させるための、請求項3に記載された化合物の使用。
- プロスタグランジン産生を減少させるための、請求項14に記載された組成物の使用。
- シクロオキシゲナーゼ酵素活性を減少させるための、請求項1に記載された式(I)の化合物の使用。
- シクロオキシゲナーゼ酵素がCOX‐2またはCOX‐3である、請求項33に記載の化合物の使用。
- シクロオキシゲナーゼ酵素活性を減少させるための、請求項3に記載された化合物の使用。
- シクロオキシゲナーゼ酵素がCOX‐2またはCOX‐3である、請求項35に記載の化合物の使用。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2011510967A (ja) * | 2008-02-01 | 2011-04-07 | オーキッド リサーチ ラボラトリーズ リミティド | 新規複素環化合物 |
JP2019500323A (ja) * | 2015-11-05 | 2019-01-10 | セルジーン クオンティセル リサーチ,インク. | リジン特異的デメチラーゼ−1の阻害剤を含む組成物 |
Families Citing this family (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8293530B2 (en) | 2006-10-17 | 2012-10-23 | Carnegie Mellon University | Method and apparatus for manufacturing plasma based plastics and bioplastics produced therefrom |
US8529956B2 (en) | 2002-03-18 | 2013-09-10 | Carnell Therapeutics Corporation | Methods and apparatus for manufacturing plasma based plastics and bioplastics produced therefrom |
CA2513414A1 (en) * | 2002-04-10 | 2003-10-16 | Orchid Chemicals & Pharmaceuticals Limited | Pyrimidinedione derivatives useful for the treatment of inflammation and immunological diseases |
ATE505462T1 (de) * | 2002-07-22 | 2011-04-15 | Orchid Res Lab Ltd | Neue biologischaktive molekü le |
WO2004029204A2 (en) * | 2002-09-27 | 2004-04-08 | Merck & Co., Inc. | Substituted pyrimidines |
JP4661163B2 (ja) * | 2003-11-04 | 2011-03-30 | 住友化学株式会社 | 6−アリールピリミジノン化合物及びその用途 |
CA2547209A1 (en) * | 2003-12-19 | 2005-07-07 | Merck & Co., Inc. | Mitotic kinesin inhibitors |
CN1560035A (zh) * | 2004-03-12 | 2005-01-05 | 沈阳药科大学 | 5-羟基吲哚-3-羧酸脂类衍生物 |
WO2005108376A1 (en) * | 2004-05-06 | 2005-11-17 | Smithkline Beecham Corporation | Calcilytic compounds |
NZ552984A (en) | 2004-07-02 | 2010-06-25 | Corcept Therapeutics Inc | Modified pyrimidine glucocorticoid receptor modulators |
WO2006102112A2 (en) * | 2005-03-24 | 2006-09-28 | Janssen Pharmaceutica N.V. | Prokineticin 1 receptor |
EP1866290B1 (en) * | 2005-03-24 | 2013-05-01 | Janssen Pharmaceutica N.V. | Prokineticin 1 receptor antagonists |
WO2006129181A2 (en) * | 2005-06-03 | 2006-12-07 | Orchid Research Laboratories Limited | Preparation of 4-pyrimidone derivatives for treating inflammatory diseases |
WO2007007161A2 (en) * | 2005-07-08 | 2007-01-18 | Orchid Research Laboratories Limited | Novel bio-active derivatives |
WO2007083182A2 (en) | 2006-01-19 | 2007-07-26 | Orchid Research Laboratories Limited | Novel heterocycles |
US7863446B2 (en) | 2006-01-19 | 2011-01-04 | Orchid Research Laboratories Limited | Heterocycles |
US8529959B2 (en) | 2006-10-17 | 2013-09-10 | Carmell Therapeutics Corporation | Methods and apparatus for manufacturing plasma based plastics and bioplastics produced therefrom |
CZ303564B6 (cs) * | 2007-07-09 | 2012-12-12 | Katchem Spol. S R. O. | Zpusob výroby polyamidového sorbentu pro stabilizaci nápoju a polyamidový sorbent |
KR101732732B1 (ko) * | 2011-02-01 | 2017-05-08 | 광주과학기술원 | 신규한 우라실 유도체 및 이의 용도 |
AU2012231265B2 (en) | 2011-03-18 | 2016-07-07 | Corcept Therapeutics, Inc. | Pyrimidine cyclohexyl glucocorticoid receptor modulators |
JP5731718B2 (ja) | 2011-11-11 | 2015-06-10 | ファイザー・インク | 2−チオピリミジノン |
MA42035A (fr) | 2015-05-05 | 2018-03-14 | Pfizer | 2-thiopyrimidinones |
WO2019055832A1 (en) * | 2017-09-15 | 2019-03-21 | The Regents Of The University Of California | COMPOSITIONS AND METHODS FOR INHIBITING N-SMASE2 |
WO2019236487A1 (en) | 2018-06-04 | 2019-12-12 | Corcept Therapeutics Incorporated | Pyrimidine cyclohexenyl glucocorticoid receptor modulators |
US11903945B2 (en) | 2019-12-11 | 2024-02-20 | Corcept Therapeutics Incorporated | Methods of treating antipsychotic-induced weight gain with miricorilant |
CA3182272A1 (en) | 2020-05-06 | 2021-11-11 | Corcept Therapeutics Incorporated | Polymorphs of pyrimidine cyclohexyl glucocorticoid receptor modulators |
CA3202353A1 (en) | 2020-12-21 | 2022-06-30 | Jeffrey Mark Dener | Method of preparing pyrimidine cyclohexyl glucocorticoid receptor modulators |
WO2024119067A1 (en) | 2022-12-02 | 2024-06-06 | Neumora Therapeutics, Inc. | Methods of treating neurological disorders |
Family Cites Families (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2433489A (en) * | 1944-01-27 | 1947-12-30 | Boots Pure Drug Co Ltd | Production of amidines |
DE1445038A1 (de) * | 1961-08-16 | 1969-02-13 | Hoechst Ag | Verfahren zur Herstellung von Oxopyrimidinen |
NL6513320A (ja) * | 1965-10-14 | 1967-04-17 | ||
DE2126148A1 (en) * | 1971-05-26 | 1972-12-07 | Farbenfabriken Bayer Ag, 5090 Leverkusen | Prepn of uracil derivs - useful as plant - protection agents and their inters |
DE2142317A1 (de) * | 1971-08-24 | 1973-03-01 | Bayer Ag | Hypnotisches mittel |
EP0102318B1 (de) * | 1982-07-08 | 1987-01-14 | Ciba-Geigy Ag | Herstellung von beta-Amino-alpha,beta-ungesättigten Carbonsäureestern |
US4625030A (en) * | 1984-05-23 | 1986-11-25 | Union Carbide Corporation | Potentiated nickel catalysts for amination |
DE3605002A1 (de) * | 1986-02-18 | 1987-08-20 | Bayer Ag | Phosphorsaeureester |
US5470975A (en) * | 1990-10-16 | 1995-11-28 | E.R. Squibb & Sons, Inc. | Dihydropyrimidine derivatives |
US5166137A (en) * | 1991-03-27 | 1992-11-24 | Nobipols Forskningsstiftelse | Guluronic acid polymers and use of same for inhibition of cytokine production |
FR2676734B1 (fr) * | 1991-05-23 | 1995-05-19 | Roussel Uclaf | Nouveaux derives de la pyrimidine, leur procede de preparation, les nouveaux intermediaires obtenus, leur application a titre de medicaments et les compositions pharmaceutiques les renfermant. |
US5726124A (en) * | 1992-07-17 | 1998-03-10 | Rohm And Haas Company | 2-arylpyrimidines and herbicidal use thereof |
US5300477A (en) * | 1992-07-17 | 1994-04-05 | Rohm And Haas Company | 2-arylpyrimidines and herbicidal use thereof |
US5616601A (en) * | 1994-07-28 | 1997-04-01 | Gd Searle & Co | 1,2-aryl and heteroaryl substituted imidazolyl compounds for the treatment of inflammation |
US5527546A (en) * | 1994-08-10 | 1996-06-18 | Bayer Corporation | Human interleukin 6 inhibitor |
US6004813A (en) * | 1995-05-11 | 1999-12-21 | Applied Research Systems Ars Holding N.V. | Il-6 activity inhibitor |
DK0880504T3 (da) * | 1996-01-26 | 2003-07-21 | Searle & Co | Heterocyclosubstituerede imidazoler til behandling af inflammation |
JP2000504730A (ja) * | 1996-02-15 | 2000-04-18 | ケンブリッジ・ニューロサイエンス・インコーポレーテッド | 製薬学的活性物質及び使用方法 |
JP2000506532A (ja) * | 1996-03-13 | 2000-05-30 | スミスクライン・ビーチャム・コーポレイション | サイトカイン介在疾患の治療にて有用な新規ピリミジン化合物 |
JP2002514195A (ja) * | 1996-12-05 | 2002-05-14 | アムジエン・インコーポレーテツド | 置換ピリミジン化合物およびそれの使用 |
US6410729B1 (en) * | 1996-12-05 | 2002-06-25 | Amgen Inc. | Substituted pyrimidine compounds and methods of use |
US6096753A (en) * | 1996-12-05 | 2000-08-01 | Amgen Inc. | Substituted pyrimidinone and pyridone compounds and methods of use |
CZ9902016A3 (cs) * | 1996-12-05 | 1999-11-17 | Amgen Inc. | Substituované pyrimidinonové a pyridonové sloučeniny a způsoby jejich použití |
KR100643419B1 (ko) * | 1998-03-27 | 2006-11-10 | 얀센 파마슈티카 엔.브이. | Hiv를 억제하는 피리미딘 유도체 |
US6525036B2 (en) * | 2000-01-06 | 2003-02-25 | Merck & Co., Inc. | Compounds and compositions as protease inhibitors |
DE60107835T2 (de) * | 2000-04-26 | 2005-12-22 | Eisai Co., Ltd. | Medizinische zusammensetzungen zur förderung der aktivierung der eingeweide |
WO2002006242A2 (en) * | 2000-07-18 | 2002-01-24 | Neurogen Corporation | 5-substituted 2-aryl-4-pyrimidinones |
-
2003
- 2003-04-09 US US10/409,161 patent/US20030232813A1/en not_active Abandoned
- 2003-04-09 US US10/409,045 patent/US20030225075A1/en not_active Abandoned
- 2003-04-09 AU AU2003216585A patent/AU2003216585A1/en not_active Abandoned
- 2003-04-09 AU AU2003216591A patent/AU2003216591A1/en not_active Abandoned
- 2003-04-09 WO PCT/IB2003/001287 patent/WO2003084937A2/en not_active Application Discontinuation
- 2003-04-09 WO PCT/IB2003/001305 patent/WO2003084936A2/en not_active Application Discontinuation
- 2003-04-10 WO PCT/IB2003/001306 patent/WO2003084938A2/en active Application Filing
- 2003-04-10 AU AU2003216592A patent/AU2003216592A1/en not_active Abandoned
- 2003-04-10 AU AU2003216586A patent/AU2003216586A1/en not_active Abandoned
- 2003-04-10 WO PCT/IB2003/001289 patent/WO2003084935A2/en not_active Application Discontinuation
- 2003-04-10 EP EP03712500A patent/EP1492774A2/en not_active Withdrawn
- 2003-04-10 JP JP2003582135A patent/JP2005535570A/ja active Pending
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2011510967A (ja) * | 2008-02-01 | 2011-04-07 | オーキッド リサーチ ラボラトリーズ リミティド | 新規複素環化合物 |
JP2019500323A (ja) * | 2015-11-05 | 2019-01-10 | セルジーン クオンティセル リサーチ,インク. | リジン特異的デメチラーゼ−1の阻害剤を含む組成物 |
JP6995043B2 (ja) | 2015-11-05 | 2022-02-04 | セルジーン クオンティセル リサーチ,インク. | リジン特異的デメチラーゼ-1の阻害剤を含む組成物 |
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AU2003216591A1 (en) | 2003-10-20 |
AU2003216586A8 (en) | 2003-10-20 |
AU2003216586A1 (en) | 2003-10-20 |
WO2003084937A2 (en) | 2003-10-16 |
WO2003084937A3 (en) | 2004-06-03 |
AU2003216585A8 (en) | 2003-10-20 |
WO2003084938A2 (en) | 2003-10-16 |
WO2003084936A8 (en) | 2004-01-15 |
AU2003216591A8 (en) | 2003-10-20 |
EP1492774A2 (en) | 2005-01-05 |
US20030232813A1 (en) | 2003-12-18 |
WO2003084936A2 (en) | 2003-10-16 |
US20030225075A1 (en) | 2003-12-04 |
WO2003084935A2 (en) | 2003-10-16 |
WO2003084935A3 (en) | 2004-05-21 |
AU2003216585A1 (en) | 2003-10-20 |
WO2003084938A3 (en) | 2004-02-05 |
AU2003216592A8 (en) | 2003-10-20 |
WO2003084936A3 (en) | 2004-03-18 |
AU2003216592A1 (en) | 2003-10-20 |
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