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Indazol compound for inhibiting protein kinase and medicine composition and their application

A technology of compounds and prodrugs, applied in the field of diaminothiazole compounds

Inactive Publication Date: 2004-05-12
AGOURON PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] However, there remains a need for small molecule compounds that are easily synthesized and that effectively inhibit one or more CDKs or CDK / cell cycle regulatory protein complexes

Method used

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  • Indazol compound for inhibiting protein kinase and medicine composition and their application
  • Indazol compound for inhibiting protein kinase and medicine composition and their application
  • Indazol compound for inhibiting protein kinase and medicine composition and their application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0147] Example 1(a): 3-[E-2-(3,4-dimethoxy-phenyl)vinyl]-6-(3-methoxy-4-hydroxy-phenyl)-1H- Indazole

[0148]

[0149]3-[E / Z-2-(3,4-dimethoxy-phenyl)vinyl]-6-[3-methoxy-4-(methoxymethoxy)phenyl]- 1H-Indazole (-205 mg, 0.461 mmol (theoretical)) was dissolved in tetrahydrofuran (THF, 10 ml) and then treated with water (10 ml) and trifluoroacetic acid (TFA, 20 ml). The reaction mixture was stirred at 23°C for 30 minutes. The mixture was diluted with toluene and the volatiles were removed under reduced pressure (30 mmHg, 35°C) to give a concentrated volume of ~5ml. Additional toluene (100ml) was then added and the mixture concentrated under reduced pressure to give crude material still containing some acid. The material was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic material was separated, dried over sodium sulfate, decanted and concentrated under reduced pressure. The residue, the isomer of the olefin (-185 mg, 0.461 mmol (theoretical))...

Embodiment 2

[0177] Example 2(a): 3-(naphthalen-2-yl)-6-(3-methoxy-4-hydroxy-phenyl)-1H-indazole

[0178]

[0179]Dissolve 6-(4-benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1H-indazole (25mg, 0.055mmol) in ethyl acetate (2ml), benzene (2ml ) and methanol (2ml). Palladium-coated activated carbon (25 mg, 10% wt) was added to the solution, and the reaction vessel was pumped / blown with hydrogen for 5 cycles. The reaction mixture was stirred at 23°C for 3 days and filtered through celite. Concentration and purification by silica gel chromatography afforded 3-(naphthalen-2-yl)-6-(3-methoxy-4-hydroxy-phenyl)-1H-indazole (8 mg, 40%): 1 H NMR (CDCl 3 )δ10.3(bs, 1H), 8.50(s, 1H), 8.20(d, 1H, J=8Hz), 7.98(d, 1H, J=8Hz), 7.90(m, 1H), 7.7-6.8( m, 9H), 3.98 (s, 3H). MS(ES) [M+H] / z Calcd 367, Found 367, [m-H] / z Calc'd 365, Found 365.

[0180] The starting materials were prepared as follows:

[0181] (i)

[0182]

[0183] 2-Bromnaphthalene (117mg, 0.564mmol, 6.0eq) was dissolved in THF (0.75...

Embodiment 3

[0200] Example 3: 3-(1H-indol-2-yl)-6-(,3-methoxy-4-hydroxy-phenyl)-1H-indazole

[0201]

[0202] According to the method described in Example 1 (a), 3-(1H-benzimidazol-2-yl)-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H- Indazole was converted to 4-[3-(1H-benzimidazol-2-yl)-1H-indazol-6-yl]-2-methoxyphenol (5.3 mg, 28%). HRMS (FAB) [m+H] / z calcd. 357.1351, found 357.1349.

[0203] The starting materials were prepared as follows:

[0204]

[0205] 6-(3-Methoxy-4-methoxymethoxy-phenyl)-1H-indazole-3-carbaldehyde (step (vi) of Example 1(a)) (20 mg, 0.064 mmol, 1 equiv) was dissolved in degassed 1:1 MeOH-water (0.7ml) and treated with acetic acid (19 μl, 5 equiv), 1,2-phenylenediamine (8.3 mg, 1.2 equiv) and ketone acetate (II ) (18 mg, 1.4 equivalents) treatment. The mixture was stirred for 30 minutes, diluted with ethanol (3ml) and water (2ml), washed with SH 2 Air flow was bubbled for 3 minutes to obtain a black precipitate. The mixture was stirred for 12 hours. The mi...

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Abstract

Indazole compounds that modulate and / or inhibit the activity of certain protein kinases are described. These compounds and pharmaceutical compositions containing them are capable of mediating tyrosine kinase signal transduction and thereby modulate and / or inhibit unwanted cell proliferation. The invention is also directed to the therapeutic or prophylactic use of pharmaceutical compositions containing such compounds, and to methods of treating cancer and other disease states associated with unwanted angiogenesis and / or cellular proliferation, such as diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, and psoriasis, by administering effective amounts of such compounds.

Description

[0001] This application is a divisional application of Chinese patent application CN 00809821.2 entitled "Indazole Compounds and Pharmaceutical Compositions Inhibiting Protein Kinase and Their Applications". technical field [0002] The present invention relates to diaminothiazole compounds that regulate and / or inhibit the activity of certain protein kinases, and pharmaceutical compositions containing these compounds. The present invention also relates to the therapeutic or prophylactic use of these compounds and compositions, and to methods of treating cancer and other diseases associated with undesirable angiogenesis and / or cell proliferation by administering an effective amount of these compounds. Background technique [0003] Protein kinases are a class of enzymes that catalyze the phosphorylation of hydroxyl groups on specific tyrosine, serine, or threonine residues in proteins. Typically, this phosphorylation drastically interferes with protein function, and protein ki...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/416A61K31/4178A61K31/4184A61K31/4188A61K31/4196A61K31/4245A61K31/427A61K31/437A61K31/4439A61K31/444A61K31/454A61K31/4709A61K31/496A61K31/5377A61P3/10A61P9/10A61P17/06A61P19/02A61P27/02A61P27/06A61P29/00A61P35/00A61P43/00C07D209/18C07D231/00C07D231/56C07D401/04C07D401/06C07D401/12C07D401/14C07D403/04C07D403/12C07D403/14C07D405/04C07D405/06C07D405/14C07D409/06C07D409/12C07D409/14C07D413/12C07D413/14C07D417/06C07D417/12C07D417/14C07D471/04C07D491/04C07D491/056
CPCC07D417/06C07D209/18C07D471/04C07D403/04C07D401/06C07D405/04C07D409/14C07D413/12C07D409/06C07D405/06C07D401/14C07D401/12C07D417/14C07D231/56C07D491/04C07D405/14C07D417/12C07D403/12C07D401/04A61P17/00A61P17/06A61P19/00A61P19/02A61P27/00A61P27/02A61P27/06A61P29/00A61P3/00A61P35/00A61P43/00A61P9/00A61P9/10A61P3/10
Inventor R·S·卡尼亚S·L·本德A·J·博哈特J·F·布拉加扎S·J·克里普斯华烨M·D·约翰逊T·O·小约翰逊H·T·卢C·L·帕尔梅S·H·赖希A·M·坦皮齐克-拉塞尔滕敏C·托马斯M·D·瓦尼M·B·沃雷斯M·R·柯林斯
Owner AGOURON PHARMA INC
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