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Compounds and compositions as HEDGEHOG signaling pathway modulators

A compound, selected technology, applied in the direction of drug combination, active ingredients of heterocyclic compounds, organic chemistry, etc.

Inactive Publication Date: 2009-08-05
IRM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, aberrant activity of the Hedgehog signaling pathway (e.g. due to increased activation) may have pathological consequences

Method used

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  • Compounds and compositions as HEDGEHOG signaling pathway modulators
  • Compounds and compositions as HEDGEHOG signaling pathway modulators
  • Compounds and compositions as HEDGEHOG signaling pathway modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0136] R-[4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-[6-(2-methyl-morpholin-4-yl)-isoquinoline-1 - Yl]-amine

[0137]

[0138] Step 1. R-2-Methylmorpholine hydrochloride:

[0139]

[0140] N-benzylethanolamine (9.06g, 60mmol) and (R)-(+)-propylene oxide (6.96g, 99%, 120mmol) were stirred overnight at 45°C in a sealed test tube. The excess propylene oxide was evaporated in vacuum to obtain a diol residue, which was used directly in the next step.

[0141] The above diol was dissolved in dioxane (60 mL, anhydrous). KOH (10.08g, 180mmol, powder) and tris(3,6-dioxaheptyl)amine (200mg, 0.62mmol) were added, the mixture was cooled to 0°C, and then tosyl chloride (12.58g, 66mmol, In 60mL anhydrous dioxane). The reaction mixture was stirred at 0°C for 45 minutes, then it was warmed to room temperature and stirred for another 4 hours. The reaction mixture was filtered (removal of insoluble materials, KCl, KOH), and the filtrate was evaporated in vacuo. HCl (2N, 200 mL) was adde...

Embodiment 2

[0153] R-[4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-[2-(2-methyl-morpholin-4-yl)-quinoline-5- base]- amine

[0154]

[0155] Step 1. Add 3-chloroperoxybenzoic acid (1.35g, up to 77%, ~1.5eq.) to a solution of 5-iodoquinoline (1.02g, 4.00mmol) in dichloromethane (20mL) at 0°C. ), the mixture was stirred until the reaction was complete (monitored by LC-MS). Then mix the mixture in DCM (100mL) and 10% Na 2 CO 3 Partition between solutions (2×50 mL). The organic phase was further washed with HCl (1N, 50 mL), a small amount of unoxidized quinoline derivative was extracted, and dried over sodium sulfate.

[0156] Step 2. Dissolve the obtained N-oxide in anhydrous DCM (15mL), and then add POCl 3 (920mg, 1.5eq.). The mixture was refluxed for 1 hour, cooled to room temperature, and then poured into Na at 0°C 2 CO 3 Solution (10% aqueous solution, 80 mL). After 30 minutes, it was diluted with DCM (50 mL), the organic phase was separated and dried over sodium sulfate. After evapor...

Embodiment 3

[0160] R-[4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-[2-(2-methyl-morpholin-4-yl)-[1,6] Naphthyridine-5- Yl]-amine

[0161]

[0162] Step 1. At 0°C, add 3-methyl-6H-[1,6]naphthyridin-5-one (prepared according to literature [3], 2.40g, 15.0mmol) in DCM (50mL) solution at 0°C. Chloroperoxybenzoic acid (5.50g, up to 77%, ~1.6eq.). After stirring for 1 hour at 0°C, the reaction mixture was evaporated, and the residue was directly dry-loaded on a short silica gel column and purified by chromatography (DCM: methanol (methonal) = 100: 6) to obtain 6- Methyl-1-oxy-6H-[1,6]naphthyridin-5-one.

[0163] Step 2. Combine the obtained N-oxide (2.20g, 12.5mmol) with POCl 3 (8.0 mL) was heated at 105-110°C until all the N-oxide solid was dissolved. Then it was cooled and left at 60°C over the weekend. After cooling it to room temperature, pour it into Na at 0℃ 2 CO 3 Solution (10% aqueous solution, 700 mL). After 30 minutes, it was extracted with DCM (250 mL×2), the organic phase was sep...

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Abstract

The invention provides a method for modulating the activity of the hedgehog signaling pathway. In particular, the invention provides a method for inhibiting aberrant growth states resulting from phenotypes such as Ptc loss-of-function, hedgehog gain-of-function, smoothened gain-of-function or Gli gain-of-function, comprising contacting a cell with a sufficient amount of a compound of Formula I.

Description

[0001] Cross reference with related applications [0002] This application claims the priority of U.S. Provisional Patent Application No. 60 / 833,318 filed on July 25, 2006 and U.S. Provisional Patent Application No. 60 / 942,650 filed on June 7, 2007. The entire disclosures of these applications are incorporated herein by reference in their entire contents and all purposes. Technical field [0003] The present invention provides a method for regulating the activity of the hedgehog signaling pathway. In particular, the present invention provides a method for inhibiting an abnormal growth state caused by a phenotype such as loss of Ptc function, gain of hedgehog function, gain of smoothened function, or gain of Gli function, the method comprising contacting a cell with a sufficient amount of a compound of formula I . Background technique [0004] During embryonic development, the Hedgehog signaling pathway is essential for a variety of processes, such as the control of cell proliferat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/64C07D401/12C07D413/14C07D471/04A61K31/4709A61K31/4164A61K31/5377A61K31/55A61P35/00A61P17/06
Inventor 成岱韩东高文奇姜纪清潘士峰万咏勤
Owner IRM
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