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
View PDF0 Cites 6 Cited by
  • 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 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...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
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
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap