CSF-1R inhibitors for treatment of cancer and bone diseases

A CSF-1R, disease technology, applied in bone diseases, urinary system diseases, cardiovascular system diseases, etc., can solve problems such as difficult design of selective inhibitors

Inactive Publication Date: 2010-08-11
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the active sites of 491 human protein kinase domains are highly conserved, making the design of selective inhibitors a formidable challenge (Cohen 2005)

Method used

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  • CSF-1R inhibitors for treatment of cancer and bone diseases
  • CSF-1R inhibitors for treatment of cancer and bone diseases
  • CSF-1R inhibitors for treatment of cancer and bone diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0482] 4-(2-((1R,2R)-2-hydroxycyclohexylamino)quinolin-6-yloxy)-N-methylpicolinamide

[0483]

[0484] The target compounds were prepared according to the general scheme below:

[0485] step 1

[0486]

[0487] step 2

[0488]

[0489] step 3

[0490]

[0491] Preparation of step 1.4-(2-hydroxyquinolin-6-yloxy)-N-methylpicolinamide

[0492] To a solution of 2,6-quinolinediol (500 mg, 3.10 mmol, 1.0 eq) in 10 mL of NMP was added Cs at room temperature 2 CO 3 (2.52g, 7.75mmol, 2.5eq.) and 4-chloro-N-methylpicolinamide (632mg, 3.72mmol, 1.2eq.), the reaction was stirred at 80°C for about 12 hours. Then, the reaction was quenched with water (about 100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo to give the title compound which was used in the next step without further purification. M+H=[296]

[0493] Step 2. Preparation of 4-(2-chloroquinolin-6-yloxy)-N-methylpicolinamide

[04...

Embodiment 2

[0498] 4-(2-((1R,2R)-2-hydroxycyclohexylamino)quinazolin-6-yloxy)-N-methylpyridinamide

[0499]

[0500] The target compounds were prepared according to the general scheme below:

[0501] Step 1.2-(Methylthio)quinazolin-6-ol

[0502]

[0503] To a solution of 2-chloro-6-methoxyquinazoline (500mg, 2.56mmol) in DMF was added NaSMe (630mg, 8.99mmol, 3.5eq) and the reaction was heated at 80°C for about 16 hours. Subsequently, the reaction was quenched with water (about 100 mL). The aqueous layer was neutralized with a few drops of HCl and extracted with EtOAc (3 x 100 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo to give the title compound which was used in the next step without further purification. M+H=[193.1]

[0504] Step 2. Preparation of N-methyl-4-(2-(methylthio)quinazolin-6-yloxy)pyridineamide

[0505]

[0506] Cs was added to a solution of 2-(methylthio)quinazolin-6-ol (250mg, 1.30mmol, 1.0eq) in 10mL of NMP at roo...

Embodiment 3

[0514] 4-(2-(cyclohexylmethylamino)quinazolin-6-yloxy)-N-methylpyridinamide

[0515]

[0516] The title compounds were prepared according to the general scheme below.

[0517] Step 1. Preparation of N-methyl-4-(2-(methylsulfonyl)quinazolin-6-yloxy)pyridineamide

[0518]

[0519] At 0° C., to a solution of N-methyl-4-(2-(methylthio)quinazolin-6-yloxy)pyridineamide (1.0 g, 3.06 mmol, 1.0 eq) in 40.5 mL of DCM was added 4.05 mLAcOH (10%) and the mixture was stirred for 15 minutes. Then mCPBA (1.59 g, 9.20 mmol, 3.0 eq) was added in small portions, and the reaction was stirred at room temperature for 1 hour. The reaction was quenched with water (100 mL) and extracted with more DCM (3 x 100 mL). The combined organic phases were washed with saturated sodium bicarbonate solution (1 x 100 mL) and brine (1 x 100 mL), dried over sodium sulfate and concentrated in vacuo to give the title compound as a white solid which was used directly in the next step without further purificat...

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Abstract

Disclosed herein are compounds and their oxides, esters, prodrugs, solvates, and pharmaceutically acceptable salts thereof, compositions of the compounds, either alone or in combination with at least one additional therapeutic agent, with a pharmaceutically acceptable carrier, and uses of the compounds, either alone or in combination with at least one additional therapeutic agent. The embodiments are useful for inhibiting cellular proliferation, inhibiting the growth and/or metathesis of tumors, treating or preventing cancer, treating or preventing degenerating bone diseases such as rheumatoid arthritis, and/or inhibiting molecules such as CSF-1R.

Description

Background of the invention [0001] The present invention relates to CSF-1R inhibitory compounds, their oxides, esters, prodrugs, solvates or pharmaceutically acceptable salts thereof. The invention also relates to compositions of said compounds and pharmaceutically acceptable carriers. In another aspect, the present invention relates to the use of said compounds, alone or in combination with at least one other therapeutic ingredient, for the prevention or treatment of cancer and other CSF-1R mediated diseases. [0002] current technology [0003] CSF-1R is the receptor for M-CSF (macrophage colony-stimulating factor, also known as CSF-1), which mediates the biological effects of this cytokine (Sherr 1985). The cloning of the colony-stimulating factor-1 receptor (also known as C-fms) was first described in Roussel et al., Nature 325:549.552 (1987). This publication demonstrates that CSF-1R has a transforming potential dependent on changes in the protein's C-terminal tail, in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/47A61K31/4184A61K31/4188A61K31/428A61K31/429A61K31/517A61P35/00A61P19/02A61P9/10A61P13/12
CPCA61K31/47A61K31/429A61K31/4188A61K31/4184A61K31/428A61K31/517A61P9/10A61P13/12A61P19/02A61P19/10A61P35/00A61P35/02A61P43/00
Inventor J·萨顿M·森齐克王为波
Owner NOVARTIS AG
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