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Heterocyclic cyclopamine analogs and methods of use thereof

A technology of drugs and compounds, applied in the field of cyclopamine analogs

Inactive Publication Date: 2014-07-23
INFINITY DISCOVERY INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although inhibitors of the hedgehog pathway have been identified, there remains a need to identify more potent inhibitors of the hedgehog pathway

Method used

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  • Heterocyclic cyclopamine analogs and methods of use thereof
  • Heterocyclic cyclopamine analogs and methods of use thereof
  • Heterocyclic cyclopamine analogs and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0194]

[0195] Step A

[0196]

[0197] Cyclopamine 2 (5.02 g, 12.2 mmol, 1.0 equiv) was dissolved in anhydrous pyridine (25 mL). DMAP (300 mg, 2.44 mmol, 0.2 equiv) and triethylamine (5.5 mL, 39.1 mmol, 3.2 equiv) were added, followed by BtO-Cbz (10.5 g, 39.1 mmol, 3.2 equiv) and the mixture was heated at 40 °C for 2 h . The mixture was cooled to room temperature, treated with 30 mL of water, heated to give a homogeneous solution, and cooled to room temperature. The white precipitate formed was collected by filtration, the filter cake was washed with water (3X 50 mL) and air dried to give 9.53 g of crude product which was crystallized from toluene / heptane (1:9, 70 mL) to give 6.75 g of the desired product.

[0198] Step B:

[0199]

[0200]To a solution of diethylzinc (572 mg, 482 μL, 4.63 mmol, 3 equiv) in DCM (5.0 mL) was added bis(2,6-dimethylphenyl)phosphoric acid (1.42 g, 4.63 mmol) at -20 °C , 3 eq) in DCM (15 mL) while keeping the reaction temperature bel...

Embodiment 2

[0221]

[0222] A solution of compound 9 (100.0 mg, 0.17 mmol, 1.0 equiv) in ethanol (4 mL) was treated with hydrazine (16 mg, 0.34 mmol, 2.0 equiv) and heated at 70° C. for 0.5 h. The mixture was concentrated in vacuo and purified by flash silica gel chromatography (20→60% ether / hexanes) to give the protected pyrazole (72.0 mg) as a white solid.

[0223] In a flask equipped with a stir bar and rubber septum, the product carbamate isoxazole was dissolved in EtOAc (7ml). The solution was bubbled with nitrogen and 10% Pd / C (wet, Degussa type E101, Aldrich, 25 mg) was added. The mixture was bubbled with nitrogen, then hydrogen and stirred at room temperature for 2 hours. The mixture was then bubbled with nitrogen, filtered through a 0.45 μm polyethylene membrane, and concentrated to a clear oil. The oil was purified by flash chromatography on silica gel (0.5% ammonium hydroxide / 2→10% MeOH / DCM), concentration of the pure fractions gave an oil, lyophilization from 7% water / ter...

Embodiment 3

[0225]

[0226] Compound 11 was synthesized according to the method described in Example 2, using methylhydrazine instead of hydrazine. ([M+H] = 464.7 m / z).

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Abstract

The present invention relates to steroidal alkaloid-like compounds useful in the treatment of diseases associated with the hedgehog pathway, especially cancer.

Description

technical field [0001] The present invention relates generally to cyclopamine analogs, pharmaceutical compositions thereof, and methods of using such analogs and compositions. These compounds and compositions are useful in the treatment of hedgehog mediated diseases such as cancer and psoriasis. Background technique [0002] Hedgehog polypeptides are secreted proteins that serve as signaling ligands of the hedgehog pathway. Three different forms of the hedgehog protein are found in humans: Sonic hedgehog (Shh), Desert hedgehog (Dhh) and Indian hedgehog (Ihh). Sonic hedgehog is the most prevalent hedgehog member and the best characterized hedgehog family ligand in mammals. Before secretion, Shh undergoes intramolecular cleavage and lipid modification reactions. This lipid-modified peptide is responsible for signaling activities. [0003] In some cancers, inhibiting the hedgehog pathway inhibits tumor growth. For example, anti-hedgehog antibodies have been shown to antago...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/04C07D491/10A61K31/4747A61K31/675A61K31/4355
CPCC07D491/14C07D513/14A61P35/00A61P35/02A61P43/00C07D491/04A61K31/4355A61K31/675
Inventor A·C·卡斯特罗M·J·格罗甘M·特伦布莱
Owner INFINITY DISCOVERY INC
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