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Cyclopamine analogues and methods of use thereof

A kind of compound, technology of cycloalkyl, applied in cyclopamine analogue and its use field

Active Publication Date: 2007-09-26
INFINITY PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although initially promising, none of this family of compounds or their analogs have been successfully developed as anticancer drugs

Method used

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  • Cyclopamine analogues and methods of use thereof
  • Cyclopamine analogues and methods of use thereof
  • Cyclopamine analogues and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0304] Preparation of derivatives of cyclopamine:

[0305]

[0306] Part A

[0307]

[0308] To a solution of cyclopamine 2 (250 mg, 0.6 mmol, 1 eq) in DCM (10 mL) was added Fmoc-OSu (205 mg, 0.6 mmol, 1 eq) at room temperature, and the resulting mixture was stirred at room temperature overnight. The resulting crude Fmoc-cyclopamine solution was cooled to 0 °C, treated with 15% diethylzinc in toluene (0.5 mL, 0.6 mmol, 1 eq) and stirred for 30 min (flask A).

[0309] Diiodomethane (0.4 mL, 6 mmol, 10 eq) in DCM (20 mL) was treated with 15% diethylzinc in toluene (3 mL, 3 mmol, 5 eq) at 0 °C and the resulting solution was stirred for 5 min (flask B).

[0310] The contents of flask B were transferred to flask A via cannula, and the resulting suspension was stirred at room temperature for 5 hours. The reaction was quenched with HCl (1M), stirred for 10 min (until all white solid redissolved), extracted with DCM (5x). dry (MgSO 4 ) organic extract, fi...

Embodiment 2

[0315] Therapeutic cyclopamine derivatives:

[0316]

[0317] Part A

[0318]

[0319] To a solution of hydrocinnamic acid 5 (3.01 g, 20 mmol, 1 eq) in anhydrous chloroform (30 mL) was added thionyl chloride (1.75 mL, 24.1 mmol, 1.2 eq) dropwise at 75 °C during 3 minutes. The mixture was refluxed for 3.5 hours. The solvent was distilled off to obtain the crude acid chloride as a pale yellow viscous liquid. The crude product was used without further purification.

[0320] Part B

[0321]

[0322] To a biphasic mixture of 7 (3.16 g, 24.1 mmol, 1.2 eq) in DCM (30 mL) and aqueous NaOH (2.0 M, 30 mL, 3 eq) was added the acid chloride 6 (3.38 g, 20 mmol, 1 eq) at 25 °C ) in DCM (10 mL), and the resulting mixture was stirred at 25°C for 3 hours. The mixture was then neutralized with aqueous HCl (2M, 30 mL). The organic layer was separated and the aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were washed with HCl ...

Embodiment 3

[0333] Preparation of derivatives of cyclopamine:

[0334]

[0335] Part A

[0336]

[0337] Cyclopamine 2 (20 mg, 0.049 mmol, 1 equivalent) was suspended in dry toluene (0.6 mL) and cyclohexanone (150 μL, 1.47 mmol, 30 equivalents), then aluminum isopropoxide (79 mg, 0.392 mmol, 8 equivalent). The resulting mixture was heated to reflux for 2 hours, cooled to room temperature, diluted with ethyl acetate and quenched with Rochelle's salt solution. The biphasic mixture was stirred overnight, the layers were separated, the aqueous phase was extracted with ethyl acetate and washed with (MgSO 4 ), dried the combined organic extracts, filtered and concentrated in vacuo. The residue was purified by flash chromatography (DCM, DCM / methanol 98:2 and 95:5). The desired product was obtained as a white crystalline solid (70% yield).

[0338] Part B

[0339]

[0340] Diiodomethane (40 μL, 0.5 mmol, 25 equiv) in DCM (0.52 mL) was treated with 15% diethylzin...

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Abstract

The present invention provides compositions and methods for modulating smootheneddependent pathway activation. The present invention provides analogs of cyclopamine that can be used to counteract the phenotypic effects of unwanted activation of a hedgehog pathway, such as resulting from hedgehog gain-of-function, Ptc loss-of-function or smoothened gain-offunction mutations. The compounds of the present invention are particularly useful in treating cancers.

Description

[0001] related application [0002] This application is related to the following U.S. applications: Serial No. 60 / 605,020, filed August 27, 2004, Serial No. 60 / 617,170, filed August 8, 2004, Serial No. 60 / 625,676, filed November 5, 2004, 2005 Serial No. 60 / 683,169, filed May 19, 1999, each of which is incorporated herein by reference in its entirety. Background of the invention [0003] The hedgehog signaling pathway is essential for many processes during embryonic development. Members of the hedgehog family of secreted proteins control cell proliferation, differentiation and tissue patterning. Although the pathway was first deciphered in Drosophila, it has been shown to be highly conserved in invertebrates and vertebrates, including humans. After embryogenesis, the overall activity of the hedgehog signaling pathway decreases in most cells but remains active in some adult cell types. Recently, it has been shown that uncontrolled activation of the hedgehog pathway leads to c...

Claims

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Application Information

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IPC IPC(8): C07D407/04A61K31/4355C07D405/04A61K31/438C07D307/94
Inventor J·亚当斯A·C·卡斯特罗M·A·福雷S·加纳达南奈尔M·纳瓦莱恩J·R·波特M·特伦布莱
Owner INFINITY PHARMA
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