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Crystal of a free tricyclic pyrazolopyrimidine derivative

a tricyclic pyrazolopyrimidine and crystal technology, applied in the field of compounds, can solve the problems of unclear mechanism details, and achieve the effect of excellent stability

Inactive Publication Date: 2014-12-18
DAIICHI SANKYO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a crystal of a compound that can inhibit the activity of HSP90, a protein involved in cancer cell growth. This crystal is stable and can be used as an anticancer agent.

Problems solved by technology

It is assumed that HSP90 as well as multiple proteins such as cochaperones, partner proteins and immunophilins are involved in the mechanism of folding of client proteins by HSP90 and that they collaboratively assist in folding of HSP90 client proteins (Non Patent Document 1); however, the details of the mechanism are still not sufficiently clear.

Method used

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  • Crystal of a free tricyclic pyrazolopyrimidine derivative
  • Crystal of a free tricyclic pyrazolopyrimidine derivative
  • Crystal of a free tricyclic pyrazolopyrimidine derivative

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

Production of 2-{4-amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl}-N-methylacetamide (free form)

(1) 1-(2-Amino-4,6-dichloropyrimidin-5-yl)-3-buten-1-ol

[0162]

[0163]Indium powder (0.23 g) and zinc powder (1.31 g) were added to a mixture composed of commercially available 2-amino-4,6-dichloropyrimidine-5-carboaldehyde (1.92 g) and N,N-dimethylformamide (20 ml). Thereafter, sodium iodide (0.15 g) and allyl bromide (1.73 ml) were added to the mixture at room temperature. The resulting mixture was stirred for 3 hours. Thereafter, the reaction mixture was filtered through celite, and ethyl acetate was then added to the filtrate. The resulting mixture was successively washed with 1 N hydrochloric acid and a saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated. Thereafter, hexane was added to the residue, and a precipitate was then collected by filtration, so as ...

reference example 2

2-{4-Amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl}-N-methylacetamide monohydrochloride

[0242]3 M Hydrochloric acid (0.786 ml, 2.358 mmol) was added to an ethanol (30 ml) suspension of 2-{4-amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl}-N-methylacetamide (527.52 mg, 1.183 mmol) while stirring at 25° C., and the mixture was then stirred for 1 hour. Thereafter, the precipitated solid was filtered, was then washed with ethanol (6 ml), and was then dried under reduced pressure at 40° C. for 30 minutes, so as to obtain the above title compound (531.09 g, 1.101 mmol).

[0243]Elemental analysis values for C19H21Cl2N7O2S

[0244]Calculated: C, 47.31; H, 4.39; N, 20.33; 0, 6.63; Cl, 14.70; S, 6.65.

[0245]Found: C, 47.29; H, 4.40; N, 20.02; 0, 6.87; Cl, 14.99; S, 6.83

[0246]Examples will be described below. The X-ray powder diffraction was always measured using a ref...

example 1

2-{4-Amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl}-N-methylacetamide dihydrochloride crystal A

[0250]2-{4-Amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl}-N-methylacetamide (crystal B obtained by the same operations as those in the method described in the following Example 2) (10.0 g, 22.43 mmol) was suspended in acetone (750 ml), and the resulting mixture was then stirred at room temperature for 4 days. A precipitate was collected by filtration, and was washed with water (50 ml). The resultant was then dried at 60° C. overnight under reduced pressure, so as to obtain the above title compound as crystal A (8.1 g, 18.16 mmol). Yield: 81%.

[0251]The elemental analysis measurement values (theoretical values) of the obtained crystal are shown below.

[0252]For 2-{4-Amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazab...

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Abstract

To provide a crystal of a tricyclic pyrazolopyrimidine compound inhibiting the effect of HSP90. The present invention provides a crystal of 2-{4-amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl}-N-methylacetamide which inhibits the ATPase activity of HSP90 and which has antitumor activity, a medicament comprising the same, an anticancer agent comprising the same, and the like.

Description

TECHNICAL FIELD[0001]The present invention relates to a compound having a tricyclic pyrazolopyrimidine skeleton which inhibits the effect of heat shock protein 90 (HSP90).BACKGROUND ART[0002]HSP90 is a major intracellular chaperone protein. Chaperone proteins are proteins that bind to various proteins to assist in folding of the bound proteins. A group of proteins whose folding requires HSP90 are generally called HSP90 client proteins.[0003]It is assumed that HSP90 as well as multiple proteins such as cochaperones, partner proteins and immunophilins are involved in the mechanism of folding of client proteins by HSP90 and that they collaboratively assist in folding of HSP90 client proteins (Non Patent Document 1); however, the details of the mechanism are still not sufficiently clear.[0004]It is assumed that HSP90 client proteins form a complex with HSP90, cochaperones and the like and are then conformationally changed to mature proteins and that the proteins are ubiquitinated and de...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D495/16
CPCC07D495/16A61P35/00C07D417/06A61K31/519A61K31/55
Inventor UEDA, YASUSISUZUKI, NOBUYUKIOHKI, HITOSHI
Owner DAIICHI SANKYO CO LTD
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