17-allylamino-17-demethoxygeldanamycin polymorphs and formulations

A technology of demethoxygeldanamycin and allylamino, applied in the field of 17-allylamino-17-demethoxygeldanamycin polymorphs

Inactive Publication Date: 2009-11-11
KOSAN BIOSCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, albumin may be pharmaceutically undesirable for intravenous formulations

Method used

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  • 17-allylamino-17-demethoxygeldanamycin polymorphs and formulations
  • 17-allylamino-17-demethoxygeldanamycin polymorphs and formulations
  • 17-allylamino-17-demethoxygeldanamycin polymorphs and formulations

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064]The present method produces highly pure 17-AAG by removing polar impurities by slow crystallization from acetone-water at about ambient temperature. A flask containing crude 17-AAG (21 g) was set up for reflux. Acetone (20 mL per gram of solids) was added to the flask. The slurry was refluxed and maintained at this temperature for 5 min. The mixture was cooled to 25 °C over a period of 1 h. Water (volume equal to that of acetone) was added over a period of 1 h. After 20 min, the slurry was filtered. The filter cake was washed with 1:1 acetone:water (40 mL). The wet cake is filtered and saved for further processing. The 17-AAG thus produced has a chromatographic purity of 99.7% as polymorph B.

Embodiment 2

Example 2 - Preparation of Purified Polymorph C

[0065] This protocol yields 17-AAG consisting mainly of polymorph C with high crystallinity. If highly pure 17-AAG (as prepared according to the preceding examples) is used, polymorph C is obtained both highly pure and highly crystalline.

[0066] A solution of 17-AAG (1 g, purified according to Example 1) in acetone (100 mL) was refluxed. Water (100 mL) was added at a rate to keep the tank at or near reflux. Acetone was distilled off until the pot temperature reached 100°C. Additional fractions (20 mL, mostly water) were collected. The tank contents were cooled and the solids were collected by filtration using a Buchner funnel fitted with Whatman #52 filter paper and washed with 1:1 acetone:water (20 mL). The crystals were vacuum dried at >20°C for >2h, sampled, and vacuum dried at 85°C for approximately 12h to yield polymorph C.

Embodiment 3

Example 3 - Preparation of Purified Polymorph G

[0067] A solution of 17-AAG (10.0 g) in acetone (750 mL) was poured into water (1.05 L) with stirring at room temperature. The solution was stirred for another 70 min. Polymorph G crystals were collected by filtration and dried at 45°C for 18h.

[0068] In an alternative method, 17-AAG (1.0 g) was dissolved in acetone (117 mL) and stirred at room temperature. Water (117 mL) was added at a rate of 15 mL / min. The mixture was stirred for an additional 50 min, and polymorph G crystals were collected by filtration and dried at 70° C. for 44 h.

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Abstract

The present invention relates ot polymorphs and pharmaceutical formulations of 17-allylamino-17- demethoxygeldanamycin (17- AAG).

Description

[0001] invention technical field [0001] The present invention relates to novel 17-allylamino-17-demethoxygeldanamycin ("17-AAG") polymorphs (polymorphs), preparation of such novel Methods of polymorphs, pharmaceutical formulations containing 17-AAG, especially formulations containing such novel polymorphs, and methods of making and using such pharmaceutical formulations. Background of the invention [0002] Geldanamycin belongs to the Ansamycin family of natural products, members of which are characterized by a macrolactam ring spanning two mutually meta-positions on the benzene nucleus. In addition to geldanamycin, ansamycins include macbecins, herbimycins, TAN-420 (various) and reblastatin. [0003] Geldanamycin and its derivatives are the most extensively studied ansamycins. Although geldanamycin was originally identified as a result of screening for antibiotic activity, current attention is primarily on its potential as an anticancer drug. It is an inhibitor of heat s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D225/04A61K9/00
Inventor P·J·利卡里T·利夫R·P·德赛J·加拉佐G·O·布坎南S·W·瓦特A·R·埃贝林R·阿尔斯拉尼安
Owner KOSAN BIOSCI
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