Ansamycin formulations and methods of use thereof

A kind of technology of benzoquinone ansamycin and 17-AAG, applied in ansamycin (ANSAMYCIN) formulation and its application field, can solve the problems such as unsatisfied

Inactive Publication Date: 2010-02-03
INFINITY PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, there remains an unmet need to develop geldanamycin analogs (such as 17-AG and 17-AAG), and other pharmaceutical compositions thereof in solid form

Method used

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  • Ansamycin formulations and methods of use thereof
  • Ansamycin formulations and methods of use thereof
  • Ansamycin formulations and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0226] Preparation of Form I of 17-AG:

[0227]

[0228] The 22L round bottom flask is equipped with a bottom drain valve, a mechanical stirrer, a 1L stuffing funnel, an internal temperature probe, and an inlet gas bypass. Geldanamycin (500g, 1 equivalent) and dry THF (5.0L) were charged into a 22L round bottom flask. Start stirring and charge ammonia (7M) (1.0 L, 8.0 equivalents) in MeOH. The reaction was stirred for 7 hours at ambient temperature. LCMS indicated that the starting material was completely consumed after 7 hours. During the reaction, the color changed from yellow to deep purple. Heptane (14 L) was slowly added to the reaction mixture to cause the desired product to crystallize out of solution. The brick red slurry was stirred overnight. The product was isolated by suction filtration and washed with 2:1 (v / v) heptane / THF (0.5 L). Oven drying provided crude 17-AG (470 g) as a powdery dark red solid. The crude material was dissolved in a 4:1 mixture of dichlor...

example 2

[0230] Preparation of Form II of 17-AG:

[0231] Form I 17-AG (10 g) from the previous procedure was dissolved in acetone / ethanol at 30°C and purified. Rinse the flask and in-line filter, and concentrate the solution into a thick slurry via a rotary evaporator. Then 100 mL of water was added and the remaining organic solvent was removed by vacuum distillation. When distillate collection stopped, the bath temperature was increased from 40°C to 60°C and a small amount of water was removed. Then another portion of water (100 mL) was added. Distill the water for about 5 minutes at 80°C bath temperature and low vacuum. The slurry was still purple, so the vacuum was turned off and the bath temperature was raised to 100°C. The slurry was mixed for about 1 h. The slurry was then cooled to ambient temperature, held overnight and the purple solid was separated from the water. Karl Fischer analysis was 0.14%, and all residual solvents were very small (MeOH: 106 ppm, EtOH: 173 ppm, ace...

example 3

[0233] Preparation of Form III of 17-AG:

[0234]

[0235] To 400 mL of distilled water was added 1 g of a 20% solid dispersion of 17-aminogeldanamycin in PVP K-30 (prepared as in Example 14). The suspension was heated to 60°C until the solid was completely dissolved. After heating at 60°C for 5-10 min, purple crystals precipitated from the solution. The mixture was cooled to 23°C and a purple crystalline material was separated by filtration. The collected crystals were dried in a vacuum oven at 80°C for 2 days to obtain 155 mg of purple powdery 17-AG form III. The yield was 75%. MS(ESI(+))m / z 563.4(M+H 2 O) + .

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Abstract

Provided herein, inter alia, are solid forms of geldanamycin analogs, pharmaceutical compositions comprising a geldanamycin analog and a crystallization inhibitor, methods of making and using such compositions. Additionally, provided are methods for the treatment of cancer, a neoplastic disease state and / or a hyperproliferative disorder, and methods of inhibiting Heat Shock Protein 90 ('Hsp90').

Description

[0001] Cross reference to related applications [0002] This application claims USSN 60 / 874,349 filed on December 12, 2006, USSN 60 / 914,477 filed on April 27, 2007, and 60 / filed on May 24, 2007 according to 35U.SC119(e). 939,913 rights from the filing date, and the entire disclosure of each patent is incorporated herein by reference. Technical field [0003] Specifically provided herein are geldanamycin analogs in solid form, pharmaceutical compositions comprising geldanamycin analogs and crystallization inhibitors, and methods of making and using the compositions. In some embodiments, methods of treating cancer and / or hyperproliferative disorders, and methods of inhibiting heat shock protein 90 ("Hsp90") are provided. Background technique [0004] Hsp90 is a highly abundant protein that plays a role in cell survival and displays dual chaperone functions (J. Cell Biol., (2001) 154: 267-273; Trends Biochem. Sci.) (1999) 24:136-141). It plays a role in cellular stress response by ...

Claims

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Application Information

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IPC IPC(8): G01N21/25G01N33/52
Inventor 布赖恩·C·奥斯塔德罗杰·H·帕克路易·格勒涅尔詹姆斯·R·波特爱德华·B·霍尔松詹姆斯·L·赖特约翰·J·李
Owner INFINITY PHARMA
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