Generated: May 28, 2017
|Title:||Polymorphs of suberoylanilide hydroxamic acid|
|Abstract:||The present invention provides methods of selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, and/or inhibiting histone deacetylase (HDAC) by administration of pharmaceutical compositions comprising potent HDAC inhibitors. The oral bioavailability of the active compounds in the pharmaceutical compositions of the present invention is surprisingly high. Moreover, the pharmaceutical compositions unexpectedly give rise to high, therapeutically effective blood levels of the active compounds over an extended period of time. The present invention further provides a safe, daily dosing regimen of these pharmaceutical compositions, which is easy to follow, and which results in a therapeutically effective amount of the HDAC inhibitors in vivo. The present invention also provides a novel Form I polymorph of SAHA, characterized by a unique X-ray diffraction pattern and Differential Scanning Calorimetry profile, as well a unique crystalline structure.|
|Inventor(s):||Miller; Thomas A. (Brookline, MA)|
|Assignee:||Merck HDAC Research, LLC (Boston, MA)|
|Filing Date:||Mar 18, 2008|
|Claims:||1. A process for preparing a suberoylanilide hydroxamic acid (SAHA) Form I comprising the step of recrystallizing a crude preparation of SAHA from an organic solvent or a mixture of an organic solvent and water, wherein said organic solvent is methanol, ethanol, or isopropanol. |
2. The process according to claim 1, wherein said process comprises the step of recrystallizing said crude SAHA from an organic solvent.
3. The process according to claim 1, wherein said process comprises the step of recrystallizing said crude SAHA from a mixture of an organic solvent and water.
4. The process according to claim 1, wherein said mixture of organic solvent and water comprises about 1-99% of organic solvent and about 99-1% of water.
5. The process according to claim 4, wherein said mixture comprises about 15-85% of organic solvent and about 1-15% water.
6. The process according to claim 5, wherein said mixture comprises about 85% of organic solvent and about 15% water.
7. The process of claim 3, wherein said mixture of an organic solvent and water is a mixture of about 2:1 of methanol/water.
8. The process of any one of claims 1, 2, 3, 4-6, and 7, wherein the crude preparation of SAHA is prepared comprising the steps of: a. reacting suberic acid with aniline to form suberanilic acid having the structure: ##STR00057## b. reacting suberanilic acid with methanol to form methyl suberanilate having the structure: ##STR00058## c. reacting the methyl suberanilate with hydroxylamine hydrochloride to form a crude suberoylanilide hydroxamic acid in a reaction mixture.
9. The process according to claim 8, wherein step (c) further comprises the steps of: (1) adding sodium methoxide to the reaction mixture to obtain a clear solution; and (2) adding glacial acetic acid to the clear solution to form a precipitate comprising crude suberoylanilide hydroxamic acid.
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