C - Chemistry – Metallurgy – 07 – D
Patent
C - Chemistry, Metallurgy
07
D
C07D 213/00 (2006.01) A61K 31/16 (2006.01) A61K 31/165 (2006.01) A61K 31/44 (2006.01)
Patent
CA 2561617
The present invention is directed to prodrugs of hydroxamic acid based histone deacetylase (HDAC) inhibitors, e.g., suberoylanilide hydroxamic acid (SAHA). The prodrugs are acylated derivatives having increased aqueous solubility and cellular permeability as compared with the free hydroxamic acid, and are useful for inhibiting HDACs, and for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the prodrugs of the present invention are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The prodrugs of the invention are also useful in the prevention and treatment of thioredoxin (TRX)- mediated diseases, such as autoimmune, allergic, and inflammatory diseases, and in the prevention and/or treatment of diseases of the central nervous system (CNS), such as neurodegenerative diseases.
L'invention concerne des promédicaments sous forme d'inhibiteurs d'histones désacétylases à base d'acide hydroxamique (HDAC), p. ex. l'acide hydroxamique suberoylanilide (SAHA). Ces promédicaments sont des dérivés acylés possédant une solubilité aqueuse et une perméabilité cellulaire accrues comparativement à l'acide hydroxamique libre et ils sont utiles pour inhiber les HDAC et pour induire sélectivement une différenciation terminale, un arrêt de la croissance de cellules et/ou une apoptose de cellules néoplasiques de façon à inhiber la prolifération de ces cellules. Ainsi, les promédicaments selon l'invention sont utiles pour traiter un patient atteint d'une tumeur caractérisée par une prolifération de cellules néoplasiques. Ces promédicaments sont utiles également en prévention et traitement de maladies à médiation par la thiorédoxine (TRX), telles que des maladies auto-immunes, allergiques et inflammatoires, ainsi qu'en prévention et/ou traitement de maladies du système nerveux central (SNC), telles que des maladies neurodégénératives.
Belvedere Sandro
Miller Thomas A.
Witter David J.
Aton Pharma Inc.
Gowling Lafleur Henderson Llp
Merck Hdac Research Llc
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