Histone deacetylase inhibitors and methods of use thereof

#The present invention relates to histone deacetylase (“HDAC”) inhibitors, pharmaceutical compositions comprising an HDAC inhibitor, methods of increasing the sensitivity of a cancer cell to the cytotoxic effects of radiotherapy comprising contacting said cell with an HDAC inhibitor, and methods of treating cancer or a neurological disease comprising administering to a subject in need thereof, an HDAC inhibitor.

#2.1 Cancer

#Cancer is the second leading cause of death in the United States after heart disease. The American Cancer Society estimated that in 2002, there were 1.3 million new cases of cancer and 555,000 cancer-related deaths. Overall mortality rates have declined by 1% per year during the 1990s. There are currently over 9 million living Americans who have been diagnosed with cancer and the NIH estimates the direct medical costs of cancer as $60 billion per year.

#FIG. 1 illustrates the inhibitory effect of selected compounds of the invention on HDAC acitivity in HeLa nuclear cell extracts. Data is expressed as arbitrary fluorescence units (AFU)/μM obtained with the observed range of values obtained in the enzyme assays used in a series of dilutions for a standard curve. Data is shown for a blank sample (no enzyme), a control sample (no inhibitor), the known compound MD83A (as a negative control) at 3 μM, the known HDAC inhibitor TSA at 0.5 μM and 5 μM, the known HDAC inhibitor SAHA at 1 μM and 5 μM, and Compounds of the Invention 2, 3, 5, 6, 7, 8, 9, 10, 11, 21, 22, 23, 24 and 25, each at 5 μM.

#5.1 Definitions

#The term “C1-C6 alkyl” as used herein refers to a straight or branched chain, saturated or unsaturated hydrocarbon having from 1 to 6 carbon atoms. Representative C1-C6 alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-buty, pentyl, isopentyl, neopentyl, hexyl, isohexyl, neohexyl, ethylenyl, propylenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, acetylenyl, pentynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl and 3-hexynyl. A C1-C6 alkyl group may be unsubstituted or substituted with one or more of the following groups: —halo, —C1-C6alkyl, —O—(C1-C6 alkyl), —OH, —CN, —COOR′, —OC(O)R′, NHR′, N(R′)2, —NHC(O)R′ or —C(O)NHR′ groups wherein R′ is —H or unsubstituted —C1-C6 alkyl.

#The term “aryl” as used herein refers to a phenyl group or a naphthyl group. An aryl group may be unsubstituted or substituted with one or more of the following groups: —halo, —C1-C6 alkyl, —O—(C1-C6 alkyl), —OH, —CN, —COOR′, —OC(O)R′, NHR′, N(R′)2, —NHC(O)R′ or —C(O)NHR′ groups wherein R′ is —H or unsubstituted —C1-C6 alkyl.