The present invention provides hydroxamate compounds which are deacetylase inhibitors. The compounds are suitable for pharmaceutical compositions having anti-proliferative properties.
This application claims the benefit of Provisional Application No. 60/307,490 filed Jul. 24, 2001, Provisional Application No. 60/292,232 filed May 18, 2001, and Provisional Application No. 60/229,943 filed Sep. 1, 2000, the disclosure of which is herein incorporated by reference.
The present invention provides hydroxamate compounds which are deacetylase inhibitors. The compounds are suitable for pharmaceutical compositions having anti-proliferative properties.
The invention relates to a combination which comprises (a) a cyclooxygenase-2 inhibitor ("COX-2 inhibitor") and (b) a histone deacetylase inhibitor ("HDAI") for simultaneous, concurrent, separate or sequential use, especially for use in the treatment of pre-malignant colon lesions or a colon cancer or other malignancies in a mammal, particularly a human. The invention also relates to pharmaceutical compositions comprising such a combination and to a method of treating pre-malignant colon lesions (e.g. polyps) and colon cancer, as well as other malignancies, in a mammal, particularly a human, with such a combination. The present invention further also relates to a commercial package or product comprising such a combination.
The present invention provides hydroxamate compounds which are deacetylase inhibitors. The compounds are suitable for pharmaceutical compositions having anti-proliferative properties.
A process for preparing unsaturated esters useful as intermediates for HDAC inhibitors, by reacting an aldehyde or ketone having the following formula I: ##STR00001## wherein R.sub.1 is an aromatic group or a combined aliphatic and aromatic group; X is --O--, --S--, --COO--, --OOC--, --CONR.sub.7--, or --R.sub.7NCO--; L.sub.1 an aliphatic linking group, an aromatic linking group, or a combined aliphatic and aromatic linking group; R.sub.2 and R.sub.3 are each independently hydrogen, a hydroxy group, an alkoxy group, an amino group, a carboxyl group, an amide group, an ester group, a carbamate group, an aliphatic group, an aromatic group, a combined aliphatic and aromatic group, R.sub.2 and R.sub.3 together are .dbd.O, or one of R.sub.2 and R.sub.3 form a double bond with one of R.sub.4 and R.sub.5; R.sub.4 and R.sub.5 are each independently hydrogen, a hydroxy group, an alkoxy group, an amino group, a carboxy group, an amide group, an ester group, a carbamate group, an aliphatic group, an aromatic group, a combined aliphatic and aromatic group, or one of R.sub.4 and R.sub.5 form a double bond with one of R.sub.2 and R.sub.3; R.sub.6 is hydrogen, an aliphatic group, an aromatic group, or a combined aliphatic and aromatic group; R.sub.7 is hydrogen, an aliphatic group, an aromatic group, or a combined aliphatic and aromatic group; m is 0 or 1; n is 0 or 1; and p is 0 or 1; with an ester having the following formula II: ##STR00002## wherein R.sub.8 is an aliphatic group, an aromatic group, or a combined aliphatic and aromatic group; R.sub.9 and R.sub.10 each independently hydrogen, an aliphatic group, an aromatic group, a combined aliphatic and aromatic group, or one of R.sub.9 and R.sub.10 form a double bond with L.sub.2; R.sub.11 and R.sub.12 are each an aliphatic group, an aromatic group, or a combined aliphatic and aromatic group; L.sub.2 is an aliphatic linking group, an aromatic linking group, or a combined aliphatic and aromatic linking group; A is P or As; and p is 0 or 1.
Histone deacetylase inhibitors and uses thereof are provided that have the general formula: ##STR00001## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, M and L have the definitions as described herein.
