Protected HDAC (histone deacetylase) inhibitors
The invention relates to protected HDAC inhibitor compounds of formula I, in which Y, Ar 1 , Ar 2 , X, R 1 and R 2 are as defined herein. In aspects, the inventions relates to use of the compounds, and to methods of deprotecting the compounds.
1 . A compound of formula I:
in which:
R 1 is H or an alkyl group comprising 1 to 10 carbon atoms; R 2 is P—Z, in which P is an alkyl group comprising from 1 to 15 carbon atoms, optionally substituted with one or more of N atoms, —C═O, and —NHC═O; and Z is:
in which R 3 is H, a C 1 -C 9 alkyl, —CH 2 OH, —CH 2 OCH 3 , -Ph, —C 6 H 4 OH, —CH(CH 3 )OH, —C(CH 2 COOH) 2 OH, —C(═O)CH 3 , —CH 2 NH 2 , —CH 2 NH(C═O)CH 2 NH 2 , or —CH 2 NH(C═O)CH 2 NH(C═O)CH 2 NH 2 ;
Or
R 1 and R 2 form part of a heterocyclic group Y having 5 or 6 members and being substituted with P-Z, wherein P is as defined above, and wherein Z is as defined above;
Ar 1 and Ar 2 are each, independently, selected from a phenyl, pyridine, pyrimidine, thiophene, furan, benzofuran or thiazole group; and
X is —C═C—C(═O)OR 4 , in which R 4 is an alkyl group comprising from 1 to 10 carbon atoms, optionally substituted with one or more O atoms.
2 . A compound of formula I as claimed in claim 1 , in which R 3 is a C 1 -C 3 alkyl.
3 . A compound of formula I as claimed in claim 2 , in which R 3 is —CH 3 .
4 . A compound of formula I as claimed in claim 1 , in which Ar 1 is thiazole or phenyl.
5 . A compound of formula I as claimed in claim 1 , in which Ar 2 is pyridine, thiophene, or furan.
6 . A compound of formula I as claimed in claim 1 , in which R 1 and R 2 form part of a heterocyclic group Y, optionally wherein Y is piperazine.
7 . A compound of formula I as claimed in claim 6 , in which P is a C 1 -C 15 alkyl group substituted with —C(═O).
8 . A compound of formula I as claimed in claim 7 , in which P is —C(═O)(CH 2 ) 6 .
9 . A compound of formula I as claimed in claim 1 , in which R 4 is an alkyl group.
10 . A compound of formula I as claimed in claim 9 , in which R 4 is —CH 3 , —C(CH 3 ) 3 or —CH 2 CH(CH 3 ) 2 .
11 . A compound of formula I as claimed in claim 1 , in which R 1 is C 1 -C 3 alkyl, optionally wherein R 1 is —CH 3 .
12 . A compound of formula I as claimed in claim 1 , or as claimed in claim 11 , in which R 2 is P—Z, in which P is a C 1 -Cis alkyl substituted with —NHC(═O).
13 . A compound of formula I as claimed in claim 12 , in which P is —(CH 2 ) 5 NHC(═O)(CH 2 ) 6 .
14 . A compound of formula I as claimed in claim 1 , in which R 4 is —(CH 2 CH 2 O) n CH 3 in which n is an integer between 1 and 8, optionally wherein R 4 is —(CH 2 CH 2 O) 3 CH 3 .
15 . A compound of formula I as claimed in claim 1 , wherein the compound is selected from compound 92, compound 93, compound 101 and compound 102:
16 . A pharmaceutical composition comprising a compound of formula I as claimed in claim 1 , optionally in combination with one or more pharmaceutically acceptable excipients, diluents or carriers.