HDAC6 inhibitors and their uses
The present invention relates to small molecule compounds and their use as HDAC inhibitors and in the treatment of various diseases, such as cancer. The present invention further relates to methods of synthesizing the compounds and methods of treatment. H-L(HA), H is a head group selected from (head group 1), (head group 2), (head group 3), (head group 4), (head group 5) and (head group 6).
1. A compound having the general formula I
H-L(HA)
wherein
H is a head group
wherein
A is chosen from phenyl or pyridyl ring;
n is 0 or 1;
X and Y are each independently selected from CH 2 , C═O and C═S;
Z is selected from the group consisting of H, alkyl and
with m being 0 to 6;
R is selected from the group consisting of H, alkoxy, hydroxy, alkyl, alkoxyaryl, aryl, halogenyl, nitro, amino, amidyl, cyano, sulfanyl, sulfinyl, sulfonyl, formyl, acetyl,
with o being 0 to 6;
R′ and R″ are each independently selected from the group consisting of H, alkyl, aryl and substituted aryl;
L is a linker comprising a hydroxamic acid (HA) and having the formula
with q being 0 or 1;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 ,
wherein the hydroxamic acid(s) HA is/are protected by carbamate.
3. The compound of claim 1 , wherein H is
4. The compound of claim 1 having general formula II
wherein
X and Y are each independently selected from CH 2 , C═O and C═S;
Z is selected from the group consisting of alkyl and
with m being 2 to 6; and
R is selected from the group consisting of H, alkoxy,
with o being 1 to 6.
5. The compound of claim 1 , having the general formula IIa
wherein
n is 0 or 1;
X and Y are each independently selected from C═O and C═S; and
R is selected from the group consisting of H, alkoxy,
with o being 1 or 2.
6. The compound of claim 1 selected from
7. A pharmaceutical composition comprising
at least one compound according to claim 1 , and a pharmaceutically acceptable excipient and/or carrier.
8. A method for inhibiting a histone deacetylase (HDAC) wherein said method comprises administering to a subject a therapeutically effective amount of a compound according to claim 1 .
9. A method of generating a compound of claim 1 , comprising the steps of
(1) reduction of a methyl 2-(1H-indol-3-yl)-3-nitropropanoate derivative,
(2) ring closure employing a pictet-spengler reaction,
(3) transformation to the respective urea or thiourea derivative by use of 2,5-dioxopyrrolidin-1-yl carbamate derivatives, isocyanates or isothiocyanates, and
(4) ring closure mediated by a base.
10. A method of treatment of a disease, comprising the steps of
administering to a subject a therapeutically effective amount of a compound according to claim 1 ,
wherein the disease is selected from breast cancer, prostate cancer, uterus cancer, leukemia, and arthritis.
11. The method of claim 10 , comprising
administering the therapeutically effective amount of said compound
in combination with further agent(s) or drug(s)
and/or comprising sensitization of cancer cells, during radiation therapy.
12. The compound, according to claim 5 , wherein R is H.
13. The compound, according to claim 6 , wherein the compound is
14. The method, according to claim 8 , wherein the HDAC is HDAC6.