Cyclic dinucleotides for cytokine induction
A cyclic dinucleotide compound of Formula (I): wherein X 1 is H or F; X 2 is H or F; at least one among X 1 and X 2 is a fluorine atom; Z is OH, OR 1 , SH or SR 1 , wherein: R 1 is Na or NH 4 , or R 1 is an enzyme-labile group which provides OH or SH in vivo such as pivaloyloxymethyl; B 1 and B 2 are bases chosen from Adenine, Hypoxanthine or Guanine, and B 1 is a different base than B 2 and a pharmaceutically acceptable salt thereof. Pharmaceutical compositions including the cyclic dinucleotide, as well as their use in the treatment of a bacterial infection, a viral infection or a cancer are also described.
1. A cyclic dinucleotide compound of Formula (I):
wherein:
X 1 is H or F;
X 2 is H or F;
At least one among X 1 and X 2 is a fluorine atom;
Z is OH, OR 1 , SH or SR 1 , wherein:
i) R 1 is Na or NH 4 , or
ii) R 1 is an enzyme-labile group which provides OH or SH in vivo such as pivaloyloxymethyl;
B 1 and B 2 are bases chosen from:
and B 1 is a different base than B 2 ,
or a pharmaceutically acceptable salt thereof.
2. The cyclic dinucleotide of Formula (I) according to claim 1 , wherein said cyclic dinucleotide is chosen from the following compounds:
3. The cyclic dinucleotide of Formula (I) according to claim 1 , wherein said cyclic dinucleotide is an agonist of the receptor called “stimulator of interferon genes” (STING).
4. A pharmaceutical composition comprising a cyclic dinucleotide of Formula (I) according to claim 1 , and a pharmaceutically acceptable excipient.
5. A method for treating cancer comprising administering to a patient in need thereof a cyclic dinucleotide of Formula (I) according to claim 1 .
6. A method for treating a bacterial infection comprising administering to a patient in need thereof a cyclic dinucleotide of Formula (I) according to claim 1 .
7. A method for treating a viral infection comprising administering to a patient in need thereof a cyclic dinucleotide of Formula (I) according to claim 1 .
8. A method for treating a pathology that may be alleviated by the induction of an immune response via the STING pathway comprising administering to a patient in need thereof a cyclic dinucleotide of Formula (I) according to claim 1 .
9. A cyclic dinucleotide of the following formula:
10. A pharmaceutical composition comprising the cyclic dinucleotide of claim 9 and a pharmaceutically acceptable excipient.
11. A method for treating cancer comprising administering to a patient in need thereof the cyclic dinucleotide of claim 9 .
12. A method for treating a bacterial infection comprising administering to a patient in need thereof the cyclic dinucleotide of claim 9 .
13. A method for treating a viral infection comprising administering to a patient in need thereof the cyclic dinucleotide of claim 9 .
14. A method for treating a pathology that may be alleviated by the induction of an immune response via the STING pathway comprising administering to a patient in need thereof the cyclic dinucleotide of claim 9 .