Monophosphorylated lipid A derivatives
The present invention provides for monophosphorylated lipid A derivatives and carbohydrate derivatives that are useful as agents in the treatment of diseases and conditions, including cancers. Also provided are pharmaceutical compositions comprising one or more compounds of Formula I-IV. In addition, methods for the treatment of cancers are provided.
1. A compound of formula I:
(monophosphorylated lipid A)-L-X (I);
wherein L is a linker having a first end Y and a second end Z;
wherein the linker has formula
Y—(CH 2 ) 2 —NHC(O)—(CH 2 ) a —C(O)NH—(CH 2 ) b —Z,
wherein a and b are integers selected from 2 to 6; and
wherein monophosphorylated lipid A is attached at the first end Y of the linker L,
and X is attached at the second end Z of the linker L; and
wherein R 9 and R 19 are independently selected from H or one to two substituents selected from the group consisting of C 1 -C 6 alkyl, —OC 1 -C 4 alkyl, —C(O)C 1 -C 4 alkyl, and halo;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein said compound is a compound of formula I:
(monophosphorylated lipid A)-L-X (I);
wherein L is a linker having a first end Y and a second end Z;
wherein the linker has formula Y —(CH 2 ) 2 —NHC(O)—(CH 2 ) a —C(O)NH—(CH 2 ) b —Z or
wherein a and b are integers selected from 2 to 6; and
wherein monophosphorylated lipid A is attached at the first end Y of the linker L,
and X is attached at the second end Z of the linker L;
and
X is
wherein R 9 and R 10 are independently selected from H or one to two substituents selected from the group consisting of C 1 -C 6 alkyl, —OC 1 -C 4 alkyl, —C(O)C 1 -C 4 alkyl, and halo;
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein the monophosphorylated lipid A is represented by the following formula:
R 1 is —CH 2 —CH(OR 5 )(CH 2 ) m CH 3 , R 5 is H or —C(O)—(CH 2 ) n CH 3 , m is an integer selected from 10 to 12, and n is 12;
R 2 is —CH 2 —CH(OR 6 )(CH 2 ) p CH 3 , R 6 is —C(O)—(CH 2 ) q CH 3 , wherein p is 10, and q is an integer selected from 10 to 12;
R 3 is —CH 2 —CH(OR 7 )(CH 2 ) n CH 3 , R 7 is H, and r is an integer selected from 8 to 10;
R 4 is —CH 2 —CH(OR 8 )(CH 2 ) s CH 3 , R 8 is H or —C(O)—(CH 2 ) t CH 3 , s is 10 or 11, and t is an integer selected from 11 to 13;
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein the monophosphorylated lipid A is represented by the following formula:
R 1 is —(CH 2 ) m CH 3 , wherein m is an integer selected from 10 to 12;
R 2 is —CH 2 —CH(OR 6 )(CH 2 ) p CH 3 , R 6 is —C(O)—(CH 2 ) q CH 3 , wherein p is 10, and q is an integer selected from 10 to 12;
R 3 is —CH 2 —CH(OR 7 )(CH 2 ) r CH 3 , R 7 is H, and r is an integer selected from 8 to 10;
R 4 is —CH 2 —CH(OR 8 )(CH 2 ) s CH 3 , R 8 is H or —C(O)—(CH 2 ) t CH 3 , s is 10 or 11, and t is an integer selected from 11 to 13;
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein R 9 and R 10 are H;
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , wherein a and b are each 2;
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 , wherein said compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , wherein said compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
9. A compound of Formula IV:
wherein R 11 is one or two substituents independently selected from the group consisting of: C 1 -C 6 alkyl, —OC 1 -C 4 alkyl, —C(O)C 1 -C 4 alkyl, or halo; or a pharmaceutically acceptable salt thereof.