Phospholipid drug analogs
Provided in some embodiments are compositions comprising a compound having a structure according to Formula A or Formula B: or a pharmaceutically acceptable salt, tautomer or hydrate thereof, where X 2 is a bond or linker, X 3 is bond or —PO 4 —, and X 1 , R 1 , R 2 , R 3 , and n are described herein. Also provided in some embodiments are methods for making and using such compounds and compositions.
1. A compound having a structure according to Formula A or Formula B:
or a pharmaceutically acceptable salt, tautomer or hydrate thereof, wherein:
X 1 is —O—, —S—, or —NR a —;
R a is hydrogen, C1-C10 alkyl, or substituted C1-C10 alkyl, or R a and R 1 taken together with the nitrogen atom can form a heterocyclic ring or a substituted heterocyclic ring, wherein the substituents on the alkyl or heterocyclic groups are hydroxy, C1-C10 alkyl, hydroxyl C1-C10 alkenyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkylene, amino, cyano, halogen or aryl;
R 1 is hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl, C1-C10 alkoxy, substituted C1-C10 alkoxy, C3-C9 cycloalkyl, substituted C3-C9 cycloalkyl, C5-C10 aryl, substituted C5-C10 aryl, C5-C9 heterocyclic, substituted C5-C9 heterocyclic, C1-C6 alkanoyl, C1-C6 heteroalkyl, or C1-C6 alkoxycarbonyl, wherein the substituents on the alkyl, cycloalkyl, aryl or heterocyclic groups are hydroxyl, C1-C10 alkyl, hydroxyl C1-C10 alkylene, C1-C6 alkoxy, C3-C9 cycloalkyl, C5-C9 heterocyclic, C1-6 alkoxy C1-6 alkenyl, amino, cyano, halogen or aryl;
each R 2 independently is hydrogen, —OH, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, —C(O)—C1-C6 alkyl (alkanoyl), substituted —C(O)—C1-C6 alkyl, —C(O)—C6-C10 aryl (aroyl), substituted —C(O)—C6-C10 aryl, —C(O)OH (carboxyl), —C(O)O—C1-C6 alkyl (alkoxycarbonyl), substituted —C(O)O—C1-C6 alkyl, —NR a R b , —C(O)NR b R c (carbamoyl), substituted C(O)NR b R c , C5-C9 cyclic, substituted C5-C9 cyclic, C5-C9 heterocyclic, substituted C5-C9 heterocyclic, halo, nitro, or cyano, wherein the substituents on the alkyl, cyclic, aryl or heterocyclic groups are hydroxy, C1-C10 alkyl, hydroxyl C1-C10 alkylene, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkylene, amino, cyano, halogen or aryl;
each R b and R c independently is hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl, C1-C10 alkoxy, substituted C1-C10 alkoxy, C3-C9 cycloalkyl, substituted C3-C9 cycloalkyl, C5-C10 aryl, substituted C5-C10 aryl, C5-C9 heterocyclic, substituted C5-C9 heterocyclic, C1-C6 alkanoyl, C1-C6 heteroalkyl, or C1-C6 alkoxycarbonyl, wherein the substituents on the alkyl, cycloalkyl, aryl or heterocyclic groups are hydroxyl, C1-C10 alkyl, hydroxyl C1-C10 alkylene, C1-C6 alkoxy, C3-C9 cycloalkyl, C5-C9 heterocyclic, C1-6 alkoxy C1-6 alkenyl, amino, cyano, halogen or aryl;
X 2 is a bond or a linker; n is 0, 1, 2, 3 or 4; and
X 3 is a bond or a —PO 4 —;
R 3 is a C1-C6 alkyl substituted with —OC(O)—R d and —OC(O)—R e ; C1-C6 alkyl substituted with —OC(O)—R d , —OC(O)—R e , and one or more further substituents; C1-C6 alkenyl substituted with —OC(O)—R d and —OC(O)—R e ; or C1-C6 alkenyl substituted with —OC(O)—R d , —OC(O)—R e , and one or more further substituents; wherein the one or more further substituents independently are hydroxyl, C1-C10 alkyl, hydroxyl C1-C10 alkylene, C1-C6 alkoxy, C3-C9 cycloalkyl, C5-C9 heterocyclic, C1-6 alkoxy C1-6 alkylene, amino, cyano, halogen or aryl;
—OC(O)—R d and —OC(O)—R e independently are —OC(O)—(CH 2 ) 10 —CH 3 or —OC(O)—(CH 2 ) 12 —CH 3 .
2. The compound of claim 1 , wherein —OC(O)—R d and —OC(O)—R e are —OC(O)—(CH 2 ) 10 —CH 3 .
3. The compound of claim 1 , wherein —OC(O)—R d and —OC(O)—R e are —OC(O)—(CH 2 ) 12 —CH 3 .
4. The compound of claim 1 , wherein X 1 is O.
5. The compound of claim 1 , wherein R 1 is a C1-C10 alkyl substituted with C1-6 alkoxy.
6. The compound of claim 1 , wherein n is 0 and X 2 is —C(O)NH—(CH 2 ) 2 —.
7. The compound of claim 1 , wherein X 1 is O, R 1 is —(CH 2 ) 2 —OCH 3 , n is 0, X 2 is —C(O)NH—(CH 2 ) 2 —, R 3 is a C3 alkyl substituted with —OC(O)—R d and —OC(O)—R e , and —OC(O)—R d and —OC(O)—R e are —OC(O)—(CH 2 ) 10 —CH 3 .
8. The compound of claim 1 , which is in a liposome.
9. The compound of claim 1 and an antigen.
10. The compound of claim 1 , wherein the compound has the structure:
11. An immunostimulatory composition comprising a compound having a structure of Formula A or Formula B according to claim 1 and a pharmaceutically acceptable carrier.
12. The composition of claim 11 , which comprises an antigen.
13. The composition of claim 11 , which comprises a vaccine.
14. A composition comprising a compound having a structure according to Formula A or Formula B:
or a pharmaceutically acceptable salt, tautomer or hydrate thereof, wherein:
X 1 is —O—, —S—, or —NR a —;
R a is hydrogen, C1-C10 alkyl, or substituted C1-C10 alkyl, or R a and R 1 taken together with the nitrogen atom can form a heterocyclic ring or a substituted heterocyclic ring, wherein the substituents on the alkyl or heterocyclic groups are hydroxy, C1-C10 alkyl, hydroxyl C1-C10 alkenyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkylene, amino, cyano, halogen or aryl;
R 1 is hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl, C1-C10 alkoxy, substituted C1-C10 alkoxy, C3-C9 cycloalkyl, substituted C3-C9 cycloalkyl, C5-C10 aryl, substituted C5-C10 aryl, C5-C9 heterocyclic, substituted C5-C9 heterocyclic, C1-C6 alkanoyl, C1-C6 heteroalkyl, or C1-C6 alkoxycarbonyl, wherein the substituents on the alkyl, cycloalkyl, aryl or heterocyclic groups are hydroxyl, C1-C10 alkyl, hydroxyl C1-C10 alkylene, C1-C6 alkoxy, C3-C9 cycloalkyl, C5-C9 heterocyclic, C1-6 alkoxy C1-6 alkenyl, amino, cyano, halogen or aryl;
each R 2 independently is hydrogen, —OH, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, —C(O)—C1-C6 alkyl (alkanoyl), substituted —C(O)—C1-C6 alkyl, —C(O)—C6-C10 aryl (aroyl), substituted —C(O)—C6-C10 aryl, —C(O)OH (carboxyl), —C(O)O—C1-C6 alkyl (alkoxycarbonyl), substituted —C(O)O—C1-C6 alkyl, —NR a R b , —C(O)NR b R c (carbamoyl), substituted C(O)NR b R c , C5-C9 cyclic, substituted C5-C9 cyclic, C5-C9 heterocyclic, substituted C5-C9 heterocyclic, halo, nitro, or cyano, wherein the substituents on the alkyl, cyclic, aryl or heterocyclic groups are hydroxy, C1-C10 alkyl, hydroxyl C1-C10 alkylene, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkylene, amino, cyano, halogen or aryl;
each R b and R c independently is hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl, C1-C10 alkoxy, substituted C1-C10 alkoxy, C3-C9 cycloalkyl, substituted C3-C9 cycloalkyl, C5-C10 aryl, substituted C5-C10 aryl, C5-C9 heterocyclic, substituted C5-C9 heterocyclic, C1-C6 alkanoyl, C1-C6 heteroalkyl, or C1-C6 alkoxycarbonyl, wherein the substituents on the alkyl, cycloalkyl, aryl or heterocyclic groups are hydroxyl, C1-C10 alkyl, hydroxyl C1-C10 alkylene, C1-C6 alkoxy, C3-C9 cycloalkyl, C5-C9 heterocyclic, C1-6 alkoxy C1-6 alkenyl, amino, cyano, halogen or aryl;
X 2 is a bond or a linker; n is 0, 1, 2, 3 or 4; and
X 3 is a bond or a —PO 4 —;
R 3 is a C1-C6 alkyl substituted with —OC(O)—R d and —OC(O)—R e ; C1-C6 alkyl substituted with —OC(O)—R d , —OC(O)—R e , and one or more further substituents; C1-C6 alkenyl substituted with —OC(O)—R d and —OC(O)—R e ; or C1-C6 alkenyl substituted with —OC(O)—R d , —OC(O)—R e , and one or more further substituents; wherein the one or more further substituents independently are hydroxyl, C1-C10 alkyl, hydroxyl C1-C10 alkylene, C1-C6 alkoxy, C3-C9 cycloalkyl, C5-C9 heterocyclic, C1-6 alkoxy C1-6 alkylene, amino, cyano, halogen or aryl;
—OC(O)—R d and —OC(O)—R e are independently —OC(O)—(CH 2 ) 10 —CH 3 or —OC(O)—(CH 2 ) 12 —CH 3 ; and
a pharmaceutically acceptable carrier.
15. The composition of claim 14 , wherein —OC(O)—R d and —OC(O)—R e are —OC(O)—(CH 2 ) 10 —CH 3 .
16. The composition of claim 14 , wherein —OC(O)—R d and —OC(O)—R e are —OC(O)—(CH 2 ) 12 —CH 3 .
17. The composition of claim 14 , wherein X 1 is O.
18. The composition of claim 14 , wherein R 1 is a C1-C10 alkyl substituted with C1-6 alkoxy.
19. The composition of claim 14 , wherein n is 0 and X 2 is —C(O)NH—(CH 2 ) 2 —.
20. The composition of claim 14 , wherein X 1 is O, R 1 is —(CH 2 ) 2 —OCH 3 , n is 0, X 2 is —C(O)NH—(CH 2 ) 2 —, R 3 is a C3 alkyl substituted with —OC(O)—R d and —OC(O)—R e and —OC(O)—R d and —OC(O)—R e are —OC(O)—(CH 2 ) 10 —CH 3 .
21. The composition of claim 14 , which is in a liposome.
22. The composition of claim 14 , which comprises an antigen.
23. The composition of claim 14 , wherein the compound has the structure:
24. The compound of claim 1 , wherein —X 2 —X 3 —R 3 taken together form a structure according to Formula C:
25. The composition of claim 14 , wherein —X 2 —X 3 —R 3 taken together form a structure according to Formula C: