Compounds for preparing immunological adjuvant
The present invention provides methods for preparing TLR-4 receptor agonist E6020: and stereoisomers thereof, which compounds are useful as an immunological adjuvants when co-administered with antigens such as vaccines for bacterial and viral diseases. Also provided are synthetic intermediates useful for implementing the inventive methods.
1. A compound of formula (15):
wherein:
A is —(CH 2 ) x —O— or a covalent bond;
n is 0 or 1;
x is 1-6;
R 1a is hydrogen, a C 1 -C 6 alkyl group, a C 3 -C 6 alkenyl group, a C 3 -C 6 alkynyl group, or a phosphite oxygen protecting group or a phosphate oxygen protecting group;
one of R 2a and R 2b is H and the other is a monovalent nitrogen protecting group; or R 2a and R 2b taken together are a divalent nitrogen protecting group;
when A is —(CH 2 ) x —O—, one of R 3a and R 3b is H and the other is a monovalent nitrogen protecting group, or R 3a and R 3b taken together are a divalent nitrogen protecting group;
when A is a covalent bond, R 3a and R 3b are a C 1 -C 6 alkyl group, or R 3a and R 3b taken together are —(CH 2 ) 4 —, —(CH 2 ) 5 —, or —(CH 2 ) 2 —O—(CH 2 ) 2 —;
R 4 is a C 5 -C 12 alkyl group or a C 5 -C 12 alkenyl group; and
R 5 is a C 5 -C 15 alkyl group or a C 5 -C 15 alkenyl group;
or a salt thereof.
2. A compound of formula (15):
wherein:
A is —(CH 2 ) x —O— or a covalent bond;
n is 0 or 1;
x is 1-6;
R 1a is hydrogen, a C 1 -C 6 alkyl group, a C 3 -C 6 alkenyl group, a C 3 -C 6 alkynyl group, or a phosphite oxygen protecting group or a phosphate oxygen protecting group;
one of R 2a and R 2b is H and the other is a monovalent nitrogen protecting group; or R 2a and R 2b taken together are a divalent nitrogen protecting group;
when A is —(CH 2 ) x —O—, one of R 3a and R 3b is H and the other is a monovalent nitrogen protecting group, or R 3a and R 3b taken together are a divalent nitrogen protecting group;
when A is a covalent bond, R 3a and R 3b are a C 1 -C 6 alkyl group, or R 3a and R 3b taken together are —(CH 7 ) 4 —, —(CH 2 ) 5 —, or —(CH 2 ) 2 O(CH 2 ) 2 —;
R 4 is a C 5 -C 12 alkyl group or a C 5 -C 12 alkenyl group;
R 5 is a C 5 -C 15 alkyl group or a C 5 -C 15 alkenyl group; and
wherein the nitrogen protecting group of R 2a and R 2b or R 3a and R 3b are independently selected from the group consisting of Boc, Fmoc, TROC, TMS-ethylcarbonyl, cyanoethylcarbonyl, allyloxycarbonyl, (C 6 H 5 ) 2 C═, tetrachlorophthalamide, or azide;
or a salt thereof.
3. The compound of claim 1 , wherein the protecting group on the nitrogen linked to R 2a and R 2b can be removed under a first condition selected from acidic, basic, oxidative, and reductive conditions; and the protecting group on the nitrogen linked to R 3a and R 3b can be removed under a second condition selected from the remaining three conditions that are different from the first condition.
4. The compound of claim 1 , wherein A is —(CH 2 ) 2 —O—; n is 0; R 4 is a C 7 alkyl; and R 5 is a C 11 alkyl.
5. The compound of claim 4 , having the formula ER-820842:
6. The compound of claim 1 , wherein A is —(CH 2 ) 2 —O—; n is 1 ; R 4 is a C 7 alkyl; and R 5 is a C 11 alkyl.
7. The compound of claim 6 , having the formula ER-819344:
8. The compound of claim 1 , wherein A is a covalent bond, n is 0; R 4 is a C 7 alkyl; and R 5 is a C 11 alkyl.
9. The compound of claim 8 , having the formula ER-819385:
10. The compound of claim 1 , wherein A is a covalent bond, n is 0; R 3a and R 3b are each isopropyl; R 4 is a C 7 alkyl; and R 5 is a C 11 alkyl.
11. The compound of claim 10 , having the formula ER820116:
12. The compound of claim 2 , wherein the protecting group on the nitrogen linked to R 2a and R 2b can be removed under a first condition selected from acidic, basic, oxidative, and reductive conditions; and the protecting group on the nitrogen linked to R 3a and R 3b can be removed under a second condition selected from the remaining three conditions that are different from the first condition.
13. The compound of claim 2 , wherein A is —(CH 2 ) 2 —O—; n is 0; R 4 is a C 7 alkyl; and R 5 is a C 11 alkyl.
14. The compound of claim 13 , having the formula ER-820842:
15. The compound of claim 2 , wherein A is —(CH 2 ) 2 —O—; n is 1; R 4 is a C 7 alkyl; and R 5 is a C 11 alkyl.
16. The compound of claim 15 , having the formula ER-819344:
17. The compound of claim 2 , wherein A is a covalent bond, n is 0; R 4 is a C 7 alkyl; and R 5 is a C 11 alkyl.
18. The compound of claim 17 , having the formula ER-819385:
19. The compound of claim 2 , wherein A is a covalent bond, n is 0; R 3a and R 3b are each isopropyl; R 4 is a C 7 alkyl; and R 5 is a C 11 alkyl.
20. The compound of claim 19 , having the formula ER820116: