Triterpene saponins, methods of synthesis, and uses thereof
The present invention relates to triterpene glycoside saponin-derived adjuvants, syntheses thereof, intermediates thereto, and uses thereof. QS-7 is a potent immuno-adjuvant that is significantly less toxic than QS-21, a related saponin that is currently the favored adjuvant in anticancer and antiviral vaccines. Tedious isolation and purification protocols have hindered the clinical development of QS-7. A novel semi-synthetic method is provided wherein a hydrolyzed prosapogenin mixture is used to synthesize QS-7, QS-21, and related analogs, greatly facilitating access to QS-7 and QS-21 analogs for preclinical and clinical evaluation.
1. A compound of formula X:
or a pharmaceutically acceptable salt thereof, wherein:
is a single or double bond;
W is Me, —CHO,
—CH 2 OR x , or —C(O)R y ;
V is hydrogen or —OR x ;
Y is CH 2 , —O—, —NR—, or —NH—;
Z is a carbohydrate domain having the structure:
wherein:
R 2 is hydrogen, halogen, OH, OR, OC(O)R 4 , OC(O)OR 4 , OC(O)NHR 4 , OC(O)NRR 4 , OC(O)SR 4 , NHC(O)R 4 , NRC(O)R 4 , NHC(O)OR 4 , NHC(O)NHR 4 , NHC(O)NRR 4 , N(R 4 ) 2 , NHR 4 , NRR 4 , N 3 , or an optionally substituted group selected from C 1-10 aliphatic, C 1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
R 3 is hydrogen, halogen, CH 2 OR 1 , or an optionally substituted group selected from the group consisting of acyl, C 1-10 aliphatic, C 1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 hetero atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; with the proviso that R 3 is not methyl;
R 4 is
wherein X is —O— or —NR—; or
T-R z , wherein:
T is a covalent bond or a bivalent C 1-26 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and
R z is hydrogen, halogen, —OR, —OR x , —OR 1 , —SR, —NR 2 , —NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C 1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; or
two R 4 on the same nitrogen atom are taken with the nitrogen to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
each occurrence of R x is independent hydrogen or an oxygen protecting group selected form the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates
R y is —OH, —OR, or a carboxyl protecting group, wherein the carboxyl protecting group when taken with its attached carbonyl group, is an ester, amides, or hydrazide;
each occurrence of R x′ is independently an optionally substituted group selected from 6-10-membered aryl, C 1-6 aliphatic, or C 1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or:
two R x′ are taken together to form a 5-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and
each occurrence of R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C 1-12 aliphatic, or C 1-12 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or:
two R on the same nitrogen atom are taken with the nitrogen to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and
wherein each occurrence of R 1 is independently selected from the group consisting of:
wherein R 5 and R 6 are independently hydrogen, an optionally substituted group selected from the group consisting of acyl, C 1-10 aliphatic, C 1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
2. The compound according to claim 1 , wherein R 2 is N 3 , OC(O)R 4 , OC(O)NHR 4 , NHC(O)R 4 , NRC(O)R 4 , NHC(O)OR 4 , or NHC(O)NHR 4 .
3. The compound according to claim 1 , wherein R 2 is NHC(O)R 4 .
4. The compound according to claim 3 , wherein R 4 is -T-R z .
5. The compound according to claim 4 , wherein -T- is
6. The compound according to claim 4 , wherein R z is hydrogen, halogen, —OR x , OR 1 , —OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C 1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.
7. The compound according to claim 6 , wherein R z is selected from hydrogen, methyl, or
8. The compound according to claim 1 , wherein each of R 3 , R 5 , and R 6 is independently an optionally substituted C 1-10 aliphatic group.
9. The compound according to claim 8 , wherein each of R 5 and R 6 is independently methyl.
10. The compound according to claim 8 , wherein each of R 3 , R 5 , and R 6 is independently CH 2 OR.
11. The compound according to claim 8 , wherein one or more of R 3 , R 5 , and R 6 is CH 2 OH.
12. The compound according to claim 8 , wherein each of R 3 , R 5 , and R 6 is CH 2 OH.
13. A pharmaceutical composition comprising:
a compound of formula X:
or a pharmaceutically acceptable salt thereof, wherein:
is a single or double bond;
W is Me, —CHO,
—CH 2 OR x , or —C(O)R y ;
V is hydrogen or —OR x ;
Y is CH 2 , —O—, —NR—, or —NH—;
Z is a carbohydrate domain having the structure:
wherein:
each occurrence of R 1 is R x or a carbohydrate domain having the structure:
wherein:
each occurrence of a, b, and c is independently 0, 1, or 2; d is an integer from 1-5,
wherein each d bracketed structure may be the same or different; with the proviso that the d bracketed structure represents a furanose or pyranose moiety, and the sum of b and c is 1 or 2;
R 0 is hydrogen, an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; or an optionally substituted moiety selected from the group consisting of acyl, C 1-10 aliphatic, C 1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
each occurrence of R a , R b , R c , and R d is independently hydrogen, halogen, OH, OR, OR x , NR 2 , NHCOR, or an optionally substituted group selected from acyl, C 1-10 aliphatic, C 1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
R 2 is hydrogen, halogen, OH, OR, OC(O)R 4 , OC(O)OR 4 , OC(O)NHR 4 —, OC(O)NRR 4 , OC(O)SR 4 , NHC(O)R 4 , NRC(O)R 4 , NHC(O)OR 4 , NHC(O)NHR 4 , NHC(O)NRR 4 , N(R 4 ) 2 , NHR 4 , NRR 4 , N 3 , or an optionally substituted group selected from C 1-10 aliphatic, C 1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
R 3 is hydrogen, halogen, CH 2 OR 1 , or an optionally substituted group selected from the group consisting of acyl, C 1-10 aliphatic, C 1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; with the proviso that R 3 is not methyl;
R 4 is
wherein X is —O— or —NR—; or T-R z ,
wherein:
T is a covalent bond or a bivalent C 1-26 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and
R z is hydrogen, halogen, —OR, —OR 1 , —OR 1 , —SR, —NR 2 , —NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl C 1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; or two R 4 on the same nitrogen atom are taken with the nitrogen to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
each occurrence of R x is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates;
R y is —OH, —OR, or a carboxyl protecting group, wherein the carboxyl protecting group when taken with its attached carbonyl group, is an ester, amide, or hydrazide;
each occurrence of R x ′ is independently an optionally substituted group selected from 6-10-membered aryl, C 1-6 aliphatic, or C 1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or:
two R x ′ are taken together to form a 5-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and
each occurrence of R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C 1-12 aliphatic, or C 1-12 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or:
two R on the same nitrogen atom are taken with the nitrogen to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
a pharmaceutically acceptable excipient; and
an immunologically effective amount of an antigen.