Monoacylated betulin and dihydrobetulin derivatives, preparation thereof and use thereof
View Patent ↗Betulin and dihydrobetulin acyl derivatives according to the present invention have been found to have potent anti-HIV activity. The compounds of the present invention have Formula I as described herein, or pharmaceutically acceptable salts thereof; wherein R 1 is a C 2 -C 20 substituted or unsubstituted carboxyacyl or ester thereof; R 2 is hydrogen, halogen, hydroxyl or —OR 3 , R 3 is C 2 -C 20 substituted or unsubstituted carboxyacyl; and R 4 is hydrogen or C(C 6 H 5 ) 3 ; wherein the dashed line represents an optional double bond between C20 and C29.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein: R 1 is one of:
(i) —C(O)CH 2 CR′R″(CH 2 ) b COOH,
(ii) —C(O)(CH 2 ) d CR′R″(CH 2 ) b COOR 5 , or
(iii) —C(O)CH 2 O(CH 2 ) a COOH
wherein when R 1 is (i), R′ and R″ are each C 1 -C 4 alkyl, or R′ and R″ are taken together to form a di-, tri-, tetra-, penta-, hexa-, or heptamethylene linkage, and
when R 1 is (ii), R′ and R″ are each C 1 -C 4 alkyl, or R′ is hydrogen and R″ is C 1 -C 4 alkyl, or R′ and R″ are taken together to form a di-, tri-, tetra-, penta-, hexa-, or heptamethylene linkage;
R 5 is C 1 -C 6 alkyl or C 1 -C 6 carboxyalkyl,
a is from zero to twelve,
b is from zero to twelve,
d is from zero to twelve;
R 2 is hydrogen, halogen, hydroxyl or —OR 3 ;
R 3 is C 2 -C 20 substituted or unsubstituted carboxyacyl; and
R 4 is hydrogen or C(C 6 H 5 ) 3 ;
wherein the dashed line represents an optional double bond between C20 and C29.
2. A compound according to claim 1 , wherein R 2 is hydrogen.
3. A compound according to claim 1 , wherein R 2 is halogen or —OR 3 , where R 3 is hydrogen or C 2 -C 20 substituted or unsubstituted carboxyacyl.
4. A compound according to claim 1 , wherein R 1 has the formula:
—C(O)CH 2 CR′R″(CH 2 ) b COOH
where R′ and R″ are each C 1 -C 4 alkyl, or R′ and R″ are taken together to form a di-, tri, tetra-, penta-, hexa-, or heptamethylene linkage, and b is from zero to twelve.
5. A compound according to claim 4 , wherein b is zero to 4.
6. A compound according to claim 5 , wherein R′ and R″ are each methyl, and b is zero or 1.
7. A compound according to claim 1 , wherein R 1 has the formula:
—C(O)CH 2 O(CH 2 ) a COOH,
where a is from zero to twelve.
8. A compound according to claim 1 , wherein R 1 has the formula:
—C(O)(CH 2 ) d CR′R″(CH 2 ) b COOR 5 ,
wherein;
R′ and R″ are each C 1 -C 4 alkyl, or R′ is hydrogen and R″ is C 1 -C 4 alkyl, or R′ and R″ are taken together to form a di-, tri, tetra-, penta-, hexa-, or heptamethylene linkage;
d is from zero to twelve;
b is from zero to twelve; and
R 5 is C 1 -C 6 alkyl or C 1 -C 6 carboxyalkyl.
9. A compound according to claim 8 , wherein R 5 is ethyl.
10. A compound according to claim 1 , wherein R 2 is hydrogen and a double bond exists between C20 and C29.
11. A compound according to claim 1 , wherein R 2 is:
—O—C(O)CH 2 CR′R″(CH 2 ) b COOH,
where R′ and R″ are each methyl, and b is zero or one.
12. A compound according to claim 1 , wherein:
R 1 is one of:
R 2 is hydrogen or hydroxyl.
13. A compound according to claim 1 , wherein:
R 1 is
R 2 is hydrogen.
14. A compound according to claim 1 , wherein:
R 1 is
15. A compound according to claim 1 , wherein:
R 1 is
R 2 is H; and
a double bond exists between C20 and C29.
16. A compound according to claim 1 , wherein:
R 1 is
R 2 is H; and
a single bond exists between C20 and C29.
17. A compound according to claim 1 , wherein R 1 and R 3 can be optionally substituted with one to three hydroxyl or halogen.
18. A pharmaceutical composition comprising one or more compounds according to claim 1 , or a pharmaceutically acceptable salt, ester, or prodrug thereof, and ester, salt, ether, sulfate, or glucuronide thereof, and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition according to claim 18 , further comprising one or more drugs selected from an anti-viral agent or an immunostimulating agent.
20. A pharmaceutical composition according to claim 19 , wherein said anti-viral agent is selected from the group consisting of one or more of zidovudine, lamivudine, zalcitabine, stavudine, didanosine, tenofovir, abacavir, nevirapine, delavirdine, emtricitabine, efavirenz, saquinavir, ritonavir, indinavir, nelfinavir, lopinavir, amprenavir, atazanavir, enfuvirtide, hydroxyurea, interleukin-2, gamma globulin, amantadine, guanidine hydroxybenzimidazole, interferon-α, interferon-β, interferon-γ, a thiosemicarbazone, methisazone, rifampin, ribavirin, a pyrimidine analog, a purine analog, foscarnet, phosphonoacetic acid, acyclovir, a dideoxynucleoside, and gancyclovir.
21. A pharmaceutical composition comprising one or more compounds according to claim 4 , or a pharmaceutically acceptable salt, ester, or prodrug thereof, ester, salt, ether, sulfate, or glucuronide thereof, and a pharmaceutically acceptable carrier.
22. A pharmaceutical composition according to claim 21 , further comprising a drug selected from an anti-viral agent or an immunostimulating agent.
23. A pharmaceutical composition according to claim 22 , wherein said anti-viral agent is selected from the group consisting of one or more of zidovudine, lamivudine, zalcitabine, stavudine, didanosine, tenofovir, abacavir, nevirapine, delavirdine, emtricitabine, efavirenz, saquinavir, ritonavir, indinavir, nelfinavir, lopinavir, amprenavir, fosamprenavir, atazanavir, enfuvirtide, hydroxyurea, interleukin-2, gamma globulin, amantadine, guanidine hydroxybenzimidazole, interferon-α, interferon-β, interferon-γ, a thiosemicarbazone, methisazone, rifampin, ribavirin, a pyrimidine analog, a purine analog, foscarnet, phosphonoacetic acid, acyclovir, a dideoxynucleoside, and ganciclovir.