Oxidative dearomatization of berbines
View Patent ↗The present disclosure provides oxidized berbine derivatives, processes for their preparation, and methods of using the oxidized berbine derivatives.
1. A compound of Formula (VIIIa), Formula (VIIIb), or a pharmaceutically acceptable salt thereof:
wherein:
R is hydrocarbyl or substituted hydrocarbyl;
R 1 , R 2 , R 3 , and R 4 independently are hydrogen, halogen, OR 15 , NO 2 , NR 15 R 16 , cyano, thiol, hydrocarbyl, substituted hydrocarbyl, or together R 2 and R 3 form {—}O(CH 2 ) n O{—};
R 5 , R 6 , when present, R 7 , and R 8 , when present, independently are hydrogen, halogen, OR 15 , NO 2 , NR 15 R 16 , cyano, thiol, hydrocarbyl, or substituted hydrocarbyl;
R 0 , R 9 , R 10 , R 11 , and R 12 independently are hydrogen, halogen, hydrocarbyl, or substituted hydrocarbyl;
R 15 and R 16 independently are hydrogen, hydrocarbyl, or substituted hydrocarbyl; and
n is an integer from 1 to 3.
2. The compound of claim 1 , wherein R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, or substituted aryl; R 1 , R 2 , R 3 , and R 4 independently are hydrogen, halogen, OR 15 , NO 2 , NR 15 R 16 , or together R 2 and R 3 form {—}O(CH 2 ) n O{—}; R 0 , R 9 , R 10 , R 11 , and R 12 independently are hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, or substituted aryl; R 5 , R 6 , when present, R 7 , and R 8 , when present, independently are hydrogen, halogen, OR 15 , NO 2 , or NR 15 R 16 ; and R 15 and R 16 independently are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, or substituted aryl.
3. The compound of claim 2 , wherein each of R 0 , R 1 , R 4 , R 9 , R 10 , R 11 , and R 12 is hydrogen; R 2 and R 3 independently are hydrogen, halogen, hydroxy, C 1 -C 6 alkoxy, aryloxy, amine, amino, nitro, or together R 2 and R 3 form {—}O(CH 2 ) n O{—}; and R 5 , R 6 , when present, R 7 , and R 8 , when present, independently are hydrogen, halogen, hydroxy, C 1 -C 6 alkoxy, aryloxy, amine, amino, or nitro.
4. The compound of claim 3 , wherein R 2 is hydroxy or C 1 -C 6 alkoxy and R 3 is hydrogen, or together R 2 and R 3 form {—}O(CH 2 )O{—}.
5. The compound of claim 4 , wherein R is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl.
6. A composition comprising one of the compounds of claim 1 and at least one pharmaceutically acceptable excipient.
7. A process for preparing a compound of Formula (VIIIa) or Formula (VIIIb), the process comprising either step a) or step b):
a) contacting a compound of Formula (VIIa) with an oxidizing agent to form the compound of Formula (VIIIa) according to the following reaction scheme:
or
b) contacting a compound of Formula (VIIb) with an oxidizing agent to form the compound of Formula (VIIIb) according to the following reaction scheme:
wherein:
R is hydrocarbyl or substituted hydrocarbyl;
R 1 , R 2 , R 3 , and R 4 independently are hydrogen, halogen, OR 15 , NO 2 , NR 15 R 16 , cyano, thiol, hydrocarbyl, substituted hydrocarbyl, or together R 2 and R 3 form {—}O(CH 2 ) n O{—};
R 5 , R 6 , when present, R 7 , and R 8 , when present, independently are hydrogen, halogen, OR 15 , NO 2 , NR 15 R 16 , cyano, thiol, hydrocarbyl, or substituted hydrocarbyl;
R 0 , R 9 , R 10 , R 11 , and R 12 independently are hydrogen, halogen, hydrocarbyl, or substituted hydrocarbyl;
R 15 and R 16 independently are hydrogen, hydrocarbyl, or substituted hydrocarbyl;
n is an integer from 1 to 3; and
wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , when present, R 7 , and R 8 , when present, is other than hydroxy.
8. The process of claim 7 , wherein R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, or substituted aryl; R 1 , R 2 , R 3 , and R 4 independently are hydrogen, halogen, OR 15 , NO 2 , NR 15 R 16 , or together R 2 and R 3 form {—}O(CH 2 ) n O{—}; R 0 , R 9 , R 10 , R 11 , and R 12 independently are hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, or substituted aryl; R 5 , R 6 , when present, R 7 , and R 8 , when present, independently are hydrogen, halogen, OR 15 , NO 2 , or NR 15 R 16 ; and R 15 and R 16 independently are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, or substituted aryl.
9. The process of claim 8 , wherein each of R 0 , R 1 , R 4 , R 9 , R 10 , R 11 , and R 12 is hydrogen; R 2 and R 3 independently are hydrogen, halogen, hydroxy, C 1 -C 6 alkoxy, aryloxy, amine, amino, nitro, or together R 2 and R 3 form {—}O(CH 2 ) n O{—}; and R 5 , R 6 , when present, R 7 , and R 8 , when present, independently are hydrogen, halogen, hydroxy, C 1 -C 6 alkoxy, aryloxy, amine, amino, or nitro.
10. The process of claim 9 , wherein R is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl; R 2 is hydroxy or C 1 -C 6 alkoxy and R 3 is hydrogen, or together R 2 and R 3 form {—}O(CH 2 )O{—}; R 5 is hydrogen or halogen; R 6 , when present, is hydrogen, R 7 is hydroxy or C 1 -C 6 alkoxy; and R 8 , when present, is hydrogen.
11. The process of claim 7 , wherein the oxidizing agent is a halogen or a quinone; the mole to mole ratio of the compound of Formula (VIIa) or Formula (VIIb) to the oxidizing agent is from about 1:1 to about 1:10; and the contacting is conducted at a temperature from about −50° C. to about 200° C.
12. The process of claim 7 , wherein the contacting is conducted in the presence of a non-oxidizable solvent; and the volume to mass ratio of the solvent to the compound of Formula (VIIa) or Formula (VIIb) is from about 10:1 to about 300:1.
13. The process of claim 7 , wherein the contacting is conducted in the presence of proton acceptor chosen from an acetate salt, a bicarbonate salt; a borate salt, a carbonate salt, a hydroxide salt, a phosphate salt, a butoxide, an organic base, or a combination thereof; and the mole to mole ratio of the compound of Formula (VIIa) or Formula (VIIb) to the proton acceptor is from about 1:1 to about 1:10.
14. The process of claim 11 , wherein the contacting is conducted in the presence of a solvent chosen from an alcohol or acetonitrile; and the volume to mass ratio of the solvent to the compound of Formula (VIIa) or Formula (VIIb) is from about 50:1 to about 250:1.
15. The process of claim 14 , wherein the contacting is conducted in the presence of an acetate salt; and the mole to mole ratio of the compound of Formula (VIIa) or Formula (VIIb) to the acetate salt is from about 1:3 to about 1:7.
16. A method for inhibiting the growth of a cancer cell, the method comprising contacting the cancer cell with an effective amount of a compound of Formula (VIIIa), Formula (VIIIb), or a pharmaceutically acceptable salt thereof:
wherein:
R is hydrocarbyl or substituted hydrocarbyl;
R 1 , R 2 , R 3 , and R 4 independently are hydrogen, halogen, OR 15 , NO 2 , NR 15 R 16 , cyano, thiol, hydrocarbyl, substituted hydrocarbyl, or together R 2 and R 3 form {—}O(CH 2 ) n O{—};
R 5 , R 6 , when present, R 7 , and R 8 , when present, independently are hydrogen, halogen, OR 15 , NO 2 , NR 15 R 16 , cyano, thiol, hydrocarbyl, or substituted hydrocarbyl;
R 0 , R 9 , R 10 , R 11 , and R 12 independently are hydrogen, halogen, hydrocarbyl, or substituted hydrocarbyl;
R 15 and R 16 independently are hydrogen, hydrocarbyl, or substituted hydrocarbyl; and
n is an integer from 1 to 3.
17. The method of claim 16 , wherein R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, or substituted aryl; R 1 , R 2 , R 3 , and R 4 independently are hydrogen, halogen, OR 15 , NO 2 , NR 15 R 16 , or together R 2 and R 3 form {—}O(CH 2 ) n O{—}; R 0 , R 9 , R 10 , R 11 , and R 12 independently are hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, or substituted aryl; R 5 , R 6 , when present, R 7 , and R 8 , when present, independently are hydrogen, halogen, OR 15 , NO 2 , or NR 15 R 16 ; and R 15 and R 16 independently are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, or substituted aryl.
18. The method of claim 17 , wherein each of R 0 , R 1 , R 4 , R 9 , R 10 , R 11 , and R 12 is hydrogen; R 2 and R 3 independently are hydrogen, halogen, hydroxy, C 1 -C 6 alkoxy, aryloxy, amine, amino, nitro, or together R 2 and R 3 form {—}O(CH 2 ) n O{—}; and R 5 , R 6 , when present, R 7 , and R 8 , when present, independently are hydrogen, halogen, hydroxy, C 1 -C 6 alkoxy, aryloxy, amine, amino, or nitro.
19. The method of claim 18 , wherein R is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl; R 2 is hydroxy or C 1 -C 6 alkoxy and R 3 is hydrogen, or together R 2 and R 3 form {—}O(CH 2 )O{—}; R 5 is hydrogen or halogen; R 6 , when present, is hydrogen, R 7 is hydroxy or C 1 -C 6 alkoxy; and R 8 , when present, is hydrogen.
20. The method of claim 16 , wherein the cancer cell is in vitro.