7-N-substituted phenyl tetracycline compounds
View Patent ↗7-substituted tetracycline compounds, methods of treating tetracycline responsive states, and pharmaceutical compositions containing the 7-substituted tetracycline compounds are described.
1. A method for synthesizing a compound of formula I:
wherein:
R 4 and R 4′ are each alkyl;
R 5 is hydrogen, hydroxyl, or a prodrug moiety;
R 6 and R 6′ are each independently hydrogen, hydroxyl, alkyl, or taken together, alkenyl;
R 7 is an N-substituted phenyl;
or a pharmaceutically acceptable salt thereof;
comprising:
(a) treating unsubstituted sancycline with at least one equivalent N-iodosuccinimide under acidic conditions to form 7-iodosancycline; and
(b) reacting said 7-iodosancycline with a N-substituted phenylboronic acid to form a compound of formula I.
2. The method of claim 1 , further comprising quenching the reaction of step (a).
3. The method of claim 2 , further comprising purifying the 7-iodosancycline.
4. The method of claim 1 , wherein said step (b) further comprises reacting said 7-iodosancycline and a palladium catalyst in a solvent with sodium carbonate and a N-substituted phenylboronic acid to form a compound of formula I.
5. The method of claim 4 , further comprising purifying the compound of formula I.
6. The method of claim 4 , wherein said palladium catalyst is Pd(OAc) 2 .
7. The method of claim 1 , wherein said compound of formula I is selected from: 7-(2-nitrophenyl)sancycline, 7-(2-aminophenyl)sancycline, 7-(2-N,N-dimethylaminophenyl)sancycline, 7-(2-N,N-diethylaminophenyl)sancycline, 7-(2-N,N-dipropylaminophenyl)sancycline, 7-(2-N,N-dibutylaminophenyl)sancycline, 7-(3-nitrophenyl)sancycline, 7-(3-aminophenyl)sancycline, 7-(3-N,N-dimethylaminophenyl)sancycline, 7-(3-N,N-diethylaminophenyl)sancycline, 7-(3-N,N-dipropylaminophenyl)sancycline, 7-(3-N,N-dibutylaminophenyl)sancycline, 7-(4-aminophenyl)sancycline, 7-(4-nitrophenyl)sancycline, 7-(4-N,N-diethylaminophenyl)sancycline, 7-(4-N,N-dipropylaminophenyl)sancycline, or 7-(4-N,N-dibutylaminophenyl)sancycline and 7-(4-N,N-dimethylaminophenyl)sancycline.
8. A method for synthesizing a compound of formula I:
wherein:
R 4 and R 4′ are each alkyl;
R 5 is hydrogen, hydroxyl, or a prodrug moiety;
R 6 and R 6′ are each independently hydrogen, hydroxyl, alkyl, or taken together, alkenyl;
R 7 is an N-substituted phenyl;
or a pharmaceutically acceptable salt thereof;
comprising:
(a) treating unsubstituted sancycline with at least one equivalent N-iodosuccinimide under acidic conditions to form 7-iodosancycline;
(b) adding a tin reagent to said 7-iodosancycline and treating with a palladium catalyst to form a compound of formula I.
9. The method of claim 8 , wherein said tin reagent is a tributylstannyl reagent.
10. The method of claim 8 , wherein said palladium catalyst is Pd(PPh 3 ) 2 Cl 2 .
11. The method of claim 8 , wherein said palladium catalyst is Pd(AsPh 3 ) 2 Cl 2 .
12. The method of claim 8 , wherein said step (b) further comprises treating with a copper salt.
13. The method of claim 12 , wherein said copper salt is CuI.
14. The method of claim 8 , further comprising purifying the compound of formula I.
15. The method of claim 8 , wherein said compound of formula I is selected from: 7-(2-nitrophenyl)sancycline, 7-(2-aminophenyl)sancycline, 7-(2-N,N-dimethylaminophenyl)sancycline, 7-(2-N,N-diethylaminophenyl)sancycline, 7-(2-N,N-dipropylaminophenyl)sancycline, 7-(2-N,N-dibutylaminophenyl)sancycline, 7-(3-nitrophenyl)sancycline, 7-(3-aminophenyl)sancycline, 7-(3-N,N-dimethylaminophenyl)sancycline, 7-(3-N,N-diethylaminophenyl)sancycline, 7-(3-N,N-dipropylaminophenyl)sancycline, 7-(3-N,N-dibutylaminophenyl)sancycline, 7-(4-aminophenyl)sancycline, 7-(4-nitrophenyl)sancycline, 7-(4-N,N-diethylaminophenyl)sancycline, 7-(4-N,N-dipropylaminophenyl)sancycline, or 7-(4-N,N-dibutylaminophenyl)sancycline and 7-(4-N,N-dimethylaminophenyl)sancycline.