7-phenyl-substituted tetracycline compounds

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 halo-substituted or unsubstituted 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 halo-substituted or unsubstituted 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 aqueous sodium carbonate and a halo-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-phenyl sancycline, 7-(2-chlorophenyl)sancycline, 7-(2-bromophenyl)sancycline, 7-(2-fluorophenyl)sancycline, 7-(2-iodophenyl)sancycline, 7-(3-chlorophenyl)sancycline, 7-(3-bromophenyl)sancycline, 7-(3-fluorophenyl)sancycline, 7-(3-iodophenyl)sancycline, 7-(4-chlorophenyl)sancycline, 7-(4-bromophenyl)sancycline, 7-(4-fluorophenyl)sancycline, 7-(4-iodophenyl)sancycline, 7-(4-trifluoromethylphenyl)sancycline, 7-(4-tribromomethylphenyl)sancycline, 7-(4-trichloromethylphenyl)sancycline, 7-(4-triiodomethylphenyl)sancycline, 7-(2,4-dichlorophenyl)sancycline, 7-(2,4-dibromophenyl)sancycline, 7-(2,4-difluorophenyl)sancycline, 7-(2,4-diiodophenyl)sancycline, 7-(2,6-dichlorophenyl)sancycline, 7-(2,6-dibromophenyl)sancycline, 7-(2,6-difluorophenyl)sancycline and 7-(2,6-diiodophenyl)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 halo-substituted or unsubstituted 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) 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-phenyl sancycline, 7-(2-chlorophenyl)sancycline, 7-(2-bromophenyl)sancycline, 7-(2-fluorophenyl)sancycline, 7-(2-iodophenyl)sancycline, 7-(3-chlorophenyl)sancycline, 7-(3-bromophenyl)sancycline, 7-(3-fluorophenyl)sancycline, 7-(3-iodophenyl)sancycline, 7-(4-chlorophenyl)sancycline, 7-(4-bromophenyl)sancycline, 7-(4-fluorophenyl)sancycline, 7-(4-iodophenyl)sancycline, 7-(4-trifluoromethylphenyl)sancycline, 7-(4-tribromomethylphenyl)sancycline, 7-(4-trichloromethylphenyl)sancycline, 7-(4-triiodomethylphenyl)sancycline, 7-(2,4-dichlorophenyl)sancycline, dibromophenyl)sancycline, 7-(2,4-difluorophenyl)sancycline, 7-(2,4-diiodophenyl)sancycline, 7-(2,6-dichlorophenyl)sancycline, 7-(2,6-dibromophenyl)sancycline, difluorophenyl)sancycline and 7-(2,6-diiodophenyl)sancycline.