Tetracycline derivatives with reduced antibiotic activity and neuroprotective benefits
The present disclosure is directed to compositions and methods which utilize the tetracycline scaffold, preferably the scaffold of tetracycline or minocycline, and which significantly lack antibiotic activity. The compounds have neuroprotective attributes without interfering with the drugs capacity to pass through the blood brain barrier. These compounds have neuroprotective activity because of their inhibition of neuronal cell cycle progression. The compounds are characterized in part by a fifth ring joining positions 9 and 10.
1. A compound having the formula:
where R 4 , R 6 R 9 , and R 10 are defined as follows:
R 4 is a substitution selected from the group consisting of —N(CH 3 ) 2 , N(CH 3 ) 2 , NH(CH 2 CH 2 OH), and amino alkyl, or else R 4 is a disubstitution selected from the group consisting of (i) a first substitution of —N(CH 3 ) 2 and a second substitution of substituted alkyl, and (ii) a first substitution of amino alkyl and a second substitution of lower alkyl;
R 6 is H or —CH 2 S—R″, where R″ is aryl or substituted aryl; and
either R 9 is H and R 10 is OH or lower alkyl, or else
R 10 and R 9 taken together have the formula (from R 10 -R 9 ) (a) —O—Y—HN—, where Y is CH and the bond Y—N is double, (b) —O—Y—HN—, where Y is C═O, or (c) —O—CH 2 —C(═O)—HN—;
or a pharmaceutically acceptable salt thereof,
with the proviso that when R 9 is H and R 10 is OH or lower alkyl, R 6 is not H.
2. The compound of claim 1 , where R 4 is NH(CH 2 CH 2 OH) or N(CH 3 ) 2 .
3. The compound of claim 2 , where the compound is an up epimer at R 4 .
4. The compound of claim 1 , where R 4 is the disubstitution.
5. The compound of claim 1 , where R 6 is a substitutent that reduces antibiotic potency.
6. The compound of claim 1 , where R″ at R 6 is benzyl or phenyl.