4-substituted tetracyclines and methods of use thereof
View Patent ↗The present invention pertains, at least in part, to novel substituted tetracycline compounds. These tetracycline compounds can be used to treat numerous tetracycline compound-responsive states, such as bacterial infections and neoplasms, as well as other known applications for tetracycline compounds such as blocking tetracycline efflux and modulation of gene expression.
1. A compound of formula (I):
wherein:
R 2′ and R 2 are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R 10 , R 11 and R 12 are each independently hydrogen, alkyl, aryl, benzyl, arylalkyl, or a prodrug moiety;
R 3 is hydrogen, or a prodrug moiety;
R 4 is N—OR 4a ;
R 4a is hydrogen, alkyl, alkenyl, alkynyl, or aryl;
R 5 and R 5′ are each independently hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;
R 6 and R 6′ are each independently hydrogen, methylene, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R 7 is hydrogen or dimethylamino;
R 8 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH 2 ) 0-3 (NR 8C ) 0-1 C (═E′)ER 8a ;
R 9 is hydrogen or aminoalkyl;
R 8a , R 8b , R 8c , R 8d , R 8e and R 8f are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R 13 is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
E is CR 8d R 8e , S, NR 8b or O;
E′ is O, NR 8f , or S;
X is CHC(R 13 Y′Y), C═CR 13 Y, CR 6′ R 6 , S, NR 6 , O;
Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyan, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; or a pharmaceutically acceptable salt, ester or enantiomer thereof.
2. The compound of claim 1 , wherein R 2′ , R 3 , R 10 , R 11 , and R 12 are each hydrogen or a prodrug moiety; X is CR 6′ R 6 ; and R 2 , R 5 , R 5′ , R 6 , and R 6′ are each hydrogen.
3. The compound of claim 1 , wherein X is CR 6′ R 6 ; R 5 , R 5′ , R 6 and R 6′ are each hydrogen and R 7 is dimethylamino.
4. The compound of claim 2 , wherein R 9 is hydrogen.
5. The compound of claim 2 , wherein R 7 is dimethylamino.
6. The compound of claim 2 , wherein R 8 is hydrogen.
7. The compound of claim 2 , wherein R 4 is N—OH.
8. The compound of claim 1 , wherein said compound is selected from the group consisting of:
and pharmaceutically acceptable salts, esters and enantiomers thereof.
9. A compound selected from:
and pharmaceutically acceptable salts, esters and enantiomers thereof.
10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.