Substituted Tetracycline Compounds
The present invention pertains, at least in part, to methods of treating a microorganism-associated infection in a subject comprising administering to said subject an effective amount of a tetracycline compound.
1 . A method of treating a microorganism-associated infection in a subject comprising administering to said subject an effective amount of a tetracycline compound, wherein said tetracycline compound is of formula I:
wherein
X is CHC(R 13 Y′Y), CR 6′ R 6 , C═CR 6′ R 6 , S, NR 6 , or O;
R 2 , R 2′ , R 4′ , and R 4″ are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or a prodrug moiety;
R 3 , R 4a , R 11 and R 12 are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or a prodrug moiety;
R 4 is NR 4′ R 4″ , hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or a prodrug moiety;
R 5 and R 5′ are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or a prodrug moiety;
R 6 and R 6′ are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic;
R 7 is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, oximyl, aryl, heterocyclic or —(CH 2 ) 0-3 (R 7c ) 0-1 C(═W)WR 7a ;
R 8 is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl, heterocyclic or —(CH 2 ) 0-3 (NR 8c ) 0-1 C(=E′)ER 8a ;
R 9 is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl, heterocyclic or —(CH 2 ) 0-3 (NR 9c ) 0-1 C(=Z′)ZR 9a ;
R 10 is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic;
R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 9a , R 9b , R 9c , R 9d , R 9e , and R 9f are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; R 13 is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic;
E is CR 8d R 8e , S, NR 8b or O;
E′ is O, NR 8f , or S;
W is CR 7d R 7e , S, NR 7b or O;
W′ is O, NR 7f , or S;
X is CHC(R 13 Y′Y), C═CR 13 Y, CR 6′ R 6 , S, NR 6 , or O;
Z is CR 9d R 9e S, NR 9b or O;
Z′ is O, S, or NR 9f ;
Y′ and Y are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; or a pharmaceutically acceptable salt, ester or enantiomer thereof;
such that said subject is treated.
2 . The method of claim 1 , wherein X is CR 6 R 6′ ; R 2′ , R 2″ , R 3 , R 4a , R 5 , R 5′ , R 6 , R 6′ , R 8 , R 9 , R 11 and R 12 are each hydrogen; R 4 is NR 4′ R 4″ and R 4′ and R 4″ are each alkyl.
3 . The method of claim 2 , wherein said alkyl is methyl.
4 . The method of claim 1 , wherein R 7 is aryl.
5 . The method of claim 1 , wherein said aryl is of formula XI:
wherein
A g , A h , A i , A j and A k are each independently N or C; and
when A g , A h , A i , A j and A k are C; R 7g , R 7h , R 7i , R 7j and R 7k are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R 7j and R 7i are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring; or R 7g , R 7h , R 7i , R 7j and R 7k are absent when A g , A h , A i , A j and A k are N.
6 . The method of claim 5 , wherein A g , A h , A i , A j or A k are each C.
7 . The method claim 6 , wherein R 7g , R 7h , R 7i and R 7k are each hydrogen.
8 . The method of claim 7 , wherein R 7j is carbonyl.
9 . The method of claim 1 , wherein R 7 is selected from the group consisting of phenyl, furanyl, piperidinyl, isoquinolinyl, pyridinyl, pyrrolyl, and piperazinyl.
10 . The method of claim 1 , wherein said tetracycline compound is a compound of formula II, III, IV, V, VI, VII, VIII, IX or X.
11 . The method of claim 1 , wherein said tetracycline compound is selected from the group consisting of:
and pharmaceutically acceptable salts, esters and enantiomers thereof.
12 . The method of claim 1 , wherein said microorganism-associated infection is a bacterial infection.
13 . The method of claim 12 , wherein said bacterial infection is associated with E. coli.
14 . The method of claim 12 , wherein said bacterial infection is associated with S. aureus.
15 . The method of claim 12 , wherein said bacterial infection is associated with S. pneumonia.
16 . The method of claim 12 , wherein said bacterial infection is resistant to other tetracycline antibiotics.
17 . The method of claim 1 , wherein said subject is a human.
18 . The method of claim 1 , wherein said tetracycline compound is administered with a pharmaceutically acceptable carrier.
19 . A pharmaceutical composition for the treatment of a microorganism-associated infection comprising a therapeutically effective amount of a tetracycline compound, wherein said tetracycline compound is of formula I:
wherein
X is CHC(R 13 Y′Y), CR 6′ R 6 , C═CR 6′ R 6 , S, NR 6 , or O;
R 2 , R 2′ , R 4′ , and R 4″ are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or a prodrug moiety;
R 3 , R 4a , R 11 and R 12 are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or a prodrug moiety;
R 4 is NR 4′ R 4″ , hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or a prodrug moiety;
R 5 and R 5′ are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or a prodrug moiety;
R 6 and R 6′ are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic;
R 7 is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, oximyl, aryl, heterocyclic or —(CH 2 ) 0-3 (NR 7c ) 0-1 C(═W′)WR 7a ;
R 8 is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl, heterocyclic or —(CH 2 ) 0-3 (NR 8c ) 0-1 C(=E′)ER 8a ;
R 9 is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl, heterocyclic or —(CH 2 ) 0-3 (NR 9c ) 0-1 C(=Z′)ZR 9a ;
R 10 is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic;
R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 9a , R 9b , R 9c , R 9d , R 9e and R 9f are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; R 13 is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic;
E is CR 8d R 8e , S, NR 8b or O;
E′ is O, NR 8f , or S;
W is CR 7d R 7e , S, NR 7b or O;
W′ is O, NR 7f , or S;
X is CHC(R 13 Y′Y), C═CR 13 Y, CR 6′ R 6 , S, NR 6 or O;
Z is CR 9d R 9e , S, NR 9b or O;
Z′ is O, S, or NR 9f ;
Y′ and Y are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; and pharmaceutically acceptable salts, esters and enantiomers thereof;
and a pharmaceutically acceptable carrier.
20 . The pharmaceutical composition of claim 19 , wherein said microorganism-associated infection is a bacterial infection.