Aromatic a-ring derivatives of tetracycline compounds
View Patent ↗Aromatized A-ring derivatives of tetracycline compounds are described.
1. A tetracycline compound of the formula (I)
wherein
R 1 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, heterocyclic, hydroxyl or halogen;
R 2′ , R 2″ , R 4a and R 4b are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R 10 and R 11 are each independently hydrogen, alkyl, aryl, benzyl, arylalkyl or a pro-drug moiety;
R 3′ is hydroxyl, alkoxy, arylalkyloxy, hydrogen or a pro-drug moiety;
R 4 is NR 4a R 4b , alkyl, alkenyl, alkynyl, hydroxyl or halogen;
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 hydrogen;
R 7 is hydroxyl, substituted alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso or —(CH 2 ) 0-3 NR 7c C(═W′)WR 7a ;
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 C(═E′)ER 8a ;
R 9 is hydrogen, hydroxyl, halogen, thiol, nitro, substituted alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso or —(CH 2 ) 0-3 NR 9c C(═Z′)ZR 9a ;
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, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
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 CR 6′ R 6 ;
Z is CR 9d R 9e , S, NR 9b or O; and
Z′ is O, S or NR 9f ,
and pharmaceutically acceptable salts, esters and enantiomers thereof.
2. The tetracycline compound of claim 1 , wherein R 2′ , R 3′ , R 10 and R 11 are each hydrogen or a prodrug moiety; R 4 is NR 4a R 4b ; R 4a and R 4b are each alkyl; and R 2″ , R 5 and R 5′ are each hydrogen.
3. The tetracycline compound of claim 1 , wherein it R 4 is NR 4a R 4b ; R 4a and R 4b are each alkyl; it R 5 is hydroxyl and R 5′ is hydrogen.
4. The tetracycline compound of claim 1 , wherein it R 4 is NR 4a R 4b ; R 4a and R 4b are each alkyl; R 5 and R 5′ are hydrogen atoms and R 7 is dimethylamino.
5. The tetracycline compound of claim 1 , wherein R 9 is hydrogen.
6. The tetracycline compound of claim 1 , wherein R 9 is substituted or unsubstituted aryl.
7. The tetracycline compound of claim 6 , wherein R 9 is substituted or unsubstituted phenyl.
8. The tetracycline compound of claim 6 , wherein R 9 is substituted or unsubstituted heteroaryl.
9. The tetracycline compound of claim 1 , wherein R 9 is substituted alkyl.
10. The tetracycline compound of claim 9 , wherein R 9 is aminoalkyl.
11. The tetracycline compound of claim 10 , wherein R 9 is aminomethyl.
12. The tetracycline compound of claim 11 , wherein R 9 is alkylaminomethyl.
13. The tetracycline compound of claim 1 , wherein R 9 is substituted or unsubstituted amino.
14. The tetracycline compound of claim 1 , wherein R 9 is nitro or halogen.
15. The tetracycline compound of claim 1 , wherein R 7 is substituted or unsubstituted aryl.
16. The tetracycline compound of claim 1 , wherein R 7 is substituted alkyl.
17. The tetracycline compound of claim 16 , wherein R 7 is aminoalkyl.
18. The tetracycline compound of claim 17 , wherein R 7 is aminomethyl.
19. The tetracycline compound of claim 18 , wherein R 7 is alkylaminomethyl.
20. The tetracycline compound of claim 1 , wherein R 7 is substituted or unsubstituted amino.
21. The tetracycline compound of claim 1 , wherein R 8 is hydrogen.
22. The tetracycline compound of claim 1 , wherein R 3′ is hydrogen, hydroxyl or alkoxy.
23. The tetracycline compound of claim 1 , wherein R 10 is hydrogen, alkyl, aryl or arylalkyl.
24. The tetracycline compound of claim 1 , wherein R 11 is hydrogen, alkyl, aryl or arylalkyl.
25. The tetracycline compound of claim 1 , wherein R 1 is hydrogen, halogen, hydroxyl, thiol, alkoxy or amino.
26. The tetracycline compound of claim 1 , wherein R 1 is alkyl, alkenyl, alkynyl or aryl.
27. The tetracycline compound of claim 1 , wherein said tetracycline compound is:
or
28. A pharmaceutical composition comprising an effective amount of a tetracycline compound and a pharmaceutically acceptable carrier, wherein said tetracycline compound is a compound of claim 1 .
29. A tetracycline compound of the formula (I)
wherein
R 1 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, heterocyclic, hydroxyl or halogen;
R 2′ , R 2″ , R 4a and R 4b are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R 10 and R 11 are each independently hydrogen, alkyl, aryl, benzyl, arylalkyl or a pro-drug moiety;
R 3′ is hydroxyl, alkoxy, arylalkyloxy, hydrogen or a pro-drug moiety;
R 4′ alkyl, alkenyl, alkynyl, hydroxyl or halogen;
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 hydrogen;
R 7 is hydrogen, halogen, thiol or nitro;
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 C(═E′)ER 8a ;
R 9 is hydroxyl, substituted alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso or —(CH 2 ) 0-3 NR 9c C(═Z′)ZR 9a ;
R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
E is CR 8d R 8e , S, NR 8b or O;
E′ is O, NR 8f or S;
X is CR 6′ R 6 ;
Z is CR 9d R 9e , S, NR 9b or O;
Z′ is O, S or NR 9f ,
and pharmaceutically acceptable salts, esters and enantiomers thereof.
30. The tetracycline compound of claim 29 , wherein R 2′ , R 3′ , R 10 and R 11 are each hydrogen or a prodrug moiety; R 4 is NR 4a R 4b ; R 4a and R 4b are each alkyl; and R 2″ , R 5 and R 5′ are each hydrogen.
31. The tetracycline compound of claim 29 , wherein R 4 is NR 4a R 4b ; R 4a and R 4b are each alkyl; R 5 is hydroxyl and R 5′ is hydrogen.
32. The tetracycline compound of claim 29 , wherein R 9 is substituted or unsubstituted aryl.
33. The tetracycline compound of claim 32 , wherein R 9 is substituted or unsubstituted phenyl.
34. The tetracycline compound of claim 32 , wherein R 9 is substituted or unsubstituted heteroaryl.
35. The tetracycline compound of claim 29 , wherein R 9 is substituted alkyl.
36. The tetracycline compound of claim 29 , wherein R 9 is substituted or unsubstituted amino.
37. The tetracycline compound of claim 29 , wherein R 7 is hydrogen.
38. The tetracycline compound of claim 29 , wherein R 7 is nitro or halogen.