Substituted tetracycline compounds for treatment of inflammatory skin disorders
View Patent ↗Methods and compositions for the treatment of skin disorders (e.g., acne, rosacea) are described.
1. A method for treating a subject suffering from an inflammatory skin disorder, comprising administering an effective amount of a substituted tetracycline compound to said subject, wherein said substituted tetracycline compound is a compound 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;
E is NR 7d R 7e or OR 7f ;
R 2 , R 2′ , R 4′ , R 4a and R 4b are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, or heteroaromatic;
R 3 , R 10 , R 11 and R 12 are each hydrogen;
R 4 is NR 4a R 4b , alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen;
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, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R 7a and R 7b are each independently hydrogen, alkyl, hydroxyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, aminoalkyl, acyl, aryl, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy;
R 7c , R 7d and R 7e are each independently hydrogen, alkyl, hydroxyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, aminoalkyl, acyl, aryl, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy, or R 7c and R 7d or R 7c and R 7f are linked to form a ring;
R 7f is hydrogen, allyl, alkyl, alkenyl, alkynyl, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, aminoalkyl, acyl, aryl, arylalkyl or R 7f and R 7c are linked to form a ring;
R 8 is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R 9 is hydrogen, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, aminoalkyl, amido, arylalkenyl, arylalkynyl, thionitroso, or —(CH 2 ) 0-3 (NR 9c ) 0-1 C(═Z′)ZR 9a ;
Z is CR 9d R 9e , S, NR 9b or O;
Z′ is O, S, or NR 9f ;
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, or heteroaromatic;
R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; and
Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, amido, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, or a pharmaceutically acceptable salt thereof;
such that said inflammatory skin disorder is treated.
2. The method of claim 1 , wherein X is CR 6′ R 6 , R 4 is NR 4a R 4b , R 4a and R 4b are each alkyl, and R 2 , R 2′ , R 3 , R 4′ , R 5 , R 5′ , R 6 , R 6′ , R 8 , R 9 , R 10 , R 11 and R 12 are each hydrogen.
3. The method of claim 1 , wherein said substituted tetracycline compound is:
or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein said substituted tetracycline compound has an MIC less than that of doxycycline or minocycline for S. aureus, P. acnes or S. pneumoniae.
5. The method of claim 4 , wherein said substituted tetracycline compound has an MIC less than 32 μg/ml for S. aureus, P. acnes or S. pneumoniae.
6. The method of claim 1 , wherein said substituted tetracycline compound is administered topically or orally.
7. The method of claim 2 , wherein R 7a and R 7b are hydrogen.
8. The method of claim 7 , wherein E is OR 7f .
9. The method of claim 8 , wherein R 7c is hydrogen.
10. The method of claim 9 , wherein R 7f is alkyl.
11. The method of claim 8 , wherein R 7c and R 7f are linked to form a ring.
12. The method of claim 11 , wherein said ring is a 5- or 6-membered ring.
13. The method of claim 12 , wherein said ring is
14. The method of claim 8 , wherein R 7c is alkyl.
15. The method of claim 14 , wherein said alkyl is methyl.
16. The method of claim 15 , wherein R 7f is alkyl.
17. The method of claim 16 , wherein said alkyl is methyl or ethyl.
18. The method of claim 1 , wherein said substituted tetracycline compound is
or a pharmaceutically acceptable salt thereof.
19. The method of claim 1 , wherein said substituted tetracycline compound is
or a pharmaceutically acceptable salt thereof.
20. The method of claim 1 , wherein said inflammatory skin disorder is acne or rosacea.