Claims for Patent: 8,513,223

Summary for Patent: 8,513,223

Title:	Substituted tetracycline compounds for treatment of inflammatory skin disorders
Abstract:	Methods and compositions for the treatment of skin disorders (e.g., acne, rosacea) are described.
Inventor(s):	Assefa; Haregewein (Braintree, MA), Bhatia; Beena (Mansfield, MA), Draper; Michael P. (Windham, NH), Honeyman; Laura (London, CA), Kim; Oak (Cambridge, MA), Molnar; Dennis P. (Hopkinton, MA)
Assignee:	Paratek Pharmaceuticals, Inc. (Boston, MA)
Application Number:	11/963,509
Patent Claims:	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: ##STR00126## wherein X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6, C.dbd.CR.sup.6'R.sup.6, S, NR.sup.6, or O; E is NR.sup.7dR.sup.7e or OR.sup.7f; R.sup.2, R.sup.2', R.sup.4', R.sup.4a and R.sup.4b are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, or heteroaromatic; R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each hydrogen; R.sup.4 is NR.sup.4aR.sup.4b, alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen; R.sup.5 and R.sup.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.sup.6 and R.sup.6' are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; R.sup.7a and R.sup.7b are each independently hydrogen, alkyl, hydroxyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, aminoalkyl, acyl, aryl, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R.sup.7c, R.sup.7d and R.sup.7e are each independently hydrogen, alkyl, hydroxyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, aminoalkyl, acyl, aryl, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy, or R.sup.7c and R.sup.7d or R.sup.7c and R.sup.7f are linked to form a ring; R.sup.7f is hydrogen, allyl, alkyl, alkenyl, alkynyl, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, aminoalkyl, acyl, aryl, arylalkyl or R.sup.7f and R.sup.7c are linked to form a ring; R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; R.sup.9 is hydrogen, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, aminoalkyl, amido, arylalkenyl, arylalkynyl, thionitroso, or --(CH.sub.2).sub.0-3(NR.sup.9c).sub.0-1C(.dbd.Z')ZR.sup.9a; Z is CR.sup.9dR.sup.9e, S, NR.sup.9b or O; Z' is O, S, or NR.sup.9f; R.sup.9a, R.sup.9b, R.sup.9c, R.sup.9d, R.sup.9e and R.sup.9f are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, or heteroaromatic; R.sup.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.sup.6'R.sup.6, R.sup.4 is NR.sup.4aR.sup.4b, R.sup.4a and R.sup.4b are each alkyl, and R.sup.2, R.sup.2', R.sup.3, R.sup.4', R.sup.5, R.sup.5', R.sup.6, R.sup.6', R.sup.8, R.sup.9, R.sup.10, R.sup.11 and R.sup.12 are each hydrogen. 3. The method of claim 1, wherein said substituted tetracycline compound is: ##STR00127## ##STR00128## ##STR00129## ##STR00130## ##STR00131## 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 .mu.g/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.sup.7a and R.sup.7b are hydrogen. 8. The method of claim 7, wherein E is OR.sup.7f. 9. The method of claim 8, wherein R.sup.7c is hydrogen. 10. The method of claim 9, wherein R.sup.7f is alkyl. 11. The method of claim 8, wherein R.sup.7c and R.sup.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 ##STR00132## 14. The method of claim 8, wherein R.sup.7c is alkyl. 15. The method of claim 14, wherein said alkyl is methyl. 16. The method of claim 15, wherein R.sup.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 ##STR00133## or a pharmaceutically acceptable salt thereof. 19. The method of claim 1, wherein said substituted tetracycline compound is ##STR00134## or a pharmaceutically acceptable salt thereof. 20. The method of claim 1, wherein said inflammatory skin disorder is acne or rosacea.