Claims
- 1. A substituted tetracycline compound of Formula I: wherein:X is CHC(R13Y′Y), CR6′R6, C═CR6′R6, S, NR6, or O; R2, R2′, R4′, and R4″ are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; R4 is NR4′R4″, alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen; R2′, R3, R10, R11 and R12 are each hydrogen or a pro-drug moiety; R5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy; R6 and R6′ are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; R7 is alkynyl substituted with an aryl; R9 hydrogen R8 is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; R13 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, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, and pharmaceutically acceptable salts thereof.
- 2. The tetracycline compound of claim 1, wherein R4 is NR4′R4″, X is CR6R6′; R2, R2′, R6, R6′, R8, R10, R11, and R12 are each hydrogen; R4′and R4″are lower alkyl; and R5 is hydroxy or hydrogen.
- 3. The tetracycline compound of claim 2, wherein R4′ and R4″ are each methyl and R5 is hydrogen.
- 4. The tetracycline compound of any one of claims 3, wherein said substituted alkynyl of R7 is substituted with substituted or unsubstituted phenyl.
- 5. The tetracycline compound of claim 4, wherein said substituted phenyl of R7 is substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, carboxy, alkylcarbonylamino, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, cyano, azido, alkylaryl, and aryl.
- 6. The tetracycline compound of claim 5, wherein said phenyl of R7 is substituted alkylcarbonylamino or sulphonamido.
- 7. The substituted tetracycline compound of claim 1, wherein R7 is alkynyl substituted with a group selected from pyrrole, furan, thiophene, or thiazole thereof.
- 8. A substituted tetracycline compound of Formula I: wherein:X is CHC(R13Y′Y), CR6′R6, C═CR6′R6, S, NR6, or O; R2, R2′, R4′, and R4″are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; R4 is NR4′R4″, alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R2′, R3, R10, R11 and R12 are each hydrogen or a pro-drug moiety; R5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy; R6 and R6′ are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; R7 is substituted alkynyl, wherein said substituted alkynyl is substituted with a tetracycline moiety; R9 is hydrogen; R8 is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; R13 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, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, and pharmaceutically acceptable salts thereof.
- 9. A tetracycline compound selected from the group consisting of: and pharmaceutically acceptable salts, prodrugs and esters thereof.
- 10. The compound of claim 1, 8, or 9, wherein said compound is at least 75% free of positional isomers.
- 11. The compound of claim 10, wherein said compound is at least 80% free of positional isomers.
- 12. The compound of claim 11, wherein said compound is at least 85% free of positional isomers.
- 13. The compound of claim 12, wherein said compound is at least 90% free of positional isomers.
- 14. The compound of claim 13, wherein said compound is at least 95% free of positional isomers.
- 15. A substituted tetracycline compound selected from the group consisting of: and pharmaceutically acceptable salts, esters and prodrugs thereof.
- 16. The substituted tetracycline compound of claim 15, wherein said compound is
- 17. A tetracycline compound of the formula: and pharmaceutically acceptable salts, prodrugs and esters thereof.
- 18. A tetracycline compound of the formula: and pharmaceutically acceptable salts, prodrugs and esters thereof.
- 19. A tetracycline compound of the formula: and pharmaceutically acceptable salts, prodrugs and esters thereof.
- 20. A tetracycline compound of the formula: and pharmaceutically acceptable salts, prodrugs and esters thereof.
- 21. A tetracycline compound of the formula: and pharmaceutically acceptable salts, prodrugs and esters thereof.
- 22. A tetracycline compound of the formula: and pharmaceutically acceptable salts, prodrugs and esters thereof.
- 23. A method for treating bacterial infection in a subject, comprising administering to said subject a pharmaceutical effective amount of the tetracycline compound of any one of claims 1-3, 4-8, 9-15, or 16-22, such that said subject is treated.
- 24. The method of claim 23, wherein said bacterial infection is associated with E. Coli.
- 25. The method of claim 23, wherein said bacterial infection is associated with S. aureus.
- 26. The method of claim 23, wherein said bacterial infection is associated with E. faecalis.
- 27. The method of claim 23, wherein said bacterial infection is resistant to other tetracycline antibiotics.
- 28. The method of claim 23, wherein said subject is a human.
- 29. The method of claim 23, wherein said tetracycline compound is administered with a pharmaceutically acceptable carrier.
- 30. A pharmaceutical composition comprising a therapeutically effective amount of a tetracycline compound of claim 1-3, 4-8, 9, 15, or 16-22 and a pharmaceutically acceptable carrier.
RELATED APPLICATIONS
This application claims priority to U.S. Provisional Patent Application Ser. No. 60/275,576, entitled “7-Substituted Tetracycline Compounds” filed Mar. 13, 2001, and U.S. Provisional Patent Application Ser. No. 60/216,760, entitled “7-Substituted Sancycline Compounds” filed on Jul. 7, 2000; the entire contents of each of these applications are hereby incorporated herein by reference.
US Referenced Citations (16)
Foreign Referenced Citations (4)
Number |
Date |
Country |
1469384 |
Apr 1977 |
GB |
WO 0028983 |
May 2000 |
WO |
WO 0187824 |
Nov 2001 |
WO |
WO 0198259 |
Dec 2001 |
WO |
Non-Patent Literature Citations (6)
Entry |
Koza, Organic Letters vol. 2 No. 6 pp 815-817 Mar. 2000* |
Barden, T.C. et al. “‘Glycylcyclines’. 3. 9-aminodoxycyclinecarboxamides,” J. Med. Chem. 37:3205-11 (1994. |
Berge, S.M. et al. “Pharmaceutical Salts”, J. Pharm. Sci. 66(1):1-19 (1977). |
Koza, D.J. “Synthesis of 7-substituted tetracycline derivatives,” Org. Lett. 2(6):815-17 (2000). |
Nilsson, B.M. et al. “Derivatives of the muscarinic agent N-methl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide,” J. Med. Chem. 31(3):577-82 (1988). |
Van den Bogert, C. et al. “Doxycycline in combination chemotherapy of a rat leukemia,” Cancer Res., 48:6686-6690 (Dec. 1, 1988). |
Provisional Applications (2)
|
Number |
Date |
Country |
|
60/275576 |
Mar 2001 |
US |
|
60/216760 |
Jul 2000 |
US |