7-substituted tetracycline compounds
View Patent ↗The present invention pertains, at least in part, to novel 7-substituted tetracycline compounds. These tetracycline compounds can be used to treat numerous tetracycline compound-responsive states, such as bacterial infections and neoplasms, as well as other known applications for minocycline and tetracycline compounds in general, such as blocking tetracycline efflux and modulation of gene expression.
1. A substituted tetracycline compound of Formula I:
wherein:
X is CHC(R 13 Y′Y) or CR 6′ R 6 ;
R 2 , R 2′ , R 4′ , and R 4″ are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R 4 is NR 4′ R 4″ , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen;
R 3 , R 10 , R 11 and R 12 are each hydrogen or a pro-drug moiety;
R 5 is 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, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R 7 is substituted phenyl or a substituted or unsubstituted multicyclic aryl group, wherein said substituted phenyl is substituted with alkyl, alkenyl, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkyithiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, unsubstituted amino, alkylamino; amino substituted with alkenyl, alkynyl, carbonyl, alkoxy or aryl; acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, azido, heterocyclyl, alkylaryl, aryl or heteroaryl;
further wherein said multicyclic aryl group is selected from the group consisting of: naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, deazapurine, and indolizine;
further wherein said substituted multicyclic aryl group is substituted with halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino, alkyl amino, dialkylamino, arylamino, diarylamino, alkylarylamino, acylamino, alkylcarbonylamino, arylcarbonylamino, carbamoyl, ureido, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety;
R 9 is hydrogen;
R 8 is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
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, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, and pharmaceutically acceptable salts thereof.
2. The tetracycline compound of claim 1 , wherein R 4 is NR 4′ R 4″ , X is CR 6 R 6′ ; R 2 , R 2′ , R 6 , R 6′ , R 8 , R 10 , R 11 , and R 12 are each hydrogen; R 4′ and R 4″ are lower alkyl; and R 5 is hydroxy or hydrogen.
3. The tetracycline compound of claim 2 , wherein R 4′ and R 4″ are each methyl and R 5 is hydrogen.
4. The tetracycline compound of claim 1 , wherein R 7 is substituted phenyl.
5. The tetracycline compound of claim 4 , wherein said substituted phenyl is substituted with substituted or unsubstituted alkyl.
6. The tetracycline compound of claim 5 , wherein said alkyl is substituted with a heterocycle.
7. The tetracycline compound of claim 6 , wherein said heterocycle is morpholine, piperdine, or pyrrolidine.
8. The tetracycline compound of claim 4 , wherein said phenyl is substituted with an unsubstituted amino group.
9. The tetracycline compound of claim 4 , wherein said phenyl is substituted with an amino group substituted with one or more substituents selected from the group consisting of alkenyl, alkynyl, carbonyl, alkoxy and aryl group.
10. The tetracycline compound of claim 9 , wherein said amino group is substituted with an alkoxy group.
11. The tetracycline compound of claim 9 , wherein said amino group is substituted with a substituted or unsubstituted phenyl group.
12. The tetracycline compound of claim 11 , wherein said substituted phenyl is substituted with a halogen.
13. The tetracycline compound of claim 11 , wherein said substituted phenyl amino group is substituted with a second substituted amino group.
14. The tetracycline compound of claim 13 , wherein said second substituted amino group is substituted or unsubstituted aryl.
15. The tetracycline compound of claim 14 , wherein said second substituted amino group is a second substituted phenyl.
16. The tetracycline compound of claim 4 , wherein said phenyl group is substituted with alkoxy.
17. The tetracycline compound of claim 4 , wherein said phenyl group is substituted with an alkoxycarbonylamino group.
18. The tetracycline compound of claim 1 , wherein said substituted or unsubstituted multicyclic aryl group is substituted or unsubstituted naphthyl.
19. The tetracycline compound of claim 18 , wherein said naphthyl group is substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, carboxy, 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, formyl, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl, alkylaryl, aryl and heteroaryl.
20. The tetracycline compound of claim 19 , wherein said substituent is amino or formyl.
21. A pharmaceutical composition comprising a therapeutically effective amount of a tetracycline compound of claim 1 .
22. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
23. A tetracycline compound, wherein said compound is:
and pharmaceutically acceptable salts thereof.
24. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
25. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
26. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
27. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
28. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
29. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
30. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
31. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
32. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof
33. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
34. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
35. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
36. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
37. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
38. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof
39. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
40. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
41. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
42. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
43. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
44. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
45. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
46. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
47. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
48. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
49. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
50. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
51. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
52. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
53. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
54. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
55. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
56. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
57. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
58. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
59. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
60. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
61. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
62. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
63. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
64. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
65. A tetracycline compound, wherein said compound is:
and pharmaceutically acceptable salts thereof.
66. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
67. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
68. A tetracycline compound, wherein said compound is:
and pharmaceutically acceptable salts thereof.
69. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
70. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
71. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
72. A tetracycline compound, wherein said compound is:
and pharmaceutically acceptable salts thereof.
73. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
74. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
75. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
76. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
77. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
78. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
79. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
80. A tetracycline compound, wherein said compound is:
and pharmaceutically acceptable salts thereof.
81. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof
82. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
83. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
84. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
85. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
86. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof
87. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
88. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
89. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
90. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
91. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
92. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
93. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
94. A tetracycline compound, wherein said compound is:
and pharmaceutically acceptable salts thereof.
95. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
96. A tetracycline compound, wherein said compound is:
and pharmaceutically acceptable salts thereof.
97. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
98. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof
99. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
100. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
101. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
102. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
103. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
104. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
105. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
106. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
107. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
108. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
109. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
110. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof
111. A tetracycline compound, wherein said compound is:
and pharmaceutically acceptable salts thereof.
112. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
113. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof
114. A tetracycline compound, wherein said compound is:
and pharmaceutically acceptable salts thereof
115. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
116. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
117. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
118. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
119. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
120. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
121. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
122. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
123. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
124. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
125. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
126. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
127. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
128. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof
129. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
130. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
131. The tetracycline compound of claim 1 , wherein said compound is
and pharmaceutically acceptable salts thereof.
132. A tetracycline compound, wherein said compound is
and pharmaceutically acceptable salts thereof.
133. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof
134. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof
135. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
136. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.
137. The tetracycline compound of claim 1 , wherein said compound is:
and pharmaceutically acceptable salts thereof.