US2012245130A1PendingUtilityA1
Methods of Using Substituted Tetracycline Compounds to Modulate RNA
Est. expiryOct 24, 2022(expired)· nominal 20-yr term from priority
A61P 9/00A61P 3/06A61P 9/10A61P 43/00A61P 7/06A61P 3/10A61P 31/12A61P 25/28A61P 25/14A61P 35/00A61P 31/14A61P 3/04A61P 11/00A61P 11/06A61K 31/65A61P 19/02C07C 237/26
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Claims
Abstract
A method for modulating RNA with tetracycline compounds is described.
Claims
exact text as granted — not AI-modified1 . A method for treating a subject for a DTMR, comprising: administering to said subject an effective amount of a tetracycline compound of formula (I):
in which
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 3 , R 10 , R 11 and R 12 are each hydrogen, alkyl, alkenyl, alkynyl, substituted carbonyl, or a prodrug moiety;
R 4 is NR 4′ R 4″ , alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen;
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, methylene, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R 7 is hydrogen, hydroxyl, halogen, thiol, nitro, 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, 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 , and R 9f are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
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 CHC(R 13 Y′Y), C═CR 13 Y, CR 6 R 6 , S, NR 6 , or O;
Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
Z is CR 9d R 9e ; S, NR 9b or O; and
Z′ is O, S, or NR 9f , or a pharmaceutically acceptable salt, ester, or enantiomer thereof, such that said DTMR is treated.
2 . The method of claim 1 , wherein said effective amount is effective to modulate translation of said subject's RNA.
3 . The method of claim 1 , wherein said effective amount is effective to modulate the half-life of said subject's RNA.
4 . The method of claim 1 , wherein said effective amount is effective to affect message translocation.
5 . The method of claim 1 , wherein said effective amount is effective to modulate the binding of proteins to said subject's RNA.
6 . The method of claim 1 , wherein said effective amount is effective to modulate splicing of said subject's RNA.
7 . The method of claim 1 , wherein R 2 , R 2′ , R 4′ , and R 4″ are each independently hydrogen or alkyl;
R 3 , R 10 , R 11 and R 12 are each hydrogen;
R 4 is NR 4′ R 4″ ;
R 5 is hydrogen;
R 6 and R 6′ are each independently hydrogen;
R 7 is substituted alkenyl, substituted alkynyl, substituted phenyl, substituted or unsubstituted furanyl, acyl, or aminoalkyl;
R 8 is hydrogen;
R 9 is hydrogen; and
X is CR 6′ R 6 .
8 . The method of claim 7 , wherein R 2 , R 2′ , and R 12 are each hydrogen, and R 4′ and R 4″ are each methyl.
9 . The method of claim 8 , wherein R 7 is substituted or unsubstituted furanyl.
10 . The method of claim 8 , wherein R 7 is substituted phenyl.
11 . The method of claim 10 , wherein said substituted phenyl is substituted with one or more substituents and further wherein said substituents are each independently alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, aryl or heterocyclic moiety.
12 . The method of claim 8 , wherein R 7 is substituted alkenyl.
13 . The method of claim 8 , wherein R 7 is substituted alkynyl.
14 . The method of claim 8 , wherein R 7 is dialkylamino.
15 . The method of claim 8 , wherein R 7 is acyl.
16 . The method of claim 1 , wherein said tetracycline compound is:
or a pharmaceutically acceptable salt thereof.
17 . The method of claim 1 , wherein said subject is a mammal.
18 . The method of claim 17 , wherein said mammal is a human.
19 . The method of claim 1 , wherein said tetracycline compound is:
or a pharmaceutically acceptable salt thereof.
20 . The method of claim 1 , wherein said tetracycline compound is selected from the group consisting of:
and pharmaceutically acceptable salts, esters and enantiomers thereof.Cited by (0)
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