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US 2006/0166944 A1Published application
4-Aminotetracyclines and methods of use thereof
AssigneeParatek Pharmaceuticals, Inc.
InventorsJoel Berniac, Beena Bhatia, Mark Grier, Mark Nelson, Jingwen Pan
Life of this patent
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Abstract
The present invention pertains, at least in part, to novel 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 tetracycline compounds such as blocking tetracycline efflux and modulation of gene expression.
Claims56
A tetracycline compound of formula (I):
- wherein:
- R2′ and R2″ are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
- R10, R11 and R12 are each independently hydrogen, alkyl, aryl, benzyl, arylalkyl, or a pro-drug moiety;
- R3′ is hydroxyl, hydrogen, or a pro-drug moiety;
- R4 is O or N—OR4a;
- R4a is hydrogen, alkyl, alkenyl, alkynyl, or aryl;
- R5 and R5′ 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;
- 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 hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH2)0-3(NR7c)0-1C(═W′)WR7a;
- R8 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH2)0-3(NR8c)0-1C(=E′)ER8a;
- R9 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH2)0-3(NR9c)0-1C(=Z′)ZR9a;
- R7a, R7b, R7c, R7d, R7e, R7f, R8a, R8b, R8c, R8d, R8e, R8f, R9a, R9b, R9c, R9d, R9e, and R9f are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
- R13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
- E is CR8dR8e, S, NR8b or O;
- E′ is O, NR8f, or S;
- W is CR7dR7e, S, NR7b or O;
- W′ is O, NR7f, for S;
- X is CHC(R13Y′Y), C═CR13Y, CR6′R6, S, NR6, 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 CR9dR9e, S, NR9b or O;
- Z′ is O, S, or NR9f, and pharmaceutically acceptable salts, esters and enantiomers thereof.
18 more elements
A tetracycline compound of formula (II):
- wherein:
- R2′ and R2″ are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
- R10, R11 and R12 are each independently hydrogen, alkyl, aryl, benzyl, arylalkyl, or a pro-drug moiety;
- R3′ is hydroxyl, hydrogen, or a pro-drug moiety;
- R4 is NR4cCR4d;
- R4c and R4d are each independently hydrogen, sulfonyl, arylcarbonyl, arylaminocarbonyl, aryloxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, alkyloxycarbonyl, acyl, alkyl, alkenyl, alkynyl, or aryl;
- R5 and R5′ 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;
- 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 hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH2)0-3(NR7c)0-1CC(═W′)WR7a;
- R8 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH2)0-3(NR8c)0-1C(=E′)ER8a;
- R9 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH2)0-3(NR9c)0-1C(=Z′)ZR9a;
- R7a, R7b, R7c, R7d, R7e, R7fR8a, R8b, R8c, R8d, R8e, R8f, R9a, R9b, R9c, R9d, R9c, and R9f are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
- R13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
- E is CR8dR8e, S, NR8b or O;
- E′ is O, NR8f, or S;
- W is CR7dR7e, S, NR7b or O;
- W′ is O, NR7f, or S;
- X is CHC(R13Y′Y), C═CR13Y, CR6′R6, S, NR6, 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 CR9dR9e, S, NR9b or O;
- Z′ is O, S, or NR9f, and pharmaceutically acceptable salts, esters and enantiomers thereof.
18 more elements
Dependencies are inferred from the claim text.