3, 10, AND 12a SUBSTITUTED TETRACYCLINE COMPOUNDS

摘要

The present invention pertains to novel 3, 10, and/or 12a-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.

主权项

1. A tetracycline compound of Formula I:wherein:
X is CHC(R13Y′Y) or CR6′R6; R2″ is —C(═O)NR2R2′ or —CN; R2, R2′, R4a and R4b are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; R3, R11 and R12″ are each independently hydrogen, alkyl, alkenyl, aryl, alkynyl, aryallkyl, acetyl, alkylcarbonyl, alkenylcarbonyl, arylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, alkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, alkyloxythiocarbonyl, alkenyloxythiocarbonyl, alkynyloxythiocarbonyl, aryloxythiocarbonyl, alkylaminothiocarbonyl, alkenylaminothiocarbonyl, alkynylaminothiocarbonyl, arylaminothiocarbonyl, alkylthiothiocarbonyl, alkenylthiothiocarbonyl, alkynylthiothiocarbonyl or arylthiothiocarbonyl; R10 is hydrogen, alkenyl, aryl, alkynyl, arylalkyl, alkenylcarbonyl, arylcarbonyl, alkynylcarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, alkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, alkyloxythiocarbonyl, alkenyloxythiocarbonyl, alkynyloxythiocarbonyl, aryloxythiocarbonyl, alkylaminothiocarbonyl, alkenylaminothiocarbonyl, alkynylaminothiocarbonyl, arylaminothiocarbonyl, alkylthiothiocarbonyl, alkenylthiothiocarbonyl, alkynylthiothiocarbonyl or arylthiothiocarbonyl; R12 is hydrogen, alkyl, alkenyl, aryl, alkynyl, arylalkyl, alkenylcarbonyl, alkynylcarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, alkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, alkyloxythiocarbonyl, alkenyloxythiocarbonyl, alkynyloxythiocarbonyl, aryloxythiocarbonyl, alkylaminothiocarbonyl, alkenylaminothiocarbonyl, alkynylaminothiocarbonyl, arylaminothiocarbonyl, alkylthiothiocarbonyl, alkenylthiothiocarbonyl, alkynylthiothiocarbonyl or arylthiothiocarbonyl, provided that at least one of R3, R10, R11 or R12 is not hydrogen when R12′ is OR12; R4 and R4′ are each independently NR4aR4b, alkyl, alkenyl, alkynyl, hydroxyl, halogen or hydrogen; 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 arylalkyl; R7 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso or —(CH2)1-3NR7cC(═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)0-3NR8cC(=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)0-3NR9cC(═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; R12′ is OR12 or NR12R12″; R13 is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino or 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; Z is CR9dR9e, S, NR9b or O; Z′ is O, S or NR9f; and Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino or arylalkyl;or pharmaceutically acceptable salts, esters or enantiomers thereof.