7-and 9-carbamate, urea, thiourea, thiocarbamate, and heteroaryl-amino substituted tetracycline compounds

A method for treating a tetracycline responsive state in a mammal, comprising administering to said mammal a substituted tetracycline compound of formula (I):

• wherein
• X is CHC(R13Y′Y), CR6′R6, S, NR6, or O;
• R2 is hydrogen, alkyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
• R4 and R4′ are each hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
• R2′, R3, R10, R11 and R12 are each hydrogen or a pro-drug moiety;
• R5 is hydrogen, hydroxyl, or a prodrug moiety;
• R6, R6′, and R8 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, or halogen;
• R7 is hydrogen, dialkylamino, or heteroaryl-amino;
• R13 is hydrogen, hydroxy, alkyl;
• alkenyl;
• alkynyl;
• alkoxy;
• alkylthio;
• alkylsulfinyl;
• alkylsulfonyl;
• alkylamino;
• or an arylalkyl;
• Y′ and Y are each independently hydrogen;
• halogen;
• hydroxyl;
• cyano, sulfhydryl;
• amino;
• alkyl;
• alkenyl;
• alkynyl;
• alkoxy;
• alkylthio;
• alkylsulfinyl;
• alkylsulfonyl;
• alkylamino;
• or an arylalkyl;
• R9 is hydrogen, or heteroaryl-amino;
• and pharmaceutically acceptable salts thereof, provided that when R9 is not hydrogen when R7 is hydrogen or dialkylamino.

A pharmaceutical composition comprising a therapeutically effective amount of a substituted tetracycline compound and a pharmaceutically acceptable carrier, wherein said substituted tetracycline is of the formula:

• wherein:
• X is CHC(R13Y′Y), CR6′R6, S, NR6, or O;
• R2 is hydrogen, alkyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
• R4 and R4′ are each hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
• R2′, R3, R10, R11 and R12 are each hydrogen or a pro-drug moiety;
• R5 is hydrogen, hydroxyl, or a prodrug moiety;
• R6, R6′, and R8 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, or halogen;
• R7 is hydrogen, dialkylamino, or heteroaryl-amino;
• R13 is hydrogen, hydroxy, alkyl;
• alkenyl;
• alkynyl;
• alkoxy;
• alkylthio;
• alkylsulfinyl;
• alkylsulfonyl;
• alkylamino;
• or an arylalkyl;
• Y′ and Y are each independently hydrogen;
• halogen;
• hydroxyl;
• cyano, sulfhydryl;
• amino;
• alkyl;
• alkenyl;
• alkynyl;
• alkoxy;
• alkylthio;
• alkylsulfinyl;
• alkylsulfonyl;
• alkylamino;
• or an arylalkyl;
• R9 is hydrogen, or heteroaryl-amino;
• and pharmaceutically acceptable salts thereof, provided that R9 is not hydrogen, when R7 is dialkylamino or hydrogen.

A method for synthesizing a 7- or 9-heteroaryl-amino substituted tetracycline compound, comprising:

• contacting a tetracycline compound with a nitrating agent, under conditions such that a nitro tetracycline compound is formed;
• contacting the nitro tetracycline compound with a hydrogenating agent, under conditions such that an amino tetracycline compound is formed;
• and
• contacting the amino tetracycline compound with an amino reactive substrate, such that a 9- or 7-heteroaryl-amine substituted tetracycline compound is formed.

A method for synthesizing a 7- or 9-substituted tetracycline compound of formula (I) comprising contacting a reactive intermediate with appropriate reagents under appropriate conditions, such that a substituted tetracycline compound is formed, wherein formula (I) is:

• wherein:
• X is CHC(R13Y′Y), CR6′R6, S, NR6, or O;
• R2 is hydrogen, alkyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
• R4 and R4′ are each hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
• R2′, R3, R10, R11 and R12 are each hydrogen or a pro-drug moiety;
• R5 is hydrogen, hydroxyl, or a prodrug moiety;
• R6, R6′, and R8 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, or halogen;
• R7 is hydrogen, dialkylamino, or heteroaryl-amino;
• R13 is hydrogen, hydroxy, alkyl;
• alkenyl;
• alkynyl;
• alkoxy;
• alkylthio;
• alkylsulfinyl;
• alkylsulfonyl;
• alkylamino;
• or an arylalkyl;
• Y′ and Y are each independently hydrogen;
• halogen;
• hydroxyl;
• cyano, sulfhydryl;
• amino;
• alkyl;
• alkenyl;
• alkynyl;
• alkoxy;
• alkylthio;
• alkylsulfinyl;
• alkylsulfonyl;
• alkylamino;
• or an arylalkyl;
• R9 is hydrogen, or heteroaryl-amino;
• and pharmaceutically acceptable salts thereof, provided that R9 is not hydrogen when R7 is dialkylamino or hydrogen.