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US 2004/0176334 A1Published application
7-and 9- carbamate, urea, thiourea, thiocarbamate, and heteroaryl-amino substituted tetracycline compounds
AssigneesParatek Pharmaceuticals, Inc., Trustees of Tufts College
InventorsMark L. Nelson, Stuart B. Levy, Roger Frechette, Todd E. Bowser, Mohamed Y. Ismail
Life of this patent
Estimating the term…
Abstract
Substituted tetracycline compounds, methods of synthesis, and methods of use are discussed. Tetracyclines useful for treating tetracycline related disorders are also discussed. Intermediates useful for synthesizing other tetracycline compounds are also included.
Claims102
A substituted tetracycline compound, wherein said compound is of the formula:
- 95
- 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, heteroaryl-amino, or NR7cC(═W′)WR7a;
- 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, NR9cC(═Z′)ZR9a, or heteroaryl-amino;
- Z is CR9dR9e, NR9b, or O;
- Z′ is O or S;
- R9a, R9b, R9c, R9d, and R9e are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arylcarbonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic, absent, or a prodrug moiety, and R9d and R9e may be linked to form a ring;
- W is CR7dR7e, NR7b or O;
- W′ is O or S;
- and
- R7a, R7b, R7c, R7d and R7e are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, arylsulfonyl, alkoxycarbonyl, arylcarbonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic, absent, or a prodrug moiety, and R7d and R7e may be linked to form a ring;
- and pharmaceutically acceptable salts thereof, provided that at least one of R9 is not hydrogen when R7 is hydrogen or dialkylamino.
38 more elements
The compound of claim 46, wherein said aryl is phenyl.
A method for treating a tetracycline responsive state in a mammal, comprising administering to said mammal a substituted tetracycline compound of formula (I):
- 103
- 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, heteroaryl-amino, or NR7cC(═W′)WR7a;
- 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, NR9cC(═Z′)ZR9a, or heteroaryl-amino;
- Z is CR9dR9e, NR9b, or O;
- Z′ is O or S;
- R9a, R9b, R9c, R9d, and R9e are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arylcarbonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic, absent, or a prodrug moiety, and R9d and R9e may be linked to form a ring;
- W is CR7dR7e, NR7b or O;
- W′ is O or S;
- and
- R7a, R7b, R7c, R7d, and R7e are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, arylsulfonyl, alkoxycarbonyl, arylcarbonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic, absent, or a prodrug moiety, and R7d and R7e may be linked to form a ring;
- and pharmaceutically acceptable salts thereof, provided that when R9 is not hydrogen when R7 is hydrogen or dialkylamino.
38 more elements
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:
- 104
- 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, heteroaryl-amino, or NR7cC(═W′)WR7a;
- 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, NR9cC(═Z′)ZR9a, or heteroaryl-amino;
- Z is CR99dR9e, NR9b, or O;
- Z′ is O or S;
- R9a, R9b, R9c, R9d, and R9e are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arylcarbonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic, absent, or a prodrug moiety, and R9d and R9c may be linked to form a ring;
- W is CR7dR7e, NR7b or O;
- W′ is O or S;
- and
- R7a, R7b, R7c, R7d, and R7c are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, arylsulfonyl, alkoxycarbonyl, arylcarbonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic, absent, or a prodrug moiety, and R7d and R7c may be linked to form a ring;
- and pharmaceutically acceptable salts thereof, provided that R9 is not hydrogen, when R7 is dialkylamino or hydrogen.
38 more elements
A method for synthesizing a 7- or 9-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-substituted tetracycline compound is formed.
1 more element
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:
- 105 106 107 108 109 110
- 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, heteroaryl-amino, or NR7cC(═W′)WR7a;
- 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, NR9cC(═Z′)ZR9a, or heteroaryl-amino;
- Z is CR9dR9c, NR9b, or O;
- Z′ is O or S;
- R9a, R9b, R9c, R9d, and R9e are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arylcarbonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic, absent, or a prodrug moiety;
- W is CR7dR7e, NR7b or O;
- W′ is O or S;
- and
- R7a, R7b, R7c, R7d, and R7e are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, arylsulfonyl, alkoxycarbonyl, arylcarbonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic, absent, or a prodrug moiety;
- and pharmaceutically acceptable salts thereof, provided that R9 is not hydrogen when R7 is dialkylamino or hydrogen.
38 more elements
A reactive intermediate, wherein said reactive intermediate is of the formula:
- 111
- wherein:
- X is CHC(R13Y′Y), CHR6, 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 and R8 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
- 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, sulthydryl;
- amino;
- alkyl;
- alkenyl;
- alkynyl;
- alkoxy;
- alkylthio;
- alkylsulfinyl;
- alkylsulfonyl;
- alkylamino;
- or an arylalkyl;
- R9 is hydrogen, thiourea, diazonium salt, thiocarboxamide, or nitro;
- R7 is hydrogen, dialkylamino, thiourea, diazonium salt, thiocarboxanide, or nitro;
- and pharmaceutically acceptable salts thereof, provided that both R9 is not hydrogen when R7 is dialkylamino or hydrogen.
31 more elements
Dependencies are inferred from the claim text.