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7-phenyl-substituted tetracycline compounds

7-phenyl-substituted tetracycline compounds description/claims

This application is a continuation of U.S. patent application Ser. No. 10/853,536, filed May 24, 2004; which is a continuation of Ser. No. 09/883,137, filed on Jun. 15, 2001; which claims priority to U.S. Provisional Application Ser. No. 60/212,030, filed on Jun. 16, 2000, and U.S. Provisional Application Ser. No. 60/212,471, filed on Jun. 16, 2000; the entire contents of each of the aforementioned applications are hereby incorporated herein by reference.

The development of the tetracycline antibiotics was the direct result of a systematic screening of soil specimens collected from many parts of the world for evidence of microorganisms capable of producing bacteriocidal and/or bacteriostatic compositions. The first of these novel compounds was introduced in 1948 under the name chlortetracycline. Two years later, oxytetracycline became available. The elucidation of the chemical structure of these compounds confirmed their similarity and furnished the analytical basis for the production of a third member of this group in 1952, tetracycline. A new family of tetracycline compounds, without the ring-attached methyl group present in earlier tetracyclines, was prepared in 1957 and became publicly available in 1967; and minocycline was in use by 1972.

Recently, research efforts have focused on developing new tetracycline antibiotic compositions effective under varying therapeutic conditions and routes of administration. New tetracycline analogues have also been investigated which may prove to be equal to or more effective than the originally introduced tetracycline compounds. Examples include U.S. Pat. Nos. 3,957,980; 3,674,859; 2,980,584; 2,990,331; 3,062,717; 3,557,280; 4,018,889; 4,024,272; 4,126,680; 3,454,697; and 3,165,531. These patents are representative of the range of pharmaceutically active tetracycline and tetracycline analogue compositions.

Historically, soon after their initial development and introduction, the tetracyclines were found to be highly effective pharmacologically against rickettsiae; a number of gram-positive and gram-negative bacteria; and the agents responsible for lymphogranuloma venereum, inclusion conjunctivitis, and psittacosis. Hence, tetracyclines became known as “broad spectrum” antibiotics. With the subsequent establishment of their in vitro antimicrobial activity, effectiveness in experimental infections, and pharmacological properties, the tetracyclines as a class rapidly became widely used for therapeutic purposes. However, this widespread use of tetracyclines for both major and minor illnesses and diseases led directly to the emergence of resistance to these antibiotics even among highly susceptible bacterial species both commensal and pathogenic (e.g., pneumococci and Salmonella). The rise of tetracycline-resistant organisms has resulted in a general decline in use of tetracyclines and tetracycline analogue compositions as antibiotics of choice.

The invention pertains to 7-substituted tetracycline compounds which are substantially free of positional isomers. The compounds have the formula:

wherein:

R4 and R4′ are each alkyl;

R5 is hydrogen, hydroxyl, or a prodrug moiety;

R6 and R6′ are each independently hydrogen, hydroxyl, alkyl, or taken together, alkenyl;

R7 is halo substituted, a N-substituted phenyl, or an unsubstituted phenyl; and pharmaceutically acceptable salts thereof.

In another embodiment, R7 is mono-, di-, or tri-halo substituted phenyl. In another embodiment, R7 is 2-halo substituted phenyl. In yet another embodiment, R7 is 3-halo substituted phenyl. In a further embodiment, R7 is 4-halo substituted phenyl. In another embodiment, R7 is a 2, 3 or 4-N-substituted phenyl.

A method is provided for preparing tetracycline compounds of the invention having a desired purity, e.g., such that the desired compound is provided in a manner substantially free of positional isomers. In a preferred embodiment, a 7-halo substituted sancycline compound, from which the tetracycline compounds of the invention may be prepared, is provided which enables the production of the desired compound in a manner substantially free of positional isomers. In a further preferred embodiment, the desired tetracycline compound is at least 75%, 80%, 85%, 90%, 95% or 100% free of positional isomers. These desired compounds may be used in methods of treating tetracycline responsive states, and pharmaceutical compositions, as substantially set forth herein.

The invention also pertains to a method for treating a tetracycline responsive state in a mammal, by administering to a mammal a compound of formula I substantially free of positional isomers. In another aspect, the invention relates to the use of a compound of formula I which is substantially free of positional isomers to treat a tetracycline responsive state. The invention also pertains to pharmaceutical compositions comprising a compound of formula I which is substantially free of positional isomers, and to the use of a compound of formula I which is substantially free of positional isomers in the manufacture of a medicament to treat a tetracycline responsive state.

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