Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 3,10-dihydroxy-2-naphthacene carboxamide or derivative doai
Reexamination Certificate
2001-06-29
2002-12-31
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
3,10-dihydroxy-2-naphthacene carboxamide or derivative doai
C532S001000
Reexamination Certificate
active
06500812
ABSTRACT:
BACKGROUND OF THE INVENTION
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.
SUMMARY OF THE INVENTION
The invention pertains to 13-substituted methacycline compounds of the formula:
wherein:
R
4
and R
4
′ are each alkyl;
R
5
is hydrogen, hydroxyl, or a prodrug moiety;
R
6
is a phenyl group, i.e., an alkoxyphenyl group, a halophenyl group, a carboxyphenyl group, an acylphenyl group, a cyanophenyl group, a nitrophenyl group, a naphthyl group, a dialkylphenyl group, or an alkylphenyl group; a t-butyl group; an aminoalkanethio group; and pharmaceutically acceptable salts thereof.
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. In another aspect, the invention relates to the use of a compound of formula I to treat a tetracycline responsive state. The invention also pertains to pharmaceutical compositions comprising a compound of formula I, and to the use of a compound of formula I in the manufacture of a medicament to treat a tetracycline responsive state.
The invention also pertains, at least in part, to a method for synthesisizing 13-substituted methacycline compounds. The method includes contacting a methacycline compound with a boronic acid (e.g., an aryl boronic acid), under appropriate conditions such that a 13-substituted methacycline compound is formed.
In another embodiment, the invention also includes a method for the synthesis of a 13-substituted methacycline compound. The method includes contacting a methacycline compound with a tertiary alcohol, under appropriate conditions (e.g., an acid catalyst) such that a 13-substituted methacycline compound is synthesized.
DETAILED DESCRIPTION OF THE INVENTION
The invention pertains to 13-substituted methacycline compounds of the formula:
wherein:
R
4
and R
4
′ are each alkyl;
R
5
is hydrogen, hydroxyl, or a prodrug moiety;
R
6
is a phenyl group, i.e., an alkoxyphenyl group, a halophenyl group, a carboxyphenyl group, an acylphenyl group, a cyanophenyl group, a nitrophenyl group, a naphthyl group or an alkylphenyl group; a t-butyl group; an aminoalkanethio group; and pharmaceutically acceptable salts and prodrugs thereof.
The term “13-substituted methacycline compounds” includes methacycline compounds with a substituent at the 13 position (e.g., a compound of formula I with a substituent at the R
6
position). In an embodiment, the substituted methacycline compound is substituted methacycline (e.g., wherein R
4
′ and R are methyl, and R
5
is hydroxyl).
In yet another embodiment, R
6
is a phenyl group, i.e., an alkoxyphenyl group, an halophenyl group, a carboxyphenyl group, an acylphenyl group, a cyanophenyl group, a nitrophenyl group, a naphthyl group or an alkylphenyl group; a t-butyl group; an aminoalkanethio group. Examples of compounds where R
6
is a phenyl group include 13-(phenyl) methacycline and 13-(4′-chlorophenyl-5-cyclohexanoate) methacycline.
In an embodiment, R
6
is an alkoxyphenyl group. Examples of such compounds include 13-(4′-methoxyphenyl) methacycline, 13-(methylenedioxyphenyl) methacycline, 13-(4′-ethoxyphenyl) methacycline. 13-(p-carbomethoxyphenyl) methacycline, and 13-(3′,4′-methylenedioxyphenyl) methacycline.
In an embodiment, R
6
is a halophenyl group. Examples of such compounds include 13-(4′-fluorophenyl) methacycline, 13-(4′-chlorophenyl) methacycline, 13-(3′-chlorophenyl) methacycline, 13-(methylenedioxyphenyl) methacycline, 13-(3′-carboxylphenyl) methacycline, 13-(3′-4′-dichlorophenyl) methacycline, 13-(4′-acetylphenyl) methacycline, 13-(4′-ethoxyphenyl) methacycline, 13-(4′-chlorophenyl-5-cyclohexanoate) methacycline, 13-(3,5-difluorophenyl) methacycline, 13-(3′-acetylphenyl) methacycline, 13-(4′-bromophenyl) methacycline, 13-(2,4-difluorophenyl) methacycline, 13-(2-chlorophenyl) methacycline, 13-(p-carbomethoxyphenyl) methacycline, and 13-(trifluoromethylphenyl) methacycline.
In an embodiment, R
6
is a carboxyphenyl group. Examples of such compounds include 13-(3′-carboxylphenyl) methacycline.
In an embodiment, R
6
is an acylphenyl group. Examples of such compounds include 13-(3′-acetylphenyl) methacycline, 13-(4′-acetylphenyl) methacycline, and 13-(3′-formyl) methacycline.
In an embodiment, R
6
is a cyanophenyl group. Examples of such compounds include 13-(p-cyanophenyl) methacycline.
In an embodiment, R
6
is a nitrophenyl group. Examples of such compounds include 13-(4′-nitrophenyl) methacycline.
In an embodiment, R
6
is a naphthyl group. Examples of such compounds include 13-(naphthyl) methacycline.
In an embodiment, R
6
is an dialkylphenyl group. Examples of such compounds include 13-(3,5-dimethylphenyl) methacycline.
In an embodiment, R
6
is an alkylphenyl group. Examples of such compounds include 13-(p-t-butylphenyl) methacycline and 13-(p-tolyl) methacycline.
In an embodiment, R
6
is a t-butyl group. Examples of such compounds include 9,13-di-t-butyl) methacycline.
In an embodiment, R
6
is an aminoalkanethio group. Examples of such compounds include 13-(dimethylaminoethanethio) methacycline.
The invention also pertains, at least in part, to a method for synthesisizing a 13-substituted methacycline compound (e.g., a compound of formula I). The method includes contacting a methacycline compound with a boronic acid, under appropriate conditions such that a 13-substituted methacycline compound is formed.
The term “methacycline compound” includes compounds which can be used to synthesize 13-substituted methacycline compounds of the invention. In one embodime
Bhatia Beena
McIntyre Laura
Nelson Mark L.
Rennie Glen
Badio Barbara P.
Hanley, Esq. Elizabeth A.
Lahive & Cockfield LLP
Paratek Pharmaceuticals, Inc.
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