Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-10
2003-11-04
Trinh, Ba K. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S441000, C514S452000, C514S466000, C549S443000, C549S444000, C549S446000
Reexamination Certificate
active
06642270
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.
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, at least in part, 7-substituted fused ring tetracycline compounds of the formula:
wherein:
X is CR
6
R
6′
;
R
4
and R
4′
are each alkyl;
R
5
is hydrogen, hydroxyl, or a prodrug moiety;
R
6
and R
6′
are each independently hydrogen, hydroxyl, alkyl, or taken together, alkenyl;
Y and Y′ are each independently optionally substituted C, N, O, or S;
m is 1 or 2; and pharmaceutically acceptable salts thereof.
In a further embodiment, Y and Y′ are each oxygen and m is 1.
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.
DETAILED DESCRIPTION OF THE INVENTION
The invention includes novel 7-substituted fused ring tetracycline compounds and methods of using them. In one embodiment, the invention pertains to 7-substituted fused ring tetracycline compound of the formula:
wherein:
X is CR
6
R
6′
;
R
4
and R
4′
are each alkyl;
R
5
is hydrogen, hydroxyl, or a prodrug moiety;
R
6
and R
6′
are each independently hydrogen, hydroxyl, alkyl, or taken together, alkenyl;
Y and Y′ are each independently optionally substituted C, N, O, or S;
m is 1 or 2; and pharmaceutically acceptable salts thereof.
Examples of R
6
and R
6′
include methyl, ethyl, propyl, butyl, pentyl. Together, R
6
and R
6′
can be methylenyl (e.g., methacycline) which may or may not be further substituted. In a further embodiment, R
5
, R
6
and R
6′
are each hydrogen. In another embodiment, R
4
and R
4′
are each lower alkyl, e.g., methyl, ethyl, propyl, butyl, pentyl. In yet another embodiment, Y and Y′ are each oxygen. In one embodiment, m is 1. In a further embodiment, the compound is 7-3′,4′-methylenedioxyphenyl sancycline.
In a further embodiment, Y and Y′ are substituted or unsubstituted such that the compound can perform its intended function. For example, if Y or Y′ is C or N, the substituent can be hydrogen, alkyl (e.g., methyl, ethyl, propyl, etc.), halogen, hydroxy, or any other substituent which either allows the compound to perform its function or enhances its ability to do so. Furthermore, the 7-substituent may also be substituted at any of the other positions of either ring. Examples of possible substituents include alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. In an embodiment, m is one and Y and Y′ are oxygen. In a further embodiment, the 7-substituent of the tetracycline compound is methylenedioxyphenyl.
The term “tetracycline compound” includes compounds with a similar ring structure to tetracycline, such as those included in formula I. Some examples of tetracycline compounds which can be modified to include a substituent at position 7 include tetracycline, oxytetracycline, methacycline, sancycline, and doxycycline; however, other derivatives and analogues comprising a similar ring structure are also included. Table 1 depicts tetracycline and several known tetracycline derivatives.
TABLE I
Tetracycline
Oxytetracycline
Demeclocycline
Methacycline
Doxycycline
Chlorotetracycline
Minocycline
The term “7-substituted fused ring tetracycline compounds” includes tetracycline compounds with a fused ring at the 7 position. In an embodiment, the substituted tetracycline compound is substituted tetracycline (e.g., wherein R
4
and R
4′
are methyl, R
5
is hydrogen, R
6
is methyl and R
6′
is hydroxyl); substituted doxycycline (e.g., wherein R
4
and R
4′
are methyl, R
5
is hydroxyl R
6
is methyl and R
6′
is hydrogen); or substituted sancycline (wherein R
4
and R
4′
are methyl; R
5
is hydrogen and R
6
and R
6′
are hydrogen atoms). In another embodiment, the compound is a derivative of tetracycline, minocycline, sancycline, doxycycline, chlortetracycline, oxytetracycline, demeclocycline, or methacycline.
The term “fused ring” includes moieties of the formula:
wherein m is 1 or 2, and Y and Y′ are each independently selected from the group consisting of substituted or unsubstituted O, N, S, or C. Y and Y′ are substituted or unsubstituted such that the compound can perform its intended function. For example, if Y or Y′ is C or N, the substituent can be, for example, hydrogen, alkyl (e.g., methyl, ethyl, propyl, etc.), halogen, hydroxy, or another substituent which allows the compound to perform its intended function. Furthermore, the fused ring may also be substituted at any of the other positions of either ring. Examples of possible substituents include alkyl, alkenyl, alkynyl,
McIntyre Laura
Nelson Mark L.
Hanley, Esq. Elizabeth A.
Lahive & Cockfield LLP
Paratek Pharmaceuticals, Inc.
Soroos Cynthia M.
Trinh Ba K.
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