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
2004-01-27
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
C552S203000
Reexamination Certificate
active
06683068
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. 2,980,584; 2,990,331; 3,062,717; 3,165,531; 3,454,697; 3,557,280; 3,674,859; 3,957,980; 4,018,889; 4,024,272; and 4,126,680. 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
In an embodiment, the invention pertains to 7,9-substituted tetracycline compounds of Formula I:
wherein:
X is CHC(R
13
Y′Y), CR
6′
R
6
, S, NR
6
, or O;
R
2
, R
2′
, R
4′
, and R
4″
are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R
4
is NR
4′
R
4″
, alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen;
R
2′
, R
3
, R
10
, R
11
and R
12
are each hydrogen or a pro-drug moiety;
R
5
is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;
R
6
and R
6′
are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R
7
is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, or —(CH
2
)
0-3
NR
7c
C(═W′)WR
7a
;
R
9
is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, thionitroso, or —(CH
2
)
0-3
NR
9c
C(═Z′)ZR
9a
;
Z is C
9d
R
9e
, S, NR
9b
or O;
Z′ is O, S, or N
9f
,
W is CR
7d
R
7e
, S, NR
7b
or O;
W′ is O, NR
7f
S;
R
7a
, R
7b
, R
7c
, R
7d
, R
7e
, R
9a
, R
9b
, R
9c
, R
d
, and R
9e
are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R
8
is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R
13
is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; and
Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, and pharmaceutically acceptable salts thereof.
The invention also pertains to a method for treating a tetracycline responsive state in a subject, by administering to the subject a tetracycline compound of the invention (e.g., of Formula I), such that the tetracycline responsive state is treated.
DETAILED DESCRIPTION OF THE INVENTION
The present invention pertains, at least in part, to novel 7,9-substituted tetracycline compounds. These tetracycline compounds can be used to treat numerous tetracycline compound-responsive states, such as bacterial infections and neoplasms, as well as other known applications for minocycline and tetracycline compounds in general, such as blocking tetracycline efflux and modulation of gene expression.
The term “tetracycline compound” includes many compounds with a similar ring structure to tetracycline. Examples of tetracycline compounds include: tetracycline, chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, doxycycline, and minocycline. Other derivatives and analogues comprising a similar four ring structure are also included. Table 1 depicts tetracycline and several known tetracycline derivatives.
TABLE I
Tetracycline
Oxytetracycline
Methacycline
Deoxycycline
The term “7,9-substituted tetracycline compounds” includes tetracycline compounds with substitution at the 7 and 9-positions. In one embodiment, the substitution at the 7- and 9-positions enhances the ability of the tetracycline compound to perform its intended function, e.g., treat tetracycline responsive states. In an embodiment, the 7,9-substituted tetracycline compound is 7,9-substituted tetracycline (e.g., wherein R
4
is NR
4′
R
4″
; R
4′
and R
4″
are methyl, R
5
is hydrogen and X is CR
6
R
6′
, wherein R
6
is methyl and R
6′
is hydroxy); 7,9-substituted doxycycline (e.g., wherein R
4
is NR
4′
R
4″
; R
4′
and R
4″
are methyl, R
5
is hydroxyl and X is CR
6
R
6′
, wherein R
6
is methyl and R
6′
is hydrogen); or 7,9-substituted sancycline (wherein R
4
is NR
4′
R
4″
; R
4
and R
4″
are methyl; R
5
is hydrogen and X is CR
6
R
6′
wherein R
6
and R
6′
are hydrogen atoms. In an embodiment, the substitution at the 7 position of the 7,9-substituted tetracycline compound is not chlorine or trimethylamino. In one embodiment, R
4
is hydrogen.
The 7,9-substituted tetracycline compounds of the invention include compounds of Formula I:
wherein:
X is CHC(R
13
Y′Y) CR
6′
R
6
, S, NR
6
, or O;
R
2
, R
2′
, R
4′
, and R
4″
are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R
4
is NR
4′
R
4″
, alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen;
R
2′
, R
3
, R
10
, R
11
and R
12
are each hydrogen or a pro-drug moiety;
R
5
is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;
R
6
and R
6′
are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthi
Bhatia Beena
Bowser Todd
Frechette Roger
Hawkins Paul
Ismail Mohamed
Badio Barbara P.
Hanley, Esq. Elizabeth A.
Lahive & Cockfield LLP
Paratek Pharmaceuticals, Inc.
Soros Cynthia M.
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