7-substituted tetracycline compounds

Details 7-substituted tetracycline compounds 7-substituted tetracycline compounds

2001-06-29

2004-11-16

Desai, Rita (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

3,10-dihydroxy-2-naphthacene carboxamide or derivative doai

C514S284000, C514S432000, C514S453000, C552S203000, C546S061000, C546S339000, C549S025000, C549S358000, C548S204000

Reexamination Certificate

active

06818635

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
The invention pertains, at least in part, to 7-substituted tetracycline compound of Formula I:
wherein:
X is CHC(R
13
Y′Y), CR
6′
R
6
, C═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 hydrogen, nitro, alkyl, alkenyl, alkynyl, aryl, heterocyclic, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, amido, arylalkenyl, arylalkynyl, or —(CH
2
)
0-3
NR
7c
C(═W′)WR
7a
;
R
9
is hydrogen, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, amido, arylalkenyl, arylalkynyl, thionitroso(e.g., —N═S), or —(CH
2
)
0-3
NR
9c
C(═Z′)ZR
9a
;
Z is CR
9d
R
9e
, S, NR
9b
or O;
Z′ is O, S, or NR
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
9d
, 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, amido, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, and pharmaceutically acceptable salts thereof.
The invention also pertains to 7-substituted sancycline compounds of the formula:
wherein:
R
4′
and R
4″
are each alkyl;
R
7
is a fused ring moiety of the formula
where Q is C or a heteroatom; an acylfuranyl group; a tri-, tetra- or penta-halo substituted phenyl group; an aminomethylphenyl group; an acylaminomethyl group; an alkylesterphenyl group; an acylphenyl group; an acylalkynyl group; an acylalkoxyphenyl group; a methylphenyl group; a dimethylphenyl group; a carboxyphenyl group; a carboxyalkynyl group; a thiophene group; a halothiophene group; an alkoxycarbonylphenyl group; an alkoxyphenyl group; an alkoxyphenylalkynyl group; an alkoxypyridyl group; an alkylenepyridine group; a cyclopentyl or cyclopentenyl group; a cyclohexylalkynyl group; a cyclohexenylalkynyl group; a cyclohexenylhaloalkenyl group; a hydroxycyclohexylalkynyl group; a phenylalkynyl group; a phenylalkenyl group; an aminoalkynyl group; a cyclobutylalkenyl group; a pyridylalkynyl group; a pyridylalkenyl group; a nitrophenylalkynyl group; a nitrophenylalkenyl group; a cyanoalkynyl group; an alkynyl group; a cyanoalkenyl group; a cyanophenyl group; a dialkylamidoalkenyl group; a dialkylamidophenyl group; an aminophenylethyl group; an aminophenylethynyl group; a haloethenyl group; a halophenylalkynyl group; or an alkylester-substituted pentenyl group; 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 7-substituted tetracycline compound of the invention (e.g., of Formula I or II), such that the tetracycline responsive state is treated.
The invention also includes pharmaceutical compositions comprising an effective amount of a 7-substituted tetracycline compound of the invention and, optionally, a pharmaceutically acceptable carrier.


REFERENCES:
patent: 2980584 (1961-04-01), Hammer
patent: 2990331 (1961-06-01), Neumann et al.
patent: 3062717 (1962-11-01), Hammer
patent: 3165531 (1965-01-01), Blackwood et al.
patent: 3338963 (1967-08-01), Petisi et al.
patent: 3454697 (1969-07-01), Joyner et al.
patent: 3557280 (1971-01-01), Weber et al.
patent: 3674859 (1972-07-01), Beutel et al.
patent: 3901942 (1975-08-01), Bernardi et al.
patent: 3957980 (1976-05-01), Noseworthy
patent: 4018889 (1977-04-01), Armstrong
patent: 4024272 (1977-05-01), Rogalski et al.
patent: 4126680 (1978-11-01), Armstrong
patent: 5532227 (1996-07-01), Golub et al.
patent: 5789395 (1998-08-01), Amin et al.
patent: 5834450 (1998-11-01), Su
patent: 1469384 (1977-04-01), None
patent: WO 00/28983 (2000-05-01), None
patent: WO 01/87824 (2001-11-01), None
patent: WO 01/98259 (2001-12-01), None
Koza, Organic Letters vol. 2 No. 6 pp 815-817 Mar. 2000*
Barden, T.C. et al. “‘Glycylcyclines’. 3. 9-aminodoxycyclinecarboxamides,”J. Med. Chem.37:3205-11 (1994.
Berge, S.M. et al. “Pharmaceutical Salts”,J. Pharm. Sci.66(1):1-19 (1977).
Koza, D.J. “Synthesis of 7-substituted tetracycline derivatives,”Org. Lett.2(6):815-17 (2000).
Nilsson, B.M. et al. “Derivatives of the muscarinic agent N-methl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide,”J. Med. Chem.31(3):577-82 (1988).
Van den Boger

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