Cephalosporin antibiotics and prodrugs thereof

Details Cephalosporin antibiotics and prodrugs thereof Cephalosporin antibiotics and prodrugs thereof

2001-08-08

2003-07-29

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S204000, C544S226000, C544S227000

Reexamination Certificate

active

06599893

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel cephalosporin antibiotics and prodrugs thereof. It also relates to methods for the synthesis of the compounds and for their use against a broad spectrum of bacteria, including many that are resistant to conventional beta-lactam antibiotics.
BACKGROUND OF THE INVENTION
The following is provided to aid in the understanding of the present invention. Nothing in this section is to be construed as prior art to the present invention.
Over the past three decades a variety of antibiotics have become available for clinical use. One class of antibiotics that has seen remarkable growth is the cephalosporins, over 70 of which have entered clinical use since 1965.
Unfortunately, the widespread use of antibiotics has resulted in an alarming increase in the number of resistant bacterial strains, especially among clinically important bacterial such as those of the genera Staphylococcus, Salmonella, Enterobacteriaceœ and Pseudomonas, in particular, the species
S. aureus
and
S. pneumoniœ.
Bacterial resistance to cephalosporins arises primarily by (a) destruction of the antibiotic by &bgr;-lactamases; (b) decreased penetration due to changes in bacterial outer membrane composition; and (c) interference with &bgr;-lactam binding to penicillin-binding proteins (PBPs). The last mechanism is especially important because the binding of &bgr;-lactams to PBPs is an essential step in the inhibition of glycoprotein biosynthesis by this class of antibiotics (glycoprotein being a required bacterial cell-wall component).
Certain gram-positive bacteria are highly resistant to beta-lactam antibiotics such as methicillin-resistant
Staphylococcus aureus
(MRSA) and various enterococci species. The resistance of MRSA is due to the presence of a PBP known as PBP2a, which binds very poorly to &bgr;-lactam antibiotics. Currently, to overcome this resistance, the glycopeptides vancomycin and teicoplanin, which are not dependent on PBP-binding are the antibiotics of choice for treatment of MRSA-induced bacteremia. The quinolone antibacterials and some carbapenems, such as imipenem, also have been reported to be active against a few MRSA strains, but their use is being rapidly limited by the emergence of resistant MRSA strains.
Recent advances in compounds, compositions and methods for treating infections caused by &bgr;-lactam antibiotic resistant bacteria are described in commonly owned International Application No. PCT/US95/03976 and U.S. patent applications Ser. Nos. 08/222,262, filed Apr. 1, 1994; 08/369,798, filed Jan. 6, 1995; 08/413,713, 08/413,714, 08/415,065, 08/413,712, 08/415,064, and 08/415,069, all of which were filed on Mar. 29, 1995; 08/455,969, filed May 31, 1995; 08/457,673, filed Jun. 1, 1995; 08/940,508 and 08/937,812, both of which were filed Sep. 29, 1997; 08/730,041, 08/730,039, 08/728,232, 08/430,042, 08/728,233, and 08/730,040, all of which were filed Oct. 11, 1996; and 08/842,915, filed Apr. 17, 1997 and 60/155,496, filed Sep. 22, 1999; all of which are incorporated by reference herein, including any drawings. In addition, International Application No. PCT/WO95/07283, filed Sept. 8, 1994, describes new cephem compounds, and is likewise incorporated by reference herein.
Despite the advances being made in the battle against &bgr;-lactam resistant bacteria, there remains a need for newer and better antibiotics to combat the ever-increasing incidence of resistance. The present invention provides such compounds.
SUMMARY OF THE INVENTION
The present invention relates to compounds, compositions and methods for treating infections in mammals arising from beta-lactam antibiotic resistant bacteria. Preferred compounds will have a minimum inhibitory concentration (MIC) that is less than the MIC of cefotaxime or imipenem against a beta-lactam resistant organism, in particular a methicillin-resistant Staphylococcal organism. Of course, the compounds of this invention will also be an effective alternative to conventional beta-lactam antibiotics against organisms that are still susceptible to the conventional compounds.
Thus, in one aspect, the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, having the chemical structure
wherein
R
1
is selected from the group consisting of
R
2
is selected from the group consisting of hydrogen, CH
3
—, FCH
2
—, F
2
CH—,
R
3
is selected from the group consisting of
wherein X is selected from the group consisting of hydrogen, halogen, cyano, —NH
2
, —N(CH
3
)
2
, —NHSO
2
NH
2
, —SO
2
NH
2
and —SCH
3
; and,
n is 0 or 1.
An aspect of this invention is compound 1, wherein R
1
is selected from the group consisting of
An aspect of this invention is compound 1, wherein R
2
is selected from the group consisting of hydrogen, and
An aspect of this invention is compound 1, wherein R
3
is selected from the group consisting of
wherein X is selected from the group consisting of hydrogen, halogen, cyano, —NH
2
, —N(CH
3
)
2
, —NHSO
2
NH
2
, —SO
2
NH
2
and —SCH
3
.
An aspect of this invention is compound 1, wherein R
1
is selected from the group consisting of
An aspect of this invention is compound 1, wherein R
1
is selected from the group consisting of
An aspect of this invention is compound 1, wherein R
2
is selected from the group consisting of CH
3
—, FCH
2
—, F
2
CH—,
An aspect of this invention is compound 1, wherein R
2
is selected from the group consisting of
An aspect of this invention is compound 1, wherein R
3
is selected from the group consisting of
wherein X is selected from the group consisting of hydrogen, halogen, cyano, —NH
2
, —N(CH
3
)
2
, —NHSO
2
NH
2
, —SO
2
NH
2
and —SCH
3
.
In the above compound, X is —NH
2
in another aspect of this invention.
An aspect of this invention is compound 1, wherein R
1
is selected from the group consisting of
An aspect of this invention is compound 1, wherein R
2
is selected from the group consisting of:
An aspect of this invention is compound 1, wherein
R
2
is hydrogen; and
wherein X is —NH
2
.
An aspect of this invention is a compound having structure 1 wherein
R
2
is hydrogen; and
wherein X is —NH
2
.
An aspect of this invention is a compound having structure 1 wherein the compound is active against methicillin-resistant Staphylococci, as demonstrated by a lower minimum inhibitory concentration than methicillin against
S. aureus
Col (Meth
R
)(bla−),
S. aureus
76 (Meth
R
)(bla+),
S. aureus
ATCC 33593 (Meth
R
),
S. aureus
Spain #356 (Meth
R
), and/or
S. haemolyticus
05 (Meth
R
).
An aspect of this invention is a method for treating a methicillin-resistant Staphylococcal infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound having structure 1.
An aspect of this invention is an antibacterial composition comprising a therapeutically effective amount of a compound having structure 1 together with a pharmaceutically acceptable carrier.
An aspect of this invention is the use of the above composition for the treatment of a methicillin-resistant Staphylococcal infection.
An aspect of this invention is a prodrug, or pharmaceutically acceptable salt thereof, having chemical structure 2:
wherein
R
1
is selected from the group consisting of
R
2
is selected from the group consisting of hydrogen, CH
3
—, FCH
2
—, F
2
CH—,
R
3
is selected from the group consisting of
wherein X is selected from the group consisting of hydrogen, halogen, cyano, —NH
2
, —N(CH
3
)
2
, —NHSO
2
NH
2
, —SO
2
NH
2
and —SCH
3
;
R
4
is selected from the group consisting of
R
5
is selected from the group consisting of hydrogen and CH
3
—;
R
6
is selected from the group consisting of CH
3
—, CH
3
CH
2
—, CH
3
CH
2
CH
2
—, CH
3
CH(CH
3
)—, (CH
3
)
3
C—, CH
3
O—, CH
3
CH
2
O—, CH
3
CH
2
CH
2
O—, CH
3
CH(CH
3
)O— and (CH
3
)
3
CO—; and, n is 0 or 1.
An aspect of this invention is prodrug 2, wherein R
1
is selected from the group consisting of
An aspect of this invention is prodrug 2, wherein R
2
is selected from the group consisting of
hydrogen, an

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