Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-24
2002-05-28
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S310000
Reexamination Certificate
active
06395726
ABSTRACT:
FIELD OF INVENTION
The present invention is directed to &bgr;-lactamase inhibitors useful in combination with &bgr;-lactam antibiotics. More specifically, the present invention is directed to novel 3,6-disubstituted penam sulfone derivatives which demonstrate potent &bgr;-lactamase inhibitory activity.
BACKGROUND OF THE INVENTION
Penicillins and cephalosporins are the most frequently and widely used &bgr;-lactam antibiotics. However, the development of bacterial resistance to these antibiotics has had a damaging effect on maintaining the effective treatment of bacterial infections.
The most significant, known mechanism related to the development of bacterial resistance to the &bgr;-lactam antibiotics is the production of Class A and Class C serine &bgr;-lactamases. These &bgr;-lactamases compounds degrade the &bgr;-lactam antibiotics, resulting in a loss of antibacterial activity. It is known that Class A serine &bgr;-lactamases, which have molecular weights of about 29 kDa, preferentially hydrolyze penicillins, whereas Class C serine &bgr;-lactamases which have molecular weights of about 39 kDa, preferentially hydrolyze cephalosporins. Bacterial resistance to these antibiotics could be greatly reduced by administering the &bgr;-lactam antibiotic in combination with a compound which inhibits these enzymes.
A number of &bgr;-lactamase inhibitors are known in the art. For example, U.S. Pat. No. 4,234,579 discloses penicillanic acid 1,1-dioxide (i.e., Sulbactam) useful for enhancing the activity of a number of &bgr;-lactam antibiotics. U.S. Pat. No. 4,562,073 discloses a penicillin derivative (Tazobactam) useful as a &bgr;-lactamase inhibitor. Likewise, U.S. Pat. Nos. 4,287,181 and 5,637,579 disclose penicillanic acid derivatives useful in enhancing the effectiveness of &bgr;-lactam antibiotics. However, the compounds disclosed in these patents are active only towards Class A serine &bgr;-lactamases and demonstrate poor activity against Class C serine &bgr;-lactamases.
Two positions can be modified in the penam sulfone base structure: the 3 &bgr;-methyl group and the 6-position. In the compounds discussed above, only one of the 3 or 6 positions is modified. Thus far, such a singular modification on the penam sulfone structure has not produced the desired activity against both Class A and Class C serine &bgr;-lactamases. Accordingly, it can be seen that there is a need for compounds having such dual activities.
SUMMARY OF THE INVENTION
The present invention provides compounds having &bgr;-lactamase inhibitory activity against both Class A and Class C serine &bgr;-lactamases.
The present invention is directed to compounds of the following formulae I and II:
wherein
n is 0 or 1 and
when n=1, R is a 5 or 6 membered heterocyclic ring, hydroxy, halogen, oxo, carbamoyl, alkoxy, disubstituted amino, or
when n=0, R is an ester, cyano or amide group;
X is CH or NH;
R
3
is cyano, methoxy or acetamido; and
R
1
is hydrogen, alkyl, a negative charge, a cation selected from the group consisting of sodium, potassium and tetraalkylammonium and acyloxyalkyl, or alkoxycarbonyloxyalkyl; and
R
2
is hydrogen, acyl, trisubstituted silyl carbamoyl or an amino acid residue; or pharmaceutically acceptable salts thereof.
REFERENCES:
patent: 4234579 (1980-11-01), Barth
patent: 4287181 (1981-09-01), Kellogg
patent: 4503040 (1985-03-01), Barth
patent: 4562073 (1985-12-01), Micetich et al.
patent: 4591459 (1986-05-01), Barth
patent: 5637579 (1997-06-01), Hubschwerlen et al.
patent: 0041047 (1981-12-01), None
patent: 0083977 (1983-07-01), None
Fessenden, R.J. and Fessenden, J.S., “Organic Chemistry”, 1982, Willard Grant Press, Boston, p. 451.*
Hawley, Gessner, “The Condensed Chemical Dictonary”, 1977, Van Nostrand, New York, p. 436.*
Streitwieser, A. and Heathcock, C.H., “Introduction to Organic Chemistry, 2nd Ed.”, Macmillan, New York, 1981, p. 1061.*
Panayota Bitha et al, 6-(1-Hydroxyalykyl)Penam Sulfone Derivatives as Inhibitors of Class 1 and Class C &bgr;-Lactamases II, Bioorganic & Medicinal Chemistry Letters 9 (1999) 997-1002.
Bitha Panayota
Francisco Gerardo D.
Li Zhong
Lin Yang-I.
American Cyanamid Company
Hogan Jr. John W.
McKenzie Thomas
Shah Mukund J.
LandOfFree
3,6-disubstituted penam sulfone derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 3,6-disubstituted penam sulfone derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 3,6-disubstituted penam sulfone derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2844121