Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-29
2004-02-10
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S311000, C514S312000, C514S314000, C546S153000, C546S156000, C546S160000, C546S167000, C546S168000, C546S180000
Reexamination Certificate
active
06689769
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to substituted quinolone derivatives wherein an oxazolidinone, isoxazolinone, or isoxazoline compound is chemically combined with a quinolone. The present invention also relates to a method of preparing pharmacologically active quinolone derivatives and various intermediates used in the method. The present quinolone derivatives are useful as broad spectrum antimicrobial agents effective against a number of human and veterinary Gram positive and Gram negative pathogens, including the Staphylococci, for example
S. aureus
; Enterococci, for example
E. faecalis
; Streptococci, for example
S. pneumoniae
; Haemophilus, for example
H. influenza
; Moraxella, for example
M. catarrhalis
; and Escherichia for example
E. coli
; Mycobacteria, for example
M. tuberculosis
; intercellular microbes, for example Chlamydia and Rickettsiae; and Mycoplasma, for example
M. pneumoniae
, amongst others. The present invention also relates to pharmaceutical compositions containing the quinolone derivatives, to methods of treating a bacterial infection using the quinolone derivatives, and to a process for producing the quinolone derivatives.
BACKGROUND OF THE INVENTION
The increase in bacterial resistance to existing antibacterial agents is a major clinical problem. Accordingly, there is a need in the art for compounds, compositions, and methods of treating warm-blooded animals that suffer from a bacterial infection and are resistant to conventional antibacterial treatments. The development and increase in resistance to the quinolone carboxylic acid class of antibacterial compounds has not been as pervasive as with other antibacterial agents. Therefore, new quinolone carboxylic acid compounds may be useful in combating resistant bacteria.
The 7-substituted quinolone carboxylic acid derivatives, represented by the general formula (II), wherein Y is either C-R
5
or N, and R
1
through R
5
include a wide variety of substituents, are well known as anti-fungal and anti-bacterial agents, and as synthetic intermediates to related compounds. The 7-substituted derivatives of compound (II) include the antibacterials cinoxacin (U.S. Pat. No. 3,669,965); ciprofloxacin (U.S. Pat. Nos. 4,563,459 and 4,620,007); ofloxacin (U.S. Pat. No. 4,382,892); and levofloxacin (U.S. Pat. Nos. 4,985,557, 5,053,407, and 5,142,046).
Oxazolidinones having a general structural formula (III) also are a well known class of orally active, synthetic antibacterial agents. The literature contains numerous references to oxazolidinones (III), wherein R
1
through R
3
include a wide variety of substituents. Oxazolidinones having one or two substituents on the phenyl ring are disclosed in U.S. Pat. Nos. 4,705,799; 5,523,403; and 5,654,435, for example. Oxazolidinones (III) include the antibacterial agent designated as DuP 721, see
J. Med. Chem.,
32, 1673 (1989).
Oxazolidinones (III) having an arylbenzene substituent on the oxazolidinone ring are disclosed in U.S. Pat. Nos. 4,948,801 and 5,130,316. 3-[(Di- or fused-ring substituted)phenyl]-2-oxazolidinones are disclosed in U.S. Pat. Nos. 4,977,173; 4,921,869; 4,801,600; and 5,164,510. European Patent Applications 0 697 412; 0 694 544; 0 694 543; and 0 693 491, and International Patent Publication No. WO 93/09103, disclose 5- to 9-membered substituted aryl- and heteroaryl-phenyl oxazolidinones as antibacterial agents. U.S. Pat. No. 5,254,577 discloses aminomethyloxooxazolidinyl arylbenzene derivatives as antibacterial agents. Other references disclosing oxazolidinones include U.S. Pat. Nos. 4,801,600 and 4,921,869. Some of the pyridine-substituted phenyl oxazolidinone derivatives disclosed in the above patents are effective against Gram positive bacteria, such as
Staphylococcus aureus
and
Streptococcus pneumoniae
. However, the oxazolidinones are not active against Gram negative bacteria, such as
Escherichia coli
, Klebsiella, Proteus, and
Seratia marcenses
. Moreover, oxazolidinones cannot be administered as an injection solution because their free amino forms are sparingly soluble.
Isoxazolinone derivatives having a general structural formula (IV) are disclosed in WO 00/10566 as anti-bacterial agents. Simple isoxazolinones also are used as preemergent herbicides. For example, U.S. Pat. No. 4,065,463 discloses 2-methyl-4-(chloro-m-tolyl)-3-isoxazolin-5-one, which is useful in preventing weed growth.
Isoxazoline derivatives having a general structural formula (V) are disclosed in WO 99/41244, WO 98/07708 and U.S. Pat. No. 3,769,295 as anti-microbial agents. Simple isoxazolines also are used as preemergent herbicides. In addition, U.S. Pat. No. 4,283,403 discloses 3-aryl-2-isoxazolines, which are useful in preventing plant fungal diseases.
Although quinolones, oxazolidinones, isoxazolinones, and isoxazolines are known, applicants are aware of no reference which discloses covalently bonding a quinolone to an oxazolidinone, an isoxazolinone, or an isoxazoline, and using the resulting quinolone derivatives as broad spectrum anti-bacterial agents against both Gram positive and Gram negative bacteria.
The present invention is directed to structurally novel compounds produced by covalently bonding an antibacterial oxazolidinone, isoxazolinone, or isoxazoline compound to a substituted quinolone compound. The compounds of the present invention have a quinolone structure substituted with an oxazolidinone, isoxazolinone, or isoxazoline via a linking group at the 1- or 7-position of the quinolone.
The present compounds are active against Gram negative bacteria and Gram positive bacteria, and accordingly are useful as broad spectrum antibacterial agents. The present compounds are surprisingly effective against a number of human and veterinary pathogens, including Staphylococci, for example
S. aureus
; Enterococci, for example
E. faecalis
; Streptococci, for example
S. pneumoniae
; Haemophilus, for example
H. influenza
; Moraxella, for example
M. catarrhalis
; and Escherichia for example
E. coli
. Other examples include Mycobacteria, for example
M. tuberculosis
; intercellular microbes, for example Chlamydia and Rickettsiae; and Mycoplasma, for example
M. pneumoniae
. The present compounds also are envisioned as cytotoxic anticancer agents.
Syntheses of simple quinolone derivatives are well known in the art. However, the synthesis of a quinolone covalently linked to an oxazolidinone, an isoxazolinone, or an isoxazoline is not straightforward. Thus, a method of synthesizing compounds of the present invention also is disclosed.
SUMMARY OF THE INVENTION
One aspect of the present invention is to provide substituted quinolone derivatives having a structural formula (I):
or a pharmaceutically acceptable salt, hydrate, or prodrug thereof,
wherein Y
1
is CH or N;
Y
2
, Y
3
, and Y
4
, independently, are C or N;
L is a bond or is a linker group attached to a carbon at the seven quinolone ring position or to an N at the one quinolone ring position, and selected from the group consisting of a bond, NR
7
, and NR
8
(CR
9
2
)
n
NR
8
;
m is 0 or 1,
n is 0-3;
Q is selected from the group consisting of
R
1
is selected from the group consisting of null, H, C
1
-C
4
alkyl, C
3
-C
5
cycloalkyl, C
1
-C
4
haloalkyl, and halophenyl;
R
2
is null when Y
2
is N, or is selected from the group consisting of H, alkyl, C
1
-C
2
alkoxy, halo, and haloalkoxy, when Y
2
is C, or when Y
2
is C, R
1
and R
2
can be taken together to form a 5- or 6-membered, optionally substituted, heteroalkyl or heteroaryl ring;
R
3
is H or F when Y
3
is C, or R
3
is null when Y
3
is N;
R
4
is selected from the group consisting of H, methyl, amino, and F; R
5
is selected from the group consisting of H, methyl, hydroxy, and halo;
R
6
is selected from the group consisting of H, methyl, hydroxy, and halo, when Y
4
is C, or R
6
is null when Y
4
is N;
R
7
is selected from the group consisting of H, C
1
-C
4
alkyl, formyl, alkylcarbonyl, alkylsulfonyl, and alkoxycarbonyl;
R
8
, independently, are H or C
1
-C
4
alkyl, or are taken together to form a 4- to
Barbachyn Michael R.
Gage James R.
Gordeev Mikhail F.
Patel Dinesh V.
Pharmacia & Upjohn Company
Pharmacia & Upjohn Company
Wootton Thomas A.
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