Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-02-04
2004-12-07
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S008000
Reexamination Certificate
active
06828317
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel thiadiazinone derivatives of oxazolidinones, pharmaceutical compositions thereof, methods for their use, and methods for preparing the thiadiazinone derivatives. These compounds have potent activities against gram-positive and gram-negative bacteria.
BACKGROUND OF THE INVENTION
Due to ever-increasing antibiotic resistance, structurally novel antibacterials with a new mode of action have become increasingly important in the treatment of bacterial infections. Effective antibacterials should exhibit potent activity against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci and streptococci, anaerobic microorganisms such as bacteroides and clostridia species, and acid-fast microorganisms such as
Mycobacterium tuberculosis
and
Mycobacterium avium.
Among newer antibacterial agents, oxazolidinone compounds are the most recent synthetic class of antimicrobials active against a number of pathogenic microorganisms. However, oxazolidinones generally do not demonstrate useful levels of activity against aerobic gram-negative microorganisms. Thus, the use of these oxazolidinone antibacterial agents is limited to infectious states caused by gram-positive bacteria.
Accordingly, it is among the objects of the present invention to provide pharmaceutical compounds that have broad antibacterial activity, including against gram-positive bacteria and gram-negative bacteria.
SUMMARY OF THE INVENTION
The present invention provides structurally novel pharmaceutical compounds with an expanded spectrum of antibacterial activity, including activity against gram-positive microorganisms and gram-negative microorganisms.
The present invention relates to a compound of the following formula I:
or a pharmaceutically acceptable salt thereof wherein:
A is a structure of the following formula i, ii, iii, or iv
X is O or S;
Y is
(a) —NHC(═O)R
1
,
(b) —NHC(═S)R
1
,
(c) —NHC(═NCN)R
1
,
(d) —NH-het
1
,
(e) —O-het
1
,
(f) —S-het
1
,
(g) —het
2
, or
(h) —OH;
R
1 is
(a) —H
(b) —NH
2
,
(c) —NHC
1-4
alkyl,
(d) —C
1-4
alkyl,
(e) —C
2-4
alkenyl,
(f) —C
1-4
heteroalkyl,
(g) —(CH
2
)
m
C(═O)C
1-4
alkyl,
(h) —OC
1-4
alkyl,
(i) —SC
1-4
alkyl,
(j) —(CH
2
)
p
C
3-6
cycloalkyl,
(k) —(CH
2
)
r
C(═O)-aryl, or
(l) —(CH
2
)
s
C(═O)-het
1
;
R
2
, R
3
, R
7
, and R
8
are independently
(a) —H,
(b) —Cl,
(c) —F,
(d) —CH
3
,
(e) —NH
2
, or
(f) —OH;
R
4
is
(a) —H,
(b) —C
1-4
alkyl,
(c) —C
1-4
heteroalkyl,
(d) —(CH
2
)
q
C(═O)OC
1-4
alkyl,
(e) —(CH
2
)
m
C(═O)C
1-4
alkyl,
(f) -aryl, or
(g) -het
1
;
R
5
and R
6
are independently
(a) —H,
(b) —F,
(c) —C
1-4
alkyl,
(d) —C
3-6
cycloalkyl,
(e) —C
1-4
heteroalkyl,
(f) -aryl,
(g) -het
1
,
(h) —OC
1-4
alkyl,
(i) —O(C═O) C
1-4
alkyl,
(j) —O(C═O)OH,
(k) —(C═O)OC
1-4
alkyl; or
(l) R
5
and R
6
taken together are C
3-6
cycloalkyl; and
m, n, p, q, r and s at each occurrence, is independently 0, 1, or 2.
The dotted line within structure iii indicates an optional double bond at that position.
The alkyl, alkenyl, or cycloalkyl groups at each occurrence above independently are optionally substituted with one, two, or three substituents selected from the group consisting of halo, aryl, het
1
, and het
2
. Het
1
at each occurrence is independently a C-linked 5 or 6 membered heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Het
2
at each occurrence is independently a N-linked 5 or 6 membered heterocyclic ring having 1 to 4 nitrogen and optionally having one oxygen or sulfur within the ring.
The compounds of formula I of the present invention exhibit an expanded spectrum of antibacterial activity, including activity against gram-positive microorganisms and gram-negative microorganisms, such as
Haemophilus influenzae
and
Moraxella catarrhalis.
In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In an additional aspect, the present invention provides a method for treating gram-positive microbial infections in humans or other warm-blooded animals by administering to the subject in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The compound of formula I may be administered orally, parenterally, transdermally, topically, rectally, or intranasally.
In a further aspect, the present invention provides a method for treating gram-negative microbial infections in humans or other warm-blooded animals by administering to the subject in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The compound of formula I may be administered orally, parenterally, transdermally, topically, rectally, or intranasally.
In yet another aspect, the present invention provides novel intermediates and processes for preparing compounds of formula I.
REFERENCES:
patent: WO 93/09103 (1993-05-01), None
patent: WO 93/23384 (1993-11-01), None
patent: WO 94/13649 (1994-06-01), None
Gordeev Mikhail F.
Leuhr Gary W.
Patel Dinesh V.
Berch Mark L.
Habte Kahsay
Pharmacia & Upjohn Company
Yang Lucy X.
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