Oxazolidinone antibacterial agents having a thiocarbonyl...

Details Oxazolidinone antibacterial agents having a thiocarbonyl... Oxazolidinone antibacterial agents having a thiocarbonyl...

1998-11-27

2001-07-03

Lambkin, Deborah C. (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S236800, C544S060000, C544S138000

Reexamination Certificate

active

06255304

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to new and useful oxazolidinone compounds and their preparations, and more particularly to oxazolidinone compounds in which the carbonyl functionality of -NH-C(O)-R is converted to a thiocarbonyl functionality, such as a thiourea -NH-C(S)-NH
2
, an alkyl thiourea -NH-C(S)-NH-(C
1-4
alkyl), thioamide-NH-C(S)-(C
1-4
alkyl) or -NH-C(S)-H.
Replacement of the oxygen atom with a sulfur atom has unexpectedly improved the antimicrobial properties of the compounds. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including Gram-positive aerobic bacteria such as multiply-resistant staphylococci and streptococci, Gram-negative organisms such as
H. influenzae
and
M. catarrahlis
as well as anaerobic organisms such as bacteroides and clostridia species, and acid-fast organisms such as
Mycobacterium tuberculosis
and
Mycobacterium avium.
The compounds are particularly useful because they are effective against the latter organisms which are known to be responsible for infection in persons with AIDS.
SUMMARY OF THE INVENTION
In one aspect the subject invention is a compound of the Formula I
or pharmaceutical acceptable salts thereof wherein:
G is
R
1
is
a) H,
b) NH
2
,
c) NH-C
1-4
alkyl,
d) C
1-4
alkyl,
e) -OC
1-4
alkyl,
f) -S C
1-4
alkyl,
g) C
1-4
alkyl substituted with 1-3 F, 1-2 Cl, CN or -COOC
1-4
alkyl,
h) C
3-6
cycloalkyl,
i) N(C
1-4
alkyl)
2
or
j) N(CH
2
)
2-5
;
A is
d) a 5-membered heteroaromatic moiety having one to three atoms selected from the group consisting of S, N, and O, wherein the 5-membered heteroaromatic moiety is bonded via a carbon atom,
wherein the 5-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl ring,
wherein the heteroaromatic moiety is optionally substituted with one to three R
48
,
e) a 6-membered heteroaromatic moiety having at least one nitrogen atom,
wherein the heteroaromatic moiety is bonded via a carbon atom,
wherein the 6-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl ring,
wherein the heteroaromatic moiety is optionally substituted with one to three R
55
,
f) a &bgr;-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring, optionally substituted with one to three R
55
,
wherein R
2
is
a) H,
b) F,
c) Cl,
d) Br,
e) C
1-3
alkyl,
f) NO
2
, or
g) R
2
and R
3
taken together are -O-(CH
2
)
h
-O-;
R
3
is
a) -S(═O)
i
R
4
,
b) -S(═O)
2
-N═S(O)
j
R
5
R
6
,
c) -SC(═O)R
7
,
d) -C(═O)R
8
,
e) -C(═O)R
9
,
f) -C(═O)NR
10
R
11
,
g) -C(═NR
12
)R
8
,
h) -C(R
8
)(R
11
)-OR
13
,
i) -C(R
9
)(R
11
)-OR
13
,
j) -C(R
8
)(R
11
)-OC(═O)R
13
,
k) -C(R
9
)(R
11
)-OC(═O)R
13
,
l) -NR
10
R
11
,
m) -N(R
10
)-C(═O)R
7
,
n) -N(R
10
)-S(═O)
i
R
7
,
o) -C(OR
14
)(OR
15
)R
8
,
p) -C(R
8
)(R
16
)-NR
11
, or
q) C
1-8
alkyl substituted with one or more ═O other than at alpha position, -S(═O)
i
R
17
, -NR
10
R
11
, C
2-5
alkenyl, or C
2-5
alkynyl;
R
4
is
a) C
1-4
alkyl optionally substituted with one or more halos, OH, CN, NR
10
R
11
, or -CO
2
R
13
,
b) C
2-4
alkenyl,
c) -NR
16
R
18
,
d) -N
3
,
e) -NHC(═O)R
7
,
f) -NR
20
C(═O)R
7
,
g) -N(R
19
)
2
,
h) -NR
16
R
19
, or
i) -NR
19
R
20
,
R
5
and R
6
at each occurrence are the same or different and are
a) C
1-2
alkyl, or
b) R
5
and R
6
taken together are -(CH
2
)
k
-;
R
7
is C
1-4
alkyl optionally substituted with one or more halos;
R
8
is
a) H, or
b) C
1-8
alkyl optionally substituted with one or more halos, or C
3-8
cycloalkyl;
R
9
is C
1-4
alkyl substituted with one or more
a) -S(═O)R
17
,
b) -OR
13
,
c) -OC(═O)R
13
,
d) -NR
10
R
11
, or
e) C
1-5
alkenyl optionally substituted with CHO;
R
10
and R
11
at each occurrence are the same or different and are
a) H,
b) C
1-4
alkyl, or
c) C
3-8
cycloalkyl;
R
12
is
a) -NR
10
R
11
,
b) -OR
10
; or
c) -NHC(═O)R
10
;
R
13
is
a) H, or
b) C
1-4
alkyl;
R
14
and R
15
at each occurrence are the same or different and are
a) C
1-4
alkyl, or
b) R
14
and R
15
taken together are -(CH)
1
-;
R
16
is
a) H,
b) C
1-4
alkyl, or
c) C
1-4
cycloalkyl;
R
17
is
a) C
1-4
alkyl, or
b) C
3-8
cycloalkyl;
R
18
is
a) H)
b) C
1-4
alkyl,
c) C
2-4
alkenyl,
d) C
3-4
cycloalkyl,
e) -OR
13
or
f) -NR
21
R
22
;
R
19
is
a) Cl,
b) Br, or
c) I;
R
20
is a physiologically acceptable cation;
R
21
and R
22
at each occurrence are the same or different and are
a) H,
b) C
1-4
alkyl, or
c) -NR
21
R
22
taken together are -(CH
2
)
m
-;
wherein R
23
and R
24
at each occurrence are the same or different and are
a) H,
b) F,
c) Cl,
d) C
1-2
alkyl,
e) CN
f) OH,
g) C
12
alkoxy,
h) nitro, or
i) amino;
Q is
m) a diazinyl group optionally substituted with X and Y,
n) a triazinyl group optionally substituted with X and Y,
o) a quinolinyl group optionally substituted with X and Y,
p) a quinoxalinyl group optionally substituted with X and Y.
q) a naphthyridinl group optionally substituted with X and Y,
Q and R
24
taken together are
wherein Z
1
is
a) -CH
2
-,
b) -CH(R
104
)-CH
2
-,
c) -C(O)-, or
d) -CH
2
CH
2
CH
2
-;
wherein Z
2
is
a) -O
2
S-,
b) -O-,
c) -N(R
107
)-,
d) -OS-, or
e) -S-;
wherein Z
3
is
a) -O
2
S-,
b) -O-,
c) -OS-, or
d) -S-;
wherein A
1
is
a) H-, or
b) CH
3
;
wherein A
2
is
a) H-,
b) HO-,
c) CH
3
-,
d) CH
3
O-,
e) R
102
-CH
2
-C(O)-NH-
f) R103O-C(O)-NH-,
g) (C
1
-C
2
)alkyl-O-C(O)-,
h) HO-CH
2
-,
i) CH
3
O-NH-,
j) (C
1
-C
3
)alkyl-O
2
C-
k) CH
3
-C(O)-,
l) CH
3
-C(O)-CH
2
-,
A
1
and A
2
taken together are:
wherein R
102
is
a) H-,
b) CH
3
-,
c) phenyl-CH
2
-, or
d) CH
3
C(O)-;
wherein R103 is
a) (C
1
-C
3
)alkyl-, or
b) phenyl-;
wherein R
104
is
a) H-, or
b) HO-;
wherein R
105
is
a) H-,
b) (C
1
-C
3
)alkyl-,
c) CH
2
═CH-CH
2
-, or
d) CH
3
-O-(CH
2
)
2
-;
wherein R
106
is
a) CH
3
-C(O)-,
b) H-C(O)-,
c) Cl
2
CH-C(O)-,
d) HOCH
2
-C(O)-,
e) CH
3
SO
2
-,
g) F
2
CHC(O)-,
i) H
3
C-C(O)-O-CH
2
-C(O)-,
j) H-C(O)-O-CH
2
-C(O)-,
l) HC≡C-CH
2
O-CH
2
-C(O)-, or
m) phenyl-CH
2
-O-CH
2
-C(O)-;
wherein R
107
is
a) R
102
O-C(R
110
)(R
111
)-C(O)-,
b) R103O-C(O)-,
c) R
108
-C(O)-,
f) H
3
C-C(O)-(CH
2
)
2
-C(O)-,
g) R
109
-SO
2
-,
i) HO-CH
2
-C(O)-,
j) R
116
-(CH
2
)
2
-,
k) R
113
-C(O)-O-CH
2
-C(O)-,
l) (CH
3
)
2
N-CH
2
-C(O)-NH-,
m) NC-CH
2
-,
n) F
2
-CH-CH
2
-, or
o) R
150
R
151
NSO
2
wherein R
108
is
a) H-,
b) (C
1
-C
4
)alkyl,
c) aryl -(CH
2
)
p
,
d) ClH
2
C-,
e) Cl
2
HC-,
f) FH
2
C-,
g) F
2
HC-,
h) (C
3
-C
6
)cycloalkyl, or
i) CNCH
2
-.
wherein R
109
is
a) alkyl C
1
-C
4
,
b) -CH
2
Cl
c) -CH
2
CH═CH
2
,
d) aryl, or
e) -CH
2
CN;
wherein R
110
and R
111
are independently
a) H-,
b) CH
3
-; or
wherein R
112
is
a) H-,
b) CH
3
O-CH
2
O-CH
2
-, or
c) HOCH
2
-;
wherein R
113
is
a) CH
3
-,
b) HOCH
2
-,
c) (CH
3
)
2
N-phenyl, or
d) (CH
3
)2N-CH
2
-;
wherein R
114
is
a) HO-,
b) CH
3
O-,
c) H
2
N-,
d) CH
3
O-C(O)-O-,
e) CH
3
-C(O)-O-CH
2
-C(O)-O-,
f) phenyl-CH
2
-O-CH
2
-C(O)-O-,
g) HO-(CH
2
)
2
-O-,
h) CH
3
O-CH
2
-O-(CH
2
)
2
-O-, or
i) CH
3
O-CH
2
-O-;
wherein R
113
is
a) CH
3
-,
b) HOCH
2
-,
c) (CH
3
)
2
N-phenyl, or
d) (CH
3
)
2
N-CH
2
-;
wherein R
115
is
a) H-, or
b) Cl-;
wherein R
115
is
a) HO-
b) CH
3
O-, or
c) F;
wherein R
150
and R
151
are each H or alkyl C
1
-C
4
or R
150
and R
151
taken together with the nitrogen atom to which each is attached form a monocyclic heterocyclic ring having from 3 to 6 carbon atoms;
B is an unsaturated 4-atom linker having one nitrogen and three carbons;
M is
a) H,
b) C
1-8
alkyl,
c) C
3-8
cycloalkyl,
d) -(CH
2
)
m
OR
13
, or
e) -(CH
2
)
h
-NR
21
R
22
;
Z is
a) O,
b) S, or
c) NM;
W is
a) CH,
b) N, or
c) S or O when Z is NM;
Y is
a) H,
b) F,
c) Cl,
d) Br,
e) C
1-3
alkyl, or
f) NO
2
;
X is
a) H,
b) -CN,
c) OR
27
,
d) halo,
e) NO
2
,
f) tetrazoyl,
g) -SH,
h) -S(═O)
i
R
4
,
i) -S(═O)
2
-N═S(O)
j
R
5
R
6
,
j) -SC(═O)R
7
,
k) -C(═O)R
25
,
m) -C(═NR
9
)R
25
,
n) -C(R
25
)(R
28
)-OR
13
,
o) -C(R
25
)(R
28
)-OC(═O)R
13
,
p) -C(R
25
)(OR
13
)-(CH
2
)
h
-NR
27
R
28
,
q) -NR
27
R
28
,
r) -N(R
27

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