US2004176609A1PendingUtilityA1
Oxazolidinones having a benzannulated 6- or 7-membered heterocycle
Priority: Nov 17, 2000Filed: Mar 19, 2004Published: Sep 9, 2004
Est. expiryNov 17, 2020(expired)· nominal 20-yr term from priority
A61P 31/04C07D 413/04
54
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Claims
Abstract
The present invention provides oxazolidinones having a benzannelated 6- or 7-membered heterocycle as antibacterial agents.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound of formula I
or a pharmaceutically acceptable salt thereof wherein
Y is
a) —NHC(═W)R 1 ,
b) —O-het, —S-het, or —NH-het;
X is
a) —O—,
b) —S(═O) i —, or
C) —S(═O)(═NR 4 )—;
W is
a) O, or
b) S;
R 1 is
a) H,
b) C 1-8 alkyl,
c) C 3-6 cycloalkyl,
d) OC 1-4 alkyl,
e) SC 1-4 alkyl,
f) NH 2 ,
g) NHC 1-6 alkyl, or
h) N(C 1-6 alkyl) 2 ;
R 2 is
a) H,
b) halo, or
c) C 1-4 alkyl;
R 3 is
a) H,
b) C 1-8 alkyl,
c) aryl,
d) het,
e) C(═W)R 5 ,
f) C(═O)OR 6 , or
g) S(═O) i R 7 ;
R 4 is
a) H, or
b) C 1-8 alkyl;
R 5 is
a) H,
b) aryl,
c) het,
d) NR 8 R 9 ,or
e) C 1-8 alkyl;
R 6 is
a) C 1-8 alkyl,
b) aryl, or
c) het;
R 7 is
a) aryl,
b) het,
c) NR 8 R 9 , or
d) C 1-8 alkyl;
R 8 and R 9 are independently
a) H,
b) C 1-8 alkyl, or
c) aryl;
wherein >G-E- is >N—C— and Q is a carbon atom, or >G-E is >C=C— and Q is a nitrogen atom;
aryl is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic;
het is a C-linked five- (5) or six- (6) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, which is optionally fused to a benzene ring;
at each occurrence, alkyl or cycloalkyl is optionally substituted with one or more OR 8 , halo, aryl, S(═O) i R 7 , C(═W)R 8 , OC(═O)C 1-6 alkyl, or NR 8 R 9 ;
at each occurrence, aryl is optionally substituted with one or more halo, OH, CF 3 , OC 1-6 alkyl, CN, C 1-6 alkyl, S(═O) i R 7 , C(═W)R 8 , OC(═O)R 8 , NHC(═O)R 8 , or NR 8 R 9 ;
at each occurrence, het is optionally substituted with one or more halo, OH, CF 3 , OC 1-6 alkyl, CN, C 1-6 alkyl, S(═O) i R 7 , C(═W)R 8 , OC(═O)R 8 , NHC(═O)R 8 , or NR 8 R 9 , oxo, or oxime;
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, 3, or 4; with the proviso that m and n taken together are 3 or 4; and
i is 0, 1, or 2.
2 . A compound of claim 1 which is a compound of formula IA:
3 . A compound of claim 2 wherein R 2 is H.
4 . A compound of claim 2 wherein R 1 is C 1-6 alkyl.
5 . A compound of claim 2 wherein R 1 is methyl.
6 . A compound of claim 4 wherein X is NR 3 .
7 . A compound of claim 6 wherein R 3 is C(═O)R 5 , or C(═O)OR 5 .
8 . A compound of claim 6 wherein R 3 is C(═O)CH 2 OH.
9 . A compound of claim 6 wherein R 3 is CHO.
10 . A compound of claim 7 wherein R 5 is C 1-4 alkyl, optionally substituted with C(═O)C 1-4 alkyl, OC(═O)C 1-4 alkyl, C(═O)phenyl, or phenyl, wherein said phenyl is optionally substituted with I, or CF 3 .
11 . A compound of claim 7 wherein R 5 is phenyl.
12 . A compound of claim 6 wherein R 3 is C(═S)R 5 , wherein R 5 is aryl, alkyl or NR 8 R 9 , wherein R 8 and R 9 are independently H, C 1-4 alkyl or aryl.
13 . A compound of claim 6 wherein R 3 is S(═O) i C 1-4 alkyl,
14 . A compound of claim 6 wherein R 3 is H, C 1-8 alkyl, or aryl.
15 . A compound of claim 6 or 7 wherein m is 1 and n is 3.
16 . A compound of claim 6 or 7 wherein m is 2 and n is 2.
17 . A compound of claim 6 or 7 wherein m is 0 and n is 4.
18 . A compound of claim 6 or 7 wherein m is 1 and n is 2.
19 . A compound of claim 6 or 7 wherein m is 2 and n is 1.
20 . A compound of claim 4 wherein X is S, SO, or SO 2 .
21 . A compound of claim 4 wherein X is O.
22 . A compound of claim 20 or 21 wherein m is 1 and n is 2.
23 . A compound of claim 20 or 21 wherein m is 2 and n is 1.
24 . A compound of claim 20 or 21 wherein m is 2 and n is 2.
25 . A compound of claim 1 which is a compound of formula IB:
wherein A is O, S or NH and het is isoxazol-3-yl, isoxazol-5-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl, 1,2,4-thiadiazol-3-yl or 1,2,5-thiadiazol-3-yl.
26 . A compound of claim 1 which is a compound of formula IC:
27 . A compound of claim 1 which is a compound of formula ID
wherein A is O, S or NH and het is isoxazol-3-yl, isoxazol-5-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl, 1,2,4-thiadiazol-3-yl or 1,2,5-thiadiazol-3-yl.
28 . A method for treating microbial infections comprising: administering to a mammal in need thereof an effective amount of a compound of claim 1 .
29 . The method of claim 28 wherein said compound is administered orally, parenterally, transdermally, or topically.
30 . The method of claim 28 wherein said compound is administered in an amount of from about 0.1 to about 150 mg/kg of body weight/day.
31 . The method of claim 28 wherein said compound is administered in an amount of from about 3 to about 100 mg/kg of body weight/day.
32 . The method of claim 28 wherein said infection is skin infection.
33 . The method of claim 28 wherein the infection is eye infection.
34 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
35 . The method of claim 28 wherein said compound is administered in an amount of 600 mg per day by IV or by oral.
36 . The method of claim 22 wherein said mammal is human or an animal.
37 . A compound of claim 1 which is
a) (−)-N-[[(5S)-3-(3,4-dihydro-1H-2-benzopyran-6-yl)-2-oxo-5-oxazolidinyl]methyl]acetamide,
b) (+)-N-[[(5S)-3-(3,4-dihydro-1H-2-benzopyran-6-yl)-2-oxo-5-oxazolidinyl]methyl]ethanethioamide,
c) (−)-N-[[(5S)-3-(3,4-dihydro-1H-2-benzothiopyran-6-yl)-2-oxo-5-oxazolidinyl]methyl]acetamide,
d) (+)-N-[[(5S)-3-(3,4-dihydro-1H-2-benzothiopyran-6-yl)-2-oxo-5-oxazolidinyl]methyl]ethanethioamide, or
e) (+)-N-[[(5S)-3-(3,4-dihydro-2,2-dioxido-1H-2-benzothiopyran-6-yl)-2-oxo-5-oxazolidinyl]methyl]ethanethioamide.
38 . A compound of claim 1 which is
a) (+)-N-[[(5S)-3-(3,4-dihydro-1H-2-benzopyran-7-yl)-2-oxo-5-oxazolidinyl]methyl]ethanethioamide,
b) (−)-N-[[(5S)-3-(3,4-dihydro-1H-2-benzothiopyran-7-yl)-2-oxo-5-oxazolidinyl]methyl]acetamide,
c) (+)-N-[[(5S)-3-(3,4-dihydro-1H-2-benzothiopyran-7-yl)-2-oxo-5-oxazolidinyl]methyl]ethanethioamide,
d) (+)-N-[[(5S)-3-(3,4-dihydro-2,2-dioxido-1H-2-benzothiopyran-7-yl)-2-oxo-5-oxazolidinyl]methyl]ethanethioamide, or
e) N-[[(5S)-3-(3,4-dihydro-2-oxido-1H-2-benzothiopyran-7-yl)-2-oxo-5-oxazolidinyl]methyl]acetamide.
39 . A compound of claim 1 which is
a) N-{[(5S)-3-(3-formyl-1,2,4,5-tetrahydro-1H-3-benzazepin-7-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide,
b) N-{[(5S)-3-(3-glycoloyl-1,2,4,5-tetrahydro-1H-3-benzazepin-7-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide,
c) benzyl 7-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate,
d) N-{[(5S)-3-(3-glycoloyl-1,2,4,5-tetrahydro-1H-3-benzazepin-7-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}ethanethioamide,
e) N-{[(5S)-3-(3-acetyl-1,2,4,5-tetrahydro-1H-3-benzazepin-7-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl }acetamide,
f) methyl 7-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl }-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate,
g) N-{[(5S)-3-(3-benzoyl-1,2,4,5-tetrahydro-1H-3-benzazepin-7-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide,
h) N-({(5S)-3-[3-(5-amino-1,3,4-thiadiazol-2-yl)-1,2,4,5-tetrahydro-1H-3-benzazepin-7-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide
i) N-({(5S)-3-[3-(methylsulfonyl)-1,2,4,5-tetrahydro-1H-3-benzazepin-7-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide,
j) N-({(5S)-3-[3-(5-methylthio-1,3,4-thiadiazol-2-yl)-1,2,4,5-tetrahydro-1H-3-benzazepin-7-yl]-2-oxo-1,3-oxazolidin-5-yl }methyl)acetamide,
k) N-({(5S)-3-[3-(5-methyl-1,3,4-thiadiazol-2-yl)-1,2,4,5-tetrahydro-1H-3-benzazepin-7-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide,
l) phenyl 7-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl }-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate,
m) N-[((5S)-3-{3-(phenyl)acetyl-1,2,4,5-tetrahydro-1H-3-benzazepin-7-yl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide,
o) N-[((5S)-3-{3-[5-(formylamino)-1,3,4-thiadiazol-2-yl]-1,2,4,5-tetrahydro-1H-3-benzazepin-7-yl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide,
p) N-[5-(7-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-1,3,4-thiadiazol-2-yl]-2-hydroxyacetamide,
q) N-[((5S)-3-{3-[(4-iodophenyl)acetyl]-1,2,4,5-tetrahydro-1H-3-benzazepin-7-yl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide,
r) N-[((5S)-3-{3-[(3-trifluoromethyl)phenyl)acetyl]-1,2,4,5-tetrahydro-1H-3-benzazepin-7-yl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide,
s) 2-(7-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-2-oxoethyl 4-[(dimethylamino)methyl]benzoate,
t) N-[((5S)-3-{3-[(4-trifluoromethyl)phenyl)acetyl]-1,2,4,5-tetrahydro-1H-3-benzazepin-7-yl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide,
u) N-({(5S)-2-oxo-3-[3-(5-oxopentanoyl)-1,2,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1,3-oxazolidin-5-yl}methyl)acetamide,
v) N-({(5S)-2-oxo-3-[3-(5-oxohexanoyl)-1,2,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1,3-oxazolidin-5-yl}methyl)acetamide,
x) N-{[(5S)-3-(2-formyl-1,3,4,5-tetrahydro-1H-2-benzazepin-7-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide,
w) N-{[(5S)-3-(2-glycoloyl-1,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide,
x) benzyl 7-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-1,3,4,5-tetrahydro-3H-2-benzazepine-2-carboxylate,
y) N-{[(5S)-3-(2-acetyl-1,3,4,5-tetrahydro-1H-2-benzazepin-7-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide,
z) methyl 7-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-1,3,4,5-tetrahydro-3H-2-benzazepine-2-carboxylate,
aa) 7-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-N-phenyl-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxamide,
bb) N-{[(5S)-3-(1-formyl-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide, or
cc) N-{[(5S)-3-(1-formyl-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}ethanethioamide.
40 . A compound of claim 1 which is
a) N-[[(5S)-2-oxo-3-(1,2,4,5-tetrahydro-3-benzothiepin-7-yl)-5-oxazolidinyl]methyl]acetamide,
b) N-[[(5S)-2-oxo-3-(1,2,4,5-tetrahydro-3,3-dioxido-3-benzothiepin-7-yl)-5-oxazolidinyl]methyl]acetamide,
c) N-[[(5S)-2-oxo-3-(1,2,4,5-tetrahydro-3-benzothiepin-7-yl)-5-oxazolidinyl]methyl]ethanethioamide, or
d) N-[[(5S)-2-oxo-3-(1,2,4,5-tetrahydro-3,3-dioxido-3-benzothiepin-7-yl)-5-oxazolidinyl]methyl]ethanethioamide.Cited by (0)
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