Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-17
2002-05-14
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S224200, C514S249000, C514S314000, C514S376000, C544S058400, C544S058700, C544S105000, C544S353000, C546S165000, C546S166000, C548S231000, C548S232000
Reexamination Certificate
active
06387896
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel bicyclic oxazolidinone compounds and their preparations, more specifically, to R
1
-substituted bicyclic oxazolidinones as shown in formula I. These compounds have potent activities against gram positive and gram-negative bacteria.
BACKGROUND OF THE INVENTION
The oxazolidinone antibacterial agents are a novel synthetic class of antimicrobials with potent activity against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci and streptococci, anaerobic organisms such as bacteroides and clostridia species, and acid-fast organisms such as
Mycobacterium tuberculosis
and
Mycobacterium avium.
However, oxazolidinones generally do not demostrate an activity at a useful level against aerobic gram-negative organisms. Thus, the use of these oxazolidinone antibacterial agents is limited to infectious states due to gram-positive bacteria. Accordingly, it is among the objects of the present invention to provide pharmaceutical compounds which have broader antibacterial activity including the activity against aerobic gram-negative organisms. We have now discovered that the incorporation of a R
1
group at the bicyclic oxazolidinone imparts an unexpected increase in antibacterial activity as well as in the spectrum of activity to include gram-negative organisms such as
Haemophilus influenza
and
Moraxella catarrhalis.
More importantly, this increase in the potency and spectrum of activity is only seen in the specified diastereomers of formula I.
INFORMATION DISCLOSURE
U.S. Pat. No. 5,164,510 discloses 5′-indolinyloxazolidin-2-ones of formula XI
which are useful as antibacterial agents.
U.S. Pat. Nos. 5,036,092; 5,036,093; 5,039,690; 5,032,605 and 4,965,268 disclose aminomethyl oxazolidinyl aza cycloalkylbenzene derivatives useful as antibacterial agents.
U.S. Pat. Nos. 5,792,765 and 5,684,023 disclose substituted oxazolidinones useful as antibacterial agents.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I
or a pharmaceutically acceptable salt thereof wherein
W is
a) O, or
b) S;
X is
a) —S(═O)
m
—, or
b) —NR
3
—;
Y is
a) —O—,
b) —NH—,
c) —CH
2
—, or
d) —S(═O)
m
—;
R
1
is C
1-4
alkyl, optionally substituted with 1-3 R
5
;
R
2
is
a) H,
b) C
1-6
alkyl, optionally substituted with 1-3 halo;
c) cyclopropyl,
d) —OC
1-4
alkyl,
e) —NH
2
,
f) —NHC
1-6
alkyl, or
g) —N(C
1-6
alkyl)
2
;
R
3
is
a) C
1-8
alkyl, optionally substituted with 1-3 halo, CN, NO
2
, OH, SH or NH
2
,
b) —C(═O)R
4
, or
c) —C(═S)NHC
1-4
alkyl;
R
4
is
a) H,
b) C
1-6
alkyl, optionally substituted with OH, C
1-4
alkoxy, NH
2
, SH or halo, or
c) —CH
2
OC(═O)C
1-4
alkyl;
R
5
is
a) halo,
b) —CN,
c) —OH,
d) —SH,
e) —NH
2
,
f) —OR
6
,
g) —NHR
6
,
h) —N(R
6
)
2
, or
i) —S(═O)
m
R
6
;
R
6
is
a) C
1-6
alkyl,
b) —C(═O)C
1-4
alkyl,
c) —C(═O)OC
1-4
alkyl,
d) —C(═O)NH
2
,
e) —C(═O)NHC
1-4
alkyl, or
f) —SO
2
C
1-4
alkyl;
m is 0, 1 or 2;
n is 0 or 1;
with the proviso that where n is 0, Y is —CH
2
—.
In another aspect, the present invention also provides:
a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient (the composition preferably comprises a therapeutically effective amount of the compound or salt),
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,
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 invention also provides some novel intermediates and processes disclosed herein that are useful for preparing compounds of formula I.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions are used, unless otherwise described.
The term halo refers to fluoro, chloro, bromo, or iodo.
The term alkyl, alkoxy, etc. refer to both straight and branched groups, but reference to an individual radical such as “propyl” embraces only the straight chain radical, a branched chain isomer such as “isopropyl” being specifically referred to.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C
i-j
indicates a moiety of the integer “i” to the integer “j” carbon atoms, inclusive. Thus, for example, C
1-7
alkyl refers to alkyl of one to seven carbon atoms, inclusive.
The compounds of the present invention are generally named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. “Ph” for phenyl, “Me” for methyl, “Et” for ethyl, “h” for hour or hours and “rt” for room temperature).
It will be appreciated by those skilled in the art that compounds of the present may have additional chiral centers and be isolated in optically active or racemic form. The present invention encompasses any racemic, optically-active (such as enantiomers, diastereomers), tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention.
Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
Specifically, C
1-4
alkyl, C
1-6
alkyl and C
1-8
alkyl can be an alkyl group having one to four, one to six, or one to eight carbon atoms respectively such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and their isomeric forms thereof; C
1-4
alkoxy can be an alkyl group having one to four carbon atoms attached to an oxygen atom of hydroxyl group such as, for example, methoxy, ethoxy, propyloxy, butyloxy and their isomeric forms thereof.
A preferred value for halo is fluoro or chloro.
A preferred value for W is sulfur atom.
A preferred value for X is —NR
3
— wherein R
3
is as defined above.
A preferred value for Y is —CH
2
— or oxygen atom.
A preferred value for R
1
is methyl or methyl substituted with fluoro.
A more preferred value for R
1
is methyl.
A specific value for R
2
is C
1-6
alkyl, C
1-6
alkyl substituted with 1-3 halo, NH
2
, NHC
1-6
alkyl, or N(C
1-6
alkyl)
2
;
A preferred value for R
2
is methyl, ethyl, dichloromethyl, dichloroethyl, or NH
2
.
A more preferred value for R
2
is methyl and ethyl.
A specific value for R
3
is C
1-8
alkyl, C
1-8
alkyl substituted with 1-3 halo, CN, NO
2
, OH, SH or NH
2
, C(═S)NHC
1-4
alkyl, or C(═O)R
4
wherein specific value for R
4
is H, C
1-6
alkyl, optionally substituted with OH, C
1-4
alkoxy, NH
2
, SH or halo, or CH
2
OC(═O)C
1-4
alkyl.
A preferred value for R
3
is 2-fluoroethyl, glycolyl, formyl, methoxyacetyl, oxoethylacetate, acetyl, or methylaminocarbothioyl.
A more preferred value for R
3
is formyl or acetyl.
A specific value for R
5
is halo, —CN, —OH, —SH, —NH
2
, —OR
6
, —NHR
6
, —N(R
6
)
2
, or —S(═O)R
6
.
A specific value for R
6
is C
1-6
alkyl, —C(═O)C
1-4
alkyl, —C(═O)OC
1-4
alkyl, —C(═O)NH
2
, —C(═O)NHC
1-4
alkyl, or —SO
2
C
1-4
alkyl.
Examples of the present invention are:
a) N-({(5S)-3-[(2R)-1-(2-fluoroethyl)-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
b) N-{[(5S)-3-((2R)-1-glycoloyl-2-methyl-2,3-dihydro-1H-indol-5-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide;
c) N-({(5S)-3-[(2R)-1-glycoloyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
d) N-({(5S)-3-[(2R)-1-formyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
e) N-({
Barbachyn Michael Robert
Genin Michael J.
Hester, Jr. Jackson B.
Johnson Paul D.
Coleman Brenda
O′Brien Jonathan P.
Pharmacia & Upjohn Co.
Yang Lucy X.
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