Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-11-27
2004-02-03
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S362000, C514S363000, C514S364000, C514S369000, C514S374000, C514S376000, C548S125000, C548S127000, C548S128000, C548S131000, C548S138000, C548S143000, C548S196000, C544S405000
Reexamination Certificate
active
06686363
ABSTRACT:
BACKGROUND OF THE INVENTION
Oxazolidinones represent the first new class of antibacterials to be developed since the quinolones. The oxazolidinones are synthetic antibacterial compounds that are orally or intravenously active against problematic multidrug resistant Gram positive organisms and are not cross-resistant with other antibiotics. See Riedl et al, Recent Developments with Oxazolidinone Antibiotics,
Exp. Opin. Ther. Patents
(1999) 9(5), Ford et al., Oxazolidinones: New Antibacterial Agents,
Trends in Microbiology
196 Vol. 5, No. 5, May 1997 and WO 96/35691.
This invention relates to new oxazolidinones having a cyclopropyl moiety, which are effective against aerobic and anerobic pathogens such as multi-resistant staphylococci, streptococci and enterococci, Bacteroides spp., Clostridia spp. species, as well as acid-fast organisms such as
Mycobacterium tuberculosis
and other mycobacterial species.
SUMMARY OF THE INVENTION
The present invention relates to compounds of formula I:
its enantiomer, diastereomer, or pharmaceutically acceptable salt, hydrate or prodrug thereof wherein:
R
1
represents
i) hydrogen,
ii) NR
5
NR
6
,
iii) CR
7
R
8
R
9
, C(R)
2
OR
14
, CH
2
NHR
14
, C(═O)R
13
, C(═NOH)H, C(═NOR
13
)H, C(═NOR
13
)R
13
, C(═NOH)R
13
, C(═O)N(R
13
)
2
, C(═NOH)N(R
13
)
2
, NHC(═X
1
)N(R
13
)
2
, (C═NH)R
7
, N(R
13
)C(═X
1
)N(R
13
)
2
, COOR
13
, SO
2
R
14
, N(R
13
)SO
2
R
14
, N(R
13
)COR
14
, or (C
1-6
alkyl)CN, CN, CH═C(R)
2
, OH, C(═O)CHR
13
, C(═NR
13
)R
13
, NHC(═X
1
)R
13
; or
iv) C
5-10
heterocycle optionally substituted with 1-3 groups of R
7
, which may be attached through either a carbon or a heteroatom;
represents aryl or heteroaryl, heterocycle, heterocyclyl or heterocyclic, provided that in the case of a heteroaryl, heterocycle, heterocyclyl or heterocyclic, the cyclopropyl is not attached to a nitrogen atom on the ring;
R
3
represents
i) NR
13
(C=X
2
)R
12
,
ii) NR
13
(C=X
1
)R
12
,
iii) NR
13
SO
2
R
14
,
iv) NR
13
(CHR
13
)
0-4
aryl,
v) NR
13
(CHR
13
)
0-4
heteroaryl,
vi) S(CHR
13
)
0-4
aryl,
vii) S(CHR
13
)
0-4
heteroaryl,
viii) O(CHR
13
)
0-4
aryl, or
ix) O(CHR
13
)
0-4
heteroaryl;
x) OCR
13
=NR
16
R
4
and R
4a
independently represent
i) hydrogen,
ii) halogen,
iii) C
1-6
alkoxy,
iv) C
1-6
alkyl,
v) CN,
vi) Aryl, or
vii) heteroaryl
r and s independently are 1-3, with the provision that when (R
4a
)
s
and (R
4
)
r
are attached to an Ar or HAr ring the sum of r and s is less than or equal to 4;
represents an optionally substituted aromatic heterocyclic group containing at least one nitrogen in the ring and which is attached through a bond on any N, and which is unsubstituted or contains 1 to 3 substituents of R
16
;
R
5
and R
6
independently represent
i) hydrogen,
ii) C
1-6
alkyl optionally substituted with 1-3 groups of halogen, CN, OH, C
1-6
alkoxy, amino, imino, hydroxyamino, alkoxyamino, C
1-6
acyloxy, C
1-6
alkylsulfenyl, C
1-6
alkylsulfinyl, C
1-6
alkylsulfonyl, aminosulfonyl, C
1-6
alkylaminosulfonyl, C
1-6
dialkylaminosulfonyl, 4-morpholinylsulfonyl, phenyl, pyridine, 5-isoxazolyl, ethylenyloxy, or ethynyl, said phenyl and pyridine optionally substituted with 1-3 halogen, CN, OH, CF
3
, C
1-6
alkyl or C
1-6
alkoxy;
iii) C
1-6
acyl optionally substituted with 1-3 groups of halogen, OH, SH, C
1-6
alkoxy, naphthalenoxy, phenoxy, amino, C
1-6
acylamino, hydroxylamino, alkoxylamino, C
1-6
acyloxy, aralkyloxy, phenyl, pyridine, C
1-6
alkylcarbonyl, C
1-6
alkylamino, C
1-6
dialkylamino, C
1-6
hydroxyacyloxy, C
1-6
alkylsulfenyl, phthalimido, maleimido, succinimido, said phenoxy, phenyl and pyridine optionally substituted with 1-3 groups of halo, OH, CN, C
1-6
alkoxy, amino, C
1-6
acylamino, CF
3
or C
1-6
alkyl;
iv) C
1-6
alkylsulfonyl optionally substituted with 1-3 groups of halogen, OH, C
1-6
alkoxy, amino, hydroxylamino, alkoxylamino, C
1-6
acyloxy, or phenyl; said phenyl optionally substituted with 1-3 groups of halo, OH, C
1-6
alkoxy, amino, C
1-6
acylamino, CF
3
or C
1-6
alkyl;
v) arylsulfonyl optionally substituted with 1-3 of halogen, C
1-6
alkoxy, OH or C
1-6
alkyl;
vi) C
1-6
alkoxycarbonyl optionally substituted with 1-3 of halogen, OH, C
1-6
alkoxy, C
1-6
acyloxy, or phenyl, said phenyl optionally substituted with 1-3 groups of halo, OH, C
1-6
alkoxy, amino, C
1-6
acylamino, CF
3
or C
1-6
alkyl;
vii) aminocarbonyl, C
1-6
alkylaminocarbonyl or C
1-6
dialkylaminocarbonyl, said alkyl groups optionally substituted with 1-3 groups of halogen, OH, C
1-6
alkoxy or phenyl;
viii) five to six membered heterocycles optionally substituted with 1-3 groups of halogen, OH, CN, amino, C
1-6
acylamino, C
1-6
alkylsulfonylamino, C
1-6
alkoxycarbonylamino, C
1-6
alkoxy, C
1-6
acyloxy or C
1-6
alkyl, said alkyl optionally substituted with 1-3 groups of halogen, or C
1-6
alkoxy;
ix) C
3-6
cycloalkylcarbonyl optionally substituted with 1-3 groups of halogen, OH, C
1-6
alkoxy or CN;
x) benzoyl optionally substituted with 1-3 groups of halogen, OH, C
1-6
alkoxy, C
1-6
alkyl, CF
3
, C
1-6
alkanoyl, amino or C
1-6
acylamino;
xi) pyrrolylcarbonyl optionally substituted with 1-3 of C
1-6
alkyl;
xii) C
1-2
acyloxyacetyl where the acyl is optionally substituted with amino, C
1-6
alkylamino, C
1-6
dialkylamino, 4-morpholino, 4-aminophenyl, 4-(dialkylamino)phenyl, 4-(glycylamino)phenyl; or
R
5
and R
6
taken together with any intervening atoms can form a 3 to 7 membered heterocyclic ring containing carbon atoms and 1-2 heteroatoms independently chosen from O, S, SO, SO
2
, N, or NR
8
;
R
7
represents
i) hydrogen, halogen, OH, C
1-6
alkoxy, C
1-6
alkyl, alkenyl,
ii) amino, C
1-6
alkylamino, C
1-6
dialkylamino, hydroxylamino or C
1-2
alkoxyamino all of which can be optionally substituted on the nitrogen with C
1-6
acyl, C
1-6
alkylsulfonyl or C
1-6
alkoxycarbonyl, said acyl and alkylsulfonyl optionally substituted with 1-2 of halogen or OH;
R
8
and R
8
independently represent
i) H, CN,
ii) C
1-6
alkyl optionally substituted with 1-3 halogen, CN, OH, C
1-6
alkoxy, C
1-6
acyloxy, or amino,
iii) phenyl optionally substituted with 1-3 groups of halogen, OH, C
1-6
alkoxy; or
R
7
and R
8
taken together can form a 3-7 membered carbon ring optionally interrupted with 1-2 heteroatoms chosen from O, S, SO, SO
2
, NH, and NR
8
;
X
1
represents O, S or NR
13
, NCN, or NSO
2
R
14
;
X
2
represents O, S, NH or NSO
2
R
14
;
R
10
represents hydrogen, C
1-6
alkyl or CO
2
R
15
;
R
11
represents hydrogen, C
1-6
alkyl, C
1-6
alkanoyl, halogen, amino, C
1-6
acylamino, C
1-6
alkoxy, OH or CF
3
,; NHC
1-6
alkyl, or N(C
1-6
alkyl)
2
, where said alkyl may be substituted with 1-3 groups of halo, OH or C
1-6
alkoxy;
R
12
represents hydrogen, C
1-6
alkyl, C
1-6
cycloalkyl, heteroaryl, wherein said heteroaryl may be substituted with 1-2 groups of C
1-6
alkyl, NH
2
, C
1-6
alkylamino, C
1-6
alkoxy or C
1-6
dialkylamino, where said alkyl may be substituted with 1-3 groups of halo, OH or C
1-6
alkoxy; alkylthio, alkylsulfinyl, alkylsulfonyl or cyano;
Each R
13
represents independently hydrogen, C
1-6
alkyl, NR
5
R
6
, SR
8
, S(O)R
8
, S(O)
2
R
8
, CN, C
1-6
alkylS(O)R, OH, C
1-6
alkoxycarbonyl, C
6-10
arylcarboxy, hydroxycarbonyl, C
1-6
acyl,
C
3-7
membered carbon ring optionally interrupted with 1-4 heteroatoms chosen from O, S, SO, SO
2
, NH and NR
8
where said C
1-6
alkyl or C
1-6
acyl groups may be independently substituted with 0-3 halogens, hydroxy, N(R)
2
, CO
2
R, C
6-10
aryl,
C
5-10
heteroaryl, or C
1-6
alkoxy groups;
When two R
13
groups are attached to the same atom or two adjacent atoms they may be taken together to form a 3-7 membered carbon ring optionally interrupted with 1-2 heteroatoms chosen from O, S, SO, SO
2
, NH, and NR
8
;
R represents hydrogen or C
1-6
alkyl;
R
14
represents amino, C
1-6
alkyl, C
1-6
haloalkyl, five to six membered heterocycles or phenyl, said phenyl and heterocycles optionally substituted with 1-3 group of halo, C
1-6
alkoxy, C
1-6
acylamino,
Kyorin Pharmaceutical Co. Ltd.
McDermott & Will & Emery
McKane Joseph K.
Small Andrea D.
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