Piperidinyloxy and pyrrolidinyloxy oxazolidinone antibacterials

Details Piperidinyloxy and pyrrolidinyloxy oxazolidinone antibacterials Piperidinyloxy and pyrrolidinyloxy oxazolidinone antibacterials

2000-12-05

2003-02-11

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S210030, C514S256000, C514S336000, C514S376000, C544S335000, C546S209000, C546S256000, C548S229000, C548S950000

Reexamination Certificate

active

06518285

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the field of piperidinyloxy, pyrrolidinyloxy and azetidinyloxy oxazolidinone compounds having antibacterial activity, pharmaceutical compositions containing the compounds, and methods of treating bacterial infections with the compounds.
BACKGROUND OF THE INVENTION
Oxazolidinones have been identified, within the last twenty years, as a new class of antibacterials which are active against numerous multidrug-resistant gram positive organisms. Particularly problematic pathogens include methicillin-resistant
Staphylococcus aureus
(MRSA), vancomycin-resistant enterococci (VRE) and penicillin- and cephalosporin-resistant
Streptococcus pneumoniae
. As a class oxazolidinones exhibit a unique mechanism of action. Studies have shown that these compounds selectively bind to the 50S ribosomal subunit and inhibit bacterial translation at the initiation phase of protein synthesis. Exemplary members of oxazolidinones are linezolid (see WO 95/07271) and eperezolid.
The following references relate to various oxazolidinone type compounds disclosed as having antibacterial activity:
U.S. Pat. No. 4,705,799 to W. A. Gregory discloses aminomethyl oxooxazolidinyl benzene derivatives, including the sulfides, sulfoxides, sulfones and sulfonamides, such as (1)-N-[3-[4-(methylsulfinyl)-phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.
U.S. Pat. No. 5,565,571 to Barbachyn et al. discloses substituted aryl- and heteroarylphenyloxazolidinones.
U.S. Pat. No. 5,792,765 to Riedl et al. relates to new substituted oxazolidinones.
U.S. Pat. No. 5,910,504 to Hutchinson discloses phenyloxazolidinone compounds having a nitrogen containing hetero-aromatic ring substitution attached through one of the nitrogen atoms.
WO 93/09103 (Barbachyn et al.) discloses substituted aryl- and heteroarylphenyloxazolidinones.
WO 95/07271 (Barbachyn et al.) discloses oxazine and thiazine oxazolidinone derivatives.
WO 98/54161 (Hester et al.) provides oxazolidinone antibacterial agents having a thiocarbonyl functionality.
SUMMARY OF THE INVENTION
The invention provides new piperidinyloxy, pyrrolidinyloxy and azetidinyloxy compounds of Formula I
wherein
(a) R
3
is selected from H, alkyl, —COR
4
, —(CH
2
)
t
heteroaryl, —CHR
5
R
6
, —(CH
2
)
t
aryl, —SO
2
NR
5
R
6
, and —SO
2
R
9
;
(b) R
4
is selected from H, —OR
5
, alkyl, alkylaryl, —(CH
2
)aryl, —(CH
2
)
t
heteroaryl, —(CH
2
)
t
OR
5
, —(CH
2
)
t
NR
7
R
8
, —CHR
5
R
6
, and —NR
5
R
6
optionally forming a cyclic amino derivative;
(c) R
5
and R
6
are independently selected from H, alkyl, alkylaryl, haloaryl, —(CH
2
)
t
aryl, —(CH
2
)
t
heteroaryl, and acyl;
(d) R
7
and R
8
are independently selected from H, alkyl, —COR
9
, —SO
2
R
9
and —CO
2
R
9
; and
(e) R
9
is selected from H, alkyl, aryl and alkylaryl;
R
2
is selected from C(O)R
9
, C(O)OR
9
,
 R
2a
is H or acyl with the proviso that when R
3
is selected from alkyl, —(CH
2
)
t
aryl, —(CH
2
)
t
heteroaryl, and —CHR
5
R
6
, R
2a
is H;
X is N or CH;
Y is selected from H, halogen, alkoxy, and alkyl; and
t is an integer of 0 to 4;
or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt thereof.
Compounds of the above formula are useful as antibacterial agents for the treatment of bacterial infections in a subject such as human and animal.
The present invention is also directed to a method of treating a subject having a condition caused by or contributed to by bacterial infection, which comprises administering to said subject a therapeutically effective amount of the compound of Formula I.
The present invention is further directed to a method of preventing a subject from suffering from a condition caused by or contributed to by bacterial infection, which comprises administering to the subject a prophylactically effective amount of the compound of Formula I.
Other objects and advantages will become apparent to those skilled in the art from a review of the ensuing specification.
DETAILED DESCRIPTION
Relative to the above description, certain definitions apply as follows.
Unless otherwise noted, under standard nomenclature used throughout this disclosure the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.
Unless specified otherwise, the terms “alkyl”, “alkenyl”, and “alkynyl,” whether used alone or as part of a substituent group, include straight and branched chains having 1 to 8 carbon atoms, or any number within this range. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. “Alkoxy” radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. “Cycloalkyl” groups contain 3 to 8 ring carbons and preferably 5 to 7 ring carbons. The alkyl group and alkoxy group may be independently substituted with one or more members of the group including, but not limited to, mono-, di-, tri-, or per-halogen, alkyl, alkoxy, aryl, heteroaryl, heterocyclyl, amino, substituted amino, OH, CN, mercapto, nitro, and C
1-8
acyloxy.
The term “acyl” as used herein, whether used alone or as part of a substituent group, means an organic radical having 2 to 6 carbon atoms (branched or straight chain) derived from an organic acid by removal of the hydroxyl group.
The term “Ac” as used herein means acetyl.
The term “halo” or “halogen” means fluoro, chloro, bromo and iodo. (Mono-di-, tri-, and per-)halo-alkyl is an alkyl radical substituted by independent replacement of the hydrogen atoms thereon with halogen.
“Aryl” or “Ar,” whether used alone or as part of a substituent group, is a carbocyclic aromatic radical including, but not limited to, phenyl, 1- or 2-naphthyl and the like. The carbocyclic aromatic radical may be substituted by independent replacement of 1 to 3 of the hydrogen atoms thereon with halogen, —OH, —CN, mercapto, nitro, amino, substituted amino, alkyl, —O-alkyl, —S-alkyl, —NH-alkyl, —N(alkyl)
2
, (mono-, di-, tri-, and per-)halo-alkyl, formyl, —COR
5
, —COOR
5
, —CONHR
5
, —CONR
5
R
6
, —SOR
5
, —SO
2
R
5
, —SO
2
NHR
5
, —SO
2
NR
5
R
6
, alkyl-COO, alkyl-CONHR
5
, or carboxamide or a second aryl ring, wherein R
5
and R
6
are defined as hereinabove. Illustrative aryl radicals include, for example, phenyl, naphthyl, diphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. “Ph” or “PH” denotes phenyl.
Whenever the term “alkyl”, “acyl”, or “aryl” or either of their prefix roots appear in a name of a substituent (e.g., aralkyl, dialkylamino) it shall be interpreted as including those limitations given above for “alkyl”, “acyl”, and “aryl.” Designated numbers of carbon atoms (e.g., C
1-8
) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
Whether used alone or as part of a substituent group, “heteroaryl” refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O, and N; 0-2 ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon. The radical being joined to the rest of the molecule via any of the ring atoms, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, and the like. The heteroaryl group may be substituted by independent replacement of 1 to 3 of the hydrogen atoms thereon with halogen, —OH, —CN mercapto, nitro, amino, substituted amino, alkyl, —O-alkyl, —S-alkyl, —NH-alkyl, —N(alkyl)
2
, (mono-, di-, tri-, and

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