Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-03
2001-11-06
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S234000, C548S518000, C548S566000
Reexamination Certificate
active
06313307
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to new and useful N-phenyloxazolidinone compounds and their preparations, and more particularly to N-phenyloxazolidinone compounds in which the phenyloxazolidinone moiety is linked to a variety of saturated, or partially saturated, 4-8 membered heterocycles containing oxygen, nitrogen, and sulfur through a carbon-carbon bond.
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, as well as anaerobic organisms such as bactericides 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.
INFORMATION DISCLOSURE
A series of Delalande patent applications (Derwent Abstracts 61219Y/35, 67436R-B, 84475A/47) disclose a saturated nitrogen heterocycle linked through the nitrogen atom to a phenyloxazolidinone moiety.
French Patent (FR2500450 A1 820827) discloses cyclohexenone attached at the 3-position to a phenyloxazolidinone.
Other references disclose fully aromatic heterocycles attached to a phenyloxazolidinone, including European Patent Publication 0352 781 A2, U.S. Pat. No. 5,130,316, U.S. Pat. No. 5,254,577, U.S. Pat. No. 4,948,801, and WO 9309103-A1, whereas in our present invention the heterocycle is saturated or partially saturated.
SUMMARY OF THE INVENTION
The present invention provides new compounds of the Formula (I)
or pharmaceutical acceptable salts thereof wherein:
X is
NR
1
, S(O)
g
, or O;
R
1
is
a) H,
b) C
1-6
alkyl, optionally substituted with one or more OH, CN, or halo,
c) —(CH
2
)
h
-aryl,
d) —COR
1-1
,
e) —COOR
1-2
,
f) —CO—(CH
2
)
h
—COR
1-1
,
g) —SO
2
—C
1-6
alkyl,
h) —SO
2
—(CH
2
)
h
-aryl, or
i) —(CO)
i
-Het;
R
1-1
is
a) H,
b) C
1-6
alkyl, optionally substituted with one or more OH, CN, or halo,
c) —(CH
2
)
h
-aryl, or
d) —(CH
2
)
h
—OR
1-3
;
R
1-2
is
a) C
1-6
alkyl, optionally substituted with one or more OH, CN, or halo,
b) —(CH
2
)
h
-aryl, or
c) —(CH
2
)
h
—OR
1-3
;
R
1-3
is
a) H,
b) C
1-6
alkyl,
c) —(CH
2
)
h
-aryl, or
d) —CO(C
1-6
alkyl);
R
2
is
a) H,
b) C
1-6
alkyl,
c) —(CH
2
)
h
-aryl, or
d) halo;
R
3
and R
4
are the same or different and are
a) H, or
b) halo;
R
5
is
a) H,
b) C
1-12
alkyl, optionally substituted with one or more halo,
c) C
3-12
cycloalkyl,
d) C
1-6
alkoxy;
g is 0, 1, or 2;
h is 1, 2, 3, or 4;
i is 0 or 1;
m is 0, 1, 2, 3, 4, or 5;
n is 0, 1, 2, 3, 4, or 5;
and with the provision that m and n taken together are 1, 2, 3, 4, or 5.
More particularly, the present invention provides compounds of formula (I) wherein R
1
is H, fluoroethyl, cyanomethyl, methyl sulfonyl, formyl, hydroxyacetyl, acetyl, methoxyacetyl, benzyloxyacetyl, acetoxyacetyl, dichloroacetyl, methoxy carbonyl, tert-butoxy carbonyl, benzyloxy carbonyl, 3-hydroxypropionyl, 3-methoxypropionyl, 4-oxopentanoyl, 2-indole carbonyl, 5-isoxazole carbonyl, 5-nitro-2-thiazoyl, 4-oxo-2-thiazolinyl, or 5-methyl-1,2,4-thiadiazol-2-yl.
R
2
is H, F, or CH
3
;
R
3
and R
4
are the same or different and are H or F; and
R
6
is methyl or methyl substituted with one or more F or Cl.
The present invention also provides a method for treating microbial infections in patients by administering to a patient in need thereof an effective amount of a compound of Formula (I). The compound can be administered orally, parenterally or topically in a pharmaceutical composition. Preferably, the compound is administered in an amount of from about 0.1 to about 100 mg/kg of body weight/day.
DETAILED DESCRIPTION OF THE INVENTION
For the purpose of the present invention, the term “C
1-6
alkyl” and the term “C
1-12
alkyl” refer to any straight or branched alkyl group having one to six or one to twelve carbons respectively such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, osopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and the like.
The term “C
1-6
alkyl sulfonyl” refers to any straight or branched alkyl group having one to six carbons attached to —SO
2
forming such groups as, for example, methyl sulfonyl, ethyl sulfonyl, isopropyl sulfonyl and the like.
The term “C
3-12
cycloalkyl” refers to three to twelve carbon atoms forming cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
The term “C
1-4
alkoxy” and the term “C
1-6
alkoxy” refer to any straight or branched alkyl group having one to four or one to six carbons, respectively, attached to an oxygen forming such groups as, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, isobutyloxy, sec-butyloxy, t-butyloxy, n-pentyloxy, isopentyloxy, n-hexyloxy, iso-hexyloxy and the like.
The term halo refers to fluoro, chloro, bromo, or iodo.
The term “aryl” refers to a phenyl, pyridyl or napthyl moiety which can be optionally substituted with one or more F, Cl, Br, I, CN, OH, SH, C
1-6
alkyl, C
1-6
alkoxy, or C
1-6
thioalkyl.
The term “Het” refers to 5 to 10 membered heterocyclic rings containing one or more oxygen, nitrogen, and sulfur forming such groups as, for example, pyridine, thiophene, furan, pyrazoline, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl, 1-phthalazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl, 5-oxazolyl, 4,5,-dihydrooxazole, 1,2,3-oxathiole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2-indolyl, 3-indolyl, 3-indazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-benzimidazolyl, 2-benzofuranyl, 3-benzofuranyl, benzoisothiazole, benzisoxazole, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl, 1,2,3,-oxathiazole-1-oxide, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 5-oxo-1,2,4-oxadiazol-3-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 3-oxo-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 2-oxo-1,3,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3,4-tetrazol-5-yl, 5-oxazolyl, 1-pyrrolyl, 1-pyrazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 1-tetrazolyl, 1-indolyl, 1-indazolyl, 2-isoindolyl, 7-oxo-2-isoindolyl, 1-pruinyl, 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl, 1,3,4-oxadiazole, 4-oxo-2-thiazolinyl, or 5-methyl-1,3,4-thiadiazol-2-yl, thiazoledione, 1,2,3,4-thiatriazole, 1,2,4-dithiazolone. Each of these moieties may be substituted as appropriate.
The term “pharmaceutically acceptable salts” refers to salts useful for administering the compounds of this invention and include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citrate, 2-hydroxyethyl sulfonate, fumarate and the like. These salts may be in hydrated form.
In the structural representation of Formula (I) the dotted line in the heterocyclic ring means that this bond can be either single or double. In the case where the dotted line is a double bond, the R
2
group will not be present.
In a preferred embodiment of the N-phenyloxazolidinone compounds of the present invention, the X group is preferably NR
1
, SO
2
, or oxygen.
The R
1
substituent on the nitrogen atom can be introduced by synthetic methods known to those skilled in the art from commercially available reagents.
The preferred R
1
substituent is H, fluoroethyl, cyanomethyl, methyl sulfonyl, formyl, hydroxyacetyl, acetyl, methoxyacetyl, benzylosyacetyl, acetoxyacetyl, dichloroacetyl, methoxy carbonyl, tert-butoxy carbonyl, benzyloxy carbonyl, 3-hydroxypropionyl, 3-methoxypropionyl, 4-oxopentanoyl, 2-i
Anderson David John
Ennis Michael Dalton
Hoffman Robert Louis
Hutchinson Douglas K.
Poel Toni-Jo
Patel Sudhaker B.
Pharmacia & Upjohn Company
Raymond Richard L.
Yang Lucy X.
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