Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-28
2002-10-15
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252110, C514S252190, C514S253100, C514S254030, C514S254040, C544S121000, C544S295000, C544S357000, C544S364000, C544S367000, C544S369000
Reexamination Certificate
active
06465456
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed toward new isoxazolinones, methods for their use, and processes for their production. These novel isoxazolinone derivatives are useful as antimicrobial agents which are effective against a number of human and veterinary pathogens, including gram positive bacteria such as multiply-resistant staphylococci, streptococci, and enterococci (e.g. methicillin-resistant
Staphylococcus aureus
or vancomycin-resistant
Enterococcus faecium
).
2. Background
The literature contains a limited number of isoxazolinones used as pre-emergence herbicides. For example in U.S. Pat. No. 4,065,463, 2-methyl-4-(trifluoromethyl-m-tolyl)-3-isoxazolin-5-one and 2-methyl-4-(chloro-m-tolyl)-3-isoxazolin-5-one are disclosed as being useful in preventing the growth of weeds which have a deleterious effect on crop production.
U.S. Pat. No. 4,000,155 discloses the related compound 1,2-dimethyl-4-(trifluoromethyl-m-tolyl)-3-pyrazolin-5-one for the same utility.
The applicants are not aware of any literature which discloses the use of these compounds as broad spectrum anti-bacterial agents. A different ring system is disclosed in WO 98/07708, which discusses the use of isoxazoline derivatives as anti-bacterial agents,
where W is a substituted aryl or heteroaryl system and V is H, or C
1
-C
4
alkyl optionally substituted with F, Cl, OH, C
1
-C
4
alkoxy, or acyloxy.
Oxazolidinones II shown below are a well known class of orally active antibacterial agents. The prior art contains numerous references to these compounds where Y and Z can include a wide variety of substituents. Specific substituted oxazolidinones are discussed in U.S. Pat. Nos. 4,705,799 and 5,523,403 (substituted phenyl 2-oxazolidinones), U.S. Pat. Nos. 4,948,801; 5,254,577; and 5,130,316 (arylbenzene oxazolidinyl compounds), U.S. Pat. No. 6,069,145 (piperazinophenyloxazolidinones) and European Patent Applications 0,697,412; 0,694,544; 0694,543; and 0,693,491 (5 to 9-membered heteroaryl substituted oxazolidinones).
Additionally, certain compounds containing a substituted furanone ring have been reported to possess antibiotic activity. WO 97/14690 discloses
where T is hydroxy or NHC(O)C
1
-C
4
alkyl, M and L are each independently hydrogen or fluoro, G and H are are each independently hydrogen or methyl, K-L is of the formula C═CH, CHCH
2
or C(OH)CH
2
, I is O, SO, SO
2
or a substituted nitrogen, and Q-R is CH
2
—CH
2
or CH═CH
2
. Other substituted furanones are discussed in U.S. Pat. No. 5,708,169, WO 97/43280 and WO 97/10235.
Isoxazolinones of type III have been disclosed in PCT Publication WO 00/10566, but the compounds of the present invention are not disclosed or suggested in this publication.
SUMMARY OF THE INVENTION
A first embodiment of a first aspect of the present invention is a compound of formula I
or a pharmaceutically acceptable salt thereof, wherein:
L is oxygen or sulfur;
L
1
is selected from the group consisting of: R
4
—(CH
2
)
m
—CR
5
(NR
6
R
7
)C(O)—, R
8
R
9
N—(CH
2
)
n
—C(O)—, C
1-6
alkylC(O)CH
2
C(O)—, R
10
—X—CH
2
C(O)—, R
10
—CH═CH—C(O)—, R
10
—NHC(O)CH
2
—, R
10
—(CH
2
)
p
— and R
10
—S(O)
2
—;
m is 0 or an integer from 1 to 4;
n is an integer from 1 to 4;
p is an integer from 2 to 6;
X is selected from the group consisting of: a bond, sulfur, oxygen, NH and N(C
1-4
alkyl);
R
1
is selected from the group consisting of: hydrogen, C
1-8
alkyl, C
3-6
cycloalkyl and C
1-8
alkoxy, said C
1-8
alkyl optionally substituted with one or more fluoro, chloro, hydroxy, C
1-8
alkoxy or C
1-8
acyloxy;
R
2
and R
3
are each independently selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, amino, cyano, C
1-6
alkyl, C
1-6
alkoxy and trifluoromethyl;
R
4
is selected from the group consisting of: hydrogen, hydroxy, C
1-6
thioalkoxy, imidazolyl, indolyl, —CO
2
H and —NHC(═NH)NH
2
;
R
5
is hydrogen or C
1-6
alkyl; or R
4
and R
5
taken together can be —CH
2
— when m is 1;
R
6
and R
7
are each independently selected from hydrogen or C
1-6
alkyl; or R
4
and R
6
taken together can be —(CH
2
)
q
— when m is 1 and wherein q is 2 or 3;
R
8
and R
9
are each independently selected from hydrogen or C
1-6
alkyl; or R
8
and R
9
taken together with the nitrogen to which they are attached are morpholin4-yl, piperazin-1-yl, piperidin-1-yl or —NHC(═NH)NH
2
;
R
10
is heteroaryl, said heteroaryl selected from the group consisting of imidazolyl, benzoimidazolyl, thienyl, benzothienyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrolyl, thiadiazolyl, oxadiazolyl, triazolyl, triazinyl and tetrazolyl, and said heteroaryl optionally substituted with one to three same or different amino, hydroxy, halogen, C
1-6
alkyl, morpholin-4-yl, piperazin-1-yl, piperadin-1-yl, phenyl, —CO
2
H or —CO
2
C
1-6
alkyl; and
provided R
4
is hydrogen or C
1-6
alkyl and R
5
is C
1-6
alkyl when m is 0.
A second embodiment of a first aspect of the present invention is a compound of the first embodiment of the first aspect and of the formula Ia
or a pharmaceutically acceptable salt thereof, wherein:
L is oxygen; R
1
is C
1-8
alkyl; and R
2
and R
3
are each independently hydrogen or halogen.
A third embodiment of a first aspect of the present invention is a compound of the second embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: R
1
is methyl; and R
2
and R
3
are each independently hydrogen or fluoro.
A fourth embodiment of a first aspect of the present invention is compound of the third embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: R
2
is hydrogen; R
3
is fluoro; and L
1
is R
4
—(CH
2
)
m
—CR
5
(NR
6
R
7
)C(O)— or R
8
R
9
N—(CH
2
)
n
—C(O)—.
A fifth embodiment of a first aspect of the present invention is a compound of the fourth embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein:
L
1
is R
4
—(CH
2
)
m
—CR
5
(NR
6
R
7
)C(O)—; R
4
is selected from the group consisting of hydrogen, hydroxy, thiomethoxy, 1H-imidazol-4-yl, indolyl, —CO
2
H and —NHC(═NH)NH
2
; R
5
is hydrogen or C
1-6
alkyl, said C
1-6
alkyl selected from the group consisting of methyl, ethyl, propyl, isopropyl and 2-methyipropyl; or R
4
and R
5
taken together can be —CH
2
— when m is 0; R
6
is hydrogen or methyl; or R
4
and R
6
taken together can be —(CH
2
)
q
— when m is 1 and wherein q is 2 or 3; R
7
is hydrogen or C
1-6
alkyl, said C
1-6
alkyl selected from the group consisting of methyl, ethyl, propyl and isopropyl.
A sixth embodiment of a first aspect of the present invention is a compound of the fifth embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: R
4
and R
6
taken together are —(CH
2
)
q
wherein q is 2 or 3; and m is 1.
A seventh embodiment of a first aspect of the present invention is a compound of the fifth embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: R
4
is hydrogen; m is 0;
R
5
is C
1-6
alkyl, said C
1-6
alkyl selected from the group consisting of methyl, ethyl, propyl, isopropyl and 2-methylpropyl; and R
6
and R
7
are each independently hydrogen or methyl.
An eighth embodiment of a first aspect of the present invention is a compound of the fifth embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: R
4
is selected from the group consisting of hydroxy, thiomethoxy, 1H-imidazol-4-yl, —CO
2
H and —NHC(═NH)NH
2
; R
5
is hydrogen; R
6
and R
7
are hydrogen; and m is an integer from 1to 3.
A ninth embodiment of a first aspect of the present invention is a compound of the fourth embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein: L
1
is R
8
R
9
N—(CH
2
)
n
—C(O)—;
R
8
and R
9
are each independently selected from hydrogen or C
1-6
alkyl; said C
1-6
alkyl selected from the group consisting of methyl, ethyl and propyl; or R
8
and R
9
taken together with the nitrogen to which they are attached are m
Goodrich Jason T.
Meng Zhaoxing
Snyder Lawrence B.
Springer Dane M.
Bernhardt Emily
Bristol--Myers Squibb Company
Morse David M.
LandOfFree
Isoxazolinone antibacterial agents does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Isoxazolinone antibacterial agents, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Isoxazolinone antibacterial agents will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2968752