Oxazolidinone thioamides with piperazine amide substituents

Details Oxazolidinone thioamides with piperazine amide substituents Oxazolidinone thioamides with piperazine amide substituents

2002-01-09

2003-11-04

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S254030, C514S254040, C514S254100, C544S367000, C544S369000, C544S374000, C544S379000

Reexamination Certificate

active

06642238

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel oxazolidinone thioamides which have new piperazine amide substituents; and their preparations. These compounds have potent activities against gram positive and gram-negative bacteria.
BACKGROUND OF THE INVENTION
The oxazolidlinone 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 demonstrate 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 oxazolidinone thioawnides of the present invention increase the spectrum of activity to include gram-negative organisms such as Haemophilus influenza and Moraxella catarrhalis.
INFORMATION DISCLOSURE
PCT International Publication WO 98/54161 discloses oxazolidinone antibacterial agents having a thiocarbonyl functionality.
PCT International Publication WO 93/23384 discloses oxazolidinones containing a substituted diazine moiety and their use as antimicrobials.
PCT International Publication WO 95/07271 discloses substituted oxazine and thiazine oxazolidinones and their use as antimicrobials.
PCT International Publication WO 99/12914 discloses antimicrobial thiourea derivatives.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I
or a pharmaceutically acceptable salt thereof wherein:
A is a structure i, ii, iii or iv:
W is NHC(=S)R
1
, or −Y-het; provided that when A is a structure iv, W is not −Y-het;
Y is NH, O, or S;
R
1
is H, NH
2
, NHC
1-4
alkyl, C
1-4
alkenyl, OC
1-4
alkyl, or SC
1-4
alkyl,
(CH
2
)
n
—C
3-6
cycloalkyl, or C
1-4
alkyl, optionally substituted with 1-3 F, 1-2 Cl or CN;
R
2
and R
3
are independently H, F, Cl or C
1-2
alkyl;
R
4
is
(a) —C(=O)—CR
5
R
6
—O—R
7
,
(b) —C(=O)—CH
2
S(O)
n
—CH
3
,
(c) —C(=O)—CH
2
—S(=O)(=NR
8
)CH
3
,
(d) —C(=S)—R
9
,
(e) —C(=O)—CH
2
—O—R
10
,
(f) —C(=O)—(CH
2
)
m
—C(=O)—CH
3
,
(g) —C(=O)—(CH
2
OH)
2
—CH
3
,
(h) —C(=O)—CH
2
—CH
2
—OR
14
, or
(i) —CN;.
R
5
is H;
R
6
is phenyl, benzyl, CH
2
OH or CH
2
OCH
3
; or R
5
and R
6
taken together form C
3-5
cycloalkyl;
R
7
is H, CH
3
or C
1-4
alkanoyl;
R
8
is H, C
1-4
alkyl, C
1-4
alkanoyl, —C(=O)NH—C
1-4
alkyl or —CO
2
C
1-4
alkyl;
R
9
is C
1-4
alkyl, CH
2
OR
11
, S—C
1-4
alkyl, OC
1-4
alkyl, or NR
12
R
13
;
R
10
is phenyl, —CO
2
—(CH
2
)
2
—OCH
3
, —P(=O)(OH)
2
, —C(=O)—NR
12
R
13
, or —C(=O)—(CH
2
)
2
—CO
2
H;
R
11
is H, phenyl, benzyl, CH
3
or C(=O)CH
3
;
R
12
and R
13
are independently H or C
1-3
alkyl; or R
12
and R
13
taken together form a 5- or 6-membered saturated heterocycle, wherein said saturated heterocycle may further contain one or two additional hetero-atoms selected from a group consisting of
0
, S(O)
n
or NR
7
;
R
14
is H, CH
3
or benzyl;
het is a C-linked five-(5) membered heteroaryl ring having 1-4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or het is a C-linked six (6) membered heteroaryl ring having 1-3 nitrogen atoms; and
n is 0, 1 or 2; and m is 0 or 1.
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 carrier,
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, and
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 may also contain novel intermediates and processes that are useful for preparing compounds of formula I.


REFERENCES:
patent: 6362189 (2002-03-01), Hester et al.
patent: 6465456 (2002-10-01), Springer et al.
patent: 0 074 268 (1983-03-01), None
patent: 11-322729 (1999-11-01), None
patent: WO93/23384 (1993-11-01), None
patent: WO95/07271 (1995-03-01), None
patent: WO95/14684 (1995-06-01), None
patent: 98/54161 (1998-12-01), None
patent: WO99/12914 (1999-03-01), None
patent: WO00/73301 (1999-12-01), None
patent: WO99/64417 (1999-12-01), None
patent: WO00/21960 (2000-04-01), None
patent: WO00/27830 (2000-05-01), None
patent: 01/40222 (2001-06-01), None
Patent Abstracts of Japan vol. 2000, No. 02, Feb. 29, 2000 & JP 11 322729 A (Hokuriku Seiyaku CO LTD), Nov. 24, 1999 Cpds. 125,126 on p. 12; cpd. 48 on p. 85 abstract.

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