Bis quaternary MRSA cephem derivatives

Details Bis quaternary MRSA cephem derivatives Bis quaternary MRSA cephem derivatives

1999-08-04

2001-07-24

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S224000, C540S225000

Reexamination Certificate

active

06265394

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed to new cephem derivatives represented by the general formula
wherein Ar is an optionally substituted lipophilic phenyl, naphthyl or pyridyl group; L
1
and L
2
are (C
1
-C
6
)alkylene optionally substituted with hydroxy or oxo and/or optionally interrupted with a vinylene group, S, O, aryl or heteroaryl, or a group of the formula
wherein R
1
is hydrogen or (C
1
-C
6
)alkyl or can optionally contain A; A is CO
2
H, PO
3
H, SO
3
H, tetrazolyl, or
R
2
, R
3
, R
9
and R
10
are hydrogen or optionally substituted (C
1
-C
6
)alkyl, x′
{circle around (−)}
is a pharmaceutically acceptable anion; and Q is a quaternized nitrogen group. The derivatives IA, IB, IC and ID, including pharmaceutically acceptable salts and prodrugs thereof, are gram-positive antibacterial agents especially useful in the treatment of diseases caused by methicillin-resistant
Staphylococcus aureus
(also referred to below as MRSA or methicillin-resistant
S. aureus
).
2. Description of the Prior Art
The literature discloses a vast number of cephem derivatives having a wide variety of C-3 and C-7 substituents.
Cephems having at the 3-position substituents containing two quaternary nitrogens plus an acidic group, —CO
2
H or —SO
3
H, are disclosed in EP 700,916 and EP 264,091. Such publications, however, disclose compounds with different 7-substituents than in applicants' compounds and the 3-substituents are of the type
—CH═CHCH
2
—
and
—H═CH—SR.
Cephems containing two quaternary nitrogens in the C-3 substituent are disclosed in WO 96/02548, but here again the C-7 substituents differ from those in applicants' compounds and the C-3 substituents are of the type
U.S. Pat. No. 5,567,698 discloses cephems of the formula
wherein Ar is an aryl group selected from
in which R
4
, R
5
and R
6
are each independently hydrogen, halogen, trihalomethyl, nitro, C
1
-C
6
alkyl, —(CH
2
)
n
OR
7
or —(CH
2
)
n
SR
7
; n is an integer of from 1 to 6; R
7
is hydrogen or C
1
-C
6
alkyl; R
1
is —CR
8
R
9
R
10
, —(CH
2
)
n
CONR
8
R
9
and —(CH
2
)
n
COR
8
in which R
8
, R
9
and R
10
are each independently hydrogen, substituted or unsubstituted C
1
-C
15
alkyl, C
2
-C
15
alkenyl or C
2
-C
15
alkynyl, substituted or unsubstituted phenyl, phenyl(C
1
-C
6
)alkyl, naphthyl or naphthyl(C
1
-C
6
)alkyl or a sugar moiety of the formula
in which said alkyl, alkenyl or alkynyl group, or the alkyl portion of the said phenyl(C
1
-C
6
)alkyl or naphthyl(C
1
-C
6
)alkyl group can be substituted by one or more hydroxy groups and said phenyl or naphthyl group, or the phenyl or naphthyl portion of said phenyl (C
1
-C
6
)alkyl or naphthyl(C
1
-C
6
)alkyl group can be substituted by one or more hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halo or halo(C
1
-C
6
)alkyl groups; n is as defined above; R
2
and R
3
are each independently hydrogen, C
1
-C
6
alkyl, or amino(C
1
-C
6
)alkylcarbonyl-amino; and R
11
is hydrogen, an anionic charge or a carboxyl-protecting group provided that when R
11
is hydrogen or a protecting group, there is also a counter ion; or a pharmaceutically acceptable salt or prodrug thereof.
U.S. Pat. No. 5,559,108 discloses cephem compounds of the formula
wherein Ar is an aryl group selected from the group consisting of
in which R
3
, R
4
and R
5
are each independently hydrogen, halogen, trihalomethyl, C
1
-C
6
alkyl, —(CH
2
)
n
OR
6
or —(CH
2
)
n
SR
6
, with the proviso that when Ar is a phenyl group, R
3
, R
4
and R
5
may not all be hydrogen; n is an integer of from 1 to 6; R
6
is hydrogen or C
1
-C
6
alkyl; R
1
and R
2
are each independently hydrogen, —(CH
2
)
m
CONR
7
R
8
, —(CH
2
)
m
COR
7
, —(CH
2
)
m
CO
2
R
7
, —(CH
2
)
m
CN, —(CH
2
)
m
NR
7
R
8
, —(CH
2
)
m
OR
7
, —(CH
2
)
m
NHCONR
7
R
8
or —(CH
2
)
m
NHCOR
7
in which m is 0 or an integer of from 1 to 6 and R
7
and R
8
are each independently hydrogen, C
1
-C
6
alkyl substituted by one or two amino or hydroxyl groups or a group of the formula
or R
7
and R
8
taken together with the nitrogen atom to which they are attached represent
with the proviso that R
1
and R
2
may not both be hydrogen; and R
9
is hydrogen, an anionic charge or a carboxyl-protecting group, provided that when R
9
is hydrogen or a protecting group, there is also present a ounter ion; or a pharmaceutically acceptable salt thereof.
In co-pending application Ser. No. 08/829,126 filed Mar. 28, 1997, there are disclosed cephem derivatives of the formula
wherein Ar is a group of the formula
in which R
4
, R
5
and R
6
are each independently hydrogen, halogen, trihalomethyl, nitro, amino, hydroxy, hydroxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl, —(CH
2
)
n
OR
7
or —(CH
2
)
n
SR
7
; n is an integer of from 1 to 6; R
7
is hydrogen or(C
1
-C
6
)alkyl; R
1
represents alkyl having from 1 to 10 carbons or cycloalkyl having from 3 to 6 carbons, said alkyl or cycloalkyl group being linked by a carbon atom to the quaternary nitrogen and having a carboxy, —SO
3
H or tetrazolyl substituent, and said alkyl group being optionally interrupted by —S— or
and optionally substituted by one or more of (C
1
-C
6
)alkylthio, hydroxy, (C
1
-C
6
)alkylsulfinyl, (C
1
-C
6
)alkylsulfonyl, carbamoyl, ureido, C
2
-C
6
alkenyl, halo, oxo, hydroxyimino, heteroaryl or phenyl in which the phenyl or heteroaryl group is optionally substituted by up to three hydroxy or (C
1
-C
6
)alkoxy groups; R
7
is as defined above; R
2
, R
3
, R
9
and R
10
are each independently hydrogen, (C
1
-C
10
)alkyl or (C
1
-C
10
)alkyl substituted by one or more, preferably one or two, substituents independently selected from CO
2
H, hydroxy and NR
11
R
12
in which R
11
and R
12
are each independently hydrogen or (C
1
-C
6
)alkyl, and R
2
and R
9
or R
3
and R
10
can optionally be joined in a ring, preferably a 5-6 membered ring; and R
8
is hydrogen or a protecting group; or a pharmaceutically acceptable salt or prodrug thereof.
SUMMARY OF THE INVENTION
In one aspect the present invention provides a novel series of cephem derivatives of the general formula
wherein Ar is a group of the formula
R
4
, R
5
and R
6
are each independently hydrogen, halogen, trihalomethyl, nitro, amino, hydroxy, hydroxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl, —(CH
2
)
n
OR
7
or —(CH
2
)
n
SR
7
; n is an integer of from 1 to 6; R
7
is hydrogen or (C
1
-C
6
)alkyl; L
1
and L
2
are each independently (C
1
-C
6
)alkylene optionally substituted with hydroxy or oxo and/or optionally interrupted with a vinylene group, S, O, an aryl or heteroaryl residue, or
wherein R
1
is H or C
1
-C
6
alkyl; A is CO
2
H, PO
3
H, SO
3
H, tetrazolyl or
Q is selected from the group consisting of:
wherein R
14
and R
15
are each independently (C
1
-C
10
)alkyl optionally substituted with OH or C(O)NH
2
;
wherein X is CH
2
, O, S, SO or SO
2
;
R
7
is H, (C
1
-C
6
) alkyl, (C
3
-C
6
)cycloalkyl, OH, CONH
2
, aryl or heteroaryl and can be located anywhere on the ring including X when X is CH
2
;
wherein R
15
is (C
1
-C
6
)alkyl or (C
3
-C
6
)cycloalkyl optionally substituted with OH or CONH
2
, or R
15
is aryl or heteroaryl;
wherein Y is CH or N and R
16
is as defined above for R
7
;
wherein A through F can be CH or N, and either 1 or 2 of the non-adjacent atoms being N with the remainder being CH, exactly one N being quaternized by attachment to L
1
, L
2
, R
17
, or R
13
; R
13
and R
17
are as defined above for R
7
;
wherein G, H, I, and J are either CH or N, K is either CH
2
, NH, or S, either 1, 2, or 3 of the ring atoms being nitrogen with the remainder being CH
2
, exactly one nitrogen being quaternized by L
1
, L
2
, or R
18
; and R
18
is as defined above for R
7
; R
2
, R
3
, R
9
and R
10
are each independently hydrogen, (C
1
-C
10
)alkyl or (C
1
-C
10
)alkyl substituted by one or more substituents independently selected from hydroxy and NR
11
R
12
in which R
11
and R
12
are each independently hydrogen or (C
1
-C
6
)alkyl, and x′
{circle around (−)}
is a pharmaceutically acceptable anion; or a pharmaceuti

Affiliated with

Also associated with

Rating

Bis quaternary MRSA cephem derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Bis quaternary MRSA cephem derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Bis quaternary MRSA cephem derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2459944