Vinylpyrrolidinone cephalosporin derivatives

Details Vinylpyrrolidinone cephalosporin derivatives Vinylpyrrolidinone cephalosporin derivatives

1997-11-05

2001-09-25

Berch, Mark L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C540S224000, C540S225000, C540S226000, C540S227000

Reexamination Certificate

active

06294668

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention is in the field of antibacterial agents which are cephalosporin derivatives.
Certain cephalosporin derivatives are disclosed in PCT International Publication No.WO 96/26943, published Sep. 6, 1996 (F. Hoffmann-La Roche A G); U.S. Pat. No. 5,523,400, issued Jun. 4, 1996 (Wei et al.); European Patent Publication No. EP 0 699 681 A1, published Mar. 6, 1996 (Bristol-Myers Co.); and European Patent Publication No. EP 0 727 426 A2, published Aug. 21, 1996 (Bristol-Myers Co.).
SUMMARY OF THE INVENTION
The present invention provides cephalosporin derivatives of the formula
where
R
1
is halogen, lower alkyl, phenyl, benzyl, styryl, naphthyl or heterocyclyl; the lower alkyl, phenyl, benzyl, styryl, naphthyl and heterocyclyl being optionally substituted by at least one of halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted phenyl, amino, lower alkylamino, di-lower alkylamino, carboxy, lower alkylcarboxy, carbamoyl or lower alkylcarbamoyl;
R
4
, R
5
independently are hydrogen, lower alkyl or phenyl;
X is S, O, NH or CH
2
;
n is 0, 1 or 2;
m is 0 or 1;
s is 0 or 1;
R
2
is hydrogen, hydroxy, —CH
2
—CONHR
6
, lower alkyl-Q
r
, cycloalkyl-Q
r
, lower alkoxy, lower alkenyl, cycloalkenyl-Q
r
, lower alkynyl, aralkyl-Q
r
, aryl-Q
r
, aryloxy, aralkoxy, a heterocyclic ring or a heterocyclyl-Q
r
, the lower alkyl, cycloalkyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aralkyl, aryl, aryloxy, aralkoxy and the heterocyclic ring may be substituted with at least one group selected from carboxy, amino, nitro, cyano, —SO
2
NHR
6
, optionally fluoro substituted lower alkyl, lower alkoxy, hydroxy, halogen, —CONR
6
R
7
, —CH
2
CONR
6
R
7
, —N(R
7
)COOR
8
, R
7
CO—, R
7
OCO—, R
7
COO—, —C(R
7
R
9
)CO
2
R
8
, —C(R
7
R
9
)CONR
7
R
10
, wherein
R
6
is hydrogen, lower alkyl, cycloalkyl or aryl;
R
7
and R
9
are independently hydrogen or lower alkyl;
R
8
is hydrogen, lower alkyl, lower alkenyl or a carboxylic acid protecting group; and
R
10
is hydrogen, &ohgr;-hydroxy-alkyl, phenyl, naphthyl or heterocyclyl, the phenyl, naphthyl or heterocyclyl being unsubstituted or substituted with at least one of the groups of optionally protected hydroxy, halogen, optionally substituted lower alkyl or &ohgr;-hydroxyalkyl, optionally substituted lower alkoxy and/or cyano, or R
7
and R
10
form together group of formula
Q is —CHR—, —CO— or —SO
2
—;
r is 0 or 1;
R is hydrogen or lower alkyl; and
R
3
is hydroxy, —O
−
, lower-alkoxy, or —OM and M represents an alkali metal;
as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and of their esters and salts.
The compounds of formula I possess antibacterial activity against beta-lactam sensitive and resistant gram-positive bacteria, such as staphylococci, pneumococci, and enterococci. These compounds are useful both in vivo in the treatment of infectious diseases caused by such bacteria, as well as ex vivo as a disinfectant.
This invention also provides a process for producing a compound of the formula
wherein
R
1
is halogen, lower alkyl, phenyl, benzyl, styryl, naphthyl or heterocyclyl; the lower alkyl, phenyl, benzyl, styryl, naphthyl and heterocyclyl being optionally substituted by at least one of halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted phenyl, amino, lower alkylamino, di-lower alkylamino, carboxy, lower alkylcarboxy, carbamoyl or lower alkylcarbamoyl;
R
4
, R
5
independently are hydrogen, lower alkyl or phenyl;
X is S, O, NH or CH
2
;
n is 0, 1 or 2;
m is 0 or 1;
s is 0or 1;
R
2
is hydrogen, hydroxy, —CH
2
—CONHR
6
, lower alkyl-Q
r
, cycloalkyl-Q
r
, lower alkoxy, lower alkenyl, cycloalkenyl-Q
r
, lower alkynyl, aralkyl-Q
r
, aryl-Q
r
, aryloxy, aralkoxy, a heterocyclic ring or a heterocyclyl-Q
r
, the lower alkyl, cycloalkyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aralkyl, aryl, aryloxy, aralkoxy and the heterocyclic ring is optionally substituted with at least one group selected from carboxy, amino, nitro, cyano, —SO
2
NHR
6
, optionally fluoro substituted lower alkyl, lower alkoxy, hydroxy, halogen, —CONR
6
R
7
, —CH
2
CONR
6
R
7
, —N(R
7
)COOR
8
, R
7
CO—, R
7
OCO —, R
7
COO—, —C(R
7
R
9
)CO
2
R
8
, —C(R
7
R
9
)CONR
7
R
10
, wherein
R
6
is hydrogen, lower alkyl, cycloalkyl or aryl;
R
7
and R
9
are independently hydrogen or lower alkyl;
R
8
is hydrogen, lower alkyl, lower alkenyl or a carboxylic acid protecting group; and
R
10
is hydrogen, &ohgr;-hydroxy-alkyl, phenyl, naphthyl or heterocyclyl, the phenyl, naphthyl or heterocyclyl being unsubstituted or substituted with at least one of the groups of optionally protected hydroxy, halogen, optionally substituted lower alkyl or &ohgr;-hydroxyalkyl, optionally substituted lower alkoxy and/or cyano, or R
7
and R
10
form together group of formula
Q is —CHR—, —CO— or —SO
2
—;
r is 0 or 1;
R is hydrogen or lower alkyl; and
R
3
is hydroxy or —O
−
;
which process comprises treating a compound of the formula
in which
R
f
is hydrogen or trimethylsilyl; and
R
g
is hydrogen, benzhydryl, p-methoxybenzyl, t-butyl, trimethylsilyl or allyl or salt thereof,
with a reagent of the formula
in which Y is —OH or a reactive functional derivative thereof, and then removing R
g
when R
g
is benzhydryl, p-methoxybenzyl, t-butyl, trimethylsilyl or allyl or a salt thereof, thereby producing the compound of formula I.
DETAILED DESCRIPTION OF THE INVENTION
This invention provides a compound of the formula
wherein
R
1
is halogen, lower alkyl, phenyl, benzyl, styryl, naphthyl or heterocyclyl; the lower alkyl, phenyl, benzyl, styryl, naphthyl and heterocyclyl being optionally substituted by at least one of halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted phenyl, amino, lower alkylamino, di-lower alkylamino, carboxy, lower alkylcarboxy, carbamoyl or lower alkylcarbamoyl;
R
4
, R
5
independently are hydrogen, lower alkyl or phenyl;
X is S, O, NH or CH
2
;
n is 0, 1 or 2;
m is 0 or 1;
s is 0 or 1;
R
2
is hydrogen, hydroxy, —CH
2
—CONHR
6
, lower alkyl-Q
r
, cycloalkyl-Q
r
, lower alkoxy, lower alkenyl, cycloalkenyl-Q
r
, lower alkynyl, aralkyl-Q
r
, aryl-Q
r
, aryloxy, aralkoxy, a heterocyclic ring or a heterocyclyl-Q
r
, the lower alkyl, cycloalkyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aralkyl, aryl, aryloxy, aralkoxy and the heterocyclic ring is optionally substituted with at least one group selected from carboxy, amino, nitro, cyano, —SO
2
NHR
6
, optionally fluoro substituted lower alkyl, lower alkoxy, hydroxy, halogen, —CONR
6
R
7
, —CH
2
CONR
6
R
7
, —N(R
7
)COOR
8
, R
7
CO—, R
7
OCO—, R
7
COO—, —C(R
7
R
9
)CO
2
R
8
, —C(R
7
R
9
)CONR
7
R
10
, wherein
R
6
is hydrogen, lower alkyl, cycloalkyl or aryl;
R
7
and R
9
are independently hydrogen or lower alkyl;
R
8
is hydrogen, lower alkyl, lower alkenyl or a carboxylic acid protecting group; and
R
10
is hydrogen, &ohgr;-hydroxy-alkyl, phenyl, naphthyl or heterocyclyl, the phenyl, naphthyl or heterocyclyl being unsubstituted or substituted with at least one of the groups of optionally protected hydroxy, halogen, optionally substituted lower alkyl or &ohgr;-hydroxyalkyl, optionally substituted lower alkoxy and/or cyano, or R
7
and R
10
form together group of formula
Q is —CHR—, —CO— or —SO
2
—;
r is 0 or 1;
R is hydrogen or lower alkyl; and
R
3
is hydroxy, —O
−
, lower-alkoxy, or —OM and M is an alkali metal;
a readily hydrolyzable ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a hydrate of said ester or said salt.
In above compounds of formula I the substituent in position 3 can be present in the E-form:
or in the Z-form:
Compounds of formula I i.e. wherein the substituent in position 3 is in the E-form are generally preferred.
In a particular embodiment of the compounds of formula I n is 1.
The term “halogen” or “halo” used herein r

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