Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-06-22
2003-06-24
Berch, Mark L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S202000, C514S203000, C514S204000, C514S205000, C540S215000, C540S222000, C540S224000, C540S225000, C540S226000, C540S227000, C540S229000
Reexamination Certificate
active
06583133
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to cephalosporin-type antibiotics.
BACKGROUND OF THE INVENTION
Cephalosporins are known for their antibiotic properties.
SUMMARY OF THE INVENTION
The present invention provides cephalosporin derivatives of the general formula
wherein R is an organic residue with a molecular weight not exceeding 400 bonded to the adjacent sulfur atom via carbon and consisting of carbon, hydrogen, and optionally oxygen, sulfur, nitrogen and/or halogen atoms; R
1
is hydrogen, lower alkyl or phenyl; and A is a secondary, tertiary or quaternary nitrogen atom bound directly to the propenyl group and being substituted by an organic residue with a molecular weight not exceeding 400 and consisting of carbon, hydrogen, and optionally oxygen, sulfur, nitrogen and/or halogen atoms,
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.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present formula I are useful in the treatment of infectious diseases in that they have potent and broad antibacterial activity; especially against Gram-positive organisms, e.g. methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) staphylococci, enterococci and pneumococci.
In the above compounds of formula I the substituent in position 3 of the cephalosporin ring can be present
in the E-form:
or in the Z-form:
Compounds of formula I wherein the substituent in position 3 is in the E-form are generally preferred.
Compounds of formula I, in which R
1
is lower alkyl or phenyl, R
1
is attached at an asymmetric carbon atom which can have (R) or (S) configuration:
Generally, the S-form is preferred.
A subgroup of the compounds of the invention consists of compounds of the general formula
wherein
R
0
is lower alkyl or lower alkenyl, these groups being optionally substituted by one or more substituent(s) R
7
represented by:
halogen
lower cycloalkyl
naphthyl
optionally substituted phenyl or heterocyclyl
optionally substituted acyl
optionally etherified or acylated hydroxy
optionally acylated amino
(lower alkyl)amino, (di-lower alkyl)amino, lower cycloalkylamino
optionally esterified or amidated carboxy
etherified mercapto, lower alkylsulfinyl, phenylsulfinyl
lower alkylsulfonyl, phenylsulfonyl
cyano
amidino, (lower alkyl)amidino, (di-lower alkyl)amidino, guanidino, (lower alkyl)guanidino, (di-lower alkyl)guanidino; or
R
0
is phenyl, naphthyl or heterocyclyl, these groups being optionally substituted by one or more substituents R
8
represented by:
halogen
optionally substituted lower alkyl, lower alkenyl or lower cycloalkyl
optionally substituted phenyl or heterocyclyl
optionally substituted acyl
optionally etherified or acylated hydroxy
optionally acylated amino
(lower alkyl)amino, (di-lower alkyl)amino, lower cycloalkylamino
optionally esterified or amidated carboxy
etherified mercapto, lower alkylsulfinyl, phenylsulfonyl
optionally amidated sulfonyl
lower alkylsulfonyl, phenylsulfonyl
cyano;
A
0
is a quaternary nitrogen residue of the general formula
wherein R
2
, R
3
and R
4
may be the same or different and each are alkyl cycloalkyl, alkenylalkyl or saturated heterocyclyl;
or R
2
and R
3
together with the N atom represent a saturated or partly unsaturated 5 to 8 membered heterocyclic ring or a 10 to 14 membered fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen, R
4
being as above or may represent a 1-2-, 1-3- or 1-4-alkylene or a vinylene bridge to the heterocyclic ring represented by R
2
and R
3
;
or R
2
, R
3
and R
4
together with the N atom represent an aromatic 5 or 6 membered, optionally fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen; or
A
0
is a secondary or tertiary nitrogen residue of the general formula
wherein R
5
and R
6
may be the same or different and each are alkyl, cycloalkyl, alkenylalkyl or heterocyclyl or R
5
is hydrogen;
or R
5
and R
5
together with the N atom represent a saturated or partly unsaturated or aromatic 5 or 6 membered heterocyclic ring or a 10 to 12 membered fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen,
and wherein,
where R
2
, R
3
, R
4
, R
5
and/or R
6
represent alkyl, this group is optionally substituted by carbamoyloxy or one or more substituents R
7
, wherein R
7
has the above meaning; and
where R
2
, R
3
and R
4
and R
5
and R
6
represent heterocyclyl or together form part of a heterocyclic ring as defined above, this heterocyclyl group/heterocyclic ring is optionally substituted by one or more substituents R
8
, wherein R
8
has the above meaning,
as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula II and of their esters and salts.
Subgroups of the compounds of formula II are as follows:
Compounds of the general formulas
wherein R
0
and R
1
are as defined above and R
20
, R
30
and R
40
may be the same or different and each are alkyl (optionally substituted by R
7
as for R
2
, R
3
and R
4
above), cycloalkyl, alkenylalkyl or saturated heterocyclyl (optionally substituted by R
8
as for R
2
, R
3
and R
4
above);
wherein R
0
and R
1
are as defined above, Q
1
is a saturated or partly unsaturated 5 to 8 membered heterocyclic ring or a 10 to 14 membered fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen, and any of the ring atoms are optionally substituted by R
8
as for R
2
and R
3
above, and R
41
is alkyl (optionally substituted by R
7
as for R
4
above), cycloalkyl, alkenylalkyl or saturated heterocyclyl or may represent a 1-2-, 1-3- or 1-4-alkylene or a vinylene bridge to the heterocyclic ring of Q
1
;
wherein R
0
and R
1
are as defined above and Q
2
is an aromatic 5 or 6 membered heterocyclic ring or a 10 to 12 membered fused heterocyclic ring which may contain in addition to the represented nitrogen atom hetero atoms selected from oxygen, sulfur and nitrogen, and any of the ring atoms are optionally substituted by R
8
as for R
2
, R
3
and R
4
above;
wherein R
0
and R
1
are as defined above and R
50
and R
60
may be the same or different and each are alkyl (optionally substituted by R
7
as for R
5
and R
6
above), cycloalkyl, alkenylalkyl or saturated heterocyclyl (optionally substituted by R
8
as for R
5
and R
6
above) or R
50
is hydrogen;
wherein R
0
and R
1
are as defined above and Q
3
is a saturated or partly unsaturated or aromatic 5 or 6 membered heterocyclic ring or 10 to 12 membered fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen, and any of the ring atoms are optionally substituted by R
8
as for R
5
and R
6
above,
as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formulas IIA-IIE and of their esters and salts.
The term “halogen” or “halo” used herein refers to chlorine or chloro; bromine or bromo; iodine or iodo; and fluorine or fluoro, unless specified otherwise.
As used herein, the terms “alkyl” and “lower alkyl” refer to both straight and branched chain saturated hydrocarbon groups having 1 to 8, and preferably 1 to 4, carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, t-butyl and the like.
By the term “substituted lower alkyl” is meant a “lower alkyl” moiety as defined above substituted by, for example, halogen, amino, lower alkylamino, di-(lower alkyl)amino, hydroxy, lower alkoxy, cyano, carboxy, carbamoyl etc., such as carboxymethyl, carbamoylmethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, 2-hydroxyethyl, methoxymethyl, methylaminomethyl, dimethylaminoethyl and the like.
As used herein, the term “lower alkoxy” refers to a straight or branched chain hydrocarbonoxy group wherein the “alkyl” portion is a lower alkyl group as defined
Angehrn Peter
Götschi Erwin
Heinze-Krauss Ingrid
Richter Hans G. F.
Basilea Pharmaceutica AG
Berch Mark L.
Johnston George W.
Rocha-Tramaloni Patricia S.
Smith Lyman H.
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