Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-13
2004-02-17
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S222000
Reexamination Certificate
active
06693095
ABSTRACT:
The present invention relates to antimicrobial cephalosporins.
In one aspect the present invention provides a compound of formula
wherein
R
1
denotes hydrogen, acyl, carboxyl, or alkyl;
R
2
and R
3
are the same or different and independently of each other denote hydrogen, cycloalkyl, alkyl, alkenyl or alkinyl;
R
4
denotes hydrogen or a group of formula
wherein R
6
denotes amino, hydrazino, aminoalkylamino, alkoxy, aryl, cycloalkyl, aryloxy, heterocyclyl, alkyl, alkenyl, alkinyl;
R
5
denotes hydrogen or an ester moiety;
W denotes CH or N;
V denotes CH or N—O; and
Z denotes O, S or NR
7
, wherein R
7
is as defined as R
2
;
with the proviso that not all of R
2
, R
3
and R
4
denote hydrogen; and,
if R
4
denotes hydrogen, R
1
is other than H or CH
3
.
A compound of formula I includes a compound of formula
wherein W and R
5
are as defined above,
R′
1
denotes hydrogen or alkyl, e.g. including unsubstituted alkyl, e.g. (C
1-12
)alkyl, such as lower alkyl; or substituted alkyl by e.g. halogen, carboxy; e.g. hydrogen or CH
2
F;
R′
2
and R′
3
are the same or different and independently of each other denote hydrogen; alkenyl; e.g. (C
2-4
)alkenyl; or alkyl;
e.g. unsubstituted or substituted by e.g. halogen, aryl; preferably aryl; including unsubstituted aryl, or aryl substituted by e.g. alkoxy, such as C(
1-4
)alkoxy or hydroxy; e.g.
R′
2
denotes hydrogen, alkyl, or alkenyl; and
R′
3
denotes hydrogen or alkyl; and
R′
4
denotes hydrogen or a group of formula.
wherein
Z′ denotes O or NR′
7
, wherein R′
7
denotes hydrogen or alkyl, e.g. lower alkyl; and
R′
6
denotes amino, including e.g.(di)lower alkylamino; aminoalkylamino, including e.g ((di)-lower alkyl)amino-(lower)alkylamino; hydrazino; alkoxy, e.g. lower alkoxy; unsubstituted aryl or aryl substituted e.g. by (lower alkyl)carbonyloxy, lower alkoxy; cycloalkyl; a 5 to 6 membered, heterocycle containing 1 to 3 nitrogen and/or sulphur-and/or oxygen atoms, e.g. 1 to 3 nitrogen atoms such as pyrrolidinyl;
alkyl, alkenyl, alkinyl including alkyl, alkenyl, alkinyl interrupted by N, S and/or O; e.g. unsubstituted alkyl, alkenyl, alkinyl or substituted alkyl, alkenyl, alkinyl by hydroxy, aryl, hydroxyaryl, guanidino, nitroguanidino, alkoxy, aryloxy, acyloxy, carbamoyloxy, amino, alkylamino, dialkylamino, trialkylammonium, acylamino, ureido, alkoximino, oximino, imino, carboxy, oxo, halogen, nitro, a carboxylic acid derivative, a sulphonic acid derivative, or heterocyclyl;
such as alkyl, e.g. substituted alkyl, e.g. one or several-fold; by unsubstituted aryl, or substituted aryl by hydroxy, alkoxy, phenoxy; aryloxy, e.g. phenoxy; amino, including e.g. (di)lower alkylamino; hydroxy; carboxy; guanidino or nitroguanidino; or a heterocyclyl-carboximino group; with the proviso that not all of R
2
, R
3
and R
4
denote hydrogen.
If not otherwise defined herein any aliphatic group defined herein includes an aliphatic group containing up to 20, e.g. 12, such as 8 C-atoms. Acyl includes aliphatic or aromatic acyl. Lower alkyl includes (C
1-4
)alkyl. Aryl includes aryl containing up to 18, e.g. 12 C atoms, including e.g. phenyl, napthyl. Cycloalkyl includes (C
3-8
)cycloalkyl, such as (C
3-6
)cycloalkyl.
Heterocyclyl includes e.g. saturated or (partially) unsaturated heterocyclyl having 5 or 6 ring members and 1 to 5, e.g. 1 to 3 nitrogen and/or 1 to 3 sulphur and/or oxygen hetero atoms including, for example, condensed heterocyclyl, such as benzthiazolyl. Any group as defined may be unsubstituted or substituted, e.g. by groups which are conventional groups in &bgr;-lactam chemistry. Substituted heterocyclyl includes preferably substituted heterocyclyl by amino, hydroxy, alkoxy, acyloxy, carboxy or mercapto. An ester-moiety includes alkyl, preferably C
1-6
alkyl, e.g. C
1-4
alkyl; aralkyl, for example benzyl, alkoxybenzyl, such as 4-methoxybenzyl; indanyl, phthalidyl, alkoxymethyl, e.g. methoxymethyl; (C
1-6
)alkanoyloxy(C
1-6
)alkyl, (C
1-6
)alkoxy-carbonyl-oxy(C
1-6
)alkyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen4-yl)methyl; an ester moiety also includes ester moieties which form with the COO—group a physiologically hydrolysable and acceptable ester, e.g. such known to be hydrolysable ester groups in the field of cephalosporins. A compound of formula I may thus be in the form of an physiologically-hydrolysable and -acceptable ester. By physiologically-hydrolysable and -acceptable esters as used herein is meant an ester in which the COO— group is esterified and which is hydrolysable under physiological conditions to yield an acid which is itself physiologically tolerable at dosages to be administered. The term is thus to be understood as defining regular pro-drug forms. An ester moiety may be preferably a group which is easily hydrolysable under physiological conditions. Such esters may be administered preferably orally. Parenteral administration may be indicated if the ester per se is an active compound or, if hydrolysis occurs in the blood. A silyl group includes a silyl protecting group, e.g. a conventional silyl protecting group, such as a trialkylsilyl group, for example the trimethylsilyl group. A leaving group includes e.g. a leaving group which is conventional in a type of reaction described; in an acylation reaction of an amine group e.g. a carboxylic acid derivative, such as a carboxylic acid halogenide, (active) ester, (mixed) anhydride) may be an appropriate acylation agent. A cation includes a cation which may form a pharmaceutically acceptable salt with a compound of formula I; e.g. a metal salt such as sodium, potassium; or an amine (ammonium) salt, such as trialkylamine, procain, dibenzylamine, benzylamine, ammonium salt.
A compound of formula I includes a compound of formula
wherein
R
5
is as defined above;
R
2s
and R
3s
independently of each other denote alkyl, e.g. C
1-6
alkyl, such as lower alkyl; cycloalkyl, aralkyl, e.g. ar(C
1-6
)alkyl, such as ar(C
1-4
)alkyl; aryl; alkenyl, e.g. (C
2-6
)alkenyl, such as (C
2-4
) alkenyl; or alkinyl; and R
3s
additionally denotes hydrogen; e.g. R
2s
denotes alkyl, alkenyl or aralkyl; e.g. R
3s
denotes hydrogen or alkyl; e.g. a compound of formula
wherein R
5
is as defined above.
A compound of formula I includes a compound of formula
wherein R
1
, R
5
, W and V are as defined above,
R
2p
and R
3p
are the same or different and independently of each other denote hydrogen, cycloalkyl, or substituted alkyl by halogen or hydroxy,
R
6p
denotes amino, unsubstituted or substituted alkylamino or dialkylamino, alkoxy, aryl, cycloalkyl, aryloxy, an unsubstituted, 5- or 6-membered, saturated, partially saturated or unsaturated heterocycle which may be condensed containing 1 to 5 nitrogen and/or 1 to 3 sulphur- and/or oxygen atoms, a substituted 5- or 6-membered, saturated, partially saturated or unsaturated heterocycle which may be condensed containing 1 to 5 nitrogen and/or 1 to 3 sulphur- and/or oxygen atoms by amino, hydroxy, alkoxy, acyloxy, carboxy or mercapto, cycloalkyl or unsubstituted straight chain or branched (C
1-20
)alkyl, (C
1-20
)alkenyl or (C
1-20
)alkinyl, which may be interrupted by N, S and/or O, once or several times, substituted straight chain or branched (C
1-20
)alkyl, (C
1-20
)alkenyl or (C
1-20
)alkinyl, which may be interrupted by N, S and/or O, by hydroxy, alkoxy, aryloxy, acyloxy, carbamoyloxy, amino, alkylamino, dialkylamino, trialkylammonium, acylamino, ureido, oximino, imino, carboxy, oxo, halogen, nitro, a carboxylic acid derivative, a sulphonic acid derivative, an unsubstituted, 5- or 6-membered, saturated, partially saturated or unsaturated heterocycle containing 1 to 5 nitrogen and/or 1 to 3 sulphur- and/or oxygen atoms which may be condensed; or a substituted 5- or 6-membered, saturated, partially saturated or unsaturated heterocycle which may be condensed containing 1 to 5 nitrogen and/or 1 to 3 sulphur- and/or oxygen atoms by amino, hydroxy, alkoxy, acyloxy, carboxy or mercapto;
Z
p
denotes oxygen or NR
7p
, wherein R
7p
is as defined R
2p
.
A co
Ascher Gerd
Hildebrandt Johannes
Ludescher Johannes
Schranz Michael
Wieser Josef
Berch Mark L.
Biochemie Gesellschaft m.b.H.
Lopez Gabriel
Pfeiffer Hesna J.
Waibel Peter J.
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