Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-21
2002-08-27
Berch, Mark (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S206000, C540S222000
Reexamination Certificate
active
06440957
ABSTRACT:
This is a continuation of PCT/EP99/01853 filed Mar. 19, 1999.
The present invention relates to antibacterial compounds which are 7-acylamino-3-(cyclic aminoguanidine)methylene cephalosporins, including 3-cyclic aminoguanidine-like structured compounds having a triamino-methylidyne group instead of an aminoguanidine group.
In one aspect the present invention provides a compound of formula
wherein
W denotes CH or N,
V denotes CH or NO,
R
1
denotes hydrogen, acyl, carboxyl or alkyl,
R
3
denotes hydrogen or an ester moiety,
R
2
denotes a group of formula
wherein
X and Y independently of each other each denote (C
2-5
)alkylene, or (C
2-5
)alkenylene
wherein one —C═C— double bond is present, or, in case of at least C
4
-alkenylene,
wherein two —C═C— double bonds are present,
R
4
denotes hydrogen or alkyl,
R
5
denotes hydrogen, alkyl, or aminoiminomethyl,
R
6
denotes hydrogen, alkyl, cycloalkyl, amino, hydroxy, alkoxy, heterocyclyl or a group of formula —N═CHR
8
, wherein
R
8
denotes alkyl, aryl or heterocyclyl, or
R
5
and R
6
together with the nitrogen atoms to which they are attached denote heterocyclyl,
R′
6
denotes alkyl,
R
7
denotes hydrogen, or
R
6
and R
7
together with the nitrogen atom to which they are attached form heterocyclyl.
In formula I R
3
is hydrogen or an ester moiety.
An ester moiety includes alkyl; e.g. unsubstituted alkyl or substituted alkyl, e.g. by
aryl, such as benzyl, alkoxybenzyl, such as 4-methoxybenzyl, alkoxy, such as methoxymethyl; alkyloxycarbonyloxy; alkyl; alkoxy, such as glycyloxy, phenylglycyloxy, e.g. glycyloxymethyl, phenylglycyloxymethyl; heterocyclyl e.g. 5-methyl-2-oxo-1,3-dioxolen-4-yl;
indanyl, phthalidyl, alkoxycarbonyloxy and 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 physilogically 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.
In a compound of formula I:
V denotes preferably NO.
R
1
denotes preferably hydrogen or alkyl, e.g. lower alkyl, e.g. including unsubstituted alkyl and substituted alkyl; e.g. by halogen, carboxyl, preferably by halogen.
R
2
denotes preferably a group of formula a), a′), c), d), d′), e′) or f);
R
4
denotes preferably hydrogen or alkyl, e.g. lower alkyl.
X and Y independently of each other denote preferably alkylene or alkenylene, e.g. (C
1-4
)alkylene or (C
1-4
)alkenylene, such as (C
2-3
)alkylene or (C
2-3
)alkenylene, e.g. including unsubstituted and substituted alkylene or alkenylene, e.g. by
halogen, alkyl, e.g. lower alkyl; cycloalkyl, carboxyl or alkylcarbonyl; preferably by alkyl, e.g. including hydroxyalkyl, aminoalkyl; carboxyl and (lower alkyl)carbonyl.
R
5
denotes preferably hydrogen, alkyl, e.g. including unsubstituted alkyl and substituted alkyl, e.g. by
hydroxy, carboxyl, amino, e.g. including lower alkylamino or di-lower alkylamino; heterocyclyl, e.g. including 5 or 6 ring members and including one or two heteroatoms, e.g. one, e.g. selected from O, S and N; an ester of a carboxylic-, sulfonic- or phosphoric acid, e.g. an alkyl or aryl ester, e.g. wherein the carboxylic acid part contains 1 to 12 carbon atoms and wherein the ester part contains 1 to 8 carbon atoms; or
amino-iminomethyl, e.g. of formula
wherein R
11
and R
12
independently of each other denote hydrogen or alkyl, e.g. lower alkyl,
R
6
denotes preferably hydrogen; amino, alkylamino, dialkylamino, e.g. wherein the alkyl part is unsubstituted or substituted, e.g. by hydroxy, amino; arylamino; e.g. R
6
denotes a group of formula —NR
9
R
10
, wherein R
9
and R
10
independently of each other denote hydrogen, alkyl, e.g. including hydroxyalkyl, aminoalkyl, aryl;
alkyl, e.g. including unsubstituted alkyl and substituted alkyl, e.g. by
heterocyclyl, e.g. having 5 to 6 ring members and one or two heteroatoms, e.g. selected from N,O,S; e.g. including unsubstituted heterocyclyl and substituted heterocyclyl; e.g. by hydroxy;
hydroxy; alkoxy, e.g. including unsubstituted alkyoxy and substituted alkoxy, e.g. by hydroxy, alkoxy, amino;
guanidino, e.g. wherein the amine groups are unsubstituted or substituted, e.g. the terminal amine group is part of heterocyclyl;
amino, alkylamino, and dialkylamino, e.g. (lower alkyl)amino and (lower dialkyl)amino;
alkyl, e.g. lower alkyl;
guanidino; wherein any amine group is unsubstituted or substituted, e.g. by alkyl; hydroxy, cycloalkyl, e.g. including unsubstituted and substituted cycloalkyl, e.g. by amino;
heterocyclyl, e.g. including heterocyclyl having 5 or 6 ring members and one or two heteroatoms, e.g. selected from N,O,S; including e.g. unsubstituted heterocyclyl and substituted heterocyclyl e. g. by alkyl, e.g. R
6
denotes a group of formula —NR
9′
R
10′
, wherein R
9′
and R
10′
together with the nitrogen atom to which they are attached form heterocyclyl; or
a group of formula —N═CHR
8
wherein R
8
preferably denotes aryl, heterocyclyl, including substituted and unsubstituted heterocyclyl; e.g. by alkyl; e.g. having 5 or 6 ring members and one or two heteroatoms, e.g. selected from N,O,S;
R
5
and R
6
, if together with the nitrogen atoms to which they are attached form hetercyclyl, denote preferably alkylene, e.g. (C
2-4
)alkylene, such as (C
2-3
)alkylene;
R′
6
denotes preferably alkyl, e.g. lower alkyl;
If R
6
and R
7
together with the nitrogen atom to which they are attached form hetercyclyl, hetercyclyl having preferably 5 to 7 ring members and one or two hetero atoms, e.g. selected from N,O,S.
In another aspect the present invention provides a compound of formula
wherein W, R
1
, R
3
, R
5
and R
6
are as defined above.
In another aspect the present invention provides a compound of formula
wherein W, R
1
, R
3
, R
5
and R
6
are as defined above and m denotes 1 or 2.
In another aspect the present invention provides the compound 7-{[(5-amino-1,2,4-thiadiazole-3-yl)-(Z)-(fluoromethoxyimino)acetyl]amino}-3-{[(3-ethyl-2-methylimino-imidazolidine-1-yl)imino]methyl}-3-cephem-4-carboxylic acid, e.g. in the form of a hydrochloride.
In this specification unless otherwise indicated terms such as “compound of formula I, Ia and Ib” embrace the compound in any form, for example in the form of a salt and in free base form. The present invention thus includes a compound in free base form or, e.g. where such forms exist, in the form of a salt, for example in the form of an acid addition salt, inner salt, quaternary salt and/or in the form of a solvate, for example in the form of a hydrate. A salt may be a pharmaceutically acceptable salt of a compound of formula I, I
a
and I
b
, such as a metal salt or an amine salt. Metal salts include for example sodium, potassium, calcium, barium, zinc, aluminum salts, preferably sodium or potassium salts. Amine salts include for example trialkylamine, procaine, dibenzylamine and benzylamine salts. A free form of a compound of formula I, Ia and Ib may be converted into a salt form and vice versa.
In a further aspect the present invention provides a compound of formula I, Ia and Ib, in free form and in the form of a salt, for example an acid addition salt or a metal salt; and a compound of formula I, Ia and Ib e.g. in free form or in the form of a salt, in the form of a solvate.
If not otherwise stated herein any carbon containing group ma
Ascher Gerd
Heilmayer Werner
Hildebrandt Johannes
Ludescher Johannes
Schranz Michael
Berch Mark
Biochemie Gesellschaft m.b.H.
Pfeiffer Hesna J.
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