Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-09-10
2002-04-30
Fonda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S192000, C514S197000, C514S200000, C514S563000, C514S564000, C514S567000, C560S138000, C560S142000, C562S444000
Reexamination Certificate
active
06380181
ABSTRACT:
The present invention relates to new synthetic catechol derivatives, in which aromatic azomethine-carboxylic acids, benzhydrazones, amino acids, aminobenzoic acids or dipeptides, pyrrolidine- or oxazolidine-carboxylic acids, or formylcarboxymethyloximes function as structural elements, and relates to conjugates thereof with active ingredients, particularly antibiotics.
It is known that certain catechol structures play an essential role as iron-complexing structural elements in natural siderophores (“Iron Transport in Microbes, Plants and Animals”, Eds.: Winkelmann, G., van Helm, D., Neilands, J. B., V. Ch.—Verlagsgesellschaft Weinheim, 1987), e.g. enterobactin, which is a siderophore for
E. coli
and other bacterial strains, is a trimer of N-(2,3-dihydroxybenzoyl)-L-serine. The monomer is also effective as a siderophore (Hantke, K., FEMS Microbiol. Lett. 67 (1990), 5). N-(2,3-dihydroxybenzoyl)glycine has been found to be a siderophore for
B. subtilis
(Ito, T., Neilands, J. B., J. Amer. Chem. Soc. 80 (1958), 4645). Some catechol-substituted amino acid derivatives have already been produced synthetically, e.g. N-(2.3-dihydroxy-benzoyl)-L-threonine (Kanai, F., Kaneko, T., Morishima, H., Isshiki, K., Taketa. T., Takeuchi, T., Umezawa, H., J. Antibiot. 38 (1985), 39), N
2
, N
6
-bis-(2,3-dihydroxybenzoyl)-L-lysine (Corbin, J. L., Bulen, W. A., Biochemistry 8 (1969), 757; McKee, J. A., Sharma, S. K., Miller, M. J., Bioconjugate Chem. 2 (1991) 281), and N
2
,N
6
-bis-(2,3-dihydroxybenzoyl)-lysyl-N
6
-(2,3-dihydroxybenzoyl)lysine (Chimiak, A., Neilands, J. B., Structure and Bonding 58, (1984), 89). It is also known that certain glyoxylic acid benzhydrazones, oxanilic acid derivatives, etc., can serve as siderophores for different bacterial strains (Reissbrodt, R., Heinishc, L., Möllmann, U., Rabsch, W., Ulbricht, H., BioMetals 6 (1993), 155). Some dihydroxybenzylidene-aminobenzoic acids have already been described in the literature, but without any mention of their efficacy as siderophores (Takita, H., Noda, S., Inada. K., Mukaida, Y. S., Toji. M. K., Kobayashi, H., DE 3 414 049 (1984); H. Wolf, Monatsh. Chem. 31 (1910), 903).
Although various catechol compounds have been bonded to &bgr;-lactams, by means of which an increase in the antibacterial efficacy of these antibiotics has been achieved due to their transfer into the bacterial cell via bacterial transport routes for iron (e.g. Arisawa, M., Sekine, Y., Shimizu, S., Takano, H., Angehrn, P., Then, R. L., Antimicrob. Agents Chemother. 35 (1991), 653), there is a great need for other new synthetic siderophores with improved pharmacological and pharmaco-kinetic properties, which are suitable for forming conjugates with antibiotics.
On the other hand, as chelating agents for iron, siderophores are potentially capable of influencing the biological metabolism of iron, and diseases associated therewith, in various ways. Thus the siderophore desferrioxamine (desferal) is successfully used in diseases which are caused by an excess of iron (e.g. thalassaemia).
The underlying object of the present invention is to discover new synthetic catechol derivatives which comprise aromatic azomethine-carboxylic acids, benzhydrazones, amino acids, aminobenzoic acids or dipeptides, pyrrolidine- or oxazolidine-carboxylic acids, and formylcarboxymethyloximes as basic structures, which can function as siderophores and/or as biological chelating agents for iron, and which in the form of their conjugates with active ingredients, e.g. antibiotics, effect improved penetration of these compounds into bacterial cells and thereby increase the antibacterial efficacy thereof, and which make it possible to combat penetration-related resistance to antibiotics in bacterial infections in an improved manner.
The compounds according to the invention are effective as siderophores for gram-negative bacteria, i.e. they can supply bacteria with iron ions, and, in die form of their conjugates with active ingredients, e.g. with antibiotics (as “siderophore-antibiotic conjugates”), can transfer these compounds into the bacterial cell via iron transport routes and can thereby improve or even extend the efficacy thereof.
Moreover, the compounds according to the invention are more effective and can be produced more easily than previously known compounds, and in die form of their conjugates with active ingredients make it possible to combat penetration-related resistance to antibiotics in bacterial infections in an improved manner. Furthermore, the present invention provides new chelating agents for iron, which can influence the biological metabolism of iron and which can thus influence diseases associated therewith in various ways.
New synthetic catechol derivatives are provided, of general formula I
wherein the R
1
radicals are identical to or independent of each other and denote OH and/or Oacyl, and R
2
represents the following groups in the 3- and/or 4-position:
a. aromatic azomethine-carboxylic acid residues and/or azobenzene-carboxylic acid residues:
X=CM, N, CH=CH-CH
Y=OA, where A=H, alkyl, aryl, aralkyl, an alkali metal ion (preferably Na, K), an ammonium ion or a substituted ammonium ion, or
Y=an active ingredient residue which contains an OH or NH group,
R
3
=one or two Oacyl radicals when R
1
=OH or Oacyl, or
R
3
=H when R
1
=Oacyl, or
R
15
=radicals which, identically to or independently of each other, represent H and/or Oacyl, or
Y=OA, where A=H, alkyl, aryl, aralkyl, an alkali metal ion (preferably Na, K), an ammonium ion or a substituted ammonium ion, or
Y=an active ingredient residue which contains an OH or NH group,
R
3
=radicals which, identically to or independently of each other, denote H, OH, Oacyl,
b. benzhydrazone radicals:
R
15
=radicals which, identically to or independently of each other, denote H, OH, Oacyl,
R
4
and/or R
5
is H or COY, wherein
Y=OA, with A=H, alkyl, aryl, aralkyl, an alkali metal ion (preferably Na, K), an ammonium ion or a substituted ammonium ion, or
Y=an active ingredient residue which contains an OH or NH group,
c. aminobenzoic acid residues
Y=OA, where A=H, alkyl, aryl, aralkyl, an alkali metal ion (preferably Na, K), an ammonium ion or a substituted ammonium ion, or
Y=an active ingredient residue which contains an OH or NH group,
R
19
=H, alkyl,
R
20
=H, alkyl, halogen, OH, Oalkyl, Oacyl, or
R
19
and R
21
, identically to or independently of each other, each denote H, OH, Oacyl or Oalkyl in the 2,3- and/or 3,4-position
d. amino acid residues:
Y=OA, where A=H, alkyl, aryl, aralkyl, an alkali metal ion (preferably Na, K), an ammonium ion or a substituted ammonium ion, or
Y=an active ingredient residue which contains an OH or NH group,
R
6
=alkyl, hydroxyalkyl (comprising C
1
-C
5
when R
1
=Oacyl and C
3
-C
5
when R
1
=OH), or alkoxyalkyl, acyloxyalkyl, arylalkoxyalkyl, or
R
15
represents, identically to or independently of each other, H, OH, Oacyl,
n is an integer between 1 and 5 when R
1
is Oacyl and R
15
is H and/or Oacyl, or
n is an integer between 1 and 3 when R
1
is OH and R
15
is H and/or OH, or
R
15
=radicals which, identically to or independently of each other, denote H, OH, Oacyl, n
1
and n
2
represent an integer between 1 and 5,
e. pyrrolidine- and/or oxazolidine-carboxylic acid residues
Z=O, CH
2
,
R
16
and R
17
, independently of each other, denote H, alkyl or aryl,
Y=OA where A=H, alkyl, aryl, aralkyl, an alkali metal ion (preferably Na, K), an ammonium ion or a substituted ammonium ion, or
Y=an active ingredient residue which contains an NH or OH group,
f. formyl-O-carboxymethyloximes
R
2
=CH═NOCH
2
COY, where
Y=OA, where A=H, alkyl, aryl, aralkyl, an alkali metal ion (preferably Na, K), an ammonium ion or a substituted ammonium ion, or
Y=an active ingredient residue which contains an OH or NH group.
In the above formulae and
Heinisch Lothar
Moellmann Ute
Reissbrodt Rolf
Schnabelrauch Matthias
Fonda Kathleen K.
Gruenenthal GmbH
Maier Leigh C.
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