Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-12-26
1997-10-07
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 11, 530317, A61K 3800
Patent
active
056748400
DESCRIPTION:
BRIEF SUMMARY
This invention concerns synthetic aglucodalbaheptides of general formula (I) ##STR1## wherein: W and Z, each independently, represent the relative portions of the aglycon of an antibiotic of the dalbaheptide group (aglucodalbaheptides); carboxylic group; of the amino function.
The invention includes the salts of the above represented synthetic aglucodalbaheptides with acids or bases as well as their inner salts.
A further object of this invention is a process for producing the aglucodalbaheptide antibiotics of formula (I) above starting from the tetrapeptides of formula (II) ##STR2## wherein: W and Z, each independently, represent the relative portions of the aglycon of an antibiotic of the dalbaheptide group (aglucodalbaheptides); carboxylic group; amino group; and
The tetrapeptides of general formula (II) above, their salts and their method of manufacture are described in International Application Publication No. W092/10517. The above mentioned International Application contains also an exhauxtive description of the naturally occurring dalbaheptide antibiotics and their classification in four sub-groups referred respectively as ristocetin-type, vancomycin-type, avoparcin-type and synmonicin-type dalbaheptides.
The pentapeptide precursors suitable for the preparation of the above mentioned tetrapeptides are described in European Patent Application Publication No. 409 045.
With the term dalbaheptides are usually defined all antibiotic substances having in common a highly modified linear heptapeptidic structure made up of seven amino acids, five of which are constantly aryl- and arylmethyl-amino acids, said structure being determinant of a common mechanism of action, i.e. the specific complexation with the D-alanyl-D-alanine terminus of one or more intermediates of the cell wall synthesis which leads to cell disruption (see also: F. Parenti and B. Cavalleri, "Novel glycopeptide antibiotics of the dalbaheptide group", Drugs of the future, Vol. 15 (1): 57-72, (1990) and B. Cavalleri, F. Parenti: "Glycopeptides (dalbaheptides)", in Kirk-Othmer's Encyclopedia of Chemical Technology, Vol. 2, 995-1018, J. Wiley & Sons, 1992).
According to a preferred embodiment of this invention the synthetic aglucodalbaheptides of the formula (I) above comprise those derivatives wherein: ##STR3## Z= ##STR4## wherein: i): A is hydrogen or a protecting group of the phenolic hydroxy moiety; R.sub.6, R.sub.7 and R.sub.8 are, each independently, hydrogen or halogen wherein the halogen preferably is chloro or bromo and, most preferably, are in the ortho position with respect to the ether bond; R.sub.9 and R.sub.10 are, each independently, hydrogen or a group OR.sub.15 wherein R.sub.15 is hydrogen or a protecting group of the benzylic hydroxy moiety.
As shown in formula (I) above, the group W is simultaneously linked to the second, fourth and sixth amino acid (starting from the right) moiety of the heptapeptidic chain of the aglucodalbaheptides; the para and ortho position with respect to the bond connecting the two phenyl rings and the radical R.sub.11 and R.sub.12, each independently, represent hydrogen or a protecting group of the phenolic hydroxy moiety; the group OR.sub.13, preferably, is in the position ortho with respect to the bond connecting the two phenyl rings and the radical R.sub.13 represents hydrogen or a protecting group of the phenolic hydroxy moiety; the group R.sub.14, preferably, is in the position meta with respect to the bond connecting the two phenyl rings and represents hydrogen or halogen, preferably, hydrogen or chloro.
As represented in formula (I) above, the group Z is linked to the amino acids corresponding to the fifth and seventh amino acid (starting from the right) moieties of the heptapeptidic chain of the aglucodalbaheptides.
The encircled numbers in the aromatic rings indicate the respective amino acids of the aglucodalbaheptide chain to which the specific aryl or aralkyl moiety is bound.
The symbol Y in formula (I), represents a carboxylic group, a functional derivative thereof, preferably, an ester.
REFERENCES:
patent: 5438117 (1995-08-01), Malabarba et al.
Malabarba et al., J. Antibiotics, 42, (1989), 1684-1697.
Malabarba et al., J. Med. Chem., Oct. 30, 1992, 35(22), 4054-60.
Ciabatti Romeo
Malabarba Adriano
Delacroix-Muirhead C.
Gruppo Lepetit SpA
Homan Ruth E.
Tsang Cecilia J.
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