Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-08-25
2003-09-23
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
Reexamination Certificate
active
06624143
ABSTRACT:
This application is a national stage filing under 35 U.S.C. §371 of international application no. PCT/EP99/00930, filed on Feb. 12, 1999.
The present invention relates to calcium salts of lipopeptide antibiotics, a process for their preparation, and their use.
EP 0 629 636 A1 discloses lipopeptide antibiotics of the formula I
in which R
1
is an OH or NH
2
group and R
2
is a fatty acid radical (R—C(O)—).
These lipopeptide antibiotics can be divided into two groups which differ with respect to their exocyclic amino acid: the lipopeptide antibiotics of the amphomycin type are characterized by the exocyclic amino acid aspartic acid (Asp, where R
1
in formula I is an OH group) (R. C. Strong et al., Antimicrobial Agents and Chemotherapy 1970, 42-45; M. Bodanszy et al. J. Am. Chem. Soc. 95, 2352-2357 (1973)), while the lipopeptide antibiotics of the asparagine type are distinguished by the exocyclic amino acid asparagine (Asn, where R
1
in formula I is an NH
2
group). The lipopeptide antibiotics of the amphomycin type and of the asparagine type differ from each other by substitution on the &agr;-amino group of the exocyclic amino acid (Asp or Asn) having different fatty acid radicals (R
2
in formula 1).
Furthermore, EP 0 688 789 A1 (U.S. Pat. No. 5,629,288) discloses derivatives of the lipopeptide antibiotics of the amphomycin type and of the asparagine type and their pharmaceutically tolerable salts. As pharmaceutically tolerable salts of the lipopeptide antibiotics of the formula I, EP 0 688 789 A1 (U.S. Pat. No. 5,629,288) discloses salts with inorganic and organic acids, e.g. hydrochloric acid, sulfuric acid, acetic acid, citric acid, p-toluenesulfonic acid, with inorganic and organic bases such as NaOH, KOH, Mg(OH)
2
, diethanolamine, ethylenediamine or with amino acids such as arginine, lysine and glutamic acid.
The calcium salt of amphomycin is furthermore known (Kirk-Othmer, Encyclopedia of Chemical Technology, fourth edition, Volume 3, Antibiotics to Batteries, John Wiley & Sons, page 284). It is only sparingly soluble in water and because of the toxicity of amphomycin as a result of its hemolytic activity on systemic use was used exclusively in antibiotic ointments for local application.
The lipopeptide antibiotics of the asparagine type (R
1
in formula I is an NH
2
group) and their preparation have been described for the first time in EP 0 629 636 A1. The preparation process proposed there, the fermentation of Actinoplanes sp., preferably
Actinoplanes friulensis
(deposited on Jun. 18, 1990 in accordance with the rules of the Budapest Convention under the Deposit No. DSM 7358 in the Deutschen Sammlung von Mikroorganismen und Zelikulturen GmbH, DSMZ, Mascheroder Weg 1b, D-38124 Brunswick), leads, however, to a mixture of a large number of the structurally closely related lipopeptides of the amphomycin type and of the asparagine type, which have very different properties, in particular different biological actions, such as, for example, their antibacterial action, toxicity as a result of their hemolytic action, and also different physicochemical properties, such as, for example, their solubility and stability, but can only be separated from the culture medium with difficulty. It would therefore be a great advantage to have a fermentation process which essentially leads to the production of preferably only one of the many possible lipopeptide components.
It is an object of the present invention to make available a salt of the lipopeptide antibiotics of the asparagine type which is distinguished by a relatively high stability and good antibacterial activity and can be administered systemically (parenterally) as a result of its good water solubility and as a result of its low toxicity, in particular on account of a low hemolytic activity.
It is further an object of the present invention to make available a process for the preparation of a salt of the lipopeptide antibiotics of the asparagine type and in particular an improved process for the fermentative preparation of its acid precursors, in which lipopeptide antibiotics of the asparagine type are preferably produced.
Finally, it is an object of the present invention to make available a pharmaceutical which contains a salt of the lipopeptide antibiotics of the asparagine type having the desired advantageous properties.
It has now been found in the case of the lipopeptide antibiotics of the asparagine type that the various salts of the same lipopeptide (or the same corresponding acid) can have very different properties. For example, the sodium salts as a rule have a very good antibacterial activity and are readily soluble in water. However, these can only be kept for a limited period, in particular at elevated temperatures. Since in the case of medicaments and other commercial products stability is of great importance, e.g. for the handling of the goods, stable salt forms of the lipopeptide antibiotics are necessary.
Since the lipopeptide antibiotics of the asparagine type are amphoteric compounds having an isoelectric point in the acidic range, neutral salts can be prepared with numerous bases. Possible cations are monovalent and polyvalent ions, such as, for example, alkali metal, alkaline earth metal and other metal ions, but also salts with ammonia or with organic bases, such as amines. Examples of the lafter are lysine and lysyllysine salts, which are very highly tolerable and have full activity.
Surprisingly, it has now been found that unlike the calcium salts of the lipopeptide antibiotics of the amphomycin type (in particular amphomycin), the calcium salts of the lipopeptide antibiotics of the asparagine type are not only active and tolerable, but also readily soluble in water and particularly stable, unlike the corresponding sodium salts.
Accordingly, the object set above is achieved by a calcium salt of the compound of the formula II
in which R
1
is a straight-chain or branched, saturated or unsaturated aliphatic acyl radical having 8 to 22 carbon atoms, which can optionally be interrupted by one or more phenyl or cycloalkyl groups or linked to such groups and can furthermore be optionally interrupted by oxygen.
Preferably, R1 in formula II is an acyl radical interrupted by a phenyl or cycloalkyl group or linked to such a group, for example
where n is an integer from 0 to 20.
Furthermore preferred is a calcium salt of the compound of the formula II which is distinguished in that R1 is an acyl radical interrupted by a phenyl or cycloalkyl group and by oxygen, preferably wherein R1 is
where n is an integer from 0 to 20.
Particularly preferred is a calcium salt of the compound of the formula II which is distinguished in that R1 is a straight-chain or branched, saturated or unsaturated aliphatic acyl radical having 12 to 15 carbon atoms, where R1 in formula II preferably is a fatty acid radical of the formula shown below:
The calcium salt of the compound of the formula II can be present in two forms, as a dicalcium salt or as a monocalcium salt.
Depending on the number of anions and the fatty acid substituent (R1 in formula II), the dicalcium salt can be described in greater detail
(i) for example in the case of a saturated fatty acid (R1 in formula II) by the empirical formula
C
46+n
H
68+2n
N
14
O
19
Ca
2
X
2
, (ia)
C
46+n
H
69+2n
N
14
O
19
Ca
2
X
3
or (ib)
C
46+n
H
70+2n
N
14
O
19
Ca
2
X
4
, (ic)
where in the empirical formula n is an integer from 7 to 21 and X is an anion, or
(ii) for example in the case of a monounsaturated fatty acid (R1 in formula II) by the empirical formula
C
46+n
H
66+2n
N
14
O
19
Ca
2
X
2
, (iia)
C
46+n
H
67+2n
N
14
O
19
Ca
2
X
3
or (iib)
C
46+n
H
68+2n
N
14
O
19
Ca
2
X
4
, (iic)
where in the empirical formula n is an integer from 7 to 21 and X is an anion.
For example, the abovementioned, preferred calcium salts of the compound of the formula II(3c) and (3d) can be described in greater detail by the following empirical formulae if a dicalcium salt is
Aretz Werner
Decker Heinrich
Ehlers Eberhard
Kurz Michael
Schmidt Frank Rainer
Aventis Pharma Deutschland GmbH
Carlson Karen Cochrane
Finnegan Henderson Farabow Garrett & Dunner LLP
Snedden Sheridan
LandOfFree
Calcium salts of lipopeptide antibiotics, method for... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Calcium salts of lipopeptide antibiotics, method for..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Calcium salts of lipopeptide antibiotics, method for... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3083998