Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Peptides containing saccharide radicals – e.g. – bleomycins – etc.
Reexamination Certificate
1998-10-07
2001-04-17
Russel, Jeffrey E. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Peptides containing saccharide radicals, e.g., bleomycins, etc.
C530S344000, C530S345000
Reexamination Certificate
active
06218505
ABSTRACT:
The present invention refers to an improved chemical process for preparing amide derivatives of antibiotic A 40926 of formula I:
wherein:
R
1
represents (C
9
-C
12
)alkyl;
M represents hydrogen, &agr;-D-mannopyranosyl or 6-O-acetyl-&agr;-D-mannopyranosyl;
Y represents an amino group of formula
—NR
2
-alk
1
-(NR
3
-alk
2
)
p
-(NR
4
-alk
3
)
q
-W
wherein:
R
2
represents hydrogen or (C
1
-C
4
)alkyl;
alk
1
, alk
2
and alk
3
each independently represent a linear or branched alkylene of 2 to 10 carbon atoms;
p and q are integers which independently represent zero or 1;
R
3
and R
4
each independently represent hydrogen, (C
1
-C
4
)alkyl or
R
2
and R
3
taken together represent a (C
2
-C
4
)alkylene moiety connecting the two nitrogen atoms with the proviso that p is 1; or
R
3
and R
4
taken together represent a (C
2
-C
4
)alkylene moiety connecting the two nitrogen atoms with the proviso that both p and q are 1;
W represents hydrogen, (C
1
-C
4
)alkyl, amino, (C
1
-C
4
)alkylamino, di(C
1
-C
4
)alkylamino, amino substituted with one or two amino(C
2
-C
4
)alkylene moieties or with one or two (C
1
-C
4
)alkylamino-(C
2
-C
4
)alkylene moieties or with one or two di(C
1
-C
4
)alkylamino-(C
2
-C
4
)alkylene moieties, or, when both p and q are zero, taken together with the moiety —NR
3
-alk
1
- it may also represent piperazino or 4-methylpiperazino.
Antibiotic A 40926 is a glycopeptide antibiotic complex which has been isolated from a culture of Actinomadura, named Actinomadura sp. ATCC 39727, in a culture medium containing assimilable sources of carbon, nitrogen, and inorganic salts (see U.S. Pat. No. 4,935,238). According to the procedure described in the above cited patent the recovery of the antibiotic complex, whose major factors have been named factor A, factor B, factor B
0
, factor B
1
, factor PA, and factor PB, includes submitting the fermentation broths, after filtration or after a preliminary purification, to affinity chromatography on immobilized D-alanyl-D-alanine.
The A 40926 factors so far identified can be represented by formula (II) below wherein R is carboxy, R
1
represents a (C
9
-C
12
)alkyl group, and M represents an &agr;-D-mannopyranosyl or a 6-O-acetyl-&agr;-D-mannopyranosyl group.
More particularly, antibiotic A 40926 factor A is a compound of the above formula (II) wherein R is carboxy, R
1
represents n-decyl, and M represents &agr;-D-mannopyranosyl. According to the most recent studies, the substance identified in the above mentioned EP-177882 as antibiotic A 40926 factor B, actually consists of two closely related components. Antibiotic A 40926 factor B
0
is indeed the main component of factor B, and corresponds to the compound of the above formula (II) wherein R is carboxy, R
1
represents 9-methyldecyl, and M represents &agr;-D-mannopyranosyl.
The minor component of factor B is named factor B
1
and differs from factor B
0
only in that R
1
represents n-undecyl (E. Riva et al, Chromatographia, Vol. 24, 295, 1987).
Antibiotic A 40926 factor PA and factor PB differ from the corresponding factor A and B in that the mannose unit is replaced by a 6-O-acetyl-&agr;-D-manno-pyranose unit.
Antibiotic A 40926 factors PA and PB, at least under certain fermentation conditions, are the main antibiotic products of the A 40926 producing microorganism.
Antibiotic A 40926 factors A and B are mainly transformation products of antibiotics A 40926 factor PA and factor PB, respectively, and are often already present in the fermentation broths.
It has been found that antibiotic A 40926 factor PA can be transformed into antibiotic A 40926 factor A and antibiotic A 40926 factor PB can be transformed into antibiotic A 40926 factor B under basic conditions which lead to the removal of the acetyl group of the mannose unit without displacing the acyl group on the aminoglucuronyl unit.
As a consequence, when the fermentation broth or an antibiotic A 40926 containing extract or concentrate thereof, is allowed to stand for a certain time under basic conditions (e.g. aqueous solution of a nucleophilic base, at a pH>9 overnight) an antibiotic A 40926 complex is obtained which is enriched in antibiotics A 40926 factor A and factor B.
During the usual purification procedures of antibiotic A 40926 complex, factors PA and PB are largely converted to factors A and B.
Antibiotic A 40926 factor B can be obtained from A 40926 complex by chromatographic separation using the method described in U.S. Pat. No. 4,935,238. Pure factor B
0
which under the conditions described in the above mentioned European Patent account for about 90% of factor B, can be obtained by further purification of factor B, for instance, by repeated reverse-phase chromatography procedures.
More recent studies (L. Zerilli et al., Rapid Communications in Mass Spectrometry, Vol. 6, 109, 1992) have shown that in the antibiotic complex A 40926 also some minor factors are present, which have been identified with the acronyms A
1
, RS-1, RS-2 and RS-3. These minor factors have been individuated by HPLC and their structures have been determined by applying gas chromatography/mass spectrometry analysis of the methanolysates of the A-40926 complex.
All the above mentioned minor factors have structures corresponding to the basic structure of factor A, B
0
and B
1
apart from the fatty acid residues linked to the aminoglucuronic moiety. More particularly, making reference to the formula (II), R has the same meanings as above while R
1
represents: 8-methylnonyl in factor A
1
, 7-methyloctyl in factor RS-1, n-nonyl in factor RS-2 and n-dodecyl in factor RS-3.
Although in the preparations of antibiotic A 40926 complex currently carried out under the fermentation conditions described in U.S. Pat. No. 4,935,238 the factors wherein R
1
is a (C
10
-C
11
)alkyl are largely predominant, it is possible to modify the fermentation conditions to increase the amounts of the minor components wherein R
1
is a C
9
or a C
12
alkyl.
All the sugar moieties are linked to the antibiotic A 40926 nucleus through O-glycosidic bonds.
In addition, it has been found that it is possible to transform antibiotic A 40926 complex, its single factors or a mixture of said factors in any proportion into the corresponding de-mannosyl derivatives (i.e. N-acylaminoglucuronyl aglycone complex AB, N-acylaminoglucuronyl aglycone factor A, N-acylaminoglucuronyl aglycone factor B) by controlled acid hydrolysis of the mannosyl sugar moiety of the starting material (see U.S. Pat. No. 4,868,171).
Preferred hydrolysis conditions for the production of N-acylaminoglucuronyl aglycones comprise the usage of a mixture of dimethylsulfoxide/concentrated hydrochloric acid from 8:2 to 9.5:0.5 at a temperature between 40° C. and 80° C.
Antibiotic A 40926 N-acylaminoglucuronyl aglycones are represented by the above formula (II) wherein M is hydrogen, R is carboxy and R
1
is (C
9
-C
12
)alkyl.
Antibiotic A 40926 complex, the factors thereof, the corresponding N-acylaminoglucuronyl aglycones and mixtures thereof in any proportion are mainly active against gram positive bacteria and Neisseriae.
For the purposes of the present invention, each one of the above factors or hydrolytic derivatives of antibiotic A 40926 may be employed as starting materials for the present amidation process, either as a single substance or as a mixture of two or more of them in any proportion. The term “mixtures” refers to the A 40926 complex obtained from a standard or modified fermentation process as known in the art, to the demannosylated A 40926 complex thereof, to a complex obtained by applying particular conditions in the isolation/purification of the A 40926 complex or demannosylated A 40926 complex or to mixtures obtained by mixing in the appropriate proportion the single factors of the A 40926 complex and/or the hydrolyzed factors thereof, previously isolated by means of chromatographic separation procedures.
International Pat. Appl. Publ. No. WO 92/17495, (designating also U.S.), describes ester derivatives of antibiotic A 40926 (esterified at the position 6
B
, that is the carboxy group p
Gianantonio Anacleto
Marazzi Alessandra Maria
Panzone Gianbattista
Restelli Ermenegildo
Biosearch Italia S.p.A.
Killworth, Gottman Hagan & Schaeff, L.L.P.
Russel Jeffrey E.
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