Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-03-10
2002-05-07
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S317000, C530S344000, C540S455000
Reexamination Certificate
active
06384014
ABSTRACT:
The present invention relates to a purified form of streptogramins comprising at least one component of the streptogramin B group defined below by the general formula (I) co-crystallized with at least one “minor” component of the A group defined below by the general formula (II).
Among the known streptogramins, pristinamycin (RP 7293), an antibacterial product of natural origin produced by
Streptomyces pristinaespiralis
was isolated for the first time in 1955. The pristinamycin marketed under the name of Pyostacin® consists mainly of pristinamycin IA and pristinamycin IIA.
Another antibacterial agent of the streptogramin class: virginiamycin, was prepared from
Streptomyces virginiae
, ATCC 13161 [Antibiotics and Chemotherapy, 5, 632 (1955)]. Virginiamycin (Staphylomycin®) consists mainly of factor S and factor M
1
.
U.S. Pat. No. 3,325,359 describes pharmaceutical compositions comprising antibiotic substances constituting the antibiotic 899: factor S and factor M1.
Antibacterial agents of natural origin, of the streptogramin class, consist of a mixture of 2 groups of components: components of the B group and components of the A group, each group having its own particular antibacterial activity. It has been demonstrated that the combination formed by the 2 groups of components gives rise to a synergism of action which results in increased bacteriostatic and bactericidal activity and in broadening of the spectrum of activity.
Components of the streptogramin A and B groups have been described in Streptogramine als Modelsysteme für den Kationentransport durch Membranen, Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Facultät der Georg-August Universität zu Göttingen, Göttingen 1979, in Antibiotics III, 521 (1975) and in Antibiotics of the virginiamycin family, Inhibitors which contain synergistic components, C. Cocito, Microbiological Reviews, 145-98 (1979). J. Preud'Homme, P. Tarridec, and A. Belloc, Bull. Soc. Chim. Fr., 2, 585 (1968) have also described natural pristinamycin as well as the various components constituting it.
As regards the industrial preparation of products of this class, the techniques available hitherto did not make it possible to obtain, on a preparative scale, a sufficiently purified form and the production of batches of sufficiently constant and reproducible quality to meet the requirements of the registration legislations in certain countries.
In the field of antibacterial agents, it is well known by practitioners that allergies or resistances may develop after administration of certain classes of antibiotics [The New England Journal of Medicine, 324 (9), 601 (1991)]. In hospitals, many resistant strains of
Staphylococcus aureus
are known in particular. Accordingly, it is extremely useful for doctors to have at their disposal a wide range of chemically different classes so as to be able to adapt the treatment to the specific case of the patient to be treated. The consequence of the absence of commercialization of a given class may be very serious, or even dramatic, since the result can be that patients who do not tolerate the other classes of antibiotics are deprived of treatment.
Thus, the purification tests used always had the aim of removing the minor components from streptogramins, these components being considered as not indispensable and rather as impurities.
Among the components of the A group of natural streptogramins, pristinamycin IIB (PIIB) is a minor component whose weight proportion is less than 10% in natural pristinamycin, and usually about 8% or even about 6% in virginiamycin.
It has now been found, and this forms the subject of the present invention, that the combination consisting of one or more components of the B group, of general formula:
in which
the symbol R
1
represents a methyl or ethyl radical,
the symbol R
2
represents a hydrogen atom or a hydroxyl radical, and
the symbol R
3
represents a substituted benzyl radical of general formula:
in which
1) on the condition that R
2
is simultaneously hydrogen, R represents NR
4
R
5
for which one of the symbols R
4
and R
5
is a hydrogen atom or a methyl radical and the other is a methyl radical and R′ is a chlorine or bromine atom, or represents an alkenyl radical containing 3 to 5 carbon atoms if R
4
and R
5
are methyl radicals, or alternatively
2) R is a hydrogen atom and R′ represents a halogen atom, an alkylamino or dialkylamino radical, an ether oxide residue, an alkylthio radical, an alkyl radical containing 1 to 3 carbon atoms in a straight or branched chain or a trihalomethyl radical, or alternatively
R is a halogen atom, an alkylamino radical containing 2 to 4 carbon atoms in a straight or branched chain, a dialkylamino radical in which the alkyl parts are identical or different and contain 2 to 4 carbon atoms in a straight or branched chain or a methylethylamino radical, a pyrrolidino radical, an alkenylalkylamino radical in which the alkenyl part contains 3 or 4 carbon atoms and the alkyl part is defined as above, a dialkylamino radical in which the alkenyl parts are defined as above, an alkylcycloalkylmethylamino radical in which the alkyl part is defined as above and the cycloalkyl part contains 3 or 4 carbon atoms, an ether oxide residue, an alkylthio radical, an alkylthiomethyl radical, an alkyl radical containing 1 to 6 carbon atoms in a straight or branched chain, an aryl radical or a trihalomethyl radical, and R′ is a hydrogen atom, or alternatively
R is a halogen atom, an amino, alkylamino or dialkylamino radical, an ether oxide residue, an alkylthio radical, an alkyl radical containing 1 to 6 carbon atoms in a straight or branched chain or a trihalomethyl radical and R′ represents a halogen atom, an alkylamino or dialkylamino radical, an ether oxide residue or an alkylthio or alkyl radical containing 1 to 3 carbon atoms in a straight or branched chain, and one or more “minor” components of the streptogramin A group, of general formula:
in which R″ is a hydrogen atom or a methyl or ethyl radical, is particularly advantageous on account of its in vivo biological activity.
In the general formula (I), when R or R′ (in R
3
) represents a halogen atom, it is preferably a fluorine atom, except for if R′ is a hydrogen atom, in which case R is either chlorine, bromine, fluorine or iodine; when R′ represents an alkylamino or dialkylamino radical, the alkyl radicals are preferably chosen from methyl and ethyl; when R or R′ represents is an ether oxide residue, it may be represented by a residue OR° for which R° is preferably chosen from a methyl group, an ethyl group optionally substituted with a chlorine atom, an allyl group or a trifluoromethyl group; when R or R′ represents an alkylthio radical, it is preferably a methylthio radical; when R represents an alkyl radical containing 1 to 6 carbon atoms, it preferably represents methyl, isopropyl or tert-butyl; when R represents an aryl radical, it is preferably a phenyl radical; when R or R′ represents a trihalomethyl radical, it is preferably a trifluoromethyl radical. Moreover, it is understood that, except where especially mentioned, the alkyl radicals are straight or branched and contain 1 to 4 carbon atoms.
The product of general formula (II) for which R″ is an ethyl radical, referred to hereinbelow as pristinamycin IIF (PIIF), and the product of general formula (II) for which R″ is a hydrogen atom, referred to hereinbelow as pristinamycin IIG (PIIG), are products which constitute very minor components of streptogramins, the weight proportion of which components is less than 0.5% in batches of natural product.
The co-crystallization is carried out at a constant stoichiometry of 1 mol of component(s) of general formula (I) with 2 mol of component(s) of the A group of general formula (II) [this stoichiometry corresponding to a relative proportion of about 43-49/57-51 by weight].
According to the invention, the co-crystallized combinations are prepared
Anger Pascal
Barriere Jean-Claude
Bonnavaud Bertrand
Lefevre Patrick
Paris Jean-Marc
Aventis Pharma S.A.
Berch Mark L.
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
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