Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-03-28
2004-03-02
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S009100
Reexamination Certificate
active
06699897
ABSTRACT:
The present invention relates to group A streptogramin derivatives of formula (I):
which have advantageous antibacterial activity.
Among the known streptogramins, pristinamycin (RP 7293), an antibacterial agent of natural origin produced by
Streptomyces pristinaespiralis,
was isolated for the first time in 1955. The pristinamycin sold under the name Pyostacine® comprises mainly pristinamycin IIA combined with pristinamycin IA.
Another antibacterial agent of the streptogramin class, virginiamycin, was isolated from
Streptomyces virginiae,
ATCC 13161 [Antibiotics and Chemotherapy, 5, 632 (1955)]. Virginiamycin (Staphylomycine®) comprises mainly factor M
1
(VM1) combined with factor S (VS).
The inventors have now discovered that the group A streptogramin derivatives of formula (I), wherein:
R
1
is chosen from cyano and ethynyl groups,
R
2
is chosen from a hydrogen atom, a methyl group, and an ethyl group, and
the bond
is a single bond (27R stereochemistry) or a double bond, have advantageous antibacterial activity, alone or when combined with at least one group B streptogramin derivative.
The streptogramin derivatives of formula (I) may be prepared, for example, by known, art-recognized methods. Such methods include reacting a 16-sulphonyloxy derivative of formula (II):
wherein:
R
2
is chosen from a hydrogen atom, a methyl group, and an ethyl group,
R
3
is a perfluoroalkyl group comprising from 1 to 10 carbon atoms, and
the bond
is a single bond (27R stereochemistry) or a double bond, with an alkali metal cyanide, reducing the compound obtained from that reaction, and optionally separating the 16R and 16S isomers obtained. Another method includes carbonylating an above-defined 16-sulphonyloxy derivative of formula (II) to form a lactone, reducing the lactone to a lactol, reacting the compound formed, i.e., the lactol, with dimethyl diazomethylphosphonate or dimethyl 1-diazo-2-oxopropylphosphonate, and optionally separating the 16R and 16S isomers obtained.
In one embodiment, the R
3
group is chosen from a trifluoromethyl group and a nonafluorobutyl group.
In one embodiment, the alkali metal cyanide may be chosen from potassium cyanide, sodium cyanide, and caesium cyanide.
The cyanation reaction can be carried out, for example, in the presence of a palladium derivative, for example, tetrakis(triphenylphosphine)-palladium, and copper iodide. The process can be performed, for example, in an organic solvent, such as, a nitrile (for example, acetonitrile), an ether (for example, tetrahydrofuran), an amide (for example, dimethylformamide or N-methylpyrrolidinone), at a temperature ranging, for example, from 20° C. to the reflux temperature of the reaction mixture. The process can also be performed under an inert atmosphere, for example, argon or nitrogen.
The subsequent reduction may be carried out electrochemically, under an inert atmosphere, at a temperature of about 20° C., working in a buffer solution, such as, a solution degassed with argon, of tetraethylammonium tetrafluoroborate, tetraethylammonium acetate and acetic acid, under a potential difference of about −1.5 V (I=250 mA). Example 2 below gives a more detailed assessment of the operating conditions which may be used.
Such a reaction can lead to a mixture of the 16R and 16S isomers, which may be separated according to known, art-recognized methods which do not affect the rest of the molecule. For example, the separation of the epimer forms may be carried out by chromatography, such as, High Performance Liquid Chromatography (HPLC) on normal or reverse phase, HPLC on a chiral or non-chiral phase, or by flash chromatography, by crystallization, by centrifugal partition chromatography (CPC), or by any other appropriate separation technique available in the art.
The carbonylation reaction can be carried out under an atmosphere of carbon monoxide, such as, under one atmosphere, in the presence of a palladium derivative, for example, tetrakis(triphenylphosphine)-palladium, anhydrous lithium chloride and a base such as an alkali metal carbonate or alkaline-earth metal carbonate, for example, potassium carbonate, sodium carbonate, or caesium carbonate, in an inert organic solvent, such as an ether (for example, tetrahydrofuran), a nitrile (for example, acetonitrile), an amide (for example, dimethylformamide or N-methylpyrrolidinone), at a temperature ranging, for example, from 0° C. to the reflux temperature of the reaction mixture. In one embodiment of the process, the reaction can be performed at about 20° C.
The carbonylation reaction leads to the formation of a lactone of formula (III):
wherein:
R
2
is chosen from a hydrogen atom, a methyl group, and an ethyl group, and
the bond
is a single bond (27R stereochemistry) or a double bond.
In one embodiment, the lactone can be reduced to a lactol saturated at 16,17 and then reacted with dimethyl diazomethylphosphonate or dimethyl 1-diazo-2-oxopropylphosphonate to form an ethynyl derivative.
The reduction of the lactone to a lactol may be carried out in the presence of a hydride such as, for example, lithium or potassium tri-sec-butylborohydride (L or K Selectride), in an inert organic solvent, such as an ether (for example, tetrahydrofuran) at a temperature ranging, for example, from −60° C. to 20° C., such as, at about −20° C., and under an inert atmosphere (for example, nitrogen or argon).
The reaction of dimethyl diazomethylphosphonate or dimethyl 1-diazo-2-oxopropylphosphonate can be carried out by applying the methods described by H. J. Bestmann et al., Synlett, 521 (1996) or by K. C. Nicolaou, Tetrahedron, 50(39), 11391 (1994), the relevant methods thereof are incorporated herein by reference. Such methods include a process performed in an inert solvent, such as, an ether (for example, tetrahydrofuran) or an alcohol (for example, methanol), at a temperature ranging, for example, from −78° C. to 40° C., such as, at about 20° C. The process can be performed under an inert atmosphere (for example, argon or nitrogen).
The reaction can also lead to a mixture of the 16R and 16S isomers, which may be separated according to known, art-recognized methods which do not affect the rest of the molecule. Such methods can, for example, include chromatography, such as, High Performance Liquid Chromatography (HPLC) on normal or reverse phase, HPLC on a chiral or non-chiral phase, and flash chromatography. Crystallization, centrifugal partition chromatography (CPC), or any other appropriate separation technique available in the art can also be used.
Streptogramin derivatives of formula (II) may be obtained, for example, by reacting a fluoride or anhydride, wherein the fluoride or anhydride comprises a perfluoroalkyl group comprising 1 to 10 carbon atoms, with a streptogramin derivative of formula (IV):
wherein:
R
2
is chosen from a hydrogen atom, a methyl group, and an ethyl group, and
the bond
is a single bond (27R stereochemistry) or a double bond,
in the presence of a base, such as, a tertiary amine (for example, diisopropylethylamine or triethylamine), in an inert organic solvent, such as, a chlorinated solvent (for example, dichloromethane), an ether (for example, tetrahydrofuran) or an amide (for example, dimethylformamide) at a temperature ranging from −78° C. to 20° C., such as, at about −70° C., and under an inert atmosphere (for example, argon or nitrogen).
In one embodiment, the sulphonic anhydride (for example, triflic anhydride) or the sulphonyl fluoride (for example, perfluoro-1-butanesulphonyl fluoride) corresponding to the selected R
3
group can be reacted.
The pristinamycin derivatives of formula (IV) correspond, respectively, to pristinamycin IIA (PIIA), pristinamycin IIB (PIIB), pristinamycin IIC (PIIC), pristinamycin IID (PIID), pristinamycin IIF (PIIF) and pristinamycin IIG (PIIG), which are known components of natural pristin amycin. The components PIIF and PIIG have been disclosed in European patent application no. EP-A-0 614 910. Pristinamycin IIC (PIIC) and pristinamycin IID (PIID) may be obt
Bacque Eric
Barriere Jean-Claude
Desmazeau Pascal
Ronan Baptiste
Aventis Pharma S.A.
Finnegan Henderson Farabow Garrett & Dunner LLP
Kifle Bruck
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