Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-21
2003-07-22
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254110, C514S322000, C514S338000, C514S375000, C540S456000, C540S457000
Reexamination Certificate
active
06596717
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).
F. Le Goffic et. al.,
Transformations of Pristinamycin II to Study Its Mechanism of Action,
16(1) Eur. J. Medicinal Chemistry 69 (January-February 1981), have disclosed the preparation of dihydroxy derivatives of pristinamycin IIA.
Great Britain patent application GB-A-2 206 879 discloses modified group A streptogramin derivatives of structure:
wherein:
R is a substituted alkyl radical or a heterocyclic radical and
n is 1 or 2, however, these derivatives show no activity orally.
The inventors have now found that the group A streptogramin derivatives of formula (I):
wherein:
R
1
is chosen from alkyl groups, alkenyl groups, alkynyl groups which may be mono- or polyfluoro groups, C
3
-C
6
cycloalkyl groups, a phenylmethyl group, and heterocyclylmethyl groups, wherein said heterocyclyl portion is aromatic,
R
2
is chosen from a hydrogen atom, a methyl group, and an ethyl group,
the bond
is a single bond (27R stereochemistry) or a double bond,
unless otherwise stated, the alkyl groups are chosen from straight and branched C
1
-C
6
alkyl groups,
unless otherwise stated, the alkenyl groups are chosen from straight and branched C
3
-C
6
alkenyl groups, and
unless otherwise stated, the alkynyl groups are chosen from straight and branched C
3
-C
6
alkynyl groups, have advantageous antibacterial activity, alone or when combined with at least one group B streptogramin derivative.
In one embodiment of the invention, for example, when R
1
is a heterocyclylmethyl group, the heterocyclyl portion can, for example, be chosen from a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, and a pyridyl group.
In one embodiment of the invention, for example, when R
1
is chosen from alkyl groups mono- or polysubstituted with a fluorine atom, the alkyl groups can, for example, be chosen from C
1
and C
2
alkyl groups.
In another embodiment, for example, R
1
can be chosen from alkenyl groups, such as, an allyl group. In yet another embodiment, R
1
can be chosen from alkynyl groups, such as, for example, a propargyl group.
The streptogramin derivatives of formula (I) may be prepared, for example, by:
(a) reacting, in the presence of a phase-transfer agent, a derivative of formula (IIa):
R
1
—X (IIa)
wherein:
R
1
is chosen from alkyl groups, alkenyl groups, alkynyl groups which may be mono- or polyfluoro groups, C
3
-C
6
cycloalkyl groups, a phenylmethyl group, and heterocyclylmethyl groups, wherein said heterocyclyl portion is aromatic, and
X is chosen from halogen atoms, a methylsulphonyloxy group, a p-toluenesulphonyloxy group, and a trifluoromethylsulphonyloxy group, with a dihydroxy streptogramin derivative of formula (II):
wherein:
R
2
is chosen from a hydrogen atom, a methyl group, and an ethyl group,
the bond
is a single bond (27R stereochemistry) or a double bond, and
(b) optionally protecting with a protecting group, prior to said reacting, the hydroxyl function in position 14, and then, where appropriate, removing said protecting group from position 14, and
(c) optionally protecting with a protecting group, prior to said reacting, the amide function in position 8, and then, where appropriate, removing said protecting group from position 8.
In one embodiment of the invention, for example, when X is chosen from halogen atoms, a derivative of formula (IIa), wherein X is chosen from a bromine atom and an iodine atom, can be used for said reacting.
The phase-transfer agent can, for example, be chosen from quaternary ammonium derivatives, for example, salts of tetraalkylammonium and salts of trialkylbenzylammonium, such as, chloride, bromide, and sulphate salts.
Said reacting can, for example, be carried out in a basic medium, such as, for example, a basic medium comprising at least one agent chosen from sodium hydroxide, potassium hydroxide, potassium carbonate, and caesium carbonate.
Said reacting can also, for example, be carried out in an aqueous-organic medium, such as, for example, an aqueous-organic medium comprising at least one agent chosen from hydrocarbons (for example, toluene), halogenated solvents (for example, dichloromethane), and esters (for example, ethyl acetate).
Said reacting can, for example, take place at a temperature ranging, for example, from 10° C. to 60° C., such as, for example, at about 20° C.
The process, for example, can also be performed in the presence of an excess of the derivative of formula (IIa).
The protection and deprotection of the hydroxyl radical in position 14 and of the amide radical in position 8 can be carried out according to known, art-recognized methods which do not affect the rest of the molecule, such as, for example, by applying the methods described by T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis (2nd edition), A. Wiley—Interscience Publication (1991) or by Mc Omie, Protective Groups in Organic Chemistry, Plenum Press (1973). For example, the protection of the hydroxyl radical in position 14 can be carried out with an allyl protecting group which can be installed and removed by analogy with the methods described below in the examples. The protection of the amide in position 8 may, for example, be carried out with a t-butoxycarbonyl protecting group.
When the reaction leads to a mixture of the 14- and 16-O-alkyl isomers, these isomers may be separated according to known, art-recognized methods which do not affect the rest of the molecule, such as, for example, by chromatography, i.e., high performance liquid chromatography (HPLC) on a normal or reverse phase, on a chiral or non-chiral phase, or by flash chromatography, by crystallization, or by any other appropriate separation technique known in the art.
According to the invention, the streptogramin derivatives of formula (I) may also be prepared, for example, by a process comprising:
(a) desilylation of a silyl and 14-O-allyl derivative of formula (III):
wherein:
R
2
is chosen from a hydrogen atom, a methyl group, and an ethyl group,
the bond
is a single bond (27R stereochemistry) or a double bond,
R
3
is a protecting group, and
R
4
is a silyl group,
(b) 37-O-alkylation of the product obtained in (a) above, and
(c) removal of the 14-O-allyl group and the R
3
protecting group according to known methods which do not affect the rest of the molecule.
In one embodiment of the invention, the protecting group R
3
can, for example, be a t-butoxycarbonyl group.
Representative R
4
silyl groups include, for example, trialkylsilyl groups, dialkylphenylsilyl groups, and alkyldiphenylsilyl groups, for example, a t-butyldiphenylsilyl group and a t-butyldimethylsilyl group.
The desilylation, for example, can be carried out according to known, art-recognized methods which do not affect the rest of the molecule. The process can, for example, be performed in the presence of a source of fluoride ions, such as, for example, tetra-n-butylammonium fluoride or, for example, a hydrofluoric acid/amine complex, wherein the amine, for example, can be an amine chosen from triethylamine and pyridine. The reaction, for example, can be carried out in a chlorinated solvent (for example, dichloromethane) or in an ether (for example, tetrahydrofuran) at a temperature ranging, for example, from 20° C. to 80° C.
The 37-O-alkylation reaction, for example, can be carried out by reacting a derivative of formula (IIa) as defined above,
Bacque Eric
Barriere Jean-Claude
Desmazeau Pascal
Ronan Baptiste
Aventis Pharma S.A.
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Kifle Bruck
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