Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-30
2003-05-27
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
06569854
ABSTRACT:
The present invention relates to group A streptogramin derivatives of general formula:
as well as their salts, which exhibit a particularly advantageous antibacterial activity.
Among the known streptogramins, pristinamycin (RP 7293), an antibacterial of natural origin produced by
Streptomyces pristinaespiralis
was first isolated in 1955. The pristinamycin marketed under the name Pyrostacine® consists mainly of pristinamycin IIA combined with pristinamycin IA.
Another antibacterial of the class of streptogramins: virginiamycin, has been prepared from
Streptomyces virginiae
, ATCC 13161 [Antibiotics and Chemotherapy, 5, 632 (1955)]. Virginiamycin (Staphylomycine®) consists mainly of factor M
1
combined with factor S (VS).
Semisynthetic derivatives of streptogramins of structure:
for which n is 0 to 2 have been described in patents EP 135410 and EP 191662. Combined with a semisynthetic component of group B streptogramins they manifest a synergistic action and can be used by the injection route.
In International Patent Application WO 99/05165, there have been described group A streptogramin derivatives of general formula:
in which R
1
is a radical —NR′R″ or —NR′OR′″, R
2
is hydrogen, methyl or ethyl, and he bond
- - -
is a single bond or a double bond, which are antimicrobial agents.
However, these derivatives do not achieve particularly high levels of activity and, moreover, do not always have a spectrum as broad as desired.
It has now been found that the group A streptogramin derivatives of general formula (I) in which:
R
1
represents a halogen atom or an azido or thiocyanato radical,
R
2
represents a hydrogen atom or a methyl or ethyl radical,
R
3
represents a hydrogen atom, or the residue of an aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic or heterocyclylaliphatic ester which may be substituted, and
the bond
- - -
represents a single bond (stereochemistry 27R) or a double bond,
and their salts when they exist, exhibit a particularly potent antibacterial activity, alone or combined with a group B streptogramin derivative, and/or also manifest a broadened spectrum compared with the usual spectrum for streptogramins.
According to the invention, when R
1
represents a halogen atom, it may be chosen from fluorine, chlorine, bromine or iodine;
when the radical R
3
represents the residue of an aliphatic, cycloaliphatic, aromatic, araliphatic, hydrocyclic or heterocyclylaliphatic ester which may be substituted, the latter may be chosen, by way of example, from R′
3
—CO— radicals for which R′
3
is phenyl or phenylalkyl which are unsubstituted or which are substituted on the phenyl radical [with one or more radicals chosen from alkyl, optionally carrying a radical NR′R″ in which the radicals R′ and R″, which are identical or different, may be hydrogen atoms or alkyl radicals which can form together with the nitrogen atom to which they are attached a 3- to 8-membered saturated or unsaturated heterocyclyl radical optionally comprising another heteroatom chosen from oxygen, sulfur or nitrogen, it being possible for the said heterocycle itself to be substituted with one or ore radicals (alkyl, hydroxyalkyl, alkyloxyalkyl, alkyloxycarbonylalkyl, aryl, heterocyclyl, heterocyclylalkyl, which are saturated or unsaturated and have 3 to 8 members, or —CH
2
—CO—NR′R″), or alternatively R′ and/or R″ may be a hydroxyalkyl radical, a phenyl radical, a 3- to 8-membered saturated or unsaturated heterocyclylalkyl radical, a radical —CO—NR′R″ for which NR′R″ is as defined above, or alkyl or acyl radicals which are substituted with NR′R″ which is as defined above], or alternatively R′
3
may be chosen from phenyl or phenylalkyl radicals which are substituted on the phenyl radical with one or more radicals [chosen from alkyl, which may be substituted with an alkyloxy or alkylthio radical optionally carrying themselves a carboxyl radical or a radical NR′R″ as defined above], or chosen from acyloxy which may be substituted with NR′R″ as defined above), or alternatively R′
3
may be chosen from alkyl or cycloalkyl radicals which are optionally substituted [with a carboxyl radical, a carboxyalkyldisulfanyl radical or with a radical NR′R″, —CH
2
—NR′R″, or —CO—NR′R″, or with an alkyloxycarbonyl, alkyloxy or alkyldi-sulfanyl radical which are optionally substituted with NR′R″ or —CO—NR′R″ for which NR′R″ is as defined above], or alternatively R′
3
may be chosen from 3- to 8-membered saturated or unsaturated heterocyclyl radicals which are optionally substituted [with alkyl or acyl which are themselves optionally substituted with NR′R″].
In general formula (I), unless otherwise stated, the alkyl or acyl radicals or portions are straight or branched and contain 1 to 12 carbon atoms, the heterocyclyl radicals may be chosen in particular from pyrrolidinyl, pyrrolyl, furyl, thienyl, imidazolyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrizanyl, pyrimidinyl, pyridazinyl and imidazolidinyl, and the aryl radicals may be chosen in particular from optionally substituted phenyl and more particularly from phenyl which is substituted with alkyl, alkyloxy or halogen, or with a radical —CH
2
OH, —(CH
2
)
n
—NH
2
, —(CH
2
)
n
—NHalkyl or —(CH
2
)
n
—N(alkyl)
2
.
The streptogramin derivatives of general formula (I) may be prepared by halogenating, converting to an azide or converting to a thiocyanate, a streptogramin derivative of general formula:
in which R
2
is as defined above, the bond
- - -
represents a single bond (stereochemistry 27R) or a double bond, and in which the hydroxyl function at the 14-position has been previously protected, followed by the removal of the protecting radical and where appropriate, in order to obtain a derivative of general formula (I) for which R
3
is other than a hydrogen atom, introduction of the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic or heterocyclylaliphatic ester residue which may be substituted (R
3
) according to the usual methods which do not alter the rest of the molecule.
The reactions for halogenating, converting to an azide or converting to a thiocyanate may be carried out in the presence of an aminosulfur trifluoride (for example diethylaminosulfur trifluoride, bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor®), morpholinosulfur trifluoride) or alternatively in the presence of sulfur tetrafluoride, by means of a reagent such as a tetraalkylammonium, trialkylbenzylammonium or trialkylphenylammonium halide, azide or thiocyanate or by means of an alkali metal halide, azide or thiocyanate optionally supplemented with a crown ether. The fluorination reactions may also be carried out by the action of a fluorinating agent such as a sulfur fluoride [for example morpholinosulfur trifluoride, sulfur tetrafluoride (J. Org. Chem., 40, 3808 (1975)), diethylaminosulfur trifluoride (Tetrahedron, 44, 2875 (1988)), bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor®). Alternatively, the fluorination reactions may also be carried out by means of a fluorinating agent such as hexafluoropropyldiethylamine (JP 2,039,546) or N-(2-chloro-1,1,2-trifluoroethyl)diethylamine.
While a tetraalkylammonium halide, azide or thiocyanate is used, the latter may be chosen, by way of example, from tetramethylammonium, tetraethylammonium, tetrapropylammonium, tetrabutylammonium (for example tetra-n-butylammonium), tetrapentylammonium, tetracyclohexylammonium, triethylmethylammonium, tributylmethylammonium or trimethylpropylammonium halides, azides or thiocyanates.
The procedure is carried out in an organic solvent such as a chlorinated solvent (for example dichloromethane, dichloroethane or chloroform) or in an ether (for example tetrahydrofuran) at a temperature of between −78 and 40° C. (preferably of between 0 a
Achard Daniel
Bacque Eric
Barriere Jean-Claude
Bouquerel Jean
Desmazeau Pascal
Aventis Pharma S.A.
Finnegan Henderson Farabow Garrett & Dunner LLP
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