Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-07-27
2003-04-01
Russel, Jeffrey E. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S329000
Reexamination Certificate
active
06541451
ABSTRACT:
The present invention relates to B-group streptogramin compounds of formula (I):
as well as the salts thereof, which exhibit antibacterial activity alone or in combination with an A-group streptogramin compound.
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 IA combined with pristinamycin IIA.
Another antibacterial agent of the streptogramin family, virginiamycin, was isolated from
Streptomyces virginiae
, ATCC 13161 (
Antibiotics and Chemotherapy
, 5, 632 (1955)). Virginiamycin (Staphylomycine®) comprises mainly factor S combined with factor M
1
.
Semisynthetic derivatives of streptogramins represented by formula (A):
wherein:
Ra is a radical of structure —CH
2
R′a for which R′a is a radical of the heterocyclylthio type which may be substituted, or alternativeiy represents a radical of structure ═CHR′a for which R′a is a substituted alkylamino, alkyloxy or alkylthio radical, or a radical of the heterocyclylamino, heterocyclyloxy or heterocyclylthio type which may be substituted, Rb and Rc are hydrogen atoms and Rd is a hydrogen atom or a dimethylamino radical, or alternatively Ra is a hydrogen atom and Rb is hydrogen or methyl, and Rc and Rd are hydrogen or various substituents, have been described in European Patent Nos. EP 133 097, EP 248 703, EP 770 132, and EP 772 630.
When combined with a semisynthetic component of the streptogramin A group, they can show synergistic action and can be used as antibacterial agents, administered either via injection or orally.
European Patent No. EP 133 098 also discloses B-group synergistin derivatives bearing aminomethylenyl chains in position 5&dgr;, which are synthetic intermediates.
It has now been found, in accordance with the present invention, that the compounds of formula (I), wherein:
R is chosen from —NR
1
R
2
and —SR
3
, wherein:
R
1
and R
2
, which may be identical or different, are independently chosen from a hydrogen atom and the radicals:
alkyl(1 to 8 carbons), which are unsubstituted or substituted with hydroxyl;
alkenyl (3 to 8 carbons);
cycloalkyl (3 to 8 carbons);
alkyloxy (1 to 8 carbons);
dialkylamino;
phenylalkyl, which is unsubstituted or substituted with one or more halogen atoms or radicals chosen from alkyl, hydroxyalkyl, alkyloxy, and dialkylamino;
saturated and unsaturated heterocyclylalkyl (3- to 8-membered) containing one or more hetero atoms chosen from nitrogen, sulphur and oxygen; and dialkylaminoalkyl;
or, alternatively,
R
1
and R
2
, together with the nitrogen atom to which they are attached, form a ring chosen from 3- to 12-membered, saturated, partially saturated, and unsaturated, monocyclic and polycyclic heterocycles optionally containing at least one additional hetero atom chosen from oxygen, sulphur, and nitrogen, and which are unsubstituted or substituted with one or more radicals chosen from:
hydroxyl;
alkyl;
phenyl, which is unsubstituted or substituted with a halogen atom;
phenylalkyl;
phenylalkenyl (alkenyl containing 2 to 4 carbons);
hydroxyalkyl;
acyl;
alkyloxycarbonyl; and
heterocyclyl and heterocyclylcarbonyl, wherein the heterocyclyl portion is saturated or unsaturated (4- to 6-membered) and contains one or more hetero atoms chosen from oxygen, sulphur, and nitrogen;
R
3
is chosen from:
alkyl (containing 1 to 8 carbons) and cycloalkyl (containing 3 to 8 carbons) radicals, both of which are substituted with a radical chosen from:
—NR
1
R
2
, wherein R
1
and R
2
, which may be identical or different, are chosen from:
a hydrogen atom; and
alkyl radicals;
or form, together with the nitrogen atom to which they are attached, a heterocycle as defined above;
or, alternatively,
R
3
is chosen from 3- to 7-membered, saturated and unsaturated, monocyclic and polycyclic, heterocyclyl and heterocyclylmethyl radicals optionally containing at least one additional hetero atom chosen from oxygen, sulphur, and nitrogen, and which are unsubstituted or substituted with at least one alkyl radical;
represents an unsaturated ring residue which is unsubstituted at 5&ggr;:
or a saturated ring residue which is substituted at 5&ggr; with a fluoro radical:
Ra is chosen from methyl and ethyl radicals; and
Rb, Rc, and Rd have the following definitions:
1) Rb and Rc are both a hydrogen atom; and
Rd is chosen from a hydrogen atom and methylamino and dimethylamino radicals;
2) Rb is a hydrogen atom;
Rc is chosen from hydrogen, chlorine, and bromine atoms, and alkenyl radicals (3 to 5 carbons); and Rd is a radical —NMe—R′″, wherein R′″ is chosen from:
alkyl, hydroxyalkyl (2 to 4 carbons), and alkenyl (2 to 8 carbons) radicals, which are unsubstituted or substituted with at least one radical chosen from:
phenyl;
cycloalkyl (3 to 6 carbons);
methyl;
benzyl; and
substituted benzyl, wherein one or more substitutents are chosen from:
halogen atoms and hydroxyl, alkyl, alkyloxy, alkylthio, alkylsulphinyl, alkylsulphonyl, amino, alkylamino and dialkylamino radicals; and
heterocyclylmethyl and heterocyclylethyl, wherein the heterocyclyl portion is saturated or unsaturated and 5- or 6-membered and contains 1 or 2 hetero atoms chosen from sulphur, oxygen, and nitrogen, and which are unsubstituted or substituted with one or more radicals chosen from:
alkyl, alkenyl (2 to 8 carbons), cycloalkyl (3 to 6 carbons), saturated and unsaturated 4- to 6-membered heterocyclyl, phenyl, substituted phenyl as defined above for the definition of R
1
, and benzyl radicals;
or, alternatively,
R′″ is chosen from cyanomethyl, carboxymethyl, —CORe and —CH
2
CORe radicals, wherein Re is —OR′e, and wherein R′e is chosen from:
alkyl (1 to 6 carbons);
alkenyl (2 to 6 carbons);
benzyl;
phenyl;
tolyl; and
heterocyclylmethyl radicals, wherein:
the heterocyclyl portion is 5- or 6-membered and contains 1 or 2 hetero atoms chosen from sulphur, oxygen and nitrogen;
or, alternatively,
Re is chosen from:
alkylamino;
alkylmethylamino; and
heterocyclylamino and heterocyclylmethylamino radicals, wherein:
the heterocyclyl radical is saturated and 5- or 6-membered and contains 1 or 2 hetero atoms chosen from sulphur, oxygen, and nitrogen, and is unsubstituted or substituted with a radical chosen from alkyl, benzyl, and alkyloxycarbonyl radicals;
3) Rb is a hydrogen atom;
Rd is chosen from —NHCH
3
and —N(CH
3
)
2
radicals; and Rc is chosen from chlorine and bromine atoms, and from alkenyl radicals (3 to 5 carbons) when Rd is —N(CH
3
)
2
;
4) Rb and Rd are both a hydrogen atom; and
Rc is chosen from halogen atoms and alkylamino, dialkylamino, alkyloxy, trifluoromethoxy, thioalkyl, alkyl (1 to 6 carbons), and trihalomethyl radicals;
5) Rb and Rc are both a hydrogen atom; and
Rd is chosen from halogen atoms and ethylamino, diethylamino, methylethylamino, alkyloxy, trifluoromethoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkyl (1 to 6 carbons), phenyl, and trihalomethyl radicals;
6) Rb is a hydrogen atom;
Rc is chosen from halogen atoms and alkylamino, dialkylamino, alkyloxy, trifluoromethoxy, thioalkyl, and alkyl (1 to 3 carbons) radicals; and
Rd is chosen from halogen atoms and amino, alkylamino, dialkylamino, alkyloxy, trifluoromethoxy, thioalkyl, alkyl (1 to 6 carbons), and trihalomethyl radicals; and
7) Rc is a hydrogen atom; and
Rb and Rd are both methyl radicals; show particularly advantageous activities for treating infections when administered orally and/or parenterally.
The streptogramin compounds of formula (I) may exhibit powerful oral and parenteral activity, which makes them extremely useful for treating serious infections, for example, in a hospital environment via injection, which administration may be followed by an oral ambulatory treatment which is easier to administer to the patients. Thus, the practitioner is no longer obliged to change the patient's category of medicinal product between the end of the hospital treatment a
Bacque Eric
Barriere Jean-Claude
Doerflinger Gilles
Dutruc-Rosset Gilles
Pantel Guy
Aventis Pharma S.A.
Finnegan Henderson Farabow Garrett & Dunner LLP
Russel Jeffrey E.
LandOfFree
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