Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-27
2004-11-09
Wax, Robert A. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S011400, C530S317000
Reexamination Certificate
active
06815437
ABSTRACT:
The present invention relates to group A steptogramin derivatives of general formula:
in which
R
1
is a radical —NR′R″ for which R′ is a hydrogen atom or a methyl radical, and R″ is a hydrogen atom or an alkyl, cycloalkyl, allyl, propynyl, benzyl or —OR′″ radical, R′″ being a hydrogen atom or an alkyl, cycloalkyl, allyl, propynyl or benzyl radical, or R″ represents —NR
3
R
4
, it being possible for R
3
and R
4
to represent a methyl radical, or to form together with the nitrogen atom to which they are attached a saturated or unsaturated 4- or 5-membered heterocycle which may, in addition, contain another heteroatom chosen from nitrogen, oxygen or sulphur,
R
2
is a hydrogen atom or a methyl or ethyl radical, and
the bond
represents a single bond or a double bond,
as well as their salts, which exhibit a particularly advantageous antibacterial activity and a good degree of metabolic stability.
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
7
consists mainly of pristinamycin II
A
combined with pristinamycin I
A
.
Another antibacterial of the class of streptogramins: virginiamycin, has been prepared from
Streptomyces virginiae
, ATCC 13161 [Antibiotics and Chemotherapy, 5; 632 (1955)]. Virginiamycin (Staphylomycine
7
) consists mainly of factor M
1
combined with factor S.
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 general formula (I), unless otherwise stated, the alkyl radicals are straight or branched and contain 1 to 6 carbon atoms; the cycloalkyl radicals contain 3 to 4 carbon atoms; the chain
at the 16-position means: when R″ is other than —OR′″ or —NR
3
R
4
, the R epimer or mixtures of the R and S epimers in which the R epimer is predominant, and when R″ is —OR′″ or —NR
3
R
4
, the R and S epimers and mixtures thereof.
When R″ is a radical —NR
3
R
4
for which R
3
and R
4
form together with the nitrogen atom to which they are attached a saturated or unsaturated 4- or 5-membered heterocycle, the latter may be in particular azetidine, azolidine or imidazolyl.
The streptogramin derivatives of general formula (I) may be prepared from the components of the natural pristinamycin of general formula:
in which R
2
is as defined above, by the action of an amine of general formula:
H
2
N—R″ (III)
in which R″ is as defined above, followed by the action of an agent for reducing the intermediate enamine (or oxime) obtained, and then, when it is desired to obtain a streptogramin derivative of general formula (I) for which R′ is a methyl radical, followed by a second reductive amination, by the action of formaldehyde or of a derivative generating formaldehyde in situ and the reduction of the intermediate enamine.
The action of the amine is generally carried out in an organic solvent such as an alcohol (for example methanol or ethanol), a chlorinated solvent (for example dichloromethane, dichloroethane or chloroform), a nitrile (for example acetonitrile), or pyridine, at a temperature of between 0 and 30 EC, and optionally in the presence of a dehydrating agent such as, for example, magnesium sulphate, sodium sulphate or molecular sieves. Preferably, the procedure is carried out under an inert atmosphere (for example argon). It is also possible to cause the amine salt to react. Preferably, to prepare derivatives for which the bond
represents a double bond, the procedure is carried out in an organic solvent such as a nitrile (for example acetonitrile) in the presence of an acid, such as an organic acid (for example acetic acid); in this case, the addition of a dehydrating agent is not necessary. When a streptogramin derivative of general formula (I) for which R″ is a radical —OR′″ is prepared, it is possible to isolate the intermediate oxime of general formula:
in which R
2
and R′″ are as defined above, and then to reduce this product to a derivative of general formula (I) for which R′ is a hydrogen atom, and optionally use it in the subsequent reductive amination operation.
The reduction is carried out by the action of a reducing agent, for example an alkali metal borohydride (for example sodium cyanoborohydride or triacetoxyborohydride) in the presence of an organic acid (for example acetic acid) in an organic solvent as mentioned above for the amination reaction.
Where appropriate, the subsequent reductive amination operation, intended to obtain the disubstituted amine, is carried out under similar conditions.
According to the invention, the streptogramin derivatives of general formula (I) may also be prepared by the action of the ketone corresponding to the desired R″ radical on the amine-containing derivative of general formula:
in which R
2
is as defined above, followed, when it is desired to obtain a streptogramin derivative of general formula (I) for which R′ is a methyl radical, by a second reductive amination, by the action of formaldehyde or of a derivative generating formaldehyde in situ and the reduction of the intermediate enamine.
The reaction is carried out under conditions similar to those described above.
The amine of general formula (I) may be prepared as described above, from a streptogramin derivative of general formula (II).
The pristinamycin derivatives of general formula (II) correspond respectively-to pristinamycin II
A
(PII
A
), to pristinamycin II
B
(PII
B
), to pristinamycin II
C
(PII
C
), to pristinamycin II
D
(PII
D
), to pristinamycin II
F
(PII
F
), and to pristinamycin II
G
(PII
G
), which are known components of natural pristinamycin. The components PII
F
and PII
G
have been described in European patent application EP 614910.
Pristinamycin II
C
(PII
C
) and pristinamycin II
D
(PII
D
) may be obtained as described by J. C. Barrière et al., Expert. Opin. Invest. Drugs, 3(2), 115-31 (1994).
The preparation and separation of the components of the natural group A streptogramins [streptogramins of general formula (II)] is carried out by fermentation and isolation of the constituents from the fermentation broth according to or by analogy with the method described by J. Preud'homme et al., Bull. Soc. Chim. Fr., vol. 2, 585 (1968).
Alternatively, the preparation of the natural components of group A may be carried out by specific fermentation, as described in patent application FR 2,689,518.
The streptogramin derivatives of general formula (I) may be purified, where appropriate, by physical methods such as crystallization or chromatography.
The derivatives of general formula (I) may in particular be obtained in the form of the 16R epimer. The separation of the 16R epimer form and the 16S epimer form may be carried out by flash chromatography, by high-performance liquid chromatography (HPLC) or by centrifugal partition chromatography (CPC), from the mixture of the 16R and 16S epimers.
The streptogramin derivatives of general formula (I) may be converted to the state of addition salts with acids, by known methods. It is understood that these salts are also included within the scope of the present invention.
As examples of addition salts with pharmaceutically acceptable acids, there may be mentioned the salts formed with inorganic acids (hydrochlorides, hydrobromides, sulphates, nitrates, sulphates) or with organic acids (succinates, fumarates, tartrates, acetates, propionates, maleates, citrates, methanesulphonates, ethanesulphonates, phenylsulphonates, p-toluenesulphonates, isethionates, naphthylsulphonates or camphorsulphonates, or with the substitution derivatives of these compounds).
The streptogramin derivatives according to the present in
Bacque Eric
Barriere Jean-Claude
Bouchard Herve
Commerçon Alain
Puchault Gerard
Aventis Pharma S.A.
Lukton David
Wax Robert A.
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