Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-12-06
1998-09-22
Lambkin, Deborah C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D20914
Patent
active
058115587
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB 95/00857 filed on Apr. 11, 1995.
FIELD OF THE INVENTION
This invention relates to etodolac, and in particular to novel enantiomeric salts thereof, a process for making those salts, and their use in the manufacture of medicaments.
BACKGROUND OF THE INVENTION
Etodolac is a chiral compound. It is a non-steroidal analgesic and anti-inflammatory agent which is marketed in racemic form. Its analgesic properties and preparation are described in US-A-3843681 and sustained-release formulations containing it are described in EP-A-0309157. The existence of its meglumine and glucamine acid addition salts is disclosed in US-A-4748174, although the preparation and properties of these salts is not.
It has been found that the required biological activity of etodolac generally resides in only one of its enantiomers, for instance as described by Demerson et al, J. Med. Chem., (1983) 26:1778. Consequently, there is a need for a process to produce that single enantiomer. An existing resolution procedure is disclosed in US-A-4520203, and involves crystallisation of a single diastereoisomeric salt formed with etodolac and the alkaloidal base cinchonine. However, a disadvantage with this process is that the resolving agent used is both expensive and toxic.
Another resolution procedure is disclosed in US-A- 4515961 and resolves etodolac as a conglomerate from a solution of the racemate.
SUMMARY OF THE INVENTION
According to a first aspect of the present invention, a compound that is a glucamine or an N-(C.sub.1-4 alkyl)- glucamine salt of (S)-etodolac, preferably the meglumine salt of (S)-etodolac. The meglumine salt has a surprisingly short t.sub.max, thus making it particularly suitable for rapid-onset analgesic effect. In addition, surprisingly, the use of the meglumine salt of (S)-etodolac leads to a reduction in variation in plasma concentrations from subject to subject, and also to a more complete absorption, indicated by an increase in AUC, compared to the racemate. In summary, the meglumine salt produces a significantly more consistent blood level of the (S) enantiomer than does the racemate.
According to a second aspect of the present invention, use of a water soluble (S)-etodolac salt is in the manufacture of a medicament for use in rapid-onset analgesia, e.g. in treating acute pain.
According to a third aspect of the present invention, use of a water-soluble salt of (S)-etodolac is in the manufacture of a medicament for use in managing chronic pain, eg arthritis.
The t.sub.1/2, values for racemic etodolac and (R)-etodolac are substantially eguivalent while the corresponding value for (S)-etodolac is markedly lower. This, in addition to the reduction in variation in plasma concentrations described above, supports the utility of (S)-etodolac in sustained-release formulations.
According to a fourth aspect of the present invention, a sustained-release formulation comprises (S)-etodolac, or a water-soluble salt thereof, preferably the meglumine salt of (S)-etodolac.
According to a fifth aspect of the present invention, a process for the resolution of etodolac comprises using as the resolving agent glucamine or an N-(C.sub.1-4 alkyl) -glucamine. Resolving agents of this type are cheap and readily available, and are also non-toxic which means that they can be retained in the final drug formulation, if so desired, as they form pharmaceutically-acceptable salts.
According to a sixth aspect of the present invention, a process for converting a single enantiomer of etodolac into the racemate comprises forming an ester of the carboxylate function of that enantiomer and treating with acid or with base, preferably with acid. Consequently, the above process for resolving etodolac, or indeed any other such process, can be made economically viable by recycling the unwanted enantiomer in this way.
DESCRIPTION OF THE INVENTION
The novel enantiomeric salts of the present invention are substantially enantiopure. Preferably they are in at least 80% ee, more preferably at least 90% ee, and most
REFERENCES:
patent: 4748174 (1988-05-01), Veronesi
Demerson et al. J. Med. Chem. vol. 26, pp. 1778-1780 1983.
Adger Brian Michael
Andrews John Francis Paul
Baker Helen Frances
Dyer Ulrich Conrad
Woods Martin
Chiroscience Limited
Lambkin Deborah C.
Sackey Ebenezer O.
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