Arylpropionic derivative, a process for the preparation and the

Details Arylpropionic derivative, a process for the preparation and the Arylpropionic derivative, a process for the preparation and the

1995-05-23

1996-09-10

Killos, Paul J.

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C07C 5976

Patent

active

055547893

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to a novel arylpropionic acid salt, specifically the (+)-(S)-2-(3-benzoylphenyl)propionic acid tromethamine salt, of formula (I). ##STR1##
This invention also relates to the therapeutical use of this novel compound.


TECHNOLOGICAL BACKGROUND

2-(3-Benzoylphenyl)propionic acid, also known as ketoprofen (II), is a known nonsteroidal antiinflammatory drug having a potent analgesic and antipyretic action. ##STR2##
While ketoprofen has been marketed as a racemic mixture of its (+)-(S) and (-)-(R) enantiomers, it has been observed that its therapeutic action lies principally in the S enantiomer [Yamaguchi T. et al., Folia Pharmacol. Japon. 90, 295 (1987)]. Moreover, the (+)-(S) enantiomer of the ketoprofen has been claimed to be a faster acting and more potent analgesic than the racemic, administered doses being equal [Sunshine A. et al., WO 89/04658].
Structurally ketoprofen, similarly to other arylpropionic acids, has a lipophilic aromatic moiety which is responsible for its poor solubility in water and a free carboxylic group which has been said to relate to its ulcerogenic toxicity. These disadvantages can restrict its use, the poor solubility making its administration difficult either orally or by other means.
It has been reported that the disadvantages of the arylpropionic acids may substantially be overcome by means of salification with basic amino acids, such as the lysine salt with for ibuprofen [Kwan K. Ch. EP 424028] and ketoprofen [Metz G. EP 136470, BE 882889]; or metal salts, as it is the case of ketoprofen sodium or zinc salts [Fujimura H. et al., Oyo Yakuri, 13, 709 (1977) and Buxade A. ES 2016503, respectively].
The therapeutic use of metal salts, such as the sodium salt, may be restricted as an excessive retention of said metal in the organism may be harmful, especially when the drug is administered frequently. In the case of the sodium salt, its high hygroscopicity can restrict the oral administration in form of tablets or other solid forms which are stable with time.
The compound of the present invention is a novel salt of the (+)-(S) enantiomer of ketoprofen for which there is no reference in literature. This salt was selected among a series of water soluble (+)-(S)-ketoprofen salts, such as the sodium salt, the aluminium salt, the L-lysine salt and the like. Surprisingly, compound (I) has a higher and faster solubility in water (>100% w/v) than any other (+)-(S)-ketoprofen salt. The combination of said two characteristics make this salt more advantageous than any other salt, for example the L-lysine salt is also highly soluble in water, however the dissolution rate thereof is significantly lower. Said characteristics allow the compound to be administered intramuscularly or intravenously, or as highly soluble tablets having a very fast dissolution rate. In addition to the ease of administration, the compound exhibits a faster onset of analgesic action, an enhanced analgesic response and a longer duration than racemic ketoprofen.
The novel derivative shows a fast and complete absorption in both animals and humans. The (+)-(S)-ketoprofen tromethamine salt also has a faster action and enhanced analgesic response than the racemic ketoprofen tromethamine salt.
For example, in a conventional analgesia animal model, the phenylbenzoquinone writhing test, compound (I) was evidenced to have the same analgesic effectiveness as a racemic ketoprofen double dose (Table I and II), the latter being administered intravenously as the salt and orally as the free acid.
The purification of arylpropionic acid salts with amine acid, particularly natural amine acids (L forms), by means of crystallization is known to be difficult [Bruzzese T. et al. U.S. Pat. No. 427,996]. In the case of the (S)-ketoprofen tromethamine salt, its higher solubility in ethanol (10% w/v) compared with e.g. the L-lysine salt (0.3% w/v), allows an easy crystallization from mixture of ethanol and an organic solvent such as ethyl acetate, to obtain the pure salt, completely free from the acid or t

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