Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Patent
1995-10-31
1998-09-15
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
562560, 562561, 562562, C07C 5984, C07C22926, C07D29508
Patent
active
058080694
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
Salts of 2-(3-benzoylphenyl)propionic organic bases and pharmaceutical compositions thereof
TECHNICAL FIELD
The object of the present invention relates to salts of 2-(3-benzoylphenyl)propionic acid with achiral and chiral organic bases, and to the pharmaceutical compositions containing them.
A further object of the invention relates to the process for the preparation of said salts.
More particularly, the present invention relates to the salts of the S(+) and R(-) enantiomers of 2-(3-benzoylphenyl)propionic acid with achiral amine, such as, for example, tris-(hydroxymethyl)aminomethane, also known as tromethamine, and with chiral amine such as, for example (R) and (S) 3-(4-phenylpiperazin-1-yl)propane-1,2-diol, also known as dextrodropropizine and levodropropizine, and with basic .alpha.-aminoacids such as, for example, D-lysine, L-lysine and L-arginine, all salts which may be separated as single chemical individuals of high optical purity.
BACKGROUND OF THE INVENTION
Because of its high tolerability, the (S,R) (.+-.) 2-(3-benzoylphenyl)propiornic acid, also known as ketoprofen, is one of the non-steroidal anti-inflammatories of widespread use in clinics, both for the treatment of serious inflammatory conditions and for its use as an anagelsic and antipyretic. Pharmaceutical compositions of current use containing ketoprofen, have racemate as its active principle, where the two enantiomers S(+) and R(-) are present in equimolecular ratio between themselves.
The active principle is normally used as free acid, practically insoluble in water, in pharmaceutical compositions destined for oral use, while for alternative ways of administration, for example that of parenteral administration, adaptable ketoprofen salts with organic and inorganic bases are used.
In the past, all the pharmacological activities peculiar to the racemate of 2-arylpropionic chiral acid, were thought to be constitutive of the enantiomer S(+) which only was found to inhibit the endogenous synthesis of the pro-inflammatory algogene and pirogene prostaglandines, in which respect the antipode R(-) is inactive or practically so. On the other hand, it is well known that the R(-) enantiomer of the 2-arylpropionic acids undergoes, to a variable extent and in a way animal species dependent, metabolic epimerization in the S(+) enantiomer, an event which, for a long time, has prevented a correct characterization of the pharmacological properties of the individual enantiomers.
Only recently, using flurbiprofen, a chiral 2-arylpropionic anti-inflammatory and analgesic acid, whose enantiomers are not metabolically converted one into another, K. Brune et al. (Experientia, 47, 257, 1991) have clearly shown that the inhibition of the prostaglandine synthesis mainly mediates the anti-inflammatory activity of the compound, while mechanisms independent from the inhibition of the prostaglandine synthesis contribute to the analgesic effects of the racemate. Of the two antipodes, the S(+) form inhibits the prostaglandine synthesis, the inflammation and the perception of the pain, while the R(-) antipode, which has much less effect on the inhibition of the prostaglandine synthesis and has no effect on the inflammation, blocks the perception of the pain with a potency rather similar to that of the antipode S(+).
S(+) flurbiprofen is clearly ulcerogenic for the gastroenteric mucose, unlike the R(-) enantiomer. On the basis of these results, the A.A.s conclude on the existence of additional mechanisms of analgesia and propose a new and correct therapeutic use of the R(-) 2-arilpropionic acids as analgesics.
These concepts are further charactered in a successive article (K. Brune et al., J. Clin, Pharmacol., 32, 944, 1992) where it is concluded that, having recourse to the use of individual enantiomers of the chiral 2-arylpropionic acids instead of the racemate, it is possible: biochemical inversion pathway; pain, S-enantiomers in rheumatic disorders).
DESCRIPTION OF THE INVENTION
The object of the present invention relates to pharmacologically a
REFERENCES:
patent: 4279926 (1981-07-01), Bruzzese et al.
patent: 5089405 (1992-02-01), Cerbelaud et al.
patent: 5097064 (1992-03-01), Grosselin
patent: 5331000 (1994-07-01), Young et al.
Bosone Enrico
Clavenna Gaetano
Curti Roberto
Gandolfi Carmelo
Mantovanini Marco
Dimpe' SpA
Dompe Farmaceutici SpA
Rao Deepak R.
Shah Mukund J.
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