Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1989-08-04
1990-12-11
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514427, 548530, 548561, C07D207337, A61K 3140
Patent
active
049771817
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
U.S. Pat. No. 4,256,759 discloses 1-methyl-beta-oxo-alpha-phenylcarbamoyl-2-pyrrolepropionitrile of formula I, ##STR2##
The compound of formula I is acidic and may exist in a tautomeric enolic form represented by formula Ia ##STR3##
Salts mentioned in U.S. Pat. No. 4,256,759 for the class of compounds are salts with pharmaceutically acceptable bases, such as alkali metal, alkaline earth metal, copper or zinc hydroxides; ammonia, mono-, di- or tri-lower (alkyl or hydroxyalkyl)-amines, alkyleneimines or alkylenediamines, e.g. sodium, potassium, magnesium, ammonium, mono-, di- or tri-(methyl, ethyl or hydroxy-ethyl)-ammonium, pyrrolidinium, ethylenediammonium or morpholinium salts; or various hydrates thereof.
Salts specifically disclosed for the compound of formula I are the sodium salt, potassium salt, calcium salt and tris-hydroxyethyl-ammonium (triethanolamine) salt. The sodium, potassium and calcium salts are not crystalline.
Tromethamine is the primary amine tris-(hydroxy-methyl)-aminomethane, also named 2-amino-2-(hydroxy-methyl)-1,3-propanediol, and described in Merck Index, Tenth Edition page 1395.
The tertiary amine triethanolamine has been converted chemically in the laboratory to N-nitrosodiethanolamine which has been implicated as a potential carcinogen. Some concerns have been expressed about triethanolamine salts as pharmaceuticals based on the speculation that triethanolamine might somehow be converted metabolically in mammals to N-nitrosodiethanolamine.
On the other hand, the primary amine tromethamine is not known to be chemically convertible to any N-nitroso derivative.
SUMMARY OF THE INVENTION
The present invention is concerned with the novel pharmaceutically acceptable tromethamine salt of 1-methylbeta-oxo-alpha-(phenylcarbamoyl)-2-pyrrolepropionitrile, pharmaceutical compositions comprising said salt and a method of treating inflammatory and arthritic conditions in mammals by administering said salt to mammals in need of such treatment.
DETAILED DESCRIPTION OF THE INVENTION
More specifically the present invention is concerned with the 1:1 salt of 1-methyl-beta-oxo-alpha-(phenylcarbamoyl)-2-pyrrole-propionitrile with tromethamine which can be represented by structural formula II ##STR4##
The novel salt of formula II displays antiinflammatory and antiarthritic activity. The salt of formula II also displays biological activity indicative of potential disease modifying effects in arthritis, including inhibition of cartilage matrix degradation as well as enhancement of depressed cell-mediated immunity.
The salt is well tolerated and is essentially free of undesirable side effects at therapeutically effective doses.
In acute toxicity studies in the rat, the salt of the instant invention is observed to be less toxic than the free acid of formula I or the triethanolamine salt thereof. No deaths (0/10 animals) are observed with the tromethamine salt of formula II at a dose of 2.4 millimoles/Kg p.o. (932 mg/Kg p.o.) while a 50% mortality rate is observed with the triethanolamine salt of the compound of formula I at an equimolar dose of 2.4 millimoles/Kg p.o. (1000 mg/Kg p.o.), and a 40% mortality rate is observed at an equimolar dose of 2.4 millimoles/Kg p.o. (641 mg/Kg p.o.) with the free acid of formula I.
In addition, the tromethamine salt of the instant invention is free of concerns relating to any potential metabolic conversion to an N-nitroso derivative.
The foregoing attributes render the compound of the invention particularly useful when administered alone or in combination, to mammals including man, for the treatment of e.g. rheumatoid arthritis and osteoarthritis.
The pharmacological properties, primarily anti-inflammatory, analgesic, antirheumatic, immunopotentiating and antiarthritic activity, can be demonstrated by in-vitro or in-vivo tests, using for the latter advantageously mammals, such as rats, mice, guinea pigs or dogs, as test objects. The compound can be administered to the animals either enterally, preferably orally, parenterally, e.g. subcu
REFERENCES:
patent: 3880883 (1975-04-01), Caton
patent: 4089969 (1978-05-01), Muchowski et al.
patent: 4256759 (1981-03-01), Walker
patent: 4518608 (1985-05-01), Kahan
patent: 4644010 (1987-02-01), Walker
patent: 4704405 (1987-11-01), O'Neill et al.
Berch Mark L.
Ciba-Geigy Corporation
Gruenfeld Norbert
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