Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-02-10
1995-12-12
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544282, C07D47104, A61K 31505
Patent
active
054750008
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to therapeutically useful novel 3-(1-substituted-1H-tetrazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidines and/or 3-(2-substituted-2H-tetrazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine s, salts thereof, process for their preparation, and pharmaceutical compositions containing them. These new compounds are therapeutically useful first of all as gastroprotectives in the treatment and prevention of ulcers.
BACKGROUND OF THE INVENTION
It is known that some representatives of the 4H-pyrido[1,2-a]pyrimidine-4-ones exert significant antiallergic and ulcus preventing activity (EP-PS No. 217 673 and 218 423, BE-PS No. 873 192 and 873 194 and U.S. Pat. No. 4,122,274 and 4,457,932). Cyctoprotective activity of the 9-methyl-3-tetrazolyl-4-oxo-4H-pyrido[1,2-a]pyrimidine potassium salt was shown more in detail (Gastroenterology 1985 88, 1354).
SUMMARY OF THE INVENTION
The invention is based upon the unexpected discovery that substitution of the acidic hydrogen atom of the tetrazolyl group of the 3-tetrazolyl-4-oxo-4H-pyrido[1,2-a]pyrimidines results in derivatives with a broader therapeutic spectrum.
More particularly the invention relates to novel 4-oxo-4H-pyrido[1,2-a]pyrimidines of the formula ##STR2## wherein R means a C.sub.1-6 alkyl, --(CH.sub.2).sub.n --COOR.sup.3 wherein R.sup.3 is C.sub.1 to C.sub.4 alkyl and C.sub.3-6 alkenyl, C.sub.3-6 alkynyl, C.sub.3-7 cycloalkyl, or a C.sub.7-8 aralkyl group, optionally substituted by one or more halogen atom(s), or by a nitro-group,
As used herein: the term C.sub.1-4 alkyl means straight or branched chain aliphatic saturated hydrocarbyl groups (such as the methyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, neopentyl group).
Pharmaceutically acceptable salts of the compounds of the formulae (I) and (II) mean salts formed with alkali metals, alkaline-earth metals, or acid addition salts formed with organic or inorganic acids.
According to another aspect of the invention there is provided a process for the preparation of the new compounds of the formulae (I) and (II), wherein R and R.sup.1 are the same as defined above, and their pharmaceutically acceptable salts, which comprises
reacting a 3-tetrazolyl-4-oxo-4H-pyrido[1,2-a]pyrimidine of the formula ##STR3## wherein R.sup.1 is the same as defined above, with a halogenide of the formula C.sub.3-7 cycloalkyl, or C.sub.1-4 alkoxycarbonyl group or a C.sub.7-8 aralkyl group optionally substituted by a one ore more halogen atom(s) or by nitro-group and X stands for chlorine, bromine or iodine atom; or with a sulfate of the formula ##STR4## wherein R means C.sub.1-6 alkyl, C.sub.3-6 alkenyl, C.sub.3-6 alkynyl, or C.sub.3-7 cycloalkyl group or a C.sub.7-8 aralkyl group optionally substituted by one or more halogen atom(s) or by a nitro group or with a sulfonate of the formula ##STR5## wherein R means a C.sub.1-6 alkyl, C.sub.3-6 alkenyl, C.sub.3-6 alkynyl, or C.sub.3-7 cycloalkyl group or a C.sub.7-8 aralkyl group, optionally substituted by one or more halogen atom(s) or by a nitro group and R.sup.2 means a phenyl, p-methylphenyl or methyl group; or with a phosphate of the formula ##STR6## wherein R means a C.sub.1-6 alkyl, C.sub.3-6 alkenyl, C.sub.3-8 alkynyl, C.sub.3-7 cycloalkyl group or a C.sub.7-8 aralkyl group optionally substituted by one or more halogen atom(s) or by a nitro group; or with an ester of the formula bromine atom: and n is 0 or 1,
preferably in the presence of a solvent and an acid-binding agent, and if desired separating the thus obtained mixture of the isomers of the formulae (I) and (II) from one-another by using one of the chromatographic methods or by crystallization, utilizing the differences in the solubility of the isomers, and if desired converting the isomers of the formulae (I) and (II) or the mixture thereof into their salts, and if desired liberating them from their salts and converting them to another salt thereof in a known way.
In the preparation process according to the invention compounds of the formula (III) are treated with agents suitabl
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Colton Gastroenterology, vol. 88, No. 5, Part 2, BMY-26517-31, A Mast Cell Stabilizer With Cytoprotective Properties (1985).
Balogh Maria
Gyires Klara
Hermecz Istvan
Horvath Agnes
Kapui Zoltan
Berch Mark L.
Chinoin Gyogyszer-es Vegyeszeti Termekek Gyara Rt.
Dubno Herbert
Myers Jonathan
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