Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-06-23
2000-10-10
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544295, 540575, 514212, A01N 4358
Patent
active
061302155
DESCRIPTION:
BRIEF SUMMARY
The invention refers to novel piperazinylalkylthiopyrimidine derivatives, pharmaceutical compositions containing the above derivatives, a method for the treatment of diseases of especially the central nervous system, and a process for the preparation of the novel compounds.
Specifically, the invention refers to compounds of the formula ##STR2## wherein R.sup.1 and R.sup.3 represent, independently, a hydrogen, a C.sub.1-4 alkyl group, an amino group, a (C.sub.1-4 alkanoyl) amino group, or a phenyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently, a halo, a C.sub.1-4 alkoxy group, a di(C.sub.1-4 alkyl)amino group or a benzyloxy group, (C.sub.5-7 cycloalkyl)methyl group, a (C.sub.1-4 alkoxy)carbonyl group, a hydroxy(C.sub.1-4 alkyl) group or a benzyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently, a halo, a C.sub.1-4 alkyl group, a C.sub.1-4 alkoxy group, a trifluoro methyl group, a hydroxy group, a benzyloxy group or a di(C.sub.1-4 alkyl)amino group, group, a C.sub.1-4 alkoxy group or a trifluoromethyl group, addition salts thereof.
The novel piperazinylalkylthiopyrimidine derivatives can be employed, in the first place, for the treatment of diseases due to pathological alterations of the central nervous system.
Pyrimidine derivatives connected with a piperazine ring and used for the treatment of urination disorders are described by Japanese Patent Application No. J 3 090 027. Uracil compounds of similar type are known from DE-P No. 1 942 405. One of the known uracil compounds is urapidil, a blood pressure lowering drug. However, in case of the above compounds, the two heterorings are connected through an alkylamino group.
Pyrimidine derivatives bonded to a piperazine ring through an alkoxy group and having sedative and hypotensive activity are described by BE-P Nr. 756 127.
It was found that the novel compounds of the formula I, wherein the heterorings containing nitrogen atoms are connected through an alkylthio group, have excellent biological activity influencing the serotonerg system.
In the description, a C.sub.1-4 alkyl group is a methyl, ethyl, n-propyl, isopropyl, sec.-butyl, tert.-butyl, n-butyl or isobutyl group. Preferably, C.sub.1-4 alkyl is methyl.
A C.sub.1-4 alkanoyl group is a formyl, acetyl, n-propanoyl, n-butanoyl etc. group, preferably an acetyl group.
In general, a halo is a fluoro, chloro or bromo, preferably chloro or bromo.
A C.sub.1-4 alkoxy group is generally a methoxy, ethoxy, n-propoxy or n-butoxy group, preferably a methoxy group.
The pharmaceutically acceptable acid addition salts of the compounds of the formula I are acid addition salts of the compounds formed with pharmaceutically acceptable, inorganic or organic acids. Preferred acid addition salts are hydrogen haloids such as hydrochlorides or hydrobromides, carbonates, hydrogen carbonates, sulfates, phosphates, acetates, fumarates, maleates, citrates and ascorbates.
A preferred sub-group of the compounds of the invention consists of the compounds of the formula I, wherein an amino group, an acetylatnino group or a phenyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently, a chloro group, a methoxy group, a dimethylamino group or a benzyloxy group, cyclohexylmethyl group, an ethoxycarbonyl group, a hydroxyethyl group or a benzyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently, a chloro, a fluoro, a C.sub.1-3 alkyl group, a methoxy group, a trifluoromethyl croup, a hydroxy group, a benzyloxy group or a dimethylamino group, methyl group, a methoxy group or a trifluoro methyl group, addition salts thereof.
A specifically preferred sub-group of the compounds of the invention consists of the compounds of the formula I, wherein R.sup.1 and R.sup.3 represent an amino group, substituents selected from the group consisting of, independently, a fluoro, a chloro, a methoxy group and a dimethylamino group, group, a methoxy group or a trifluorom
REFERENCES:
Sleight et al., "The Clinical Utility of Serotonin Receptor Active Agents in Neuropsychiatric Disease," Serotonin Receptor Subtypes: Basic and Clinical Aspects, pp. 211-227 (1991) Wiley-Liss, Inc.
Database CAPLUS on STN, Chemical Abstract, vol. 129, No. 310332, Balogh et al., "A new validated high-performance liquid chromatographic method for the determination of EGIS-9933 in rat plasma," abstract, Chromatographia, vol. 48, No. 1/2, pp. 158-162, 1998.
Bilkei-Gorzo Andras
Blasko Gabor
Bozsing Daniel
Egyed Andras
Gacsalyi Istvan
Egis Gyoyszergyar RT
Kessinger Ann M.
Shah Mukund J.
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