Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1990-04-21
1991-02-19
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514252, 514253, 540283, 544230, 544295, 544296, C07D40114, C07D40314, C07D40514, A61K 31505
Patent
active
049944550
DESCRIPTION:
BRIEF SUMMARY
This application is entitled to the benefit of priority of PCT U.S. Pat. No. 87/02855, filed Oct. 26, 1987, as this application was filed under 35 USC 371 within 30 months, and a proper demand for International Preliminary Examination was made by the 19th month from that priority date.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to certain 1-acyl-3-[4-(2-pyrimidinyl)-1-piperazinyl]propanes useful as antianxiety agents. More specifically it relates to such compounds wherein the acyl substituent is a heterocyclyl carbonyl or a heterocyclyl sulfonyl group.
2. Prior Art
U.S. Pat. No. 3,717,634 describes a series of N-(heteroarcyclic) piperazinylalkyl-azaspiroalkanediones of the formula ##STR1## wherein A is C.sub.2-6 alkylene; B is, inter alia, 2-pyrimidinyl; and n is 4 or 5. The compounds have tranquilizing and anti-emetic properties.
SUMMARY OF THE INVENTION
It has now been found that certain 1-acyl-3-[4(2-pyrimidinyl)-1-piperazinyl]propanes of formulae I and II are useful anti-anxiety agents. In the compounds of this invention the acyl substituents comprise certain heterocyclylcarbonyl groups (formula I), or certain heterocyclylsulfonyl groups (formula II). The general structure of formula (I) compounds is: ##STR2## wherein R is ##STR3## The general structure of formula (II) compounds is: ##STR4## wherein R.sup.1 is ##STR5##
Also included in this invention are pharmaceutically acceptable acid addition salts of compounds of formulae (I) and (II), pharmaceutically acceptable compositions comprising compounds of formula (I) or (II), or a salt of said compounds, and a pharmaceutically acceptable carrier, and the use of compounds of formulae (I) and (II) and/or their said salts for the treatment of anxiety in a mammal, especially a human, suffering therefrom.
The term pharmaceutically acceptable acid addition salts of the compounds of this invention of formulae (I) and (II) are the hydrochloride, hydrobromide, hydroiodide, sulfate, sulfamate, p-toluenesulfonate, acetate, lactate, citrate, tartrate, ascorbate, methanesulfonate salts and salts with other organic acids known to those skilled in the art and which find use in the preparation of pharmaceutically acceptable acid addition salts. Said salts are prepared by known procedures as, for example, by reacting the appropriate compound of formula (I) or (II) with one, or substantially one, equivalent of the desired acid in a reaction-inert solvent (ethanol, water, halogenated hydrocarbons) and recovering the salt by filtration or by evaporation of the solvent.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention having formula (I) are readily prepared by dehydrative coupling of 4-[4(2-pyrimidinyl)-1-pipirazinyl] butyric acid with the appropriate amine RH in a reaction-inert solvent; i.e., one which does not react with the reactants or products. Suitable dehydrating coupling agents are known to those skilled in the art and include carbodiimides such as dicyclohexylcarbodiimide and di-p-dimethylaminophenylcarbodiimide, N,N'-carbonyldiimidazole, n-ethyl-5-phenylisoxazolene-3'-sulfonate and diethylcyanophosphate. 1-hydroxybenzotriazole is generally added to the reaction mixture to facilitate coupling reaction. Representative reaction-inert solvents include methylene chloride, chloroform, tetrahydrofuran, dioxane and bis(2-methoxyethyl)ether.
While the stoichiometry of the coupling reaction requires equimolar amounts of the individual reactants, in practice the amine, acid, coupling agent and 1-hydroxybenzotriazole are generally used in a molar ratio of 1:1:1.1:1.5. Variations in the proportions of reactants used in order to optimize preparation of a given compound of formula (I) are, of course, within the skill of the art. The reaction is carried out at from about 0.degree. C. to ambient temperature. The products are recovered by well known procedures.
The acid component, 4-[4-(2-pyrimidinyl)-1piperazinyl]butyric acid is usually available as its dihydrochloride salt and is therefore, used as such in the coupli
REFERENCES:
patent: 4605655 (1986-08-01), Yevick et al.
patent: 4666911 (1987-05-01), Fujimura et al.
patent: 4668687 (1987-05-01), Yevich et al.
De Benedictis Karen
Ford John M.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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