Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-01-31
1996-11-12
Datlow, Philip I.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514218, 5142358, 514252, 514255, 540575, 540598, 544121, 544359, 544360, 544364, 544372, 544390, A61K 31495, A61K 3155, C07D295195, C07D24308
Patent
active
055740316
DESCRIPTION:
BRIEF SUMMARY
This application is the 35 USC 371 National Style of international application PCT/SE93100639 filed on Jul. 22, 1993 and published as WO94/03436 on Feb. 17, 1994.
BACKGROUND
There is an urgent need for efficient drugs in the treatment of mental disorders which are more effective and which have fewer side effects than the drugs in clinical use today. Antipsychotic drugs in current use produce a range of troublesome extrapyramidal movement disorders (e.g. acute dystonic reactions and tardive dyskinesia) and are poor in ameliorating the negative symptoms (e.g. restricted or blunted emotional arousal) of schizophrenia. The main disadvantage of the antidepressants is that they fail to alleviate depression in 30 to 40% of patients. Anxiolytics are commonly associated with addictive properties.
PRIOR ART
Various piperazine derivates pharmacologically active in the central nervous system are known in the art. Some representative examples can be mentioned. The U.S. Pat. No. 4,308,387 discloses amperozide which has shown useful antipsychotic properties in clinical investigations. Amperozide has a limbic profile of action. ##STR2##
DESCRIPTION OF THE INVENTION
According to the invention there are provided novel compounds having the general formula (I). ##STR3## wherein Ar are the same or different and selected from ##STR4## wherein R.sub.3 is halogen or hydrogen. R.sub.1 and R.sub.2 are the same or different and selected from hydrogen or alkyl;
When X is nitrogen Y is methylene.
When X is methine Y is selected from nitrogen or oxygen; A is selected from the following carboxylic derivatives: ##STR5## wherein R.sub.4 and R.sub.5 are the same or different and selected from hydrogen, alkyl, cycloalkyl or aryl. Z is selected from sulfur or oxygen. R.sub.6 is selected from ##STR6## wherein m is 1, 2, 3 or 4.
R.sub.7 is selected from hydrogen or lower alkyl. And the pharmacologically active salts thereof. Used in the foregoing definitions the term lower alkyl is meant to include straight and branched, saturated and unsaturated hydrocarbon groups having from 1 to 5 carbon atoms; the term cycloalkyl is meant to include cyclic, saturated and unsaturated hydrocarbon groups have from 3 to 8 carbon atoms. the term lower alkoxy is meant to include straight or branched, saturated or unsaturated alkoxy groups having from 1 to 5 carbon atoms: the term halogen is meant to include fluoro, and bromo.
The compounds of formula (I) have basic properties and, consequently, they may be converted to their therapeutically active acid addition salts by treatment with appropriate acids; e.g. inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid, or organic acids such as acetic, propanoic, glycolic, lactic, malonic, oxalic, succinic, fumaric, tartaric, citric and pamoic acid.
Conversely, the salt form can be convened into the flee base form by treatment with alkali.
The compounds of formula (I) and their pharmaceutically acceptable salts have valuable pharmacological properties. making them useful for the treatment of mental disorders such as psychoses, depression, anxiety and drug abuse. Stress and anxiety in animals can also be treated.
The compounds of the present invention show psychotropic properties. They have found to be selective 5-HT.sub.2 antagonists.
METHODS OF PREPARATION
The compounds having the general formula (I) may be prepared by conventional methods. ##STR7##
A compound of formula (II), wherein Ar, X and Y are as previously defined and L is a suitable leaving group such as halogen and alkyl- or arylsulfonate is reacted with a compound of formula (III) wherein R.sub.1, R2, A and n are as defined previously. The reactions may be carried out using standard N-alkylating procedures. ##STR8##
A compound of formula IV, wherein Ar, R.sub.1, R.sub.2, X, Y, Z and n are as previously defined is reacted with a compound of formula V, VI, wherein R.sub.4, R.sub.5, R.sub.6 and Z are as previously defined and L is a suitable leaving group.
A compound of formula IV is reacted with a compound of formu
REFERENCES:
patent: 4082755 (1978-04-01), van Wijngaarden
patent: 4308387 (1981-12-01), Bj ork et al.
patent: 4374990 (1983-02-01), Weber et al.
patent: 4766125 (1988-08-01), Van Daele
patent: 4874765 (1989-10-01), Lapis et al.
patent: 5026853 (1991-06-01), Van Daele et al.
Cecil Textbook of Medicine, 19th ed. (1992), Wyngaarden, M. D. editor, pp. 2075-2078.
Abramo Lisbeth
Brodszki Martin
Lundstedt Torbj orn
Nordvi Curt
Olsson Knut G.
Datlow Philip I.
Pharmacia Aktiebolag
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