Claims
- 1. A method of treating anxiety and depression which comprises administering to a patient suffering from anxiety or depression an effective dosage of a piperazine having the formula (I) ##STR13## wherein R.sup.1 is 1-adamantyl, 3-methyl-1-adamantyl, 3-noradamantyl, unsubstituted or substituted-2-indolyl, 3-indolyl, 2-benzofuranyl or 3-benzofuranyl wherein the substituents are selected from lower alkyl, lower alkoxy and halo; R.sup.2 is unsubstituted or substituted phenyl, benzyl, or pyrimidinyl wherein the substituents are selected from lower alkyl, lower alkoxy, trifluoromethyl and halo; R.sup.3 is H or lower alkyl of 1 to 3 carbon atoms; n is the integer 0 or 1; and m is the integer from 2 to 5 and the pharmaceutically acceptable salts thereof.
- 2. A method of treating psychoses and anxiety which comprises administering to a patient suffering from psychoses or anxiety an effective dosage of a piperazine having the formula (I) as defined in claim 1.
- 3. A method of treating anxiety and depression which comprises administering to a patient suffering from anxiety or depression an effective dosage of a piperazine having the formula (I) as defined in claim 1 wherein R.sup.1 is 1-adamantyl, 3-noradamantyl-3-methyl-1-adamantyl, 2-indolyl, 2-benzofuranyl; R.sup.2 is 2-pyrimidinyl or unsubstituted or unsubstituted phenyl, wherein the substituents are selected from methoxy and chloro; R.sup.3 is H; n is the integer 0 or 1; m is the integer 2 or 3 or a pharmaceutically acceptable salt thereof.
- 4. A method of treating psychoses and anxiety which comprises administering to a patient suffering from psychoses or anxiety an effective dosage of a piperazine having the formula (I) as defined in claim 3.
- 5. A method of treating anxiety and depression according to claim 3 which comprises administering to a patient suffering from anxiety or depression an effective dosage of the compound N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]tricyclo[3.3.1.1.sup.3,7 ]-decane-1-carboxamide or a pharmaceutically acceptable salt thereof.
- 6. A method of treating psychoses and anxiety according to claim 4 which comprises administering to a patient suffering from psychoses or anxiety an effective dosage of the compound N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]tricyclo[3.3.1.1.sup.3,7 ]-decane-1-carboxamide or a pharmaceutically acceptable salt thereof.
- 7. A method of treating anxiety and depression according to claim 3 which comprises administering to a patient suffering from anxiety or depression an effective dosage of the compound N-[2-[4-(2-pyrimidinyl)-u-piperazinyl]ethyl]tricyclo[3.3.1.1.sup.3,7 ]decane-1-carboxamide or a pharmaceutically acceptable salt thereof.
- 8. A method of treating psychoses and anxiety according to claim 4 which comprises administering to a patient suffering from psychoses or anxiety an effective dosage of the compound N-[2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl]tricyclo[3.3.1.1.sup.3,7 ]decane-1-carboxamide or a pharmaceutically acceptable salt thereof.
DESCRIPTION OF INVENTION
This is a continuation-in-part application of copending U.S. Ser. No. 07/493,179, filed Mar. 14, 1990, now U.S. Pat. No. 5,010,078, which is in turn a continuation-in-part application of copending U.S. Ser. No. 297,460, filed Jan. 13, 1989, now abandoned, which is in turn a continuation-in-part application of copending U.S. Ser. No. 197,890, filed May 24, 1988, now abandoned.
The recent introduction of buspirone having a selectivity for 5-HT.sub.1A receptors, as an effective anxiolytic agent U.S. Pat. No. 3,717,634), into the U.S. marketplace has stimulated interest in development of second-generation anxiolytic agents.
Furthermore, in clinical trials, gepirone U.S. Pat. No. 4,423,049) and ipsapirone (European Patent 129,128A) were found to be potent anxiolytic drugs. Since both drugs--gepirone and ipsapirone--possess a higher degree of selectivity for 5-HT.sub.1A receptors than buspirone, the clinical data support the notion that anxiety mechanisms can directly be modulated by 5-HT.sub.1A receptor drug interactions.
In addition to treatment of anxiety, 5-HT.sub.1A agonists such as gepirone are now being examined for their mixed activity as anxiolytic antidepressant agents. The therapeutic potential of 5-HT.sub.1A agonists in the treatment of multi-CNS disorders was recently extended to the development of antipsychotic anxiolytic agents represented by MDL-72832 U.S. Pat. No. 4,612,312) and KS-9172 (Br. J. Pharmocol., 90, 273P, 1987), the latter being under development as an antipsychotic agent (Scrip No. 1265, Dec. 11, 1987). This class of compounds demonstrated high affinity for both the 5-HT.sub.1A and D.sub.2 receptor binding sites.
Compounds with 5-HT.sub.1A activity are useful for the treatment of obesity, drug abuse/addition, alcohol abuse, sleep disorders and behavioral and cognitive symptoms of Alzheimer's disease.
U.S. Pat. No. 4,202,898 describes arylpiperazines useful for the treatment of anxiety and depression. U.S. Pat. No. 4,001,223 describes the synthesis of adamantane derivatives useful as cerebral vasodilators. Abou-Gharbia et al, U.S. Pat. No. 4,797,489, describes the synthesis of adamantyl and fluorenylarylpiperazines with potential CNS activity.
U.S. Pat. No. 4,202,898 discloses synthesis of arylpiperazines of the general formula ##STR2## wherein R.sup.6 is H, CO (lower alkyl), CO (monocyclic aryl), CONH (lower alkyl), CON (lower alkyl) or CONH (monocyclic aryl); R.sup.7 is H, alkyl, alkoxy, CN, halo or trifluoromethyl useful for the treatment of anxiety and depression.
U.S. Pat. No. 4,895,848 (1990) discloses the use of 2-pyrimidinyl-1-piperazine derivatives such as ipsapirone and gepirone for the treatment of alcoholism.
Bristol-Myers European Patent 0,356,997 discloses the use of azapirone compounds for the treatment of substance addiction such as food, designer drugs and recreational drugs.
The present invention relates to the use of a group of aryl- and heteroaryl piperazinyl carboxamides for the treatment of substance abuse/addiction, obesity, behavioral symptoms for Alzheimer's disease and sleep disorder characterized by the general formula ##STR3## wherein R.sup.1 is 1-adamantyl, 3-methyl-1-adamantyl, 3-noradamantyl, unsubstituted or substituted-2-indolyl, 3-indolyl, 2-benzofuranyl or 3-benzofuranyl wherein the substituents are selected from lower alkyl, lower alkoxy and halo; R.sup.2 is unsubstituted or substituted phenyl, benzyl, or pyrimidinyl wherein the substituents are selected from lower alkyl, lower alkoxy, trifluoromethyl and halo; R.sup.3 is H or lower alkyl of 1 to 3 carbon atoms; n is the integer 0 or 1; and m is the integer from 2 to 5 and the pharmaceutically acceptable salts thereof.
The most preferred compounds for use in the present invention are designated:
The term "lower alkyl" refers to moieties having 1 to 6 carbon atoms in the carbon chain. The term "alkoxy" refers to moieties having 1 to 6 carbon atoms. The term "halo" refers to fluoro, chloro and bromo.
The compounds of formula (I) can form pharmacologically acceptable salts from pharmacologically acceptable organic and inorganic acids such as hydrochloric, hydrobromic, sulfonic, sulfuric, phosphoric, nitric, maleic, fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic, acetic, propionic, tartaric, citric, lactic, malic, mandelic, cinnamic, palmitic, itaconic and benzenesulfonic.
The compounds of formula (I) which demonstrated selectivity at the 5-HT.sub.1A and 5-HT.sub.2 versus D.sub.2 receptor binding sites are useful as potential anxiolytic-antidepressant agents.
In addition, compounds of formula (I) with equal h igh affinity for the 5-HT.sub.1A and D.sub.2 -receptor binding sites are useful as mixed antipsychotic-anxiolytic agents.
Compounds of formula (I) which demonstrated central cholinergic activity are useful in the treatment of senile dementia of the Alzheimer type (SDAT) and Huntingdon's chorea.
Compounds of formula (I) can be prepared by a variety of synthetic routes by building the molecule up from smaller constituent molecules.
Compounds of formula (I) demonstrated activity at the serotonin-1A receptor subtype. Such serotonergic activity is involved in the control of food intake, compulsory behavior and sleep. Compounds of formula (I) demonstrated antiaggression activity in an animal model. Such activity is useful in controlling aggressive sympton behavior of Alzheimer's patients.
According this invention also provides a process for preparing a compound of formula (I) as defined above which comprises one of the following:
(a) acylating a compound of formula ##STR4## with an acylating agent containing the group R.sup.5 wherein R.sup.5 is:
(b) a cyclic amine having the formula (IV) ##STR5## wherein R.sup.2 is as defined above or a salt thereof is alkylated to introduce the substituted alkyl group having the formula (V) ##STR6## by reaction with a compound having the formula R.sup.4 -Y (where R.sup.4 is the group having formula (V) and Y is a leaving group, for example halo such as chloro or bromo or aryl- or alkyl-sulphonyloxy); or
(c) a cyclic amine having the formula (IV) as defined above or a salt thereof is subjected to reductive alkylation with an aldehyde having the formula (VI) ##STR7## wherein n, R.sup.1, R.sup.3 and m are as defined above; or
(d) a compound having formula (I) is converted into an acid addition salt thereof by addition of an acid or an acid addition salt of a compound having formula (I) is subjected to neutralisation to form the compound having formula (I).
With reference to process step (a) above, acylation is conveniently carried out under basic conditions using methods generally known for preparing secondary or tertiary amides. Examples of acylating agents are reactive derivatives of acids of formula R.sup.5 OH such as acid halides, e.g. the chloride, azide, anhydride, mixed anhydride (e.g. formed with carbonyldiimidazole) or activated ester (e.g. 1-benzotriazolyl, 2,3,4-trichlorophenyl or p-nitrophenyl) or O-acyl ureas obtained from carbodiimides such as dialkylcarbodiimides, e.g. dicyclohexylcarbodiimide. Descriptions of methods for forming amides are given in the literature--see for example "The Chemistry of Amides" Interscience Publisher, 1970, chapter beginning at p 73 from the series "The Chemistry of Functional Groups" edited by Saul Patai, books on peptide chemistry--e.g., The Practice of Peptide Synthesis, by M. Bodanszky and A. Bodanszky, Springer Verlag, 1984, and volume 21 of the series Reactivity and Structure Concepts in Organic Chemistry.
Process step (b) may be carried out in the conventional manner for the preparation of tertiary amines by alkylation of secondary amines. In particular the reaction may be carried out in a suitable solvent, e.g. dimethylformamide in the presence of an inorganic base or a tertiary amine, e.g. triethylamine.
Process step (c) may be carried out in the conventional manner for the preparation of tertiary amines from secondary amines and aldehydes by reductive alkylation. The reductive alkylation may be carried out with hydrogen and platinum catalyst or using sodium cyanoborohydride.
Starting materials for the processes described above are in general known compounds or can be prepared by methods known for analogous compounds where necessary by building up the molecule from readily available starting materials.
Piperazines of formula (IV) can be prepared by known methods, e.g. reaction of bis-(2-chloroethyl)amine with an amine or aniline of formula H.sub.2 NR.sup.2.
Compounds of formula R.sup.4 -Y wherein R.sup.4 is ##STR8## can be prepared by (a) acylating an hydroxy amine of formula
In a preferred process 1-adamantane carboxylic acid halide, noradamantane carboxylic acid halide, indolecarboxylic acid halide or benzofurancarboxylic acid halide of formula (II) may be conveniently reacted with the appropriately substituted aminoalkyl piperazine of formula (III) ##STR10## in CH.sub.2 Cl.sub.2 and the presence of a suitable base, such as triethylamine, to obtain the desired final product (I). ##STR11## wherein X is a halide and R.sup.1, R.sup.2, and R.sup.3, m, and n are as defined above. For the particular case when R.sup.2 is benzyl, hydrogenation of (I) followed by treatment of the product R.sup.2 is H with 2-chloropyrimidine permits an alternative synthesis of (I) where R.sup.2 is 2-pyrimidinyl.
Of course, other methods of preparation, which will occur to those skilled in the art, may also be employed to prepare the compounds of formula (I).
The starting material used in the above-described preparative routes are commercially available, or can be made according to procedures taught in the chemical literature.
The compounds of formula (I) may exist either in the form of the free base or the pharmacologically acceptable salts. Methods for converting one such form to another will be obvious to one skilled in the chemical arts.
The compounds of formula (I) display a preclinical pharmacological profile like that of the compound gepirone (4,4-dimethyl-1-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,6-piperidinedione) and ritanserin 6-[2-[4-[bis(4-fluorophenyl)methylene]-1-piperidinyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one. Gepirone and ritanserin have demonstrated clinical activity in axiolytic and antidepressant paradigms and have also displayed a unique clinical anxio-selective profile, whereby their efficacy in the treatment of anxiety neuroses is comparable to the benzodiazepine diazepam. The compounds of formula (I), in a manner similar to ritanserin and gepirone, may also display preclinical anxiolytic and antidepressant activites with expected minimal side effects. The compounds of the invention also demonstrate a pharmacological profile similar to the nonbenzodiazepine anxiolytic buspirone, which also supports their use in anxiety neurosis. Moreover, based on the central cholinergic activity, some of the compounds of formula (I) are useful in the treatment of central cholinergic dysfunction attending senile dementia of the Alzheimer type (SDAT).
When employed as anxiolytic/antidepressant, the effective dosage of the active substances for such treatment will vary according to the particular compound being employed, and the severity and nature of the condition being treated. Therapy should be initiated at lower doses, the dosage thereafter being increased, if necessary, to produce the desired effect. In general, the compounds of the invention are most desirably administered at a concentration that will generally afford effective results without causing any harmful or deleterious side effects. Compounds of formula (I) could be administered in amounts of 10-80 mg/day, b.i.d. or t.i.d.
When the compounds of formula (I) are employed as anxiolytic/antidepressant or anxiolytic/antipsychotic agents, they can be formulated into oral dosage forms such as tables, capsules and the like. The compounds can be administered alone or by combining them with conventional carriers, such as magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. Diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, tablet-disintegrating agents and the like may be employed. The compounds may be encapsulated with or without other carriers. In all cases, the proportion of active ingredients in said compositions both solid and liquid will be sufficient at least to impart the desired activity thereto on oral administration. The compounds may also be injected parenterally in which case they are used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic. Accordingly this invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The antidepressant activity of the compounds of the invention and their expected lack of extrapyramidal side effects may be demonstrated by standard pharmacological procedures, which are described more fully in the examples given hereafter.
The following examples show the preparation and pharmacological testing of compounds of formula (I).
US Referenced Citations (4)
Foreign Referenced Citations (1)
| Number |
Date |
Country |
| 0356997 |
Jul 1990 |
EPX |
Continuation in Parts (3)
|
Number |
Date |
Country |
| Parent |
493179 |
Mar 1990 |
|
| Parent |
297460 |
Jan 1989 |
|
| Parent |
197890 |
May 1988 |
|
Patent Grant
5106849
