CS258133B2 - Process for the preparation of 1-heteroaryl-4 - [(2,5-pyrrolidinedione-1-yl) alkyl] piperazine derivatives - Google Patents

Abstract

A process for the preparation of compounds of general formula I, wherein R1 is C1-4-alkyl, trifluoromethyl or optionally halogen-substituted phenyl, R2 is C1-4-alkyl or optionally halogen-substituted phenyl and R3 represents two hydrogens, or R1 and R2 together form a C4-5-alkylene bridge comprising an unfused phenyl ring, optionally halogen-substituted, or R1 and R3 together form a fused cyclohexenyl ring or phenyl ring, optionally up to tetrasubstituted with halogen and/or a nitro group, B is a benzoisothiazole, pyridine or pyrimidine residue, optionally disubstituted with C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, cyano or/and halogen and n is an integer of 2 to 4, and their acid addition salts, consisting in the reaction of compounds of formulae VI and VII, where Q is a leaving group, and optionally converting the product into a pharmaceutically acceptable salt. The compounds produced exhibit psychotropic effects and are of particular interest as anxiolytic and/or antipsychotic agents.

Description

The invention generally relates to heterocyclic carbon compounds having medicinal properties and influencing biological functions, their preparation and use. In particular, the invention describes 1,4-disubstituted piperazine derivatives in which one substituent is a substituted 2,5-pyrrolidinedione ring system linked via a nitrogen atom through an alkylene chain and the second substituent is a heterocyclic radical selected from the group consisting of pyridine, pyrimidine and benzisothiazole radicals.

Similar compounds known from the prior art can be described by the general formula, nor is there any mention of compounds according to the present invention, whose structural formula contains substituted 2,5-pyrrolidinedione residues.

The invention describes a new group of compounds acting on the central nervous system, which correspond to the general formula I i N CHp/n'

N(I)

N~ a-tk γίe-n •Λ

O

-N

These substances are essentially glutarimide derivatives in which R ¹ and R ² are alkyl groups or are joined together to form an alkylene bridge of 4 or 5 carbon atoms and B represents an aromatic or heteroaromatic system carrying optional substituents. These and related compounds have been prepared as psychotropic agents and are described in the following works.

Compounds of the above structure, where B represents a substituted or unsubstituted phenyl, pyridyl or pyrimidinyl residue, are described in the following publications:

Wu, U.S. Patent No. 3,398,151, issued August 20, 1968,

Wu, U.S. Patent No. 3,558,777, issued January 26, 1971,

Wu et al., J. Med. Chem., 12, 876-888 (1969); 15, 447-479 (1972),

Wu et al., U.S. Patent No.

717,634, granted February 20, 1973,

Wu et al., U.S. Patent No.

796,776, granted August 24, 1976,

Temple et al., U.S. Patent No.

361,565, issued November 30, 1982, Temple, co-pending application number

334,688, filed December 28, 1981.

Attention is also drawn to copending application Ser. No. 333,830, filed Dec. 23, 1981 (Temple), which lists benzisothiazole as the symbol B. This application also describes certain compounds in which the second substituent on the piperazine moiety may be 2,4-thiazolidinedione groups or spiro-substituted 2,4-thiazolidinedione groups attached to the piperazine ring through its nitrogen atom via an alkylene chain.

None of the above works describe their pharmaceutically acceptable acid addition salts.

In this general formula

R ¹ represents an alkyl group with 1 to 4 carbon atoms, a trifluoromethyl group or a phenyl group, optionally substituted by halogen, or R ¹ together with R ² forms an alkylene bridge with 4 to 5 carbon atoms carrying a fused phenyl ring, which is optionally substituted by halogen, or R ¹ together with R ³ forms a fused cyclohexenyl ring or a phenyl ring tetrasubstituted by radicals X ¹ to X ⁴ , which are independently selected from the group comprising hydrogen atom, halogen atoms and nitro group,

R ² represents an alkyl group with 1 to 4 carbon atoms, a phenyl group optionally substituted by halogen, or the residue R ² is absent in the case where R ¹ and R ³ form a fused phenyl ring system, or R ² together with R ¹ form an alkylene bridge as defined above,

R ³ represents two hydrogen atoms or together with R ¹ forms a fused phenyl ring as defined above,

B represents the radical R ⁴ or R ⁵ -disubstituted heterocyclic ring system selected from the group consisting of benzisothiazole, pyridine and pyrimidine rings, wherein R ⁴ and R ⁵ are independently selected from the group consisting of alkyl groups with 1 to 4 carbon atoms, alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, cyano group, halogen atoms and hydrogen atom, and n is a number with a value of 2 to 4.

Selected compounds of the invention, representing examples of the above-mentioned compounds of general formula I, have useful psychotropic properties, including reversal of drug-induced catalepsy and tranquilizing activity characterized by antianxiety and/or antipsychotic effects.

The compounds of the invention, corresponding to the above-mentioned general formula I and defined above, can be divided into three structural subgroups (1, 2, 3), differing in the substitution of the 2,5-pyridin-1-yl residue:

β

(3 /

In these structural formulas, R ¹ and R ² are independently selected from the group consisting of alkyl groups with 1 to 6 carbon atoms, trifluoromethyl group and phenyl group optionally substituted by halogen, X ¹ to X ^J have the above-mentioned meaning and Z represents a hydrogen or halogen atom. The preferred group consists of the residues of the above-mentioned structure (2), which can be described in more detail by the structures (a), (b) and (c) below. In this case, these are substances of the general formula I, in which B represents a 2-pyrimidinyl residue.

The term "halogen" as used herein means fluorine, iodine, and preferably chlorine or bromine, and alkyl groups of 1 to 4 carbon atoms may be straight or branched chain.

Pharmaceutically acceptable acid addition salts of the compounds of the invention are those salts in which the anion does not contribute significantly to the toxicity or pharmacological activity of the salt, so that from a pharmacological point of view these salts are equivalent to the salts of formula I. The salts described are generally preferred for use in medicine. In some cases these salts have properties which make them more suitable for the preparation of dosage forms, such as improved solubility, non-hygroscopicity, compressibility in the preparation of tablets and compatibility with other ingredients with which the compounds of the invention can be used for pharmaceutical purposes. These salts are commonly prepared by mixing a basic compound of general formula I with a selected acid, which is preferably carried out in solution, using an excess of commonly used inert solvents, such as water, ether, benzene, alcohols, for example ethanol, ethyl acetate, acetonitrile, etc. Salts can also be prepared by double decomposition or by the action of ion exchangers under conditions in which the anion of one salt of the compound of general formula I is replaced by another anion and at the same time the separation of the desired product is enabled, such as by its precipitation from solution or extraction with a solvent, or by elution from an ion exchange column, or by retention on an ion exchange column. Pharmaceutically acceptable acids suitable for the preparation of salts of compounds of general formula I include sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, citric acid, acetic acid, benzoic acid, cinnamic acid, etc. This reaction proceeds according to the following reaction scheme:

mandelic acid, nitric acid, mucic acid, isethionic acid, palmitic acid, heptanoic acid, etc.

In accordance with the invention, compounds of general formula I are prepared by the reaction of N-substituted

(VIDEO

In this reaction scheme, n, R ¹ , R ² and R ³ are as defined above and Q represents a suitable leaving group such as chloride, bromide, iodide, sulfate, phosphate, tosylate, mesylate and the like.

The above reaction can be carried out under reaction conditions suitable for the preparation of tertiary amines by alkylation of secondary amines. The reactants are heated in a suitable organic liquid to a temperature of about 60 ^° C to 150°C in the presence of an acid-binding agent. Examples of suitable organic liquid reaction media include benzene, dimethylformamide, ethanol, acetonitrile, toluene and n-butyl alcohol. The preferred acid-binding agent is potassium carbonate, but other inorganic and tertiary organic bases can also be used, including carbonates of other alkali metals and alkaline earth metals, bicarbonates and hydrides of alkali metals and alkaline earth metals, and tertiary amines.

The preparation of starting materials of general formula VI can be described by the following reaction scheme 1:

Scheme 1

R' (7)

RO.C CN 'C ^x >

II

R ⁽

V®'· ¢2. (6)

R R (5) .

,CN _FROM CN

2. >

< ly. .

· ^Λ ·*'.>£ · ^7.\,C ^H Z°./ H>

NH

R ¹ io

(pounds) (1), (2)

illal.

HN~ NH > -4 ^R -<°

N~(CH^ _n -0r

Ό (//<;>) ·<

from>

--w n-ích^V 7ih (Knows)

In reaction scheme 1, the symbols R ¹ and R ² have the meanings given above. The procedure according to scheme 1 basically consists of the Knoevenagel condensation of a ketone or aldehyde with ethyl cyanoacetate to form a series of α,,3-unsaturated cyanoacetates (6). The reaction of compound (6) with about 1.5 to 2 equivalents of potassium cyanide gives an intermediate dicyanide derivative (5), which undergoes acid-catalyzed hydrolysis to form an intermediate dicarboxylic acid (4). This compound is then subjected to a standard method of cyclization of dicarboxylates to cyclic imides — aminolysis followed by dehydration. In this way, types (1), (2) of intermediates of general formula II can be obtained. The general synthetic procedure described above, as far as individual reactions are concerned, is described in more detail in the following works:

1. New A Yevich, Synthesis, 1983, No. 5, 388-389,

2. Crooks and Sommerville, J. Pharm. Sci., 71, 291 (1982),

3. Org. Son. Collective Vol. 3, 615 to 616,

4. Chemical Abstracts, 82 170 573x (1975). Intermediate phthalimides and tetrahydrophthalimides are generally commercially available. Methods for the preparation of these compounds are also described in the chemical literature.

The compounds of the present invention are pharmacological agents with psychotropic properties. The substances in question exhibit tranquilizing activity in non-toxic doses and are of particular interest as anxiolytic and/or antipsychotic agents. The compounds of the present invention also reverse catalepsy. Selected in vivo and in vitro animal tests confirm that the preferred compounds of the general formula I, in which B represents a 2-pyrimidinyl residue, exhibit anxiolytic activity and/or antipsychotic activity. The following in vivo tests are used as a basis for determining the tranquilizing properties and possible side effects of the compounds of the present invention.

Behavioral tests: suppression of avoidance response to unpleasant stimuli (Conditioned Avoidance Response — CAR), catalepsy, protection against the lethal effect of norepinephrine

Literature

Albert, Pharmacologist, 4, 152 (1962); Wu et al., J. Med. Chem., 12, 876-881 (1969)

Costall et al., Psychopharmacologia, 34, 233-241 (1974); Birkson, J. Amer. Statist. Assoc., 48, 565-599 (1953)

Loew et al., J. Pharmacol. Exp. Ther., 93, 434-445 (1948).

To further demonstrate the psychotropic activity and specificity of the compounds of the invention, in vitro methods of determining binding to central nervous system receptors, known from the prior art, can be used. Certain compounds (generally called ligands) have been identified that preferentially bind to specific high-affinity sites found in brain tissue that are associated with psychotropic activity or may be associated with side effects. Inhibition of the binding of a radiolabeled ligand to these specific high-affinity sites is considered a measure of the ability of the compound to affect relevant central nervous system functions or to cause side effects in vivo. This principle is used in the following in vitro test, which is given as an example.

Dopamine receptor binding assay

Literature

Burt and spol., Molec. Pharmacol., 12, 800 (1976); Science, 198, 326 (1977); Creese et al., Science, 192, 481 (1976).

According to the pharmacological properties found in the above-described tests, representative compounds of formula I are potential tranquilizers showing either anxiolytic and/or antipsychotic activity, since they are relatively active in the CAR test, where their ED50 values when administered orally are below 100 mg/kg body weight. Many of these compounds are also quite inactive with regard to dopamine binding, since their IC50 values in the ³ H sptperone-dopamine receptor binding test are higher than 1000 nmol. The activity in the CAR test, together with only weak activity in the above-described binding test, is considered to be an indication of possible selective anxiolytic activity in human medicine. With regard to the possible susceptibility to side effects, certain compounds of formula I, in which ^R3 represents two hydrogen atoms, show activity in the trifluoperazine-induced catalepsy reversal test, where their ED50 values when administered orally are below 20 mg/kg. The efficacy in this test indicates that these compounds lack the ability to induce undesirable side effects associated with extrapyramidal symptomatology. Another test that can be used to assess possible side effects is to determine the protective effect against the lethal effect of norepinephrine. This procedure is essentially concerned with the blockade of α-receptors and the undesirable effects associated with it, such as sedation and a decrease in blood pressure. For most of the compounds of the invention, very little activity was found in this test, since the ED50 values of these substances were higher than 100 mg/kg.

Examples of two preferred compounds whose pharmacological properties suggest potential selective anxiolytic activity are 1'-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]spiro (1,2,3,4-tetrahydronaphthalene-2,3'-pyrrolidine-2',5'-dione) (Example 23) and 3,3-diphenyl-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-2,5-pyrrolidinedione (Example 17). Two preferred compounds that are expected to have potential non-dopaminergic antipsychotic activity are 3-(4-fluorophenyl)-3-methyl-1-(4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-2,5-pyrrolidinedione (Example 7) and 1'-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,5-pyrrolidinedione (Example 18). butylspiro (2,3-dihydro-1H-indene-1,3'-pyrrolidin-2',5'-dione) (Example 24).

The invention further provides a method of treating mammals suffering from anxiety or psychosis comprising the systemic administration of a therapeutically effective tranquilizing amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof to said mammal. An effective dose is in the range of about 0.01 to 40 mg/kg body weight, depending upon the desired effect, the route of administration and to some extent the compound selected. A preferred daily dose is about 0.5 to

1.5 mg/kg, with this total dose being administered in several divided doses. Systemic administration refers to oral, rectal and parenteral (i.e. intramuscular, intravenous and subcutaneous) administration. It has generally been found that when a compound of the invention is administered orally, a higher amount of active ingredient is required to achieve the same effect than when administered parenterally. In accordance with normal clinical practice, the compounds of the invention are preferably administered in an amount that produces the desired anxiolytic effect without any harmful or unpleasant side effects.

The compounds of the invention can be administered for anxiolytic purposes either as individual therapeutic agents or as admixtures with other therapeutic agents. These drugs are generally administered in the form of pharmaceutical preparations containing an antidepressant-effective amount of a compound of general formula I or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier. Pharmaceutical compositions containing about 1 to 500 mg of active ingredient per dosage unit are preferred. These preferred compositions are conventionally prepared tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs and aqueous solutions.

The nature of the dosage form used will of course depend on the desired route of administration. For example, oral formulations may be in the form of tablets or capsules and may contain conventional excipients and carriers such as binders (e.g. syrups, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine), lubricants (e.g. magnesium stearate, talc, polyethylene glycol or silicon dioxide), disintegrants (e.g. starch) and wetting agents (e.g. sodium auryl sulfate). For parenteral administration, solutions or suspensions of the compounds of formula I are used together with suitable pharmaceutical excipients and carriers such as aqueous solutions for intravenous injection or oily suspensions for intramuscular injection.

The invention is illustrated by the following examples, which are not intended to limit the scope of the invention in any way. The melting points in these examples are not corrected. The nuclear magnetic resonance (NMR) spectra data refer to chemical shifts (δ values) expressed in ppm relative to tetramethylsilane as an internal standard. The relative area for the various shifts in the NMR spectrum corresponds to the number of carbon atoms in the respective group of the molecule. The signal shapes are indicated by the usual abbreviations with the following meanings:

bs = broad singlet s = singlet d = doublet ra = multiplet.

Infrared spectra (1C) contain only the absorption wavelengths (cm ¹ ) needed to identify the groups necessary for determining the structure of the molecule. IR spectra are measured using the KBr technique. Elemental analyses are given in weight percent.

Example

Ethyl 2-cyano-3-methyl-3-phenyl-2-propenoate (6) ____/

.....\

About>

A mixture of 100 g (0.072 mol) of p-fluoroacetophenone, 81.8 g (0.72 mol) of ethyl cyanoacetate, 13 g (0.17 mol) of ammonium acetate and 34.7 g (0.57 mol) of acetic acid is refluxed for 24 hours in 200 ml of benzene with continuous removal of water using a Dean-Stark trap. After cooling, the reaction mixture is diluted with 150 ml of benzene and extracted twice with 300 ml of water each time. The organic phase is separated, dried with sodium sulfate and, after filtration, concentrated in vacuo to a brown oily residue, which, upon distillation, gives 108.4 g (64.3%) of the product in the form of a yellow-green oil boiling at 125-127° Celsius/4 Pa.

Example 2

2-(4-fluorenyl)-2-methylbutanenitrile (5j

CN

....CN

----7

A solution of 50 g (0.21 mol) of the product prepared above in Example 1 and 24.7 g (0.38 mol) of potassium cyanide in 500 ml of 90% aqueous ethanol was heated to reflux for 5 hours. The cooled reaction solution was concentrated in vacuo to a resinous solid which was dissolved in

250 ml of chloroform. The solution is extracted twice with 250 ml of water each time, the organic phase is separated, dried with sodium sulfate and, after filtration, concentrated in vacuo to a brown oily residue, which upon distillation yields 21.7 grams (57.6%) of the desired product in the form of a light yellow oil.

Example 3

2-(4-Fluorophenyl)-2-ylethylbutadiene acid (4)

A solution of 9.0 g (0.05 mol) of the dinitrile prepared in Example 2 and 20.0 g (0.50 mol) of sodium hydroxide in 200 ml of 40% aqueous ethanol was heated to reflux for 36 hours. The cooled reaction solution was made strongly acid with concentrated hydrochloric acid and extracted three times with 250 ml of ethyl ether. The organic extracts were combined, dried over sodium sulfate, and concentrated in vacuo to a white solid which, after recrystallization from 50 ml of water, gave 6.1 g (98%) of the product as a white solid, mp 149-152.5° Celsius.

Example 4

2-(4-Fluorophenyl)-2-methylsuccinic anhydride

A solution of 7 g (0.034 mol) of the diacid prepared in Example 3 in 18 g of acetic anhydride is heated to reflux for 3 hours to give a light brown solution. The reaction mixture is concentrated in vacuo to a syrupy anhydride which can be used without further purification or which can be purified by distillation.

Example 5

2-(4-fluorophenyl)-2-methylsuccinimide g (0.029 mol) of succinic anhydride prepared in Example 4 was mixed with 25 g of ammonium hydroxide, a violent exothermic reaction occurring. After this spontaneous reaction had subsided, the mixture of ammonium hydroxide and white solid was heated to 120 ^° C. for 30 minutes. The excess ammonium hydroxide was evaporated in vacuo and the residue was heated to 200 ^° C. for about 45 minutes, after which time the evolution of gaseous products ceased. After cooling, the clear melt solidified to a white solid, which was recrystallized from isopropyl alcohol. A total of 5.5 g (91 percent) of the desired succinamide was obtained.

Example 6

3-(4-fluorophenyl)-3-methyl-1-[4-(Ipiperazinyl)buffy 1]-2,5-pyrrolidinedione

A mixture of 14.2 g (0.06 mol) of the succinimide prepared in Example 5, 37.0 g (0.17 mol) of 1,4-dibromobutane and 15.8 g (0.11 mol) of potassium carbonate in 200 ml of acetonitrile was stirred at reflux for 12 hours. The reaction solution was filtered and concentrated in vacuo to give oily 1-(4-bromobutyl)-3-(4-fluorophenyl)-3-methyl-2,5-pyrrolidinedione (1c). This oily material can be used directly for the next reaction or can be purified by distillation.

A mixture of 28.2 g (0.08 mol) of the product 1c from the previous paragraph, 35.4 g (0.41 mol) of piperazine and 34.1 g (0.25 mol) of potassium carbonate in 250 ml of acetonitrile was heated to reflux for 48 hours. The reaction mixture was filtered and concentrated in vacuo to an oily residue which was partitioned between chloroform and water. The organic phase was separated, dried over sodium sulfate and after filtration concentrated in vacuo to an oily material which was dissolved in 100 ml of ethanol and 7 N ethanolic hydrochloric acid was added to the solution. After cooling, 27.0 g (80.5%) of the desired product was obtained in the form of a white dihydrochloride with a melting point of 240-247' C.

Example 7

3-(4-fluoroenyl)-3-methyl 1-1-(4-[4-(2-pyrimidinyl)-1-piperazinyl 1-butyl}(-2,5-pyrrolidinedione

CH, 0 z ' \ II

A\ in '..... ¹ W

N! -A

Λ < >>

N ^J and TJ

A mixture of 6.0 g (0.014 mol) of piperazine of formula VI, prepared above in Example 6, 1.07 g (0.014 mol) of 2-chloropyrimidine and 3.8 g (0.028 mol) of potassium carbonate is heated to reflux in 100 ml of acetonitrile for 12 hours. The reaction solution is filtered, slightly concentrated and 7 N ethanolic hydrochloric acid is added to it. After cooling, the desired hydrochloride crystallizes and is filtered off. 4.5 g (74.2 %/o) of a white solid product melting with decomposition at 160-163 ^C C is obtained.

Analysis: for C25H28FN5O2.HC1 calculated:

61.79% C, 6.02% H, 14.42% N, found:

61.68% C, 5.96% H, 14.11% N.

NMR (perdeuterodimelhyls Ifoxide):

1.64 (3, s), 1.67 (4, ra), 3.01 (2, Ά 3.12 (4, m), 3.49 (6, m), 4.25 (2, m), 7.25 (6, m), 8.14 (1, dd (2.0, 7.8 I\zj 8.46 (1. dd, (2.0, 5.0 liz 11.68 (.1, bsj.

IC (KBr-teclmic):

835, 1,230, 1,440, 1,510, 1,535, 1,590. 1,695, 1,775, 2,210, 2,650 and 2,940 cm A and

'the

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238133

Claims (8)

A process for the preparation of 1-heteroaryl-4 - [(2,5-pyrrolidinedione-1-yl) alkyl] piperazine derivatives of the general formula (I). / 1 N- (CH 3 _n -N Ν-β He's ripping R ¹ represents a C 1 -C 4 alkyl group, a trifluoromethyl group, a phenyl group optionally substituted by halogen, or R ¹ together with R ² forms a C 4 -C 5 alkylene bridge comprising a condensed phenyl ring optionally substituted by halogen, or R ¹ together with R ³ forms an unfused cyclohexenyl ring or a phenyl ring tetrasubstituted by radicals X ¹ to X ⁴ independently selected from the group consisting of hydrogen, halogen atoms and nitro, R ² represents a C 1 -C 4 alkyl group or a phenyl group optionally substituted by halogen, or R ² together with R ¹ forms an alkylene bridge as defined above, and when R ¹ and R ³ form a non-fused phenyl ring as defined above, it is not the remainder R ² present, R ³ represents two hydrogen atoms or together with R ¹ forms the above-defined unfused phenyl ring, B is a heterocyclic system selected from the group consisting of benzoisothiazole, pyridine and pyrimidine, wherein the heterocyclic system is disubstituted by R ⁴ and R ⁵ independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, (C 1 -C 4) alkylthio, cyano, halogen and hydrogen atoms; and n is an integer of 2 to 4, and pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of the formula VI .0 / 7- is reacted. 7 // 7 2 ⁿ \ _ / R1 (vi) with a compound of formula (VII) Q-B (VII) in which R ¹ , R ² , R ³ , B and n are as defined above and Q represents a suitable leaving group, such as chloride, bromide, iodide, sulfate, phosphate, tosylate, mesylate or the like, at a temperature of 60 to 150 ° C in the presence of an acid-binding agent, whereupon. the compound of formula I obtained is optionally converted by reaction with a pharmaceutically acceptable acid into its salt. 2. A process according to claim 1, wherein the corresponding starting materials are used to give 3-methyl-3-phenyl-1- [4- [4- (2-pyrimidinyl-1-piperazinyl) butyl] -2,5-pyrrolidinedione. or a pharmaceutically acceptable acid addition salt thereof. 3. A process according to claim 1, wherein the corresponding starting materials are used to give 3- (4-fluorophenyl) -3-methyl-1- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -. 2,5-pyrrolidinedione or pharmaceutically acceptable acid addition salts thereof. 4. The process of claim 1 wherein the corresponding starting materials are used to form 3,3-diphenyl-1- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -2,5-pyrrolidinedione or its pharmaceutically acceptable acid addition salts. 5. A process according to claim 1, wherein the corresponding starting materials are used to give 3,3-diphenyl-1,4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl. -2,5-pyrrolidinedione or pharmaceutically acceptable acid addition salts thereof. 6. A process according to claim 1, wherein the corresponding starting materials are used to form 1- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl] spiro (1,2,3,4-tetrahydronaphthalene-2). , 3'-pyrrolidin-2 ', 5'-dione or pharmaceutically acceptable acid addition salts thereof. 7. A process according to claim 1, wherein the corresponding starting materials are used to form 1 &apos; - 4- [4- (2-pyrimidinyl) -1-piperazinyl] butylpiro [2,3-dihydro-1H-indene-1]. 3'-pyrrolidin-2 ', 5'-dione or pharmaceutically acceptable acid addition salts thereof. 8. A process according to claim 1, wherein the corresponding starting materials are used to form 2- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl] -1H-isoindole-1,3 (2H) -dione or its pharmaceutically acceptable acid addition salts.