CS258133B2 - Method of 1-heteroaryl-4-((2,5-pyrrolidine dione-1-yl)alkyl)piperazine derivatives production - Google Patents

Abstract

Process for the preparation of compounds of the general formula Wherein R 1 is C 1-6 -alkyl, trifluoromethyl or optionally halogen substituted phenyl, R 2 is C 1-6 alkyl or optionally halo substituted phenyl and R3 are two hydrogen, or R1 and R2 together form a C4-5-alkylene a bridge comprising non-fused phenyl a ring, optionally halogen substituted, or R 1 and R 3 together form a fused cyclohexenyl a ring or a phenyl ring, optionally to tetrasubstituted by halogen and / or a nitro group, B is a benzoisothiazole residue, pyridine or pyrimidine, optionally disubstituted with C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 -alkylthio, cyano and / or halogen and n is an integer of o 4 to 4, and their acid addition salts, consisting of reacting compounds of formulas VI and VII, where Q is a leaving group, and, optionally, converting the product into a pharmaceutically usable salt. Produced the compounds show psychotropic effects and are particularly interesting as anxiolytic and / or antipsychotic agents.

Description

The invention relates generally to heterocyclic carbon compounds having therapeutic properties and affecting biological functions, their preparation and use. In particular, the invention provides 1,4-disubstituted piperazine derivatives wherein one substituent is a substituted 2,5-pyrrolidinedione cyclic system linked via a nitrogen atom through an alkylene chain and the other substituent is a heterocyclic radical selected from the group consisting of pyridine, pyrimidine and benzisothiazole moieties.

Similar compounds of the prior art may be described by the general formula and no mention is made of the compounds of the present invention in which the structural formula contains substituted 2,5-pyrrolidinedione moieties.

The present invention provides a novel class of central nervous system compounds of the formula I and N CHp / n '.

N (I)

N ~ a-tk γίe-n • Λ

O

-N

These materials consist essentially glutarimidovými derivatives wherein R ¹ and R ² are alkyl groups or are joined to form an alkylene bridge having 4 or 5 carbon atoms and B represents an aromatic or heteroaromatic system optionally carrying substituents. These and related compounds have been prepared as psychotropic agents and are described in the following.

Compounds of the above structure wherein B represents a substituted or unsubstituted phenyl, pyridyl or pyrimidinyl radical 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. Pat

717,634, issued February 20, 1973,

Wu et al., U.S. Pat

796,776, issued August 24, 1976,

Temple et al., U.S. Pat.

No. 361,565, issued Nov. 30, 1982, Temple, copending application Ser

No. 334,688, filed December 28, 1981.

Attention is also drawn to co-pending application No. 333,830, filed December 23, 1981 (Temple), in which benzisothiazole is represented as symbol B. Also described in this application are some compounds wherein the second substituent of the piperazine moiety may be 2,4-thiazolidinedione groups or spiro-substituted 2,4-thiazolidinedione groups attached to the piperazine ring via its nitrogen atom via an alkylene chain.

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

In this general formula

R ¹ represents a C 1 -C 4 alkyl, trifluoromethyl or phenyl group optionally substituted by halogen or R ¹ together with R ² forms a C 4 -C 5 alkylene bridge bearing a fused phenyl ring optionally substituted by halogen, or R 1 ¹ together with R ³ form a fused cyclohexenyl ring or a phenyl ring tetrasubstituted by radicals X ¹ to X ⁴ which are independently selected from the group consisting of hydrogen, halogen atoms and nitro,

R ² represents an alkyl group having 1 to 4 carbon atoms, a phenyl group optionally substituted by halogen, or the radical R ² is not present in the case that R ¹ and R ³ form a fused phenyl ring system, or R ² together with R ¹ forms the above-defined alkylene bridge,

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

B represents a 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 C 1 -C 4 alkyl, C 1 alkoxy and (c) C-C, alkyl, (C až-C alkyl) alkylthio, cyano, halogen, and hydrogen; and n is a number of 2 to 4.

Selected compounds of the invention, exemplifying the compounds of Formula I above, have useful psychotropic properties, including reversal of drug-induced catalepsy and tranquilizing activity characterized by antianxietic and / or antipsychotic activity.

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

β

(3 /

In these structural formulas, R ¹ and R ^{2 are} independently selected from the group consisting of C 1 -C 6 alkyl, trifluoromethyl and phenyl optionally substituted by halogen, X ¹ to X ^J are as defined above, and Z is hydrogen or halogen. A preferred group consists of residues of the above structure (2), which may be described in more detail by the structures (a), (b) and (c) below. The compounds of formula I are those wherein B is a 2-pyrimidinyl radical.

As used herein, the term "halogen" refers to fluorine, iodine and preferably chlorine or bromine, and alkyl groups of 1 to 4 carbon atoms may be straight or branched.

Pharmaceutically acceptable acid addition salts of the compounds of the invention are those whose anion does not significantly contribute to the toxicity or pharmacological activity of the salt, so that, from a pharmacological standpoint, these salts are equivalent to those of the general formula I. The salts described herein are generally preferred for use in medicine. In some cases, these salts have properties that make them more suitable for the preparation of dosage forms such as improved solubility, non-hygroscopicity, compressibility in terms of tablet preparation, and compatibility with other ingredients with which the compounds of the invention may be used for pharmaceutical purposes. These salts are conveniently prepared by mixing the basic compound of formula I with the selected acid, which is preferably carried out in solution, using an excess of commonly used inert solvents such as water, ether, benzene, alcohols such as ethanol, ethyl acetate, acetonitrile and the like. can also be prepared by double decomposition or by ion exchange under conditions in which the anion of one salt of a compound of formula I is replaced by another anion while allowing the desired product to be separated, such as precipitation from solution or solvent extraction, or elution from the ion exchanger column; ion exchanger column. Pharmaceutically acceptable acids suitable for the preparation of salts of the compounds of formula I include sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, citric acid, acetic acid, benzoic acid, cinnamic acid, a piperazinylalkylpyrrolidinedione of formula VI with an appropriate system introducing the residue. VII (VII). This reaction proceeds according to the following reaction scheme:

mandelic acid, nitric acid, mucic acid, isethionic acid, palmitic acid, heptanoic acid and the like.

In accordance with the invention, the compounds of formula I are prepared by the reaction of

(VID

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. Potassium carbonate is the preferred acid binding agent, but other inorganic and tertiary organic bases can also be used including carbonates of other alkali and alkaline earth metals, alkali and alkaline earth metal hydrogencarbonates and hydrides, and tertiary amines.

The preparation of the starting materials of the 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

(1), (2)

illal.

HN ~ NH> ^R -4 - <°

N - (CH 2 _n -Or)

Ό (// <;>) · <

z>

--w n ^ 7 7ih (Vi)

In Reaction Scheme 1, R ¹ and R ^{2 are} as defined above. The process of Scheme 1. consists essentially of Knoevenagel condensation of a ketone or aldehyde with ethyl cyanoacetate to form a series of α, 3-unsaturated cyanoacetates (6). Reaction of compound (6) with about 1.5 to 2 equivalents of potassium cyanide affords the intermediate dicyand derivative (5) which undergoes acid catalyzed hydrolysis to give the intermediate dicarboxylic acid (4). The standard method of cyclization of dicarboxylates to cyclic imides - aminolysis followed by dehydration is then applied to this compound. In this way, the types (1), (2) of the intermediates of formula (II) can be obtained. The general synthetic procedure described above for individual reactions 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, 615-616,

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

The compounds of the invention are pharmacological agents with psychotropic properties. Said substances exhibit tranquilizing activity in non-toxic doses and are of particular interest as anxiolytic and / or antispychotic agents. The compounds of the invention also act to reverse catalepsy. Selected in vivo and in vitro animal tests confirm that preferred compounds of formula I wherein B is a 2-pyrimidinyl moiety exhibit anxiolytic activity and / or an antipsychotic effect. The following in vivo assays are used as a basis to determine the tranquilizing properties and possible side effects of the compounds of the invention.

Tests for Conditional Avoidance Response (CAR) suppression of 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, 434-455 (1948).

In order to further demonstrate the psychotropic activity and specificity of the compounds of the invention, a method known in the art for determining binding to the central nervous system receptors in vitro can be used. Certain compounds (commonly referred to as ligands) have been identified that preferentially bind to specific sites with high affinity found in brain tissue that are related to psychotropic activity or may be related to side effects. Inhibition of radioisotope-labeled ligand binding to these specific affinity sites is considered to be a measure of the ability of a compound to affect particular central nervous system functions or to cause side effects in vivo. This principle is used in the following in vitro test, given by way of example.

Dopamine receptor binding assay

Literature

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

Depending on the pharmacological properties found in the above-described tests, representative compounds of formula I are potential tranquilizing agents showing either anxiolytic and / or antipsychotic activity, since they are relatively effective in the CAR test, where their ED50 values for oral administration are below 100 mg / kg of body weight. Many of these compounds are also considerably inactive with respect to dopamine binding since their IC 50 values in the ³ H sptperon-dopamine receptor binding assay are greater than 1,000 nmoles. CAR performance in conjunction with only poor performance in the binding assay described above is believed to be a possible selective anxiolytic activity in human medicine. Regarding possible susceptibility to side effects, exhibit certain compounds of formula I wherein R ³ represents two hydrogen atoms, the efficiency of the assay reversing catalepsy induced trifluoperazlnem, wherein the ED value at oral administration are below 20 mg / kg. Efficacy in this assay suggests that these compounds lack the ability to induce unwanted side effects associated with extrapyramidal symptomatology. Another test for possible side effects is to determine the protective effect against the lethal effect of norepinephrine. This procedure essentially relates to α-receptor blockade and related side effects such as sedation and blood pressure drop. For most compounds of the invention, very little activity was found in this assay because the ED50 values of these compounds were greater than 100 mg / kg.

Examples of two preferred substances 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). '-pyrrolidin-2', 5'-dione) (Example 23) and 3,3-diphenyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -2,5-pyrrolidinedione ( Example 17 J. Two preferred compounds for which potential non-dopaminergic antipsychotic activity is expected are 3- (4-fluorophenyl) -3-methyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl-2,5-pyrrolidinedione (Example 7) α1-4- [4- (2-pyrimidinyl-1-piperazinyl) butyl] spiro (2,3-dihydro-1H-indene-1,3'-pyrrolidine-2) 5'-dione (Example 24).

The invention further provides a method of treating a mammal suffering from anxiety or psychosis which comprises systemically administering to said mammal a therapeutically effective tranquilizing amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof. The effective dose ranges from about 0.01 to 40 mg / kg of body weight, depending on the intended effect, the route of administration and, to some extent, the compound selected. A preferred daily dose is from about 0.5 to about 0.5

1.5 mg / kg, the total dose being administered in several divided doses. By systemic administration is meant oral, rectal and parenteral (i.e., intramuscular, intravenous and subcutaneous) administration. In general, it has been found that when the compound of the invention is administered orally, a higher amount of active ingredient than parenteral administration is required to achieve the same effect. In accordance with conventional clinical practice, the compounds of the invention are preferably administered in an amount causing the desired anxiety effect without any harmful or unpleasant side effects.

The compounds of the invention may be administered for individual cytolytic purposes either as individual therapeutic agents or as mixtures with other therapeutic agents. These medicaments are generally administered in the form of pharmaceutical preparations comprising an antidepressant effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Pharmaceutical compositions containing from about 1 to about 500 mg of active ingredient per dosage unit are preferred. These preferred compositions are tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs, and aqueous solutions in a conventional manner.

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

The invention is illustrated by the following non-limiting examples. The melting points in these examples are not corrected. Nuclear Magnetic Resonance Spectrum (NMR) data refer to the chemical shifts (δ value) expressed in ppm relative to tetramethylsilane as an internal standard The relative area for the different shifts in the NMR spectrum corresponds to the number of carbon atoms in the respective group of molecules. meaning:

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

The infrared spectra (1C) contain only the absorption waves (cm ¹ ) needed to identify the groups necessary to determine the structure of the molecule. IR spectra were measured using the KBr technique. Elemental analyzes are given in percent by weight.

He did

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

..... \

O>

A mixture of 100 g (0.072 mol of p-fluoroacetophenone), 81.8 g (0.72 mole) of ethyl cyanoacetate, 13 g (0.17 mole) of ammonium acetate and 34.7 g (0.57 mole) of acetic acid was added for 24 hours. The reaction mixture was diluted with 150 ml of benzene and extracted twice with 300 ml of water each time, the organic phase was separated, dried over sodium sulfate and concentrated by filtration. in vacuo to a brown oily residue which, by distillation, afforded 108.4 g (64.3%) of the product as a yellow-green oil boiling at 125-127 ° C / 4 Pa.

Example 2

2- (4-fluorophenyl) -2-methylbutanedinitrile (5j

CN

.... CN

---- 7

A solution of 50 g (0.21 mole) of the product prepared in Example 1 above and 24.7 g (0.38 mole) of potassium cyanide in 500 ml of 90% aqueous ethanol was heated at reflux for 5 hours. in a vacuum to a resinous solid material that dissolves in

250 ml of chloroform. The solution is extracted twice with 250 ml of water each time, the organic phase is separated, dried over sodium sulphate and, after filtration, concentrated in vacuo to a brown oil which, by distillation, gives 21.7 g (57.6%) of the desired product as a pale yellow oil. .

Example 3

2- (4-fluorophenyl) -2-ethylbutadiic acid (4)

A solution of 9.0 g (0.05 mole) of the dinitrile prepared in Example 2 and 20.0 g (0.50 mole) of sodium hydroxide in 200 ml of 40% aqueous ethanol was refluxed for 36 hours. The cooled reaction solution was strongly acidified with concentrated hydrochloric acid and extracted three times with 250 ml of ethyl ether each time. 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 ° C; Celsius.

Example 4

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

A solution of 7 g (0.034 mol) of the diacid prepared in Example 3 in 18 g of acetic anhydride was heated at 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 to produce a violent exoteric reaction. After this spontaneous reaction, the mixture of ammonium hydroxide and white solid was heated at 120 ^° C for 30 minutes. Excess ammonium hydroxide was evaporated in vacuo and the residue heated to 200 ^° C for about 45 minutes, after which time the evolution of flue gas ceased. After cooling, the clear melt solidifies to a white solid which is recrystallized from isopropyl alcohol. A total of 5.5 g (91 percent) of the desired succininide is obtained.

Example 6

3- (4-Fluorophenyl) -3-methyl-1- [4- (piperazinyl) butyl] -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 Stir under reflux for 12 hours. The reaction solution is filtered and concentrated in vacuo to an oily 1- (4-bromobutyl) -3- (4-fluorophenyl) -3-methyl-2,5-pyrrolidinedione (IIc) .This oil can be used directly for the next reaction. or it can be purified by distillation.

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

Example 7

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

CH, O from II

A \ v '..... ¹ W

N! -AND

Λ <>>

N ^J i TJ

A mixture of 6.0 g (0.014 mole) of piperazine VI, prepared in Example 6 above, 1.07 g (0.014 mole) of 2-chloropyrimidine and 3.8 g (0.028 mole) of potassium carbonate was heated to reflux in 100 ml of acetonitrile for 12 hours. The reaction solution was filtered, concentrated somewhat, and 7N ethanolic hydrochloric acid was added, and upon cooling the desired hydrochloride crystallized and was filtered to give 4.5 g (74.2%) of a white solid melting. with decomposition at 160-163 ^° C.

Analysis: for C25H28FN5O2. HCl calculated:

% C, 61.79;% H, 6.02;% N, 14.42.

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

NMR (perdeuterodimelhylsu Ifoxide):

1.64 (3, with), 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 L) 8.46 (1. dd, (2.0, 5.0 liz 11.68 (.1, bsj.

IC (KBr):

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

'the

According to the above process and the specific embodiments described in the examples, the following products of formula I co

I x

Ί

AND

J í \ i

X o

and

it

Honors

Td β

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and what

Q

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q_l (Η q_i tH I f I I

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and • o · CM 3 CM

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HM HM HM HM HM HM

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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.