MXPA99005877A - 3-aryl-2-(1-substituted-4-piperidinyl)-1(1-di)oxo-3h-benzo[d]-isothiazole derivatives, their preparation and their use as modulators of neurotransmitter function - Google Patents

Abstract

This invention relates to 3-aryl-2-(1-substituted-4-piperidinyl)-1,1-dioxo-3H-benzo[d]isothiazoles and related compounds of formula (I) where X and Y are independently halogen, loweralkyl, loweralkoxy, arylloweralkoxy, acyl, hydroxy, nitro, amino, trifluoromethyl and hydrogen;n, p and q are independently integers of 1 or 2;R is hydrogen, loweralkyl, arylloweralkyl, acyl, -(CH2)m-OR1, -(CH2)mNHR1, formulas (a) and (b), where R1 is hydrogen, loweralkyl, arylloweralkyl, acyl and loweralkoxycarbonyl;Z is hydrogen, halogen, loweralkyl, loweralkoxy and acyl;m is an integer of 2 to 4;s is an integer of 1 or 2;and the pharmaceutically acceptable acid addition salts thereof and the optical isomers thereof where such isomers exist. The compounds of formula (I) of the present invention are useful as modulators of neurotransmitter function such as serotonergic and adrenergic, and as such are useful as antidepressants, and dopaminergic function, and as such may be useful for diseases where the potentiation of dopaminergic activity may be helpful, e.g. Parkinson's Disease.

Description

DERIVATIVES OF 3-ARI -2- (4-PIPERIDINYL 1-SUBSTITUTED) - l- (l-DIÍOXO-3H-BENZO / D1-ISOTIAZOL, Sü PREPARATION, AND Sg USE AS MODULATORS OF THE NEUROTRANSMITING FUNCTION To the best of our knowledge, the compounds of the present invention have not been described or suggested hitherto. The compounds of the present invention have the general form: wherein X and Y are independently halogen, lower alkyl, lower alkoxy, arylalkoxy, acyl, hydro > nitro, lower alkyl, amino, trifluoromethyl, or hydrogen; n / P and 5 sor! in. epenc-: le .- "" .. oi? ic '.; l •• mat of 1 or 2; R is hydrogen, alkyl, arylalkyl, acyl, - (CH2) m-0R1, - (CH2) mNHR1 # wherein R is hydrogen, lower alkyl, arylalkyl, and acyl, or lower alkoxycarbonyl; m is an integer from 2 to 4; Z is hydrogen, halogen, lower alkyl, lower alkoxy or acyl; s is an integer of 1 or 2; and the pharmaceutically acceptable acid addition salts thereof. Throughout the specification and the appended claims, a given chemical formula or name encompasses all its stereoisomers, where such isomers exist. In addition, this invention also encompasses the bioprecursors of Compound I, and its metabolites. As used herein, the term "bio-precursors" will mean a compound or compounds which, when introduced, for example, ingested in the body of a mammal, such as a man, are converted by biological action into the Compound. I. An example of, but not limitation to, this bio-precursor, is the well-known class of known compounds: as prodrugs. In the above definitions, the term "lower" means that the group it is describing contains from 1 to 6 carbon atoms. The term "alkyl" refers to a straight or branched chain hydrocarbon containing no unsaturation, for example, methyl, ethyl, isopropyl, 2-butyl, neopentyl, normal hexyl, etc .; the term "alkoxy" refers to a monovalent substituent consisting of an alkyl group linked through an ether oxygen having its free valence bound from the ether oxygen, for example, methoxy, ethoxy, propoxy, butoxy, pentoxy, etc.; the term "aryl11" refers to a phenyl group of the formula: where Q and t are as defined below; the term "lower arylalkyl" refers to a monovalent substituent consisting of an aryl group, eg, phenyl, o-tolyic m-methoxyphenyl, etc., linked through a lower alkylene group having its free valence linked from a carbon atom from the lower alkylene group, and having the formula: wherein Q is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, lower acyl, CF3, NH2, and t is an integer of 1 to 3; the term "alkylene" refers to a bivalent radical of the branched or unbranched lower alkyl group from which it is derived, having valence bonds from two terminal carbon atoms thereof, for example, ethylene (-CH2CH2-), propylene ( -CH2CH2CH2-), isopropylene (-CH (CH3) CH2-), etc .; the term "acyl" refers to a substituent having the formula - (C (= 0) R2, wherein R2 is aryl or lower alkyl, and the term "halogen" refers to a member of the family consisting of fluorine , chlorine, bromine and iodine The compounds of the present invention are prepared in the following manner, wherein the substituents R, R ^ x, Y, Z and the integers m, n, p, q, rys are as defined above A compound of the formula is selected: where Hal is halogen. These compounds II are well known, and can be prepared in general in the manner described in (1) Voegel's Texbook of Practical Organic Chemistry, 5th Edition, page 877, Authors: B.S. Furniss, A.J.

Hannaford, P.W.G. Smith, A.R. Tatchell. Compound JJ is reacted with an amine III of the formula: to form the compound (IV): Compounds III are well known, and can be prepared in a manner as described in Crider, A.M.; Floss, H.G.; Cassady, J.M .; Bradner, W.J .; J. Med. Chem. (1980), 23. { 8) .848-51. Many are commercially available. The reaction between Compounds II and III to produce Compound IV is conducted under conventional acylation reaction conditions. Typically, the reaction is conducted in the presence of a chlorinated hydrocarbon, such as, for example, CH2C12, CHC13 or CHC13 or C1CH2CH2C1 at a temperature of 20 ° C to 40 ° C, for 1 to 5 hours to obtain Compound IV. Then Compound IV is metalated, followed by condensation with an aldehyde of the formula: to form Compound VI of the formula: (SAW).

Typically, Compound IV is reacted with Compound V, in the presence of a suitable metallation reagent, for example, normal butyl lithium, secondary butyl lithium, tertiary butyl lithium, etc. , in an ethereal solvent, for example, dimethoxyethane (DME), etc., at a temperature of 0 ° C to 25 ° C, for 1 or 2 hours to form Compound IV. Compound VI is subjected to a cyclodehydration reaction to form Compound I of the invention. - Typically, Compound VI is treated with a conventional cyclodehydration agent selected from a mineral acid, such as concentrated H2SO4, etc., a Mitsonobu reagent, such as, DEAD PPH3, etc., in an ethereal solvent, for example, tetrahydrofuran, Et20, etc., for 1 or 2 hours to form Compound I of the invention. When R is H in Compound (I), this compound can be further reacted with a compound of the formula R1-Hal (VII), where Hal is halogen, and R1 includes all substituents of R, with the exception of hydrogen, for example, lower alkyl, etc. The reaction is usually conducted under conventional reaction conditions, such as in a dipolar aprotic solvent, for example, dimethyl formamide, dimethyl sulfoxide, etc., at a temperature of 25 ° C to 150 ° C for 10 to 20 hours to form Compound I, wherein R is R1. The compounds of Formula (I) of the present invention are useful as modulators of neurotransmitter function, such as serotonergic and adrenergic, and as such, are useful as antidepressants, and for dopaminergic function, and as such may be useful for diseases where the enhancement of the dopaminergic utility may be useful, for example, Parkinson's Disease. Three test protocols described below are used, namely: (1) inhibition of norepinephrine recovery (NE); (2) inhibition of serotonin recovery (5HT); and (3) inhibition of dopamine (DA) recovery, to assert the biological properties of the compounds of this invention. Following the descriptions of the protocols, the results are stipulated for some of the compounds of the invention in Table 1.

Inhibition of Recovery of r3H] Norepinephrine in the Whole Brain or in Rat Hypothalamic Synaphtomas Purpose: This assay is used as a biochemical selection of potential antidepressants that block the recovery of norepinephrine. Introduction: The norepinephrine reuptake neuronal mechanism (NE) is the most important physiological means to inactivate norepinephrine, by removing the transmitter from the synaptic cleft (1). The recovery of norepinephrine is carried out by means of a saturated, stereospecific, high affinity (Km = 10"7 - 10 ~ 6M), sodium-dependent transport system, which has been shown to exist both in the tissue of the peripheral nervous system and centra1 using sliced, homogenate, and purified sinaphthous preparations (2) Norepinephrine recovery is potently inhibited by cocaine, phenethyl amines, and tricyclic antidepressants (3) .It is also inhibited by ouabain, metabolic inhibitors, and phenoxybenzamine The inhibition of recovery of norepinephrine by clinically effective tricyclic antidepressants is an important link in the catecholamine hypothesis of affective disorders. (4) In this series of compounds, secondary amines (eg, desipramine) are more active than tertiary amines (eg, imipramine). In the past, extensive relationships have been studied of structure-activity for the recovery of norepinephrine. There are large regional variations in norepinephrine recovery (7-9) that correlate with endogenous levels of norepinephrine. The hypothalamus shows the highest level of norepinephrine and the greatest recovery. This region is used for an additional test of compounds showing an activity in whole brain preparations. 10 Synaptosomal recovery [3H] -NE is a useful marker for the integrity of noradrenergic neurons after injury experiments, as well as an assay for compounds that enhance the action of norepinephrine by blocking the mechanism of re-recovery. 15 Procedure A. Animals: CR Wistar rats, males (100 to 125 grams). • '* ~ -: "rB.' Reagents: 1. Krebs-20 Henseleit Bicarbonate Regulator, pH 7.4 (KHBB): A batch of 1 liter is made, which contains the following salts: It is aerated for 60 minutes with 02 to 95 percent / 02 to 5 percent, the pH is verified (7.4 + 0.1); then bovine serum albumin (Sigma cat # A-7906) is added 1 milligram / milliliter. 2. Sucrose 0.32M: 21.9 grams of sucrose, carry ..c. to 0?; , 1ii11: < os, 3. The bitartrate of L (-) - Norepinephrine is obtained from Sigma Chemical Co. A 0.1 mM supply solution in 0.01 N HCl is made. This is used to dilute the specific activity of the radiolabelled norepinephrine. 4. The Levo- [Ring-2, 5, 6-3H] -Norepinephrine (40-50 Ci / millimole) is obtained from New England Nuclear. The final desired concentration of [H] -NE in the assay is 50 nM. The dilution factor is 0.8. Accordingly, the KHBB is made to contain [3H] -NE 62.5 nM. It is added to 100 milliliters of KHBB.

* The aggregate volume is calculated from the specific activity of [3H] -NE.

. For most tests, a 1 mM supply solution of the test compound is made in a suitable solvent, and serially diluted, such that the final concentration in the assay is 2 x 10 ~ 8 to 2 x 10 ~ 5 M. Seven concentrations are used for each test. Higher or lower concentrations may be used, depending on the power of the compound. C. Tissue Preparation Male Wistar rats are decapitated, and the brain is rapidly removed. Weigh the entire brain, minus the cerebellum, or the hypothalamus, and homogenize it in 9 volumes of frozen 0.32 M sucrose using a Potter-Elvejhem homogenizer. Homogenization should be done with 4 to 5 runs up and down with medium speed to minimize synaptosome lysis. The homogenate TH is centrifuged at 1000 g for 10 minutes, from 0 ° C to 4 ° C. The supernatant (Sx) is decanted and used for recovery experiments. D. Test 800 microliters of KHBB [3H] -NE 20 microliters of vehicle or appropriate concentration of drug. 200 microliters of tissue suspension. Tubes are incubated at 37 ° C, under an atmosphere of 02 to 95 percent / 02 to 5 percent for 5 minutes. For each test, three tubes are incubated with 20 microliters of vehicle at 0 ° C in an ice bath. After incubation, all tubes are immediately centrifuged at 4000 g for 10 minutes. The supernatant fluid is aspirated, and the granules are dissolved by the addition of 1 milliliter of solubilize (Triton X-100 + 50% EtOH: 1: 4 by volume / volume). The tubes are swirled vigorously, decanted into vials, and counted in 10 milliliters of Liquiscint scintillation counting cocktail. Active recovery is the difference between cpm at 37 ° C and 0 ° C. The percentage of inhibition in each concentration of the drug is the average of three determinations. IC50 values are derived from log probe analysis.

References 1. Hertting, G. and Axelrod, J., "Fate of tritiated noradrenaline at the sympathetic nerve-endins". Nature 192: 172-173 (1961). 2. Patón, D.M., "Neuronal transport of norepinephrine and dopamines". Pharmacol. 21: 85-92 (1980). 3. Iversen, L.L., "Uptake mechanisms for neuro-transmitter amines." Biochem. Pharmacol. 23: 1927-1934 (1974). 4. Schildkraut, J.J. "The catecholamine hypothesis of affective disorders, a review of the supporting evidence".

Am. J. Psychiat. 122: 509-522 (1965). 5. Horn, A.S., Coyle, J.T. and Snyder, S.H., "Catecholamine uptake by synaptose is from mouse brain: structure-activity relationship for drugs with differential effects in dopamine and norepinephrine neurons". Mol. Pharmacol. 7: 66-80 (1971). 6. Maxwell, R.A. , Ferris, R.M. , Burcsu, J., Woodward, EC, Tang D. and Willard, K =, "The phenyl rigs of tricyc ic antidepressants and related compounds as determinants of the potency of inhibition of the amine pumps in adrenergic neursns of the rabbit aorta and in cortical synaptosomes rat ". J. Pharmacol. Exp. Ther. 191: 418-430 (1974). 7. Glowinski, J. and Iversen, L.L., "Regional studies of catecholamines in rat brain". J. Neurochem. 13: 655-669 (1966). 8. Snyder, S.H. and Coyle, J.T., "Regional differences in [3H] -norepinephrine and [3H] -dopamine uptake into rat brain homogenates." J. Pharmacol. Exp. Ther. 165: 78-86 (1969). 9. Synder, S.H., Green, A. I. and Hendley, E.D., "Kinetics of [3H] -norepinephrine accumulations into slices from different regions of the brain". J. Pharmacol. Exp. Ther. 164: 90-102 (1968).

Inhibition of the Recovery of | 3H1-Serotonin in rat whole-brain synaptosomes Purpose This assay is used as a biochemical selection of compounds that block the recovery of serotonin (5 HT), which may be useful as antidepressants and for the treatment of personality disorders, such as compulsive obsessive disorder Introduction Asberg and colleagues have suggested that subjects with serotonergic hypofunction comprise a biochemical subgroup of depressed patients (1), while others (2) claim that altered serotonergic function determines changes in mood associated with affective disorders Although the role of 5 HT in the etiology of depression is not clear, it is true that a number of antidepressant drugs block the mechanism of 5-HT re-recovery. have shown that [3] -imipramine marks 5 HT recovery sites (10). zimelidine are clinically effective antidepressants (3), with very selective effects on 5 HT recoveries (4, 5). More recently, fluoxetine has been shown to be both selective and a potent inhibitor of 5 HT recovery. The transport of [3 H] -5 HT has been characterized in the tissue of the central nervous system (6, 7), and it is found to be saturable, dependent on sodium and temperature, inhibited by ouabain, metabolic inhibitors, tryptamine analogues (8), and tricyclic antidepressants (tertiary amines »secondary amines) (9). The latest discoveries differentiate the recovery of 5 HT from the recovery of catecholamine. Recovery of [3] -5 HT can also be used as a marker for serotonin nerve terminals. Procedure A. Animals: Male Wistar CR rats (100 to 125 grams). B. Reagents: 1. Krebs-Henseleit Bicarbonate Regulator, pH 7.4 (KHBB): Make a batch of 1 liter, containing the following salts.

It is aerated for 60 minutes with 02 to 95 percent /? 2 to 5 percent. The pH is verified (7.4 + 0.1). 2. Sucrose 0.32 M: 21.9 grams of sucrose, carry up to 200 milliliters. 3. S04 of serotonin-creatinine is obtained in Sigm? Chemical Co. A supply solution of 0.1 mM ex. HCl 0.01N. This is used to dilute the specific activity of radiolabeled 5 HT. 4. The specific activity of the 5- [1, 2-3H (N)] -hydroxytryptamine-creatinine (Serotonin) sulfate, 20-30 Ci / millimole, is obtained in New England Nuclear. The final desired concentration of 3H-5 HT in the assay is 50 nM. The dilution factor is 0.8. Accordingly, the KHBB is made to contain [3 H] -5 HT 62.5 nM. It is added to 100 milliliters of KHBB.

* Calculate the volume added from the specific activity of 3H-5HT.

. For most tests, a 1 mM solution of the test compound is made in a suitable solvent, and serially diluted, such that the final concentration in the assay is 2 x 10 ~ 8 to 2 x 10"5 M. Seven concentrations are used for each assay, higher or lower concentrations may be used, depending on the potency of the compound C. Tissue Preparation Male Wistar rats are decapitated, and the brain is rapidly removed. whole brain minus the cerebellum, and homogenized in 9 volumes of ice cold 0.32 M sucrose, using a Potter-Elvejhem homogenizer.Homogenization should be done with 4 to 5 runs up and down at medium speed to minimize lysis of the synaptosome. The homogenate is centrifuged at 1000 g for 10 minutes, from 0 ° C to 4 ° C. The supernatant (S?) Is decanted and used for recovery experiments.

D. Test 800 microliters of KHBB [3H] -5HT. 20 microliters of vehicle or appropriate concentration of drug. 200 microliters of tissue suspension. Tubes are incubated at 37 ° C, under an atmosphere of 02 to 95 percent / 02 to 5 percent for 5 minutes. For each test, three tubes are incubated with 20 microliters of vehicle at 0 ° C in an ice bath. After incubation, all tubes are immediately centrifuged at 4000 g for 10 minutes. The supernatant fluid is aspirated, and the granules are dissolved by the addition of 1 milliliter of solubilizer (Triton X-100 + 50% EtOH: 1: 4 by volume / volume). The tubes are swirled vigorously, decanted into vials, and counted in milliliters of Liquiscint scintillation counting cocktail. L_ active recovery is the difference between cpm at 37 ° C and 0 ° C. The percentage inhibition of each concentration of the drug is the average of three determinations. IC50 values are derived from log probe analysis. References 1. Asberg, M., Thoren, P., Traskman, L., Bertilsson, R., V. Serotonin depression: A biochemical subgroup withih the affective disorders. Science 191: 478-480 (1975). 2. DeMontigy, C. Enhancement of 5 HT neurotransmission by antidepressant treatments J. Physiol. (Paris) 77: 455-461 (1980). 3. Freighner, J.P. Clinical efficacy of the newer antidepressants. J. Clin. Psychopharmacol, 1: 235-265 (1981). 4. Ogren, S.a., Ross, S.B., Hall, H., Holm, A.C. and Renyi, A.L. The pharmacology of zimelidine: A 5 HT selective reuptake inhibitor. Acta Psychiat. Scand. 290: 127-151 (1981). 5. Cle ents-Jewry, S., Robson, P.A. and Chidley, L.J. Biochemical investigations into the mode of action of trazodone. Neuropharmacol. 19: 1165-1173 (1980). 6. Ross, S.B. Neuronal transport of 5-hydroxy-tryptamine. Pharmacol 21: 123-131 (1980). 7. Shaskan, E.G. and Snyder, S.H. Kinetics of serotonin accumulation into slices from rat brain: Relationship to catecholamine uptake. J. Pharmacol. Exp. Ther. 175: 404-418 (1970). 8. Horn, S.A. Structure-activity relations for the inhibition of 5 HT uptake into rat hypothalamic homogenates by serotonin and tryptamine analogues. J. Neurochem. 21: 883-888 (1973). 9. Horn, A.S. and Trace, R.C.A.M. Structure-activity relations for the inhibition of 5-hydroxitryptamine uptake by tricyclic antidepressant into synaptosomes from serrotonergic neurons in mouse brain homogenates. Brit. J. Pharmacol. 51: 399-403 (1974). 10. Langer, S.Z., Moret, C., Raisman, R., Dubocovich, M.L. and Briley M. Hight affinity [3H] imipramine binding in rat hypothalamus: Association with uptake of serotonin but not norepinephrine. Science 210: 1133-1135 (1980).

Inhibition of Recovery of 3H-Dopamine in Rat Striatal Synaptosomes Purpose This test is used to show the differential effects of drugs on the recovery of dopamine against the recovery of norepinephrine, and to identify the therapeutic agents for diseases where it may be useful. enhancement of dopaminergic activity (eg, Parkinson's disease). Introduction The high affinity, saturable, temperature and sodium dependent transport of 3H-DA recovery is potently inhibited by cocaine, phenethyl amines and ouabain, but, unlike NE, is not potentially inhibited. for tricyclic antidepressants (3). The only antidepressants that inhibit DA recovery are nomifensin (4) and bupropion (5). The relationship of DA recovery with the efficacy of these compounds is unknown.

Co le and Snyder (6) did not report stereo-selectivity for the inhibition of DA recovery by d- or 1-amphetamine, but other researchers (7) have shown conformational selectivity (gauche > anti). Several authors have shown that at least part of the effect of 3H-amine accumulation by some compounds is due to direct release activity (4)., 8, 9). However, there are some discrepancies in these reports. In order to differentiate the effects on the recovery of effects on release, the effects of direct release should be determined in separate experiments. The most reliable method to determine the release of the neurotransmitter is by a superfusion technique described by Raiteri et al. (10). This is a theoretical concern for studying the recovery of any substance in vitro, but it is emphasized for the recovery of dopamine. The recovery of 3H-DA may well be used as a biochemical marker for the dopaminergic nerve terminals, especially in conjunction with injury experiments. Procedure Animals: Male rat CR istar (100 to 125 grams). B. Reagents: 1. Krebs-Henseleit Bicarbonate Regulator, pH 7.4 (KHBB): Make a batch of 1 liter, containing the following salts.

It is aerated for 60 minutes with 02 to 95 percent / 02 to 5 percent. The pH is verified (7.4 + 0.1). 2. Sucrose 0.32 M: 21.9 grams of sucrose, carry up to 200 milliliters. 3. Dopamine HCl is obtained from Sigma Chemical Co. A 0.1 mM supply solution in 0.01 N HCl is made. This is used to dilute the specific activity of radiolabeled 5 HT. 4. Amine 3, 4- [8-3H (N)] -dihydroxyphenylethyl (Dopamine), specific activity of 4-34 Ci / millil, is obtained from New England Nuclear. The final desired concentration of 3H-DA in the 40 nM assay. The dilution factor is 0.9. Therefore, the KHBB is made to contain [3H] -5 DA. It is added to 100 milliliters of KHBB.

* Calculate the aggregate volume from the specific activity of 3H-5DA.

. For most tests, a 1 mM solution of the test compound is made in a suitable solvent, and serially diluted, such that the final concentration in the test is 2 x 10"8 to 2 x 10 ~ 5 M. Seven concentrations are used for each assay, higher or lower concentrations may be used, depending on the potency of the compound C. Tissue Preparation Male Wistar rats are decapitated, and the brain is rapidly removed. The striatos corporas are weighed and homogenized in 9 volumes of 0.32 M sucrose, using a Potter-Elvejhem homogenizer, homogenization should be done with 4 to 5 runs up and down at medium speed to minimize lysis of the synaptosome The homogenate is centrifuged at 1000 g for 10 minutes, from 0 ° C to 4 ° C. The supernatant (Sx) is decanted and used for the recovery experiments D. 900-microlitre assay of KHBB [3H] -DA. 20 microliters of vehicle or appropriate concentration of drug. 100 microliters of tissue suspension. Tubes are incubated at 37 ° C, under an atmosphere of 02 to 95 percent / 02 to 5 percent for 5 minutes. For each test, three tubes with 20 microliters of vehicle are incubated 0 ° C in an ice bath. After incubation, all tubes are immediately centrifuged at 4000 g for 10 minutes. The above fluid is aspirated, and the granules are dissolved by the addition of 1 milliliter of solubilizer (Triton X-100 + 50% EtOH: 1: 4 by volume / volume). The tubes are swirled vigorously, decanted into vials, and counted in 10 milliliters of Liquiscint scintillation counting cocktail. Active recovery is the difference between cpm at 37 ° C and 0 ° C. The percentage inhibition of each concentration of the drug is the average of three determinations. IC50 values are derived from log probe analysis.

References 1. Snyder, S.H. and Coyle, J T., "Regional differences in [3H] -dopamine uptake into rat brain homogenates". J. Pharmacol. Exp. Ther. 165: 78-86 (1969). 2. Holz, R.W. and Coyle, JT, "The effects of various salts, temperature and the alkaloids veratridine and batrachotoxin on the uptake of [3H] -dopamine into synaptosomes from mouse brain 11. Mol. Pharmacol. 10: 746-758 (1974). , AS, Coyle, JT and Snyder, SH, "Catecholamine uptake by synaptosomes from mouse brain: Structure-activities of drugs with differential effects on dopamine and norepinephrine neurons." Mol Pharmacol., 7: 66-80 (1970). Hunt, R., Raynaud, JP, Leven, M. and Schacht, U., "Dopamine uptake inhihítors and releasing agents differentiated by the use of synaptosomes and field stimulated brain slices." Biochem Pharmacol. 28: 2011-2016 (1979 5. Cooper, BR, Hester, TJ and Maxwell, RA, "Behavioral and biochemical effects of the antidepressant bupropion (ellbutrin): Evidence for selective blockage of dopamine uptake in vivo." J. Pharmacol. Exp. Ther. 215: 1127-134 (1980). 6. Coyle, J.T. and Snyder, S.H. , "Catecholamine uptake by synaptosomes in homogenates of rat brain: Stereospecificity in different areas". J. Pharmacol. Exp. Ther. 170: 221-231 (1969). 7. Tuomisto, L., Tuomisto, J. and Smissman, E.E., "Dopamine uptake in striatal and hypothalamic synaptosomes: Conformational selectivity of the inhibition". Eur. J. Pharmacol. 25: 351-361 (1974). 8. Heikkila, R.E., Orlansky, H. and Cohen, G., "Studies on the distinction between uptake inhibition and release of [3H] -dopamine in rat brain tissue slices". Bioche. Pharmacol. 24: 847-852 (1975). 9. Baumann, P.A. and Maitre, L., "Is drug inhibition of dopamine uptake to misinterpretation of in vitro experimentsí". Nature 264: 789-790 (1976). 10. Raiteri, M., Angelini, F. and Levi, G., "A si pl-apparatus for studying the relay of neurotransmitters from synaptosomes". Eur, J. Pha-rriracol. "25 r 411-414 (1974).

TABLE 1 The antidepressant activity is achieved when the compounds of the invention are administered to a subject requiring such swallowing, in an oral, parenteral or intravenous effective dose of 0.1 to 50 milligrams / kilogram of body weight per day. A preferred effective dose within this range is from about 0.1 to 5 milligrams / kilogram of body weight per day. A particularly preferred effective amount is about 1 milligram / kilogram body weight per day. However, it should be understood that, for any particular subject, the specific dosage regimens should be adjusted according to the individual need and professional judgment of the person administering or supervising the administration of the compounds of the invention. It should further be understood that the dosages set forth herein are examples only, and do not limit to any extent the scope or practice of the invention. Activity against Parkinson's Disease is achieved when the compounds of the invention are administered to a subject requiring such treatment in an oral, parenteral or intravenous effective dose of 0.1 to 50 milligrams / kilogram of body weight per day. A preferred effective dose within this range is from about 0.1 to 5 milligrams / kilogram of body weight per day. A particularly preferred effective amount is about 1 milligram / kilogram of body weight per day. However, it should be understood, for any particular subject, that the specific dosage regimens should be adjusted according to the individual need and professional judgment of the person administering or supervising the administration of the compounds of the invention. It should further be understood that the dosages stipulated herein are examples only, and that they do not limit the scope or practice of the invention to any degree. Effective amounts of the compounds of the present invention can be administered to a subject by one of several methods, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. The compounds of the invention, while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable acid solution salts for purposes of stability, convenience of crystallization, greater solubility and the like. Preferred pharmaceutically acceptable acid addition salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, perchloric acids and the like, as well as organic acids, such as tartaric, citric, acetic, succinic acids. , maleic, fumaric and similar. The compounds of the present invention can be administered orally, for example, with an inert diluent, or with an edible vehicle. They can be enclosed in gelatin capsules, or they can be compressed into tablets. For the purpose of oral therapeutic administration, the compounds may be incorporated with excipients, and may be used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations may contain at least 4 percent of the compounds of the invention, the active ingredient, but may be varied depending on the particular form, and conveniently may be between 4 percent and about 70 percent of the unit's weight. The amount of the compound present in these compositions is such that a suitable dosage is obtained. Preferred compositions and preparations according to the present invention are prepared in such a way that an oral dosage form contains between 5.0 and 300 milligrams of the compounds of the invention. Tablets, pills, capsules, troches and the like may also contain the following auxiliaries: a binder, such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient, such as starch or lactose, a disintegrating agent, such as alginic acid, Primogel, corn starch, and the like; a lubricant, such as magnesium stearate or Sterotex; a brightener, such as colloidal silicon dioxide; and a sweetening agent, such as sucrose or saccharin, which can be added, or a flavoring agent, such as peppermint, methyl salicylate, or orange flavoring. When the unit dosage form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier, such as a fatty oil. Other unit dosage forms may contain other different materials that modify the physical form of the dosage unit, for example, as coatings. Accordingly, the tablets or pills can be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and dyes and flavorings. The materials used in the preparation of these different compositions must be pharmaceutically pure and non-toxic in the amounts used. For the purpose of parenteral therapeutic administration, the compounds of the present invention can be incorporated into a solution or suspension. These preparations should contain at least 0.1 percent of the compounds of the invention, but can be varied to be between 0.1 and about 50 percent of the weight thereof. The amount of the inventive compound present in these compositions is such that a suitable dosage is obtained. Preferred compositions and preparations according to the present invention are prepared in such a way that a parenteral dosage unit contains between 5.0 and 100 milligrams of the compounds of the invention. The solutions or suspensions may also include the following auxiliaries: a sterile diluent, such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; pH regulators, such as acetates, citrates or phosphates, and agents for tonicity adjustment, such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multi-dose vials made of glass or plastic. The following examples are presented for the purpose of illustrating this invention. In Table 2, the typical compounds of the invention are mentioned. Next to Table 2, representative illustrative preparations of the compounds of the invention are described.

TABLE 2 EXAMPLE 1 N- (1-benzylpiperidin-4-yl) -benzenesulfonamide To a solution of 10.0 grams, 52.6 millimoles, of 4-amino-1-benzyl-piperidine in 150 milliliters of dichloromethane, 1.36 grams (53 millimoles) were added. of benzenesulfonyl chloride. The solution was stirred for 1 hour at room temperature, diluted with 500 milliliters of dichloromethane, and washed with 5 percent aqueous sodium hydroxide, followed by water and brine. The organic phase was separated, dried (MgSO 4), and concentrated in vacuo to give 16.6 grams of the product as an oil. The compound was used without further purification.

EXAMPLE 2 1,1-2- (l-Benzylpiperidin-4-yl) -3- (4-chlorophenyl) -2,3-dihydrobenzofd1-isothiazole dioxide To a solution of 19.16 grams (58.1 mmol) of N- (l-benzylpiperidine) -4-yl) -benzenesulfonamide in 300 milliliters of dimethoxyethane at 0 ° C, was added 46.4 milliliters (116.1 millimoles) of normal butyl lithium (2.5 M) slowly via an addition funnel. The mixture was stirred using an overhead stirrer for 45 minutes at 0 ° C, and then 9.61 grams (63.9 millimoles) of p-chlorobenzaldehyde was added in one portion. The mixture was allowed to warm to room temperature, diluted with 1 liter of ethyl acetate, and washed with 2 x 500 milliliters of water, followed by 500 milliliters of brine. The organic phase was separated, dried (MgSO 4), and concentrated in vacuo. The residue was chromatographed on 300 grams of silica gel (eluted with ethyl acetate: heptane = 2: 1) to give 17.3 grams of the product as an orange paste. The above-mentioned residue was dissolved in 40 milliliters of concentrated sulfuric acid at room temperature, and stirred for 2 hours. The mixture was poured onto ice, and the solid precipitate was collected. The precipitate was divided between 200 milliliters of 5 percent aqueous sodium hydroxide and 250 milliliters of ethyl acetate. The organic phase was washed (2 x 200 milliliters) with water, followed by 200 milliliters of brine. The organic phase was separated, dried (MgSO 4) and concentrated in vacuo. The residue was passed through chromatography by evaporation on 200 grams of silica gel (eluted with ethyl acetate: heptane = 1: 1) to provide 7. 42 grams (28 percent) of a white solid, m.p. 174- 175 ° C.

EXAMPLE 3 3- (4-Chlorophenyl) -2- (4-piperidinyl) -2,3-dihydrobenzordl-isothiazole 1,1-dioxide hydrochloride hemihydrate To a solution of 2- (1- benzylpiperidin-4-yl) -3- (4-chlorophenyl) -2,3-dihydrobenzo- [d] isothiazole (7.25 grams, 16 mmol) of Example 6 (a), in 50 milliliters of dichloroethane at 0 ° C under nitrogen , chloroethyl chloroformate (1.9 milliliters, 17.6 millimoles) was added. The reaction was stirred for 5 minutes, then for 30 minutes, allowing it to warm to room temperature, and concentrated in vacuo at 30 ° C, followed by chromatography by evaporation on silica gel, eluting with heptane: ethylene acetate (1: 1). The obtained intermediate was heated in methanol for 10 minutes, chilled, and filtered, to provide 5.35 grams (84 percent yield) of a solid. This was combined with 4.1 grams of a similar preparation, and recrystallized from CH2C12 to give 9.0 grams (77.5 percent yield) of the product as the hydrochloride, m.p. > 285 ° C. ANALYSIS: Calculated for C18H19C1N202S »HC1» 0.5H20: 52.95% C 5.18% H 6.86% N Found: 53.26% C 5.20% H 6.82% N EXAMPLE 4 Maleate of 2-f -r3- (4-chlorophenyl) -1, l-dioxo-3H-benzord1-isothiazol-2-ill-piperidin-1-yl ethanol To a solution of 2.0 grams (5.01 mmol) of hemihydrate of 3- (4-chlorophenyl) -2- (4-piperidinyl) -2,3-dihydro-benzo [d] isothiazole 1,1-dioxide hydrochloride [Example 1 (a)] in 20 milliliters of dimethyl formamide, 930 milligrams (7.5 millimoles) of 2-bromoethanol were added, followed by 2.7 grams (20.0 millimoles) of potassium carbonate. The mixture was heated under reflux for 12 hours, it was allowed to cool to room temperature, diluted with ethyl acetate and washed with water. The organic phase was separated, dried (MgSO 4), and concentrated in vacuo. The residue was passed through chromatography by evaporation on silica gel [(eluted with CHCl3: MeOH = 1: 6)] to provide 823 milligrams of the aminoalcohol as a solid. To a solution of the free amine in 20 milliliters of dichloromethane, 235 milligrams (2.03 millimoles) of maleic acid was added. The solution was concentrated in vacuo and crystallized from ethyl acetate to give 980 milligrams (37 percent) of the maleate salt as a solid, m.p. 182-184 ° C. ANALYSIS: Calculated for C20H23ClN2O3S »C4H4O4: 55. 12% C 5.20% H 5.36% N Found: 54 97% C 4.94% H 5.24% N EXAMPLE 5 2- (3. {4- (Chlorophenyl) -1,2-dioxo-3H-benzord-1-isothiazol-2-yl] piperidin-1-yl}. Propyl) -isoindol-3 maleate -aiona To a solution of 2.30 grams (5.76 millimoles) of 3- (4-chlorophenyl) -2- (4-piperidinyl) -2, 3-dihydro-benzo [d] isothiazole 1,1-dioxide hydrochloride hemihydrate , in 10 milliliters of dimethyl formamide, 1.70 grams (6.34 millimoles) of N- (3-bromopropyl) -phtali ida were added, followed by 2.38 grams (17.28 millimoles) of potassium carbonate. The solution was heated to 100 ° C and stirred overnight. The solution was allowed to cool to room temperature, diluted with 200 milliliters of ethyl acetate and washed with water. The organic phase was separated, dried (MgSO), and concentrated. The residue was passed through chromatography by evaporation on silica gel (eluted with ethyl acetate) to provide 1.93 grams of an oily solid. The residue was dissolved in 10 milliliters of ethyl acetate, and 0.5 milliliters of concentrated hydrochloric acid was added. The mixture was concentrated in vacuo and dissolved in a minimum amount of dichloromethane. The hydrochloride salt was precipitated with diethyl ether to give 2.34 grams (69 percent) of the product as a solid). A solution of 1.77 grams (3.0 millimoles) of the hydrochloride salt in 200 milliliters of ethyl acetate was washed with 200 milliliters of 5 percent aqueous sodium hydroxide, followed by 200 milliliters of water and 200 milliliters of brine. The organic phase was separated, dried (MgSO 4), and concentrated in vacuo. To a solution of the residue in 20 milliliters of ethyl acetate, 371 milligrams (3.2 millimoles) of maleic acid was added. The mixture was heated, then concentrated in vacuo. The residue was recrystallized from dichloromethane: cyclohexane (1:10) to provide 1.95 grams (97 percent) of the maleate salt as a solid, m.p. 191-192 ° C. ANALYSIS: Calculated for C33H32C1N308S: 59.50% C 4.84% H 6.15% N Found: 59.22% C 4.57% H 6.15% N EXAMPLE 6 Maleate of 2- (2-f4-r3- (4-chlorophenyl) -l, l-dioxo-3H-benzoTd1 isothiazol-2-illpiperidin-l-yl> isoindol-l, 3-dione A solution of 2.00 grams (5.0 mmol) of 3- (4-chlorophenyl) -2- (4-piperidinyl) -2,3-dihydro-benzo. {D] isothiazole 1,1-dioxide hydrochloride of Example 6 (b), in 20 milliliters of dimethyl formamide, N- (2-bromoethyl) -phthalimide (1.5 grams, 6.0 mmol) was added, followed by potassium carbonate (2.1 grams, 15 mmol) .The solution was stirred and heated to 100 °. C for 2 hours The solution was allowed to cool to room temperature, diluted with 200 milliliters of ethyl acetate and washed with water and brine The organic phase was separated, dried (MgSO), and concentrated in vacuo. The residue was passed through chromatography by evaporation on silica gel [(eluted with ethyl acetate: heptane 1: 1)] to provide 1.05 grams of an oil, which was dissolved in 20 milliliters of ethyl acetate, and 1 equivalent was added. Maleic acid The mixture was concentrated in vacuo and recrystallized twice from ethyl acetate to give 0.48 grams (15 percent yield) of the maleate salt as a solid, m.p. = 189-191 ° C. ANALYSIS: Calculated for C28H26C1N304S # C4H407: 58.94% C 4.64% H 6.44% N Found: 58.85% C 4.65% H 6.31% N EXAMPLE 7 Maleate of l-f4- (3-f4-r3- (4-chlorophenyl) -1, l-dioxo-3H-benzofdl isothiazol-2-ill-1-piperidin-1-yl -propoxy) -3 -methoxyphenyl-ethanone To a solution of 2.0 grams (5.0 millimoles) of 3- (4-chlorophenyl) -2-piperidin-4-yl-2, 3-dihydro-benzo [d] isothiazole 1,1-dioxide hydrochloride of Example 1 (a), in 15 milliliters of dimethyl formamide, were added 1.24 grams (5.1 millimoles) of 4- (3-chloropropoxy) -3-methoxyacetophenone, followed by 2.0 grams (15 millimoles) of potassium carbonate. The mixture was heated under reflux for 15 hours, allowed to cool to room temperature, and diluted with 100 milliliters of ethyl acetate. The organic phase was washed with water, followed by brine. The organic phase was separated, dried (MgSO 4), and concentrated in vacuo. The residue was passed through chromatography by evaporation on silica gel (eluted with ethyl acetate) to give 2.10 grams of the product as a paste.

To a solution of the free amine in 20 milliliters of ethyl acetate, 425 milligrams (3.89 millimoles) of maleic acid was added. The solution was stirred for 10 minutes with slight heating. The solution was cooled to 0 ° C, and the maleate salt was precipitated to provide 2.34 grams of a solid. The solid was recrystallized from ethyl acetate to give 1.62 grams (47 percent) of the product as a solid, m.p. = 141-145 ° C. ANALYSIS: Calculated for C30H33ClN2O5S # C4H4O4: 59.60% C 5.44% H 4.09% N Found: 59.53% C 5.45% H 3.99% N EXAMPLE 8 1,1-2- (Benzylpiperidin-4-yl) -3- (4-fluorophenyl) -2,3-dihydrobenzofd] -isothiazole dioxide A solution of N- (1-benzylpiperidin-4-yl) benzenesulfonamide of the Example 1 above (18.7 grams, 56.5 millimoles), and 210 milliliters of dimethoxyethane, was cooled to 0 ° C under N2, followed by a slow addition over 25 minutes of 2.3 equivalents of normal butyl lithium (52 milliliters, 2.5 N / hexanes, 130 millimoles) keeping the temperature below 15 ° C. After mechanically stirring for a further 35 minutes, 4-fluorobenzaldehyde (7.4 grams, 59 mmol) was added in 50 milliliters of dimethoxyethane at 5 ° C, and the reaction was stirred for 2 hours. Ether (400 milliliters) was added, and the reaction was washed with water and brine, dried (MgSO 4), and concentrated in vacuo. The residue was passed through chromatography on silica gel, eluting with CHC13 to CHCl3: 5 percent MeOH, to provide 11.85 grams (46 percent yield) of the intermediate as a foam. The bulk of the intermediate (10.85 grams) was stirred until dissolved in 35 milliliters of concentrated sulfuric acid for 2 hours, then poured onto ice, and the resulting solid was filtered. The solid was partitioned between ethyl acetate and 5 percent NaOH, to a pH of 10, and the organic layer was dried (MgSO 4), and concentrated in vacuo. This was purified on silica gel, eluting with CHC13: 1 percent methanol, and then recrystallized from ether to give 4.9 grams (24 percent yield) of the product as a solid, m.p. = 118-119 ° C. ANALYSIS: Calculated for C25H25FN202S: 68.78% C 5.77% H 6.42% N Found: 68.75% C 5.67% H 6.37% N EXAMPLE 9 3- (4-f luorofenyl) -2- (4-piperidinyl) -2,3-dihydrobenzo-d-isothiazole 1,1-dioxide hydrochloride To a solution of 2- (1,1-dioxide) -benzylpiperidin-4-yl) -3- (4-f luorofenyl) -2, 3-dihydrobenzo [d] isothiazole (8.5 grams, 19.4 mmol) of Example 8, in 80 milliliters of dichloroethane at 5 ° C under nitrogen, Chloroethyl chloroformate (2.3 milliliters, 21.4 millimoles) was added. The reaction was stirred for 1 hour, allowing it to warm to room temperature, and then concentrated in vacuo at 30-35 ° C until an oil was obtained, which was passed through chromatography by evaporation on silica gel, eluting with CHC13 to CHC13. to CHC13: 2 percent methanol. The obtained intermediate was heated in methanol for 1 hour, evaporated, and a paste was formed with ethyl acetate, to provide 5.4 grams (72 percent yield) of a solid. This was recrystallized from methanol to give 3.4 grams (45.5 percent yield) of the product as the hydrochloride, m.p. = 271-272 ° C. ANALYSIS: Calculated for C18H19FN202SHC1: 56.47% C 5.27% H 7.32% N Found: 56.28% C 5.13% H 7.16% N

Claims (49)

1. A compound that has the formula: wherein X and Y are independently halogen, lower alkyl, lower alkoxy, arylalkoxy, acyl, hydroxy, nitro, amino, trifluoromethyl, and hydrogen; n, p and q are independently integers of 1 or 2; R is hydrogen, alkyl, arylalkyl, acyl, - (CH2) raNHR1 # where R? is hydrogen, lower alkyl, arylalkyl, acyl, or lower alkoxycarbonyl; Z is hydrogen, halogen, lower alkyl, lower alkoxy or acyl; m is an integer from 2 to 4; s is an integer of 1 or 2; and pharmaceutically acceptable acid addition salts thereof, and optical isomers thereof, wherein such isomers exist.

2. The compound as defined in the claim 1, wherein R is arylalkyl, acyl, - (CH2) m-OR? , or (CH2) NHR1.

3. The compound as defined in claim 1, wherein R is: .

The compound as defined in the claim 1, which is: 2- (3- [4- [3- (4-chlorophenyl) -1, l-dioxo-3H-benzofd] isothiazol-2-yl] piperidin-1-ylpropyl) isoindol-i, 3-dione, or a pharmaceutically acceptable salt thereof.

5. The compound as defined in claim 4, wherein the salt is maleate.

6. The compound as defined in claim 1, which is 2 [1 [3 (1-chlorophenyl) -1, l-dioxo-3H-benzo [d] isothiazol-2-yl] piperidin-1-yl] -ethanol , or a pharmaceutically acceptable salt thereof.

7. The compound as defined in the claim 6, where the salt is maleate.

8. The compound as defined in claim 1, which is l-. { 4- [3- (4-chlorophenyl) -1,1-dioxo-3H-benzo [d] isothiazol-2-yl) -l-piperidin-1-yl} -propoxy-3-methoxyphenyl] -ethanone, or a pharmaceutically acceptable salt thereof.

9. The compound as defined in claim 8, wherein the salt is maleate.

10. The compound as defined in claim 1, which is 2- (l-benzylpiperidin-4-yl) -3- (4-fluorophenyl) -2,3-dihydrobenzo [d] isothiazole 1,1-dioxide. , or a pharmaceutically acceptable salt thereof.

11. The compound as defined in the claim I, which is 3- (4-fluorophenyl) -2- (4-piperidinyl) -2,3-dihydrobenzo [d] isothiazole 1,1-dioxide, or a pharmaceutically salt thereof.

12. The compound as defined in the claim II, where the salt is hydrochloride.

The compound as defined in claim 1, which is 3- (4-chlorophenyl) -2- (4-piperidinyl) -2,3-dihydrobenzo [d] isothiazole 1,1-dioxide, or a salt pharmaceutically thereof.

The compound as defined in claim 13, wherein the salt is hydrochloride hemihydrate.

15. The compound as defined in the claim 1, which is 2- (2- { 4- [3- (4-chlorophenyl) -1, l-dioxo-3H-benzo [d] isothiazol-2-yl] pipe idin-l-il.} ethyl) isoindol-l, 3-dione, or a pharmaceutically acceptable salt thereof.

16. The compound as defined in claim 15, wherein the salt is maleuate.

17. An antidepressant composition, which comprises an effective antidepressant amount a compound of the formula: wherein X and Y are independently halogen, lower alkyl, lower alkoxy, arylalkoxy, acyl, hydroxy, nitro, amino, trifluoromethyl, and hydrogen; n, p and q are independently integers of 1 or 2; R is hydrogen, alkyl, arylalkyl, acyl, - (CH2) m.OR1, - (CH2) mNHR1, (- H, - (CH2) m «- and * -. wherein R is hydrogen, lower alkyl, arylalkyl, acyl, or lower alkoxycarbonyl; Z is hydrogen, halogen, lower alkyl, lower alkoxy or acyl; is an integer from 2 to 4; s is an integer of 1 or 2; and pharmaceutically acceptable acid addition salts thereof, and optical isomers thereof, wherein such isomers exist.

18. The composition as defined in claim 17, wherein R is hydrogen, lower alkyl and arylalkyl.

19. The composition as defined in claim 17, wherein R is hydrogen, lower alkyl, - (CH2) m .o-Q ^

20. The composition as defined in claim 17, wherein the compound is 2- (3- [4- [3- (4-chlorophenyl) -1, l-dioxo-3H-benzo [d] isothiazol-2-yl] piperidin-1-yl] propyl) isoindol-1,3-dione, or a pharmaceutically acceptable salt thereof.

21. The composition as defined in claim 17, wherein the compound is maleate.

22. The composition as defined in claim 17, wherein the compound is 2-. { 4- [3- (4-chlorophenyl) -1, l-dioxo-3H-benzo [d] isothiazol-2-yl] piperidin-1-yl] -ethanol, or a pharmaceutically acceptable salt thereof.

23. The composition as defined in claim 17, wherein the salt is maleate.

24. The composition as defined in claim 17, wherein the compound is l-. { 4- [3- (4-chlorophenyl) -1, l-dioxo-3H-benzo [d] isothiazol-2-yl) -1-piperidin-1-yl} -propoxy-3-methoxyphenyl] -ethanone, or a pharmaceutically acceptable salt thereof.

25. The composition as defined in claim 17, wherein the salt is maleate.

26. The composition as defined in claim 17, wherein the compound is 2- (l-benzylpiperidin-4-yl) -3- (4-fluorophenyl) -2,3-dihydro-benzo 1,1-dioxide. [d] isothiazole, or a pharmaceutically acceptable salt thereof.

27. The composition as defined in claim 17, wherein the compound is 3- (4-fluorophenyl) -2- (4-piperidinyl) -2,3-dihydrobenzo [d] isothiazole 1,1-dioxide, or a salt pharmaceutically thereof.

28. The composition as defined in claim 17, wherein the salt is maleate.

29. The composition as defined in claim 17, wherein the compound is 3- (4-chlorophenyl) -2- (4-piperidinyl) -2,3-dihydrobenzo [d] isothiazole 1,1-dioxide, or a pharmaceutically salt thereof.

30. The composition as defined in claim 17, wherein the salt is hydrochloride hemihydrate.

31. The composition as defined in claim 17, wherein the compound is 2- (2- { 4- [3- (4-chlorophenyl) -1, l-dioxo-3H-benzo [d] isothiazole- 2-yl] piperidin-1-yl.} Ethyl) isoindol-1,3-dione, or a pharmaceutically acceptable salt thereof.

32. The composition as defined in claim 17, wherein the salt is a maleate.

33. A method for reducing depression in a patient in need thereof, which comprises administering to a patient, an effective anti-depressant amount of a compound of the formula: wherein X and Y are independently halogen, lower alkyl, lower alkoxy, arylalkoxy, acyl, hydroxy, nitro, amino, trifluoromethyl, and hydrogen; n, p and q are independently integers of 1 or 2; R is hydrogen, alkyl, arylalkyl, acyl, - (CH2) m-ORlr - (CH ^ NHR ^ where R? is hydrogen, lower alkyl, arylalkyl, acyl, or lower alkoxycarbonyl; Z is hydrogen, halogen, lower alkyl, lower alkoxy or acyl; is an integer from 2 to 4; s is an integer of 1 or 2; and pharmaceutically acceptable acid addition salts thereof, and optical isomers thereof, wherein such isomers exist.

34. The method as defined in claim 33, wherein R is arylalkyl, acyl, - (CH) m-OR1 or (CH2) NHR1.

35. The method as defined in claim 33, wherein R is:

36. The method as defined in the claim; 33, wherein the compound is 2- (3- [4- [3- (4-chlorophenyl) -1,1-dioxo-3H-benzo [d] isothiazol-2-yl] piperidin-1-yl] propyl) isoindol-1,3-dione, or a pharmaceutically acceptable salt thereof.

37. The method as defined in the claim 33, where the salt is maleate.

38. The method as defined in claim 33, wherein the compound is 2-. { l- [3- (4-chlorophenyl) -1,1-dioxo-3H-benzo [d] isothiazol-2-yl] piperidin-1-yl] -ethanol, or a pharmaceutically acceptable salt thereof.

39. The method as defined in claim 33, wherein the salt is maleate.

40. The method as defined in claim 33, wherein the compound is l-. { 4- [3- (4-chlorophenyl) -1,1-dioxo-3H-benzo [d] isothiazol-2-yl) -l-piperidin-1-yl} -propoxy-3-methoxyphenyl] -ethanone, or a pharmaceutically acceptable salt thereof.

41. The method as defined in claim 33, wherein the salt is maleate.

42. The method as defined in the claim 33, wherein the compound is 2- (1-benzylpiperidin-4-yl) -3- (4-fluorophenyl) -2,3-dihydrobenzo [d] isothiazole 1,1-dioxide, or a pharmaceutically acceptable salt thereof .

43. The method as defined in the claim 33, wherein the compound is 3- (4-fluorophenyl) -2- (4-piperidinyl) -2,3-dihydrobenzo [d] isothiazole 1,1-dioxide, or a pharmaceutically salt thereof.

44. The method as defined in claim 33, wherein the salt is hydrochloride.

45. The method as defined in claim 33, wherein the compound is 3- (4-chlorophenyl) -2- (4-piperidinyl) -2,3-dihydrobenzo [d] isothiazole 1,1-dioxide, or a pharmaceutically salt thereof.

46. The method as defined in claim 33, wherein the salt is hydrochloride hemihydrate.

47. The method as defined in claim 33, wherein the compound is 2- (2-. {4- [3- (4-chlorophenyl) -i, l-dioxo-3H-benzo [d] isothiazole-) 2-yl] piperidin-l-yl} ethyl) isoindol-1,3-dione, or a pharmaceutically acceptable salt thereof.

48. The method as defined in claim i ~ -33, wherein the salt is maleate. J 49. A composition against Parkinson's Disease, which comprises an effective anti-depressant amount of a compound of the formula: wherein X and Y are independently halogen, lower alkyl, lower alkoxy, arylalkoxy, acyl, hydroxy, nitro, amino, trifluoromethyl, and hydrogen; n, P And sop independently whole of 1 or 2; R is hydrogen, alkyl, arylalkyl, acyl, - (CH2) m-ORl t - (CH2) "HR1, wherein R x is hydrogen, lower alkyl, arylalkyl, acyl, or lower alkoxycarbonyl; Z is hydrogen, halogen, lower alkyl, lower alkoxy or acyl; m is an integer from 2 to 4; s is an integer of 1 or 2; and pharmaceutically acceptable acid addition salts thereof, and optical isomers thereof, wherein such isomers exist. 50. A method for the treatment of Parkinson's Disease, in a patient in need thereof, which comprises administering to a patient, an effective amount against Parkinson's Disease of a compound of claim

49. SUMMARY This invention relates to 3-aryl-2- (4-piperidinyl 1-substituted) -1, 1-dioxo-3H-benzo [d] isothiazoles and related compounds of the formula (I): wherein X and Y are independently halogen, lower alkyl, lower alkoxy, arylalkoxy, acyl, hydroxy, nitro, amino, trifluoromethyl, and hydrogen; n, p and q are independently integers of 1 or 2; R is hydrogen, lower alkyl, lower aryalkyl, acyl, - (CH2) m-0R1, - (CH2) mNHR1, formulas (a) and (b), wherein R1 is hydrogen, lower alkyl, aryl lower alkyl, acyl, and lower alkoxycarbonyl; Z is hydrogen, halogen, lower alkyl, lower alkoxy, and acyl; m is an integer from 2 to 4; s is an integer of 1 or 2; and the pharmaceutically acceptable acid addition salts thereof, and the optical isomers thereof, wherein such isomers exist. The compounds of formula (I) of the present invention are useful as modulators of neurotransmitter function, such as serotonergic and adrenergic, and as such, are useful as antidepressants, and of dopaminergic function, and as such, may be useful for diseases where it may be useful to enhance the dopaminergic activity, for example, Parkinson's disease. * * * * *