ALPHA1C ADRENERGIC RECEPTOR ANTAGONISTS

Abstract: This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as selective alpha1C adrenergic receptor antagonists. One application of these compounds is in the treatment of benign prostatic hypertrophy. These compounds are selective in their ability to relax smooth muscle tissue enriched in the alpha1C receptor subtype without at the same time inducing orthostatic hypotension. One such tissue is found surrounding the urethral lining. Therefore, one utility of the instant compounds is to provide acute relief to males suffering from benign prostatic hyperplasia, by permitting less hindered urine flow. Another utility of the instant compounds is provided by combination with a human 5-alpha reductase inhibitory compound, such that both acute and chronic relief from the effects of benign prostatic hyperplasia are achieved.

Description: TITLE OF THE INVENTION ALPHA1C ADRENERGIC RECEPTOR ANTAGONISTS BACKGROUND OF THE INVENTION 1. Field of the Invention: This application is a continuation-in-part of U.S. Serial No. 08/229,276, filed April 14, 1995, the contents of which are hereby incorporated by reference. This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as selective alpha- lc adrenoceptor antagonists. One application of these compounds is in the treatment of benign prostatic hypertrophy. These compounds are selective in their ability to relax smooth muscle tissue enriched in the alphalC receptor subtype without at the same time inducing orthostatic hypotension. One such tissue is found surrounding the urethral lining. Therefore, one utility of the instant compounds is to provide acute relief to males suffering from benign prostatic hyperplasia, by permitting less hindered urine flow. Another utility of the instant compounds is provided by combination with a human 5-alpha reductase inhibitory compound, such that both acute and chronic relief from the effects of benign prostatic hyperplasia are achieved. Other advantages of the instant compounds are appreciated from the complete disclosure. ii. Background: Human adrenergic receptors are integral membrane proteins which have been classified into two broad classes, the alpha and the beta adrenergic receptors. Both types mediate the action of the peripheral sympathetic nervous system upon binding of catecholamines, norepmephrine and epmephrine. Norepinephrine is produced by adrenergic nerve endings, while epmephrine is produced by the adrenal medulla. The binding affinity of adrenergic receptors for these compounds forms one basis of the classification: alpha receptors bind norepinephrine more strongly than epinephrine and much more strongly than the synthetic compound isoproterenol. The binding affinity of these hormones is reversed for the beta receptors. In many tissues, the functional responses, such as smooth muscle contraction, induced by alpha receptor activation are opposed to responses induced by beta receptor binding. Subsequently, the functional distinction between alpha and beta receptors was further highlighted and refined by the pharmacological characterization of these receptors from various animal and tissue sources. As a result, alpha and beta adrenergic receptors were further subdivided into αi, cc2, Bl , and B2 subtypes. Functional differences between i and oc2 receptors have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed. Thus, in WO 92/0073, the selective ability of the R(+) enantiomer of terazosin to selectively bind to adrenergic receptors of the alpha 1 subtype was reported. The oci/α2 selectivity of this compound was disclosed as being significant because agonist stimulation of the cτ2 receptors was said to inhibit secretion of epinephrine and norepinephrine, while antagonism of the oc2 receptor was said to increase secretion of these hormones. Thus, the use of non- selective alpha-adrenergic blockers, such as phenoxybenzamine and phentolamine, is limited by their cx2 adrenergic receptor mediated induction of increased plasma catecholamine concentration and the attendant physiological sequelae (increased heart rate and smooth muscle contraction). For a general background on the α-adrenergic receptors, the reader's attention is directed to Robert R. Ruffolo, Jr., α- Adrenoreceptors: Molecular Biology. Biochemistry and Pharmacology. (Progress in Basic and Clinical Pharmacology series, Karger, 1991), wherein the basis of αi/ot2 subclassification, the molecular biology, signal transduction (G-protein interaction and location of the significant site for this and ligand binding activity away from the 3'-terminus of alpha adrenergic receptors), agonist structure-activity relationships, receptor functions, and therapeutic applications for compounds exhibiting α-adrenergic receptor affinity was explored. The cloning, sequencing and expression of alpha receptor subtypes from animal tissues has led to the subclassification of the αi receptors into cxiA, (Lomasney, et al., J. Biol. Chem.. 266:6365-6369 (1991), rat αiA; Bruno et al., BBRC.179:1485-1490 (1991), human o iA), otlB (Cotecchia, et al., PNAS. 85;7159-7163 (1988), hamster cxlB; Libert, et al., Science. (1989), dog αiB; Ramarao, et al., J. Biol. Chem.. 267:21936-21945 (1992), human αiB), and most recently, in a study using bovine brain, a new αic subtype was proposed (Schwinn, et al.. J. Biol. Chem.. 265:8183-8189, 1990; Hirasawa et al., BBRC 195:902-909 (1993), described the cloning, functional expression and tissue distribution of a human αic adrenergic receptor; Hoehe et al., Human Mol. Genetics 1 (5):349 (8/92) noted the existence of a two-allele Pstl restriction fragment polymoφhism in the αic adrenergic receptor gene; another study suggests that there may even be an alpha- ID receptor subtype, see Perez et al., Mol. Pharm... 40:876-883, 1992). Each αi receptor subtype exhibits its own pharmacologic and tissue specificities. Schwinn and coworkers noted that the cloned bovine αi c receptor exhibited pharmacological properties proposed for the c i A subtype. Nonetheless, based on its non-expression in tissues where the αi A subtype is expressed, and its sensitivity to chloroethylclonidine, the receptor was given a new designation. The differences in the α-adrenergic receptor subtypes have relevance in pathophysiologic conditions. Benign prostatic hypertrophy, BPH, is an illness typically affecting men over fifty years of age, increasing in severity with increasing age. The symptoms of the condition include, but are not limted to, increased difficulty in urination and sexual dysfunction. These symptoms are induced by enlargement, or hypertrophy, of the prostate gland. As the prostate increases in size, it impinges on free-flow of fluids through the male urethra. Concommitantly, the increased noradrenergic innervation of the enlarged prostate leads to an increased adrenergic tone of the bladder neck and urethra, further restricting the flow of urine through the urethra. The mechanism of prostatic hypertrophy is well understood. The male hormone, 5α-dihydrotestosterone has been identified as the principal culprit. The continual production of 5α- dihydrotestosterone by the male testes induces incremental growth of the prostate gland throughout the life of the male. Beyond the age of about fifty years, in many men, this enlarged gland begins to obstruct the urethra with the pathologic symptoms noted above. The elucidation of the mechanism summarized above has resulted in the recent development of effective agents to control, and in many cases reverse, the pernicious advance of BPH. In the forefront of these agents is Merck & Co., Inc.s' product PROSCAR® (finasteride). The effect of this compound is to inhibit the enzyme testosterone 5- alpha reductase, which converts testosterone into 5α-dihydrotesterone, resulting in a reduced rate of prostatic enlargement, and often reduction in prostatic mass. The development of such agents as PROSCAR® bodes well for the long-term control of BPH. However, as may be appreciated from the lengthy development of the syndrome, its reversal also is not immediate. In the interim, those males suffering with BPH continue to suffer, and may in fact lose hope that the agents are working sufficiently rapidly. In response to this problem, one solution is to identify pharmaceutically active compounds which complement slower-acting therapeutics by providing acute relief. Agents which induce relaxation of the urethral smooth muscle, by binding to alpha- 1 adrenergic receptors, thus reducing the increased adrenergic tone due to the disease, would be good candidates for this activity. Thus, one such agent is alfuzosin, which is reported in EP 0 204597 to induce urination in cases of prostatic hypertrophy. Likewise, in WO 92/0073, the selective ability of the R(+) enantiomer of terazosin to bind to adrenergic receptors of the αi subtype was reported. In addition, in WO 92/161213, hereby incoφorated by reference, combinations of 5- alpha-reductase inhibitory compounds and alpha 1 -adrenergic receptor blockers (terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin) were disclosed. However, no information as to the αiA, αiB» or αic subtype specificity of these compounds was provided as these refinements were not yet available. Current therapy for BPH uses existing non-selective alpha- 1 antagonists such as prazosin (Minipress, Pfizer) or Terazosin (Hytrin, Abbott). These non-selective antagonists suffer from side effects related to antagonism of the alpha- la and alpha- lb receptors in the peripheral vasculature, eg., orthostatic hypotension and syncope. Typically, identification of active compounds is through use of animal tissues known to be enriched in adrenergic receptors. Thus, rat tissues have been used to screen for potential adrenergic receptor antagonists. However, because of species variability, compounds which appear active in animal tissue may not be active or sufficiently selective in humans. This results in substantial wastage of time and effort, particularly where high volume compound screening programs are employed. There is also the danger that compounds, which might be highly effective in humans, would be missed because of their absence of appreciable affinity for the heterologous animal receptors. In this regard, it has been noted that even single amino acid changes between the sequence of biologically active proteins in one species may give rise to substantial pharmacological differences. Thus, Fong et al., (J. Biol. Chem.. 267:25668-25671, 1992) showed that there are 22 divergent amino acid residues between the sequence of the human neurokinin-1 receptor and the homologous rat receptor. They further showed, in studies with mutant receptors, that substitution of only two amino acid residues was both necessary and sufficient to reproduce the rat receptor's antagonist binding affinity in the human receptor. Oksenberg et al., (Nature. 360:161-163, 1992) showed that a single amino-acid difference confers major pharmacological variation between the human and the rodent 5 -hydroxy tryptamine receptors. Likewise, Kuhse et al., (Neuron. 5:867-873, 1990) showed that a single amino-acid exchange alters the pharmacology of the neonatal rat glycine receptor subunit. This difficulty and unpredictability has resulted in a need for a compound screen which will identify compounds that will be active in humans. These problems are solved by cloning the human adrenergic receptor of the αic subtype and the use of a screening assay which enables identification of compounds which specifically interact with the human αlC adrenergic receptor. Marshall et al (Br. J. Pharm.. 107:327 (1992)) speculated that compounds which specifically interact with the αlC adrenergic receptor may be responsible for contraction of the human prostate. As disclosed in the instant patent disclosure, a cloned human αic adrenergic receptor and a method for identifying compounds which bind the human αic receptor has now made possible the identification of specific human αic adrenergic receptor antagonists. In the instant patent disclosure, we reveal novel compounds which we have discovered specifically bind the human αi c receptor. These compounds are further tested for binding to other human alpha 1 receptor subtypes, as well as counterscreened against other types of receptors, thus defining the specificity of the compounds for the human αic adrenergic receptor. Compounds of his invention are used to reduce the acute symptoms of BPH. Thus, compounds of this invention may be used alone or in conjunction with a more long-term anti-BPH therapeutics, such as testosterone 5-alpha reductase inhibitors, including PROSCAR® (finasteride). Aside from their utility as anti-BPH agents, these compounds may be used to induce highly tissue-specific, localized αic adrenergic receptor blockade whenever this is desired. Effects of this blockade include reduction of intra-ocular pressure, control of cardiac arrhythmias, and possibly a host of alpha- 1C receptor mediated central nervous system events. SUMMARY OF THE INVENTION This invention provides compounds for the treatment of urinary obstruction caused by benign prostatic hypertropy (also known as benign prostatic hypeφlasia or BPH). The compounds selectively antagonize the human alpha- 1C adrenergic receptor at nanomolar and subnanomolar concetrations while exhibiting at least ten fold lower affinity for the alphal A and alphal B human adrenergic receptor and many other G-protein coupled receptors. This invention has the advantage over non-selective alpha- 1 adrenoceptor antagonists of reduced side effects related to peripheral adrenergic blockade. Such side effects include orthostatic hypotension, syncope, lethargy etc. These compounds have the structure: and a pharmaceutically acceptable salt, prodrug, polymoφh, or metabolite thereof wherein: n is an integer from 3 to 5; Y represents carbonyl, sulphonyl, -CO-CH2-, or -CO-NR12-; Rl2 is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted phenyl; E is carbonyl or sulphonyl; A, B, G, D are independently carbon or nitrogen; R1-R4 are independently selected from the group consisting of hydrogen; halogen; nitro; amino; substituted or unsubstituted lower alkyl; perhalogenated lower alkyl; substituted or unsubstituted lower alkoxy; sulfonyl alkyl; and substituted or unsubstituted aryl or heteroaiyl; with the proviso that if any of A, B, G, or D is a nitrogen, then the substituent R group is not present; Q is, independently, (-CH2-)r, -NH-, S, or O; r is 0-3; and X is a) or b) T is nitrogen, carbon, lower alkylene of one to three carbons or lower alkenylene of one to three carbons; R7-R10 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, and lower alkoxy; and Z is O, S, CH2, CH2θ, OCH2, SCH2, lower alkylene, lower alkenylene, NH, or NMe. In one embodiment of the invention, the compound has the structure: and a pharmaceutically acceptable salt, prodrug, polymoφh or metabolite thereof, wherein all substituents are as defined above. These compounds may be used to advantage whenever specific blockade of the alpha IC adrenergic receptor is desirable, and are particularly useful in the treatment of benign prostatic hypeφlasia (BPH) and for inhibiting contraction of prostate tissue, either alone or in combination with other active compounds. One preferred combination therapy includes the use of compounds described herein in conjuction with a compound effective to inhibit testosterone 5-alpha reductase. BRIEF DESCRIPTION OF THE FIGURES Fig. 1 : Sequence of cDNA obtained by PCR of human heart mRNA, SEQ. ID:4:. Fig. 2: Comparison of the open reading frame obtained from human heart, SEQ ID:5:, and the bovine alpha-lC adrenergic receptor sequence, SEQ. ID:6:. Fig. 3: Sequence of cDNA obtained by screening a human hippocampus cDNA library using the heart mRNA derived sequence from figure 1 , SEQ. ID:7: Fig. 4: Sequence of 3' coding region of human alpha- IC gene, obtained by PCR amplification of a human genomic DNA library with oligonucleotides, SEQ. ID: 10:. Fig. 5: Sequence of the ligated portions of human alpha- IC DNA shown in figures 3 and 4, SEQ. ID:11:. Fig. 6: The amino acid sequence of the human alpha-lC adrenergic receptor, SEQ ID: 12:. Fig. 7: The alignment of the nucleotide and amino acid sequence of the human alpha- IC adrenergic receptor, showing the 5 '-untranslated region, SEQ. ID:1 1 : and SEQ. ID:12:. Fig. 8: Expression of the human alpha-lC adrenergic receptor in COS cells: Binding data using membranes from cells transfected with the expression vector alone and the expression vector containing the human alpha- IC adrenergic receptor coding sequences. Fig. 9: Binding curves of compounds using membranes from COS cells transfected with the human alpha- IC adrenergic receptor containing expression vector. Fig. 10: Nucleotide sequence of the human alphal A receptor, SEQ. ID: 13: Fig. 1 1: Amino acid sequence of the human alphal A adrenergic receptor, SEQ. ID: 14: Fig. 12: Partial sequence of the human alphal B adrenergic receptor, SEQ. ID: 17: Fig. 13: Partial sequence of the human alpha IB adrenergic receptor, SEQ. ID:20: Fig. 14: Partial sequence of the human alphal B adrenergic receptor, SEQ. LD:23: Fig. 15: Composite human/rat alphalB adrenoreceptror, SEQ. ID:24: Fig. 16: An ino acid sequence of the composite human/rat alphal B adrenergic receptor, SEQ. LD:25: Fig. 17: Binding curves of compounds using membranes from COS cells transfected with the human alphal A, IB, and IC adrenergic receptor expression vectors. Fig. 18: Sequence of truncated human alphal C adrenergic receptor, SEQ. ID:26:. Fig. 19: Nucleotide sequence of the human αlC adrenergic receptor having a Pstl site, SEQ.ID:27:. Fig. 20: Amino acid sequence of the human αlC adrenergic receptor encoded by the Pstl site encoding allele, SEQ.ID:28:. Fig. 21 : Alignment of the nucleotide and amino acid sequences of figures 19 and 20, SEQ.ID:27: and SEQ.ID:28:. FIG. 22: Nucleotide sequence of the human αi A adrenergic receptor, Seq.ID:29:. Fig. 23: Amino acid sequence of the human αiA adrenergic receptor, SEQ.ID:30:. Fig. 24: Alignment of the nucleotide and amino acid sequences of figures 22 and 23, SEQ.ID:29: and SEQ.Lϋ:30:. DETAILED DESCRIPTION OF THE INVENTION Compounds of this invention have the structure: and a pharmaceutically acceptable salt, prodrug, polymoφh, or metabolite thereof wherein: n is an integer from 3 to 5; Y represents carbonyl, sulphonyl, -CO-CH2-, or -CO-NR12-; Rl2 is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted phenyl; E is carbonyl or sulphonyl; A, B, G, D are independently carbon or nitrogen; R1-R4 are independently selected from the group consisting of hydrogen; halogen; nitro; amino; substituted or unsubstituted lower alkyl; perhalogenated lower alkyl; substituted or unsubstituted lower alkoxy; sulfonyl alkyl; and substituted or unsubstituted aryl or heteroaryl; with the proviso that if any of A, B, G, or D is a nitrogen, then the substituent R group is not present; Q is, independently, (-CH2-)r, -NH-, S, or O; r is 0-3; and X is a) or b) T is nitrogen, carbon, lower alkylene of one to three carbons or lower alkenylene of one to three carbons; RJ-RlO are independently selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, and lower alkoxy; and Z is O, S, CH2, CH20, OCH2, SCH2, lower alkylene, lower alkenylene, NH, or NMe. In one embodiment of the invention, the compound has the structure: and a pharmaceutically acceptable salt, prodrug, polymoφh or metabolite thereof, wherein all substituents are as defined above. As used herein, the term lower alkyl, lower alkylene, or lower alkoxy means a substituted or unsubstituted, straight or branched chain of one to eight carbons. As used herein, a substituted group means that the group is halogenated, perhalogenated, particularly -CF3, alkylated, alkoxylated, or is substituted with an aryl or heteroaryl. The term sulfonyl alkyl means a sulfonyl lower alkyl. In a class of this embodiment of this invention, the compound is a piperidyl benzoxazinone substituted butyl saccharine or a spiroindanyl piperidine substituted butyl saccharine. In this embodiment of the invention, the compound is selected from: and wherein all variables are as previously defined. In specific embodiments of this invention, one of R! -R4 is preferably an electron withdrawing group such as the nitro group, a halogen or a halogenated alkyl which substituents we have discovered contribute to improved bioavailability. Representative compounds of this invention exhibit high selectivity for the human alpha IC adrenergic receptor and are therefore useful for treating benign prostatic hypeφlasia and for inhibiting contraction of prostate tissue. One implication of this selectivity for the human alpha IC adrenergic receptor is that these compounds display selectivity for lowering intraurethral pressure without substantially affecting diastolic blood pressure. Representative compounds of this invention display submicromolar affinity for the human alphal C adrenergic receptor subtype while displaying at least ten-fold lower affinity for the human alphal A and alphal B adrenergic receptor subtypes, and many other G- protein coupled human receptors. Particular representative compounds of this invention exhibit nanomolar and subnanomolar affinity for the human alpha IC adrenergic receptor subtype while displaying at least 30 fold lower affinity for the human alphal A and alpha IB adrenergic receptor subtypes, and many other G-protein coupled human receptors. Representative compounds of this invention exhibit Ki's for human alphal C adrenergic receptors over a 500 fold lower than for the human alphal A or alpha IB adrenergic receptors, while exhibiting greater than 300 fold selectivity for the human alphal C adrenergic receptor over all other human G-protein coupled receptors tested (including serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors). Furthermore, representative compounds of this invention exhibit good bioavailability in known animal models (approximately 30% in dogs and 16% in rats). These indicia are expected to provide good indications of bioavailability in humans. Compounds of this invention are prepared by a two step alkylation process beginning with a saccharine or substituted saccharine (referred to as "the saccharine moiety") prepared according to methods known in the art (see for example US Patents 4,818,756; 4,937,343; 4,988,809 and 5,187,276, hereby incoφorated by reference for this puφose). Preparation of spiropiperidines used herein in the preparation of compounds of this invention is described, for example, in published European Patent Application 90313262.9 (publication number 0 431 943 A2, 6/12/91 , herein incoφorated by reference for this puφose). The saccharine moiety is alkylated with a reagent such as 1 ,4- dibromobutane, or a similar reagent, to form the butyl-saccharine moiety (see Scheme 1 below). The butyl saccharine is then alkylated with a piperidinyl benzoxazinone (prepared as shown in Scheme 2 below) or with a spiroindanyl piperidine (prepared as shown in Scheme 3 below) to form the active compounds of this invention (see Scheme 1 below). These steps are further defined with reference to the following schemes, and the synthetic examples appended hereto. It should be understood that the specific solvents, catalysts and reactants could be substituted by analogous reagents by those skilled in the art. All substituents are as defined above: Scheme 1 or Scheme 2 P= benzyl, benzyloxycarbonyl or tert-butoxycarbonyl R = N0 2 , OH, SH, CH 2 0H, H cyclization and/or CI deprotection Scheme 3 PhCOCI Abbreviations: DMF is dimethylformamide; EtOH is ethanol. These compounds are administered in dosages effective to antagonize the alphal C receptor where such treatment is needed, as in BPH and for inhibiting contraction of prostate tissue. For use in medicine, the salts of the compounds of this invention will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological mileu. Where the compounds according to the invention have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymoφhs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention. Specific compounds within the scope of the present invention include but are not limited to: 1 ,1 -Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l -yl)-butyl)- 1 ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(3 ,4-dihy dro-2-oxo-( 1 /)-quinolin- 1-yl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxo-3 , 1 ,4-benzoxazinyl)-piperidin- 1 -y l)-butyl)- 1 ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxo-( 1 H)-quinolin- 1 -y l)-piperidin- 1 -y l)-buty 1)- 1 ,2-benzisόthiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxo-( 1 H)-quinolin- 1 -y l)-piperidin- 1 -yl)- butyl)-5-nitro-l,2-benzisothiazol-3(2H)-one; 6-Chloro- 1 , 1 -dioxido-2-(4-(4-(2-oxo-( 1 H)-quinolin- 1 -y l)-piperidin- 1 - yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 5-Chloro- 1 , 1 -dioxido-2-(4-(4-(2-oxo-( 1 H)-quinolin- 1 -y l)-piperidin- 1 - yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(4-(2-oxo-(lH)-quinolin-l-yl)-piperidin-l -yl)- butyl)-7-nitro-l,2-benzisothiazol-3(2H)-one; l,l-Dioxido-2-(4-(4-(2-oxo-(lH)-quinolin-l-yl)-piperidin-l-yl)-butyl)- 4-methoxy-l,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l-yl)-butyl)- 5-nitro- 1 ,2-benzisothiazol-3 (2H)-one; 6-Chloro-l ,1 -dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l - yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 5-Chloro-l ,1 -dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l - yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l -yl)-butyl)- 7-nitro-l,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l-yl)-butyl)-4- methoxy-l,2-benzisothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(4-(5-chloro-2-oxo-3-benzoxazolinyl)-piperidin-l -yl)- butyl)- 1 ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(3a-(R)-8a-(S)-2-oxo-3,3a,8,8a-tetrahydro-2H- indeno[l,2-d]oxazolinyl)-piperidin-l-yl)-butyl)-l ,2-benzisothiazol- 3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxonaphth[2,3-d]oxazolinyl)-piperidin- 1 -yl)- butyl)- 1 ,2-benzisothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(4-(6-methyl-2-oxo-3-benzoxazolinyl)-piperidin-l - yl)-butyl)-l,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(2-oxo-5-phenyl-3-benzoxazolinyl)-piperidin-l- yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(6-methoxy-2-oxo-3-benzoxazolinyl)-piperidin- 1 - yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(4-(6-carbomethoxy-2-oxo-3-benzoxazolinyl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(4-(5-ethylsulfonyl-2-oxo-3-benzoxazolinyl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; l,l-Dioxido-2-(4-(4-(2-oxo-3-oxazolo[4,5-b]pyridyl)-piperidin-l-yl)- butyl)- 1 ,2-benzisothiazol-3(2H)-one; l,l-Dioxido-2-(4-(4-(7-carbethoxy-2-oxo-3-benzoxazolinyl)-piperidin- 1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(5- erf-butyl-2-oxo-3-benzoxazolinyl)-piperidin- 1 - yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(5,7-dimethyl-2-oxo-3-benzoxazolinyl)-piperidin- 1 -yl)-butyl)-l ,2-benzisothiazol-3 (2H)-one; l,l-Dioxido-2-(4-(spiro(l,3-dihydro-l-oxo-2H-indene-2,4'-piperidin- 1 '-yl)butyl)-l ,2-benzisothiazol-3(2H)-one; l,l-Dioxido-2-(4-(4'-(3,4-dihydro-l-oxonapththalene)-2(lH)- spiropiperidin-1 '-yl)butyl)-l ,2-benzisothiazol-3(2H)-one; 4-(3,4-Dihydro-6-methyl-spiro[2H-l-benzopyran-2,4'-piperidine-4(3H)- one]- 1 '-yl)-butylphthalimide; 4-(Spiro(piperidine-4,6'-[6H]thieno[2,3-b]thiopyran-4'(5'H)-one-l '-yl)- butylphthalimide; 4-(Spiro[benzothiazol-2(3H),4'-piperidin-l'-yl)-butylphthalimide; 4-(3,4-Dihydro-6-methoxy-spiro[2H-l-benzopyran-2,4'-piperidine- 4(3H)-one]- 1 '-yl)-butylphthalimide; 4-(3,4-Dihydro-6-methanesulfonylamidyl-spiro[2H-l-benzopyran-2,4'- piperidine-4(3H)-one]-l'-yl)-butylphthalimide; 1 , 1 -Dioxido-2-(4-(spiro[benzothiazol-2(3H),4'-piperidin- 1 '-yl)-butyl)- 1 ,2-benzisothiazol-3(2H)-one; 4-(6-Trifluoromethyl-spiro[benzothiazol-2(3H),4'-piperidin-r-yl)- butylphthalimide; l ,l-Dioxido-2-(4-(spiro[benzofuran-2(3H),4'-piperidin]- -yl)-butyl)- 1 ,2-benzisothiazol-3(2H)-one; 4-(Spiro[benzofuran-2(3H),4'-piperidin]-l'-yl)-butylphthalimide; 4-(Spiro[2H-l,3-benzoxazine-2,4'-piperidin]- -yl)-butylphthalimide; 3,3-Dioxido-l ,2-dehydro-2-(4-(spiro[2H-indene-2,4'-piperidine-l(3H)- one]-l'-yl)-butyl)-naphth[l ,2-d]isothiazol-l-one; l ,l-Dioxido-2-(4-(spiro[2H-indene-2,4'-piperidine-l(3H)-one]-l'-yl)- butyl)-4-methoxy- 1 ,2-benzisothiazol-3(2H)-one; l,l-Dioxido-2-(4-(spiro[2H-indene-2,4'-piperidine-l(3H)-one]- -yl)- butyl)-7-methoxy- 1 ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(spiro(l,3-dihydro-l-oxo-2H-indene-2,4'-piperidin- 1 '-yl)butyl)-5-methoxy-l ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(spiro(l,3-dihydro-l-oxo-2H-indene-2,4'-piperidin- 1 '-yl)butyl)-6-methoxy-l ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(spiro(l,3-dihydro-l-oxo-2H-indene-2,4'-piperidin- 1 '-yl)butyl)-5-methyl-l ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(spiro(l,3-dihydro-l-oxo-2H-indene-2,4'-piperidin- 1 '-yl)butyl)-5-chloro-l ,2-benzisothiazol-3(2H)-one; l,l-Dioxido-2-(4-(spiro(l,3-dihydro-l-oxo-2H-indene-2,4'-piperidin- 1 '-yl)butyl)-5-fluoro-l ,2-benzisothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(spiro(l ,3-dihydro-l-oxo-2H-indene-2,4'-piperidin- 1 '-y l)butyl)-5-nitro- 1 ,2-benzisothiazol-3 (2H)-one; l ,l-Dioxido-2-(4-(spiro(l ,3-dihydro-l-oxo-2H-indene-2,4'-piperidin- l'-yl)butyl)-6-nitro-l,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(spiro(l ,3-dihydro-l-oxo-2H-indene-2,4'-piperidin- r-yl)butyl)-isothiazolo[5,4-c]pyridin-3(2H)-one; l ,l-Dioxido-2-(4-(spiro(l,3-dihydro-l-oxo-2H-indene-2,4'-piperidin- 1 '-yl)butyl)-isothiazolo[5,4-b]pyridin-3(2H)-one ; l ,l-Dioxido-2-(4-(4-(6-methyl-2-oxo-3-benzoxazolinyl)-piperidin-l - yl)-butyl)-5-nitro-l,2-benzisothiazol-3(2H)-one; 2-(4-(Sρiro(l ,3-dihydro-l-oxo-2H-indene-2,4'-piperidin-l '-yl)butyl)- pyrrolo[3,4b]pyridin-5,7(lH)-dione; ,l-Dioxido-2,3-dihydro-2-(4-(spiro[2H-indene-2,4'-piperidine-l (3H)- one]-l'-yl)-butyl)-naphth[l ,8-de]isothiazin-3-one; and , 1 -Dioxido-2-(4-(spiro[3-oxo-phthalan- 1 ,4'-piperidin- 1 '-yl)butyl)- 1 ,2- benzisothiazol-3(2H)-one; ,1 -Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-2H-benzimidazolin-l -yl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; ,l-Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-3-methyl-2H-benzimidazolin- -yl)-piperidin-l-yl)-butyl)-l,2-benzisothiazol-3(2H)-one; ,l-Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-5-methyl-2H-benzimidazolin- -yl)-piperidin-l-yl)-butyl)-l,2-benzisothiazol-3(2H)-one; , 1 -Dioxido-2-(4-(4-( 1 ,3-dihydro-2-oxo-4-methyl-2H-benzimidazolin- -yl)-piperidin-l-yl)-butyl)-l,2-benzisothiazol-3(2H)-one; ,l-Dioxido-2-(4-(4-(l,3-dihydro-2-oxo-5-methoxy-2H-benzimidazo- in-1 -yl)-piperidin-l -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; , 1 -Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-5-chloro-2H-benzimidazolin- -yl)-piperidin-l -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; ,1 -Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-5-fluoro-2H-benzimidazolin- -yl)-piperidin-l -yl)-butyl)-5-chloro-l ,2-benzisothiazol-3(2H)-one; ,1 -Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-5-methyl-2H-benzimidazolin- -yl)-piperidin-l -yl)-butyl)-5-chloro-l ,2-benzisothiazol-3(2H)-one; ,l-Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-6-methyl-2H-benzimidazolin- -yl)-piperidin-l -yl)-butyl)-5-chloro-l ,2-benzisothiazol-3(2H)-one; , 1 -Dioxido-2-(4-(4-(5-methyl-2-oxo-3-benzoxazolinyl)-piperidin- 1 - yl)-butyl)-5,6-dihydro-[l,4]dioxino[2,3-e]benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l -yl)-butyl)- 5,6-dihydro-[l,4]dioxino[2,3-e]benzisothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(4-(spiro-l ,3-dihydro-l -oxo-2H-indenyl)-2,4'- piperidin-r-yl)-butyl)-5,6-dihydro-[l ,4]dioxino[2,3-e]benzisothiazol- 3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-( 1 ,3-dihydro-2-oxo- 1 H-3 ,4-dihydroquinazolin- 1 - yl)-piperidin-l -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 2-(4-Hydroxybutyl)-l ,l-dioxido-5,6-dihydro-[l,4]dioxino[2,3- d]benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin- 1 -y l)-buty 1)- 5-ethoxy- 1 ,2-benzothiazol-3(2H)-one; l ,l -Dioxido-2-(4-(4-(spiro-l ,3-dihydro-l-oxo-2H-indenyl)-2,4'- piperidin- -yl)-butyl)-5-ethoxy-l,2-benzothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(spiro- 1 ,3-dihydro- 1 -oxo-2H-indenyl)-2,4'- piperidin- 1 '-yl)-butyl)-5-ethyl-l ,2-benzothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l-yl)-butyl)- 5-ethyl- 1 ,2-benzothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(spiro-l ,3-dihydro- 1 -oxo-2H-indenyl)-2,4'- piperidin- -yl)-butyl)-5-(2-propyl)-l,2-benzothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l-yl)-butyl)- 5-(2-propyl)-l,2-benzothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin- 1 -yl)-butyl)-6- nitro- 1 ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin- 1 -yl)-buty l)-5- fluoro-1 ,2-benzisothiazol-3(2H)-one; l,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l-yl)-butyl)-5- methyl-l,2-benzisothiazol-3(2H)-one; l,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l-yl)-butyl)-5- bromo-l,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l-yl)-butyl)-5- trifluoromethyl- 1 ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l-yl)-butyl)-5- trifluoromethoxy-1 ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxo- 1 -naphthf 1 ,2-d] oxazolinyl)-piperidin- 1 -y 1)- butyl)- 1 ,2-benzisothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(4-(5,6,7,8-tetrahydro-2-oxo-3-naphth[2,3- d]oxazolinyl)-piperidin-l-yl)-butyl)-l,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(5-methyl-2-oxo-3-benzoxazolinyl)-piperidin-l- yl)-butyl)-l,2-benzisothiazol-3(2H)-one; l,l-Dioxido-2-(4-(4-(5-carbomethoxy-2-oxo-3-benzoxazolinyl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(6-fluoro-2-oxo-3-benzoxazolinyl)-piperidin-l -yl)- butyl)-l,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(4-methyl-2-oxo-3-benzoxazolinyl)-piperidin-l- yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(4-methoxy-2-oxo-3-benzoxazolinyl)-piperidin- 1 - yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 5-Chloro-l ,l -dioxido-2-(4-(4-(6-methyl-2-oxo-3-benzoxazolinyl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 5-Methylthio-l,l-dioxido-2-(4-(4-(6-methyl-2-oxo-3-benzoxazolinyl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 5-Ethoxy-l,l-dioxido-2-(4-(4-(6-methyl-2-oxo-3-benzoxazolinyl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 5-Chloro-l,l-dioxido-2-(4-(4-(6-fluoro-2-oxo-3-benzoxazolinyl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 4-Methyl-l,l-dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l -yl)- butyl)- 1 ,2-benzisothiazol-3(2H)-one; 4-Chloro-l,l-dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l-yl)- butyl)- 1 ,2-benzisothiazol-3(2H)-one; 4-Ethoxy-l ,l-dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l- yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 4-(2-Propyloxy)-l ,1 -dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 5-Methoxy-l,l-dioxido-2-(4-(4-(6-methyl-2-oxo-3-benzoxazolinyl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin- 1 -yl)-buty l)-6- methylsulfonyl- 1 ,2-benzisothiazol-3(2H)-one; 5-Methoxy-l ,1 -dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin- 1 - yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin- 1 -yl)-buty l)-5- methylsulfonyl- 1 ,2-benzisothiazol-3(2H)-one; 5-Methylthio-l,l-dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin- l-yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 5-Methylsulfonyl-l ,l-dioxido-2-(4-(4-(6-methyl-2-oxo-3- benzoxazolinyl)-piperidin-l -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; or 1 , 1 -Dioxido-2-(4-(4-(2-oxo- 1 -oxazolo[5 ,4-b]pyridyl)-piperidin- 1 -yl)- butyl)- 1 ,2-benzisothiazol-3(2H)-one; and pharmaceutically acceptable salts, metabolites and prodrugs thereof. Preferred compounds of the present invention include: 1 , 1 -Dioxido-2-(4-(4-( 1 ,3-dihy dro-2-oxo-2H-benzimidazolin- 1 -y 1)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-3-methyl-2H-benzimidazolin- l-yl)-piperidin-l-yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-( 1 ,3-dihydro-2-oxo-5-methyl-2H-benzimidazolin- 1 -yl)-piperidin-l -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(l,3-dihydro-2-oxo-5-chloro-2H-benzimidazolin- 1 -yl)-piperidin-l -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-5-fluoro-2H-benzimidazolin- 1 -yl)-piperidin-l -yl)-butyl)-5-chloro-l ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-5-methyl-2H-benzimidazolin- 1 -yl)-piperidin-l -yl)-butyl)-5-chloro-l ,2-benzisothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-6-methyl-2H-benzimidazolin- l-yl)-piperidin-l-yl)-butyl)-5-chloro-l,2-benzisothiazol-3(2H)-one; and 1 , 1 -Dioxido-2-(4-(4-(5-methy l-2-oxo-3-benzoxazolinyl)-piperidin- 1 - yl)-butyl)-5,6-dihydro-[l,4]dioxino[2,3-e]benzisothiazol-3(2H)-one; and pharmaceutically acceptable salts, metabolites and prodrugs thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. The liquid forms in which the novel compositions of the present invention may be incoφorated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alg nate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin. In the treatment of BPH, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day. Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid^ such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. The specificty of binding of compounds showing affinity for the αlC receptor is shown by comparing affinity to membranes obtained from COS cells tranfected with the cloned αlC receptor and membranes from tissues known to express other types of alpha or beta adrenergic receptors. In addition, the cloned human αiA and a hybrid human/rat αiB (with only the cytoplasmic, carboxy terminal region being rat sequence) could be used for this puφose, along with the human αlC receptor expressed in COS cells . Expression of the cloned human αiA, αiB, and αlC receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities. Antagonism by these compounds of the human alphal C adrenergic receptor subtype may be functionally demonstrated in anesthetized animals. These compounds may be used to increase urine flow without exhibiting orthostatic hypotensive effects. The human alpha adrenergic receptor of the 1-C subtype was identified, cloned and expressed. A partial coding region for this receptor was generated by reverse transcriptase-polymerase chain reaction technology, RT-PCR. Accordingly, degenerate oligonucleotides encoding amino acids conserved in the fifth and sixth transmembrane domains of all three αl receptor subtypes (A, B, C) were used to prime RT-PCR reactions using human heart mRNA as template. The predicted sized products were cloned and sequenced. Translation of the amplified cDNA yielded an open reading frame encoding a protein 95% homologous to the bovine αlC receptor (Fig.2, SEQ. ID:5: and SEQ. 1D:6:). This partial sequence was used to obtain a larger cDNA clone from a human hippocampus library (Fig. 3, SEQ. ID:6:). The remaining coding region was obtained by PCR amplification of human genomic DNA using primers based on the cDNA sequence and the last six amino acids of bovine αlC receptor (Fig. 4, SEQ.1D:10:). The complete receptor was then assembled using the partial sequences shown in Fig. 3, SEQ.LD:6: and Fig. 4, SEQ. Lϋ:10:, to generate the sequence shown in Fig. 5, SEQ. LD:11:. The translation of this sequence is shown in Fig. 6, SEQ. ID: 12:, and the alignment of the nucleotide and amino acid sequences, and the 5'- untranslated sequences, is shown in Fig. 7, SEQ. LD:11 : and SEQ. ID:12:. The 3'-terminal six amino acids of the human αic adrenergic receptor were confirmed by screening a human genomic library with the radiolabeled 3'-terminal 512 nucleotides of the SEQ. ID: 10: clone previously obtained. A complete human exon 2 was generated in this manner and sequenced. The nucleotide sequence of this gene is provided in figure 19, SEQ. LD:27: and the amino acid sequence is provided in figure 20, SEQ. ID:28:. We discovered that this clone was identical to the original 3 '-terminal portion of the gene, except that: 1 ) There are five silent nucleotide changes between the new clone and the previously obtained clone (the last five codons, including the stop codon, each have a silent change in the third nucleotide); and 2) At nucleotide position 1636 (amino acid 347), there is a cytosine to thymine base change resulting in the formation of a Pstl site at that location and a concommitant single amino acid change of Arg to Cys. Thus, we have confirmed and localized the site of the two-allele Pstl restriction fragment polymoφhism (RFLP) noted by Hoehe et al., [Human Mol. Genetics. 1(5):349 (8/92)]. Through pharmacological studies using clones of both alleles, we have confirmed that the Arg to Cys change appear to be pharmacologically indistinguishable (see Table II, Example 11 , below). The cloned human αlC receptor, when expressed in mammalian cell lines (see Fig. 8), is used to discover ligands that bind to the receptor and alter its function. In addition, the cloned αlC receptor enables quanititation of mRNA levels in human tissues, including the aorta and prostate, by RNase protection assays. For these puφoses, a complete coding sequence of the receptor is provided. However, as long as the ligand binding and signal transduction segments of the receptor (G-protein interaction) are intact, truncation at the 3' end of the sequence does not affect the functioning of the receptor. Thus, in addition to the sequence provided in SEQ. ID: 11:, a sequence, truncated at the 3' end, SEQ. ID:26: is disclosed, which consists entirely of human alpha IC sequence. Once the human receptor is cloned and expressed in a cell such as COS cells or CHO cells, the receptor is free of other human proteins. The membranes from cells expressing different human alpha adrenergic receptor subtypes are then isolated according to methods well known in the art for membrane associated receptor binding assays. For example, the method of Schwinn, et al., (J. Biol. Chem.. 265:8183- 8189, 1990) may be used. A compound of interest is used to compete with the binding of a known, quantifiable alpha receptor ligand. Thus, radiolabled prazosin, niguldipine, 5-methyl urapidil, terazosin, dozazosin, phenoxybenzamine, WB4101 , benoxathian, HEAT (2-[β-(4- hydroxy-3-iodophenyl)ethylaminomethyl]tetralone, or phentolamine may be used for this puφose (see, for example, Robert R. Ruffolo, Jr., α-Adrenoreceptors: Molecular Biology. Biochemistry and Pharmacology. (Progress in Basic and Clinical Pharmacology series, Karger, 1991), page 29). Because of the ease of 125τ oc j me detection, 125τ-HEAT may be preferred for this puφose. By increasing the amount of unlabeled, test compound, the labeled compound is competed off the receptor. From these experiments, IC50 values for each test compound and receptor subtype is determined. A new sequence for the human αl A adrenergic receptor which is more homologous to the rat αiA adrenergic receptor sequence is also provided herein (see Example 12 and figures 22, 23, and 24, SEQ. ID:29: and SEQ. LD:30:). While no difference in ligand binding has thus far been observed based on the different amino terminal amino acid sequences between these two receptors, such differences cannot be ruled out except by screening compounds against both clones. Since a new human αiA adrenergic receptor sequence is provided herein, compounds identified using the earlier reported human αiA adrenergic receptor sequence can now be confirmed against this clone. Compounds of this invention exhibiting selective human αlC adrenergic receptor antagonism may further be defined by counterscreening. This is accomplished according to methods known in the art using other receptors responsible for mediating diverse biological functions. Compounds which are both selective amongst the various human alphal adrenergic receptor subtypes and which have low affinity for other receptors, such as the alpha2 adrenergic receptors, the β-adrenergic receptors, the muscarinic receptors, the serotonin receptors, and others are particularly preferred. The absence of these non-specific activities may be confirmed by using cloned and expressed receptors in an analogous fashion to the method disclosed herein for identifying compounds which have high affinity for the various huaman alphal adrenergic receptors. Furthermore, functional biological tests are used to confirm the effects of identified compounds as alpha IC adrenergic receptor antagonists. Compounds of this patent disclosure may be used alone at appropriate dosages defined by routine testing in order to obtain optimal antagonism of the human αlC adrenergic receptor while minimizing any potential toxicity. In addition, co-administration or sequential administration of other agents which alleviate the effects of BPH is desirable. Thus, in one embodiment, this includes administration of compounds of this invention and a human testosterone 5-α reductase inhibitor. Included in this embodiment are inhibitors of 5-alpha reductase isoenzyme 2. Many such compounds are now well known in the art and include such compounds as PROSCAR®, (also known as finasteride, a 4-Aza-steroid; see US Patents 4,377,584 and 4,760,071, for example, hereby incoφorated by reference). In addition to PROSCAR®, which is principally active in prostatic tissue due to its selectivity for human 5-α reductase isozyme 2, combinations of compounds which are specifically active in inhibiting testosterone 5- alpha reductase isozyme 1 (found particularly in skin) and compounds which act as dual inhibitors of both isozymes 1 and 2, are useful in combination with compounds of this invention. Compounds that are active as 5α-reductase inhibitors have been described in WO93/23420, EP 0572166; WO 93/23050; WO93/23038, ; WO93/23048; WO93/23041; WO93/23040; WO93/23039; W093/23376; W093/23419, EP 0572165; WO93/23051 , each of which is hereby incoφorated by reference. The present invention also has the objective of providing suitable topical, oral, systemic and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention. The compositions containing compounds of this invention as the active ingredient for use in the specific antagonism of human alpha IC adrenergic receptors can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration. For example, the compounds can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, topical with or without occlusion, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an alpha IC antagonistic agent. The daily dosage of the products may be varied over a wide range from 0.01 to 1 ,000 mg per adult human/per day. For oral administration, the compositions are preferably provided in the form of scored or unscored tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, and 50.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg./kg to about 50 mg./kg. of body weight per day. The range is more particularly from about 0.001 mg./kg to 7 mg./kg. of body weight per day. With reference to terazosin, it is predictable that the potent and more selective compounds of this invention are effective at doses equal to or between ten and a hundred fold lower than dosages utilized for that compound (see, for example, US Patent 5,212,176). The dosages of the alphal C adrenergic receptor and testosterone 5-alpha reductase inhibitors are adjusted when combined to achieve desired effects. As those skilled in the art will appreciate, less 5-alpha reductase inhibitor may be required when the acute symptoms of BPH are alleviated by treatment with the alpha IC adrenergic receptor inhibitor of this invention. On the other hand, dosages of these various agents may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone. The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated. The term inhibitorily effective amount or antagonistically effective amount as used herein means that amount of an active compound which, when contacted with a particular enzyme or receptor, interrupts the usual catalytic activity or signal transduction of that enzyme or receptor. The term "subject," as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. For the treatment of benign prostatic hypeφlasia, prostatitis and the prevention and/or treatment of prostatic cancer, compounds of this invention exhibiting alphal C adrenergic receptor blockade can be combined with a therapeutically effective amount of a 5α-reductase 2 inhibitor, such as finasteride, in addition to a 5α- reductase 1 inhibitor, such as 4,7β-dimethyl-4-aza-5α-cholestan-3- one, in a single oral, systemic, or parenteral pharmaceutical dosage formulation. Alternatively, a combined therapy can be employed wherein the alphal C adrenergic receptor antagonist and the 5α- reductase 1 or 2 inhibitor are administered in separate oral, systemic, or parenteral dosage formulations. See, e.g., U.S. Patent No.'s 4,377,584 and 4,760,071 which describe dosages and formulations for 5α-reductase inhibitors. For combination treatment with more than one active agent, where the active agents are in separate dosage formulations, the active agents can be administered concurrently, or they each can be administered at separately staggered times. The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug. In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incoφorated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. Other dispersing agents which may be employed include glycerin and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired. The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl- pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl- amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl- eneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alphal C adrenergic receptor is required. The following examples are provided to further define the invention without, however, limiting the invention to the particulars of these examples. EXAMPLE 1 PCR amplification, cloning and sequencing of phαlX: Based on the amino acid homologies of human αlA, rat αlB and bovine αlC receptors, degenerate oligonucleotides were designed to amplify cDNAs encoding all three receptor subtypes. These oligonucleotides are: WL * (SEQ. ID:1) TTTTCTAGAT TRTTNARRTA NCCNAGCC 28 MYC (SEQ. ID:2) TTTACTAGTA TCSTNGTNAT GTAYTG 16 WC (SEQ. ID:3) TTTTCTAGAG AARAANGGNA RCCARC 26 Oligonucleotides MYC and WL' were used as primers in a reverse transcription PCR amplification of human heart mRNA (Clontech) using the RNA PCR kit from Perkin Elmer Cetus. Briefly, 0.5 ug of mRNA was reverse transcribed in a volume of 20 ul using either random oligonucleotide primers (reaction 1 ) or oligo dT primer (reaction 2). Reactions 1 and 2 were pooled and served as template for PCR amplification as follows: PCR Reactions: Primary reaction (50 ul) 5 ul 10X buffer from Perkin Elmer Cetus Gene Amp Kit 8 ul 1.25 mM each stock of dATP,dCTP,dGTP, and dTTP 3ul first strand cDNA 1 ul 25 pMoles oligo MYC 1 ul 25 pMoles oligo WL' 0.25 ul 1.25 units Amplitaq DNA polymersase 31.75 ul water Reaction conditions; 40 cycles of 94°C 1'; 45 0 C 2'; 72 C 2' Secondary reaction (100 ul) 9.5 ul 10X buffer from Perkin Elmer Cetus Gene Amp Kit 16ul 1.25 mM each stock of dATP,dCTP,dGTP, and dTTP 5ul first strand cDNA 2 ul 50 pMoles oligo MYC 2 ul 50 pMoles oligo WC 0.5 ul 2.5 units Amplitaq DNA polymersase 65 ul water Reaction conditions; 40 cycles of 94 C 1'; 45°C 2'; 72 0 C 2' Prep scale tertiary reaction 3 X 200 ul: 19.5 ul 1 OX buffer 32 ul 1.25 mM each stock of dATP, dCTP, dGTP, and dTTP 5 ul secondary PCR reaction 4 ul 100 pMoles oligo MYC 4 ul 100 pMoles oligo WC 1 ul 5 units Amplitaq DNA polymerase 134.5 ul water Reaction conditions; 30 cycles of 94°C 1'; 50 O C 2'; 72 0 C 2' The PCR product was purified by Qiagen spin columns and digested with restriction endonucleases Spel and Xbal. The fragment was then ligated into Spel/Xbal cut pGEM9Zf(-). The ligation mix was used to transform E. coli XL-1 blue. Plasmid DNA was isolated from white transformants and sequenced by the dideoxy chain termination method. The base sequence obtained is shown in Fig. 1, SEQ. ID:4:. EXAMPLE 2 Isolation of partial alphal C cDNA Clone: A cDNA library prepared from mRNA isolated from human hippocampus (Stratagene) was screened by plaque hybridization using phαlX as a probe. Hybridization conditions were as follows: 5XSSC ( 1XSSC is 0.15M sodium chloride, 0.015M sodium citrate, 50% Formamide 5X Denhardt's Solution ( 1 % Ficoll, 1 % polyvinylpyrrolidone, 1% bovme serum albumin) 0.15 mg ml salmon sperm DNA hybridize overnight at 42° C. Filters were washed 3 times in 2XSSC, 0.1% SDS at room temperature for 5', then 1 time in IXSSC, 0.1% SDS at 50C for 30'. Positive clones were identified by autoradiography. Phagemid DNA was rescued from the positive plaques and sequenced by the dideoxy chain termination method. The base sequence obtained is shown in Fig. 3, SEQ. 1D:7:. EX AMPLE 3 PCR amplification, cloning and sequencing of 3'CG of alphal C: The 3' end of the coding region of human alphal C adrenergic receptor was amplified from human genomic DNA using two oligonucleotides: S3C (SEQ ID:8:) 5' TTTGAATTCT GATTTCAAGC CCTCTG 3 * and 3'C (SEQ ID:9:) 5' TTTGAATTCT TANACYTCYT CNCCRTTYTC 3' as follows: 10 ul 10X buffer from Perkin Elmer Cetus Gene Amp Kit 16 ul 1.25 mM each stock of dATP,dCTP,dGTP, and dTTP 6 ul 1 ug human genomic DNA (Promega) 2 ul 50 pMoles oligo S3C 2 ul 50 pMoles oligo 3'C 0.5 ul 2.5 units -Amplitaq DNA polymersase 63.5 ul water Reaction conditions; 40 cycles of 94 0 C 1'; 50°C 2'; 72 0 C 2' The PCR product was purified by Qiagen spin columns and digested with restriction endonuclease EcoRI. The fragment was then ligated into EcoRI cut pGEM3Zf(-). The ligation mix was used to transform E. coli XL-1 blue. Plasmid DNA was isolated from white transformants and sequenced by the dideoxy chain termination method. The base sequence is shown in Fig. 4, SEQ. ID: 10:. EXAMPLE 4 Assembly of complete coding region of human alphal c adrenergic receptor: The complete coding region of human alphal c adrenergic receptor was assembled by ligating the cDNA clone (see Example 2, figure 3, SEQ ID:7:) and 3'CG (see Example 3, figure 4, SEQ ID:10: ) at their common PvuLT site ( 1552-1557 of figure 3, SEQ ID:7: and 59-64 of figure 4, SEQ ID: 10:). The complete nucleotide sequence is shown in figure 5, SEQ ID:11 :. The amino acid sequence is shown in figure 6, SEQ. 1D:12:. Figure 7 shows the structure of the cDNA, including the 5'-untranslated sequences. The very 3' twenty seven nucleotides (6 amino acids) shown is the sequence of the PCR primer used to generate the sequence. However, the function of the receptor, both for ligand binding and signal transduction depends on sequences far removed from the carboxy terminus of the receptor. A completely human sequence is shown in figure 18, SEQ. ID:26: which is truncated at the 3' terimuns. EXAMPLE 5 Expression of the cloned alphal C adrenergic receptor: The complete sequence (SEQ ID:11 :) of the human alpha IC adrenergic receptor was subcloned into the eukaryotic expression vector pcDNAI-neo (Invitrogen). The resulting plasmid was transfected into COS -7 cells by electroporation. Cells were harvested after 72 hours and the membranes containing the expressed receptor protein were prepared as described in Schwinn, et al.. J. Biol. Chem.. 265:8183- 8189, 1990. Membranes (5-25 ug, see figure 8) prepared from the COS-7 cells transfected with the vector containing the alphal C receptor gene specifically bound the alpha 1 antagonist [125 Ij-HEAT; membranes prepared from the COS-7 cells transfected with the vector alone did not bind the alpha 1 antagonist [125 I]-HEAT (figure 8), proving the expression of the alphal C adrenergic receptor. Binding reactions (total volume = 200 ul) contained 50 mM Tris-HCl pH. 7.4, 5 mM EDTA, 150 mM NaCl, 100 pM [125 IJ-HEAT, and membranes prepared from COS-7 cells transfected with expression plasmids. Reactions were incubated at room temperature for one hour with shaking. Reactions were filtered onto Whatman GF/C glass fiber filters with a Brandel cell harvester. Filters were washed three times with ice cold buffer and bound radioactivity was determined. Non specific binding was determined in the presence of 10 uM prazosin. EX AMPLE fl Screening assay: Alpha 1 C Adrenergic Receptor Binding Membranes prepared from the transfected COS-7 cells may also be used to identify compounds that bind to the human alphal C adrenergic receptor. These competition binding reactions (total volume = 200 ul) contain 50 mM Tris-HCl pH. 7.4, 5 mM EDTA, 150 mM NaCl, 100 pM [125 I]-HEAT, membranes prepared from COS-7 cells transfected with the alpha IC expression plasmid and increasing amounts of unlabeled ligand. Reactions are incubated at room temperature for one hour with shaking. Reactions were filtered onto Whatman GF/C glass fiber filters with a Brandel cell harvester. Filters were washed three times with ice cold buffer and bound radioactivity was determined. Binding data were analyzed and IC50s determined by an iterative curve fitting program. Results are shown in Figure 9. EXAMPLE 7 Expression of human alphal A adrenergic receptor: The complete coding region for the human alphal A adrenergic receptor (Bruno, et al., BBRC 129:1485-1490, (1991); see figure 10, SEQ. LD:13: and figure 11, SEQ. 1D:14: herein) was subcloned into the eukaryotic expression vector pcDNAI-neo (Invitrogen). The resulting plasmid was transfected into COS-7 cells by electroporation. Cells were harvested after 72 hours and the membranes containing the expressed receptor protein were prepared as described in Schwinn, et al.. J. Biol. Chem.. 265:8183-8189, 1990. Membranes prepared from the COS-7 cells transfected with the vector containing the alphal A receptor gene specifically bound the alpha 1 antagonist [125 I]-HEAT; membranes prepared from the COS-7 cells transfected with the vector alone did not bind the alpha 1 antagonist [125 I]-HEAT. Binding reactions (total volume = 200 ul) contained 50 mM Tris- HC1 pH. 7.4, 5 mM EDTA, 150 mM NaCl, 100 pM [125 I]-HEAT, and membranes prepared from COS-7 cells transfected with expression plasmids. Reactions are incubated at room temperature for one hour with shaking. Reactions were filtered onto Whatman GF/C glass fiber filters with a Brandel cell harvester. Filters were washed three times with ice cold buffer and bound radioactivity was determined. Non¬ specific binding was determined in the presence of 10 uM prazosin. EXAMPLE S Expression of human alphal B adrenergic receptor: 1. PCR amplification of partial cDNA for human alpha IB adrenergic receptor: Amplification of 5XB clones 5XB,SEQ.LD:15:5 * TCTAGACCATGAAYCCNGAYCTGG3' A1B,SEQ.ID:16:5'TTTGAATTCACATWCCGACYACAA TGCCC3' Oligonucleotides 5XB and A1B were used as primers in a reverse transcription PCR amplification of human heart mRNA (Clontech) using the Invitrogen Copy Kit. Briefly, 1.0 ug of mRNA was reverse transcribed in a volume of 20 ul using oligonuleotide WC as primer. Primary reaction (50 ul) 5 ul 10X buffer from Perkin Elmer Cetus GeneAmp Kit 8 ul 1.25 mM each stock of dATP,dCTP,dGTP, and dTTP 2.5 ul first strand cDNA 1 ul 25 pMoles oligo 5XB 1 ul 25 pMoles oligo A1B 0.25 ul 1.25 units Amplitaq DNA polymersase 32.75 ul water Reaction conditions; 40 cycles of 94 C 1'; 58°C 2'; 72 0 C 2' The PCR product was directly ligated into pCR vector (Invitrogen) and used to transform E. coli FNVaF (Invitrogen). Plasmid DNA was isolated from white transformants and sequenced by the dideoxy chain termination method. The base sequence is shown in Fig. 12, SEQ. ID: 17: 2. Amplification of EFK clones EFK,SEQ.ID:18: 5'GAAGGCGCGCTTGAACTC3' 5B1,SEQ.LD:19: 5"AGAGAACCACCAAGAACC3' Oligonucleotides EFK and 5B 1 were used as primers in a reverse transcription PCR amplification of human aorta mRNA (Clontech) using the Invitrogen Copy Kit. Briefly, 1.0 ug of mRNA was reverse transcribed in a volume of 20 ul using oligo dT as primer. Primary reaction (50 ul) 5 ul 10X buffer from Perkin Elmer Cetus GeneAmp Kit 8 ul 1.25 mM each stock of dATP,dCTP,dGTP, and dTTP 2.0 ul first strand cDNA 1 ul 25 pMoles oligo EFK 1 ul 25 pMoles oligo 5B1 0.25 ul 1.25 units Amplitaq DNA polymersase 33.25 ul water Reaction conditions; 40 cycles of 94 0 C 1'; 58°C 2'; 72 C 2' The PCR product was directly ligated into pCR vector (Invitrogen) and used to transform E. coli LNVaF' (Invitrogen). Plasmid DNA was isolated from white transformants and sequenced by the dideoxy chain termination method. The base sequence is shown in Fig. 13, SEQ. ID:20:. 3. Assembly of partial cDNA for human alphal B adrenergic receptor A partial cDNA clone encoding the human alpha IB adrenergic receptor was assembled by joining the 5XB sequence (SEQ. 1D:17:) and the EFK sequence (SEQ. 1D:20:) at their common BamHI site. 4. Amplification of the 3' end of rat alpha IB adrenergic receptor S4B, SEQ. LD:21 : 5 * TTT GAA TTC ATG TTC AAG GTG GTG TTC 3 * 3'B2, SEQ. ID:22: 5' TTT GAA TTC TAA AASTGN CCN GGN SCC AGN GGC AT 3' Oligonucleotides S4B and 3'B2 were used as primers in a reverse transcription PCR amplification of rat heart mRNA using the Invitrogen Copy Kit. Briefly, 0.6 ug of mRNA was reverse transcribed in a volume of 20 ul using oligo dT as primer. Primary reaction (50 ul) 5 ul 10X buffer from Perkin Elmer Cetus GeneAmp Kit 8 ul 1.25 mM each stock of dATP,dCTP,dGTP, and dTTP 2.0 ul first strand cDNA 1 ul 25 pMoles oligo EFK 1 ul 25 pMoles oligo 5B1 0.25 ul 1.25 units Amplitaq DNA polymersase 33.25 ul water Reaction conditions; 40 cycles of 94°C 1'; 58°C 2'; 72«C 2' The PCR product was directly ligated into pCR vector (Invitrogen) and used to transform E. coli LNVαF' (Invitrogen). Plasmid DNA was isolated from white transformants and sequenced by the dideoxy chain termination method. The base sequence is shown in Fig. 14, SEQ. ID:23:. 5. Assembly and expression of a functional human/rat hybrid alphal B adrenergic receptor The partial human alphal B adrenergic receptor cDNA was joined to the 3' end of the rat alphal B adrenergic receptor cDNA at their common BssHII restriction endonuclease site. This composite sequence is shown in figure 15, SEQ. LD:24:, and the amino acid sequence is shown in Fig. 16, SEQ. ID:25: The complete coding region for the human/rat alpha IB adrenergic receptor was subcloned into the eukaryotic expression vector pcDNAI-neo (Invitrogen). The resulting plasmid was transfected into COS-7 cells by electroporation. Cells were harvested after 72 hours and the membranes containing the expressed receptor protein were prepared as described in Schwinn, et al.. J. Biol. Chem.. 265:8183- 8189, 1990. Membranes prepared from the COS-7 cells transfected with the vector containing the alphal B receptor gene specifically bound the alpha 1 antagonist [125 I] -HEAT; membranes prepared from the COS-7 cells transfected with the vector alone did not bind the alpha 1 antagonist [125 I] -HEAT. Binding reactions (total volume = 200 ul) contained 50 mM Tris-HCl pH. 7.4, 5 mM EDTA, 150 mM NaCl, 100 pM [125 IJ-HEAT, and membranes prepared from COS-7 cells transfected with expression plasmids. Reactions are incubated at room temperature for one hour with shaking. Reactions were filtered onto Whatman GF/C glass fiber filters with a Brandel cell harvester. Filters were washed three times with ice cold buffer and bound radioactivity was determined. Non specific binding was determined in the presence of 10 uM prazosin. EXAMPLE 9 Selective Binding assays Membranes prepared from COS-7 cells transfected with the human alpha 1 receptor subtype expression vectors may also be used to identify compounds that selectively bind to the human alpha IC adrenergic receptor. These competition binding reactions (total volume = 200 ul) contain 50 mM Tris-HCl pH. 7.4, 5 mM EDTA, 150 mM NaCl, 100 pM [125 i]_ HEAT, membranes prepared from COS-7 cells transfected with the respective alpha 1 subtype expression plasmid and increasing amounts of unlabeled ligand. Reactions are incubated at room temperature for one hour with shaking. Reactions were filtered onto Whatman GF/C glass fiber filters with a Brandel cell harvester. Filters were washed three times with ice cold buffer and bound radioactivity was determined. Binding data were analyzed and IC50s determined by an iterative curve fitting program. Table I shows the results from such an analysis. JC50 £nMl Compound αlA αlB αlC prazosin 0.6 2.4 1 terazosin 4 5 19 doxazosin 5 2 9 phenoxybenzamine 6.1 4.3 4.0 WB4101 1 16 1 benoxathian 2.5 68 1.5 phentolamine 36 650 14 5-methyl urapidil 42 270 3.5 S(+) niguldipine 130 670 1.4 EXAMPLE 10 IDENTIFICAΉON AND CLONING OF A NEW ALLELE FOR THE HUMAN ALPHA 1-C ADRENERGIC RECEPTOR Probes: 3'CG: A 525 bps fragment, specific to complete exon.2 of human alpha lc AR, was PCR amplified from human genomic DNA using a sense primer based on the isolated cDNA clone and an antisense primer based on the last six amino acids of bovine alphal c cDNA. This PCR product was subcloned and confirmed by sequencing (see Example 3, SEQ.ID:10:). Genomic Library Screening: Human W138 Fibroblast genomic library synthesized in the Lambda Fix II vector (2 x 10^ recombinants; Stratagene,La Jolla, CA) was screened with (3'CG). This probe was labelled with 32p_dCTP (Amersham) by random-primed labelling kit (Boehringer Mannheim,Indianapolis,LN). A Total 800,000 plaques were screened, using duplicate Hybond-N nylone filters (Amersham,UK). Prior to hybridization, filters were denatured (1.5M NaCl+0.5M NaOH), neutralized (1.5M NaCl+ IM Tris.Cl,pH 8.0) and washed (0.2M Tris.Cl pH 7.5 + 2 SSC), 5' for each. DNA was cross-linked with UV cross- linker (Stratagene,La Jolla,CA). The filters were, then, hybridized in 50% formamide, 5 x SSC(lxSSC= 0.15M NaCl, 0.015M Na citrate, pH7.0), 0.02% polyvinylpyrophosphate, 0.2% Ficoll, 0.2% bovine serum albumin, 150μg of sheared & boiled Salmon sperm DNA, lθ6 cpm of 32p_iabelled probe at 42°C for 40hrs. Filters were washed in O.lx SSC +1% SDS solution at 60°C for 20'. Two more rounds of screening for 20 "positive" plaques/clones with 3'CG probe confirmed two clones for the alphal C adrenergic receptor, which were named 48. IC and 53.1C. Clone 53.1C was subjected to further analysis/investigation. Suh-clonning of Exon.2 : 53. IC lambda DNA was amplified by plate lysis method and purified with Qiagen midi-lambda kit (Qiagen,Chatsworth,CA). A 2.6Kb band excised with EcoRI restriction enzyme was identified by Southern analysis using 3'CG probe. This fragment was then subcloned into pGEM3Zf(+) vector. DNA sequencing: Nucleotide sequence analysis of DNA in both direction was performed by Sanger chain termination method. Result and Discussion: Sequencing analysis of this genomic clone confirmed that clone 53.1 c contains sequences for complete exon.2 flanked by an intron at 5'-end. It also revels that there is a nucleotide change from cytosine (C) to thymine(T) at nucleotide position 1636, amino acid position 347. This change creates a Pstl site and changes the codon for arginine (Arg) to cystine (Cys). This data differs from the known/published cDNA sequence of the gene. Southern analysis of human genomic DNA confirms the Pstl site in the gene/exon.2. EXAMPLE 11 COMPARATIVE PHARMACOLOGY OF ALPHA 1-C ALLELES We have cloned two genes for the human alpha- lc receptor. The coding regions differ by a single nucleotide. The genes encode either Cys or Arg at amino acid 347 near the C terminus of the receptor. The nucleotide difference lies within a Pstl restriction enzyme recognition site thus creating a Restriction Fragment Length Polymoφhism (RFLP). The frequency of allele 1 (LRR) is 0.34; allele 2 (LCR) is 0.66 in 83 unrelated individuals (Hoehe et al "A two-allele Pstl RFLP for the alpha-lC adrenergic receptor gene" Human Molecular Genetics 1 : 349, 1992; Allele I is defined by a 2.1 kb Pstl fragment; allele 2 yields two bands of 1.6 and 0.5 kb). Since the amino acid difference occurs within the intracellular tail of the receptor we would not expect any pharmacological differences between the expressed receptors. To investigate the pharmacological profiles of the two allelic forms of the human alpha- lc adrenergic receptor we ligated the genomic exon 2 fragment of allele 2 to a cDNA clone of allele 1 at a common PvuII restriction site. The two allelic forms were transiently expressed in COS-7 cells using pcDNAI NEO (Invitrogen) expression vector. Competitive inhibition studies performed in the presence of 1 5ι_HEAT with various antagonists showed no significant difference in their pharmacological profiles (Table LI): Table II COMPARATIVE PHARMACOLOGY OF ALPHA 1-C ALLELES IC50 (nM) LRR LCR phentolamine 15 17 niguldipine 0.8 1.8 prazosin 1.0 0.9 5-methyl urapidi 3.1 4.3 WB4101 0.9 1.0 EXAMPLE 12 CLONING OF A NOVEL ALPHA 1 -A ADRENERGIC RECEPTOR A cosmid library containing FG293 cell line genomic DNA in the double-cos vector sCos-1 was screened as follows: The published human αla receptor cDNA clone (Bruno et al., BBRC. 179:1485-1490 (1991), and see Fig. 10, SEQ.LD:13:) was cloned into the vector pcDNAl neo to generate the clone pEXαla. Filters containing approximately 200,000 clones were screened by colony hybridization ([Sambrook, Molecular Cloning, Cold Spring Harbor Laboratory Press, New York, 1989 ]) using a mixed exon 1 probe generated by PCR corresponding to αla (TMD1-3) , αib (TMD1-5) and αic (TMD1-5): 25 cycles of 95° C 1'; 52 °C 30 sec; 72 °C 1.5' using 10 ng of pEX αlb, pEX αic or pEX αla and 10 pmoles each of primers 5' MET (5' GAATCCCGACCTGGAC ), SEQ.LD:31 :, and 3' BAM (5'GGATCCTCAGGGTC ), SEQ.ID:32:, for αlb, 5' 597 (5 * CCATGGTGTTTCTCTCGGG), SEQ.ID:33: and 3' 1219 (5' GACGCGGCAGTACATGAC ), SEQ.ID:34: for αic or 5' 76 (5' GTCATGATGGCTGGGTACTTG ), SEQ.ID:35:, for αla in a 12 μl reaction containing 1.5 μM each unlabelled dNTP and 50 μCi 3000 Ci/mmol α-[ 32 P] dCTP. The filters were incubated with 1 x 10 6 cpm/ml of probe in 5X SSC, 35% Formamide, 0.02% SDS, 0.1 % lauroyl sarcosine, 2% blocking buffer (Bohrenger Mannheim), at 42 °C for 18 hours. The filters were washed with 2 liters of 0.5X SSC, 0.1 % SDS, 55 °C and exposed to Kodak XAR-5 film. Twelve primary positives were picked from master plates and re-screened using the αia- specific probe. Cosmid DNA was prepared from second round positive clones, digested with endonucleases Eco RI or Hind LTI and subjected to Southern blot analysis: Fragments were resolved by electrophoresis, and transferred to a nitrocellulose membrane (Bohrenger Mannheim) with 20X SSC (IX SSC = 0.15M Sodium chloride, 0.015M Sodium citrate, pH 7.0) according to the method of Southern ([Southern, 1975 #14]) . The membrane was hybridized, washed and analyzed as described above. Alpha- la, αlb, and αic receptor clones were identified by comparison of restriction patterns with genomic southern blots performed with αla, αlb, or αic specific probes. A Cosmid containing αla receptor exon 1 DNA was subjected to restriction digestion by endonuclease Pst I and subjected to southern blot analysis as above using the αla -specific probe. Two fragments of 2.3 and 1.6 kb were detected and subcloned into the Pst I site of PGEM 3ZF . The presence of the correct 5' terminal sequences in the 2.3 kb fragment was confirmed by sequencing across the junction between inverted repeat and non-repeat sequences. The 5' end of the αia receptor gene was ligated to the cDNA clone at their common Pstl site, see figures 22-24, SEQ.ID:29:, and SEQ.ID:30:. EXAMPLE 13 EXEMPLARY COUNTERSCREENS 1. Assay Title: Dopamine D2,D4 in vitro screen Objective of the Assav: The objective of this assay is to eliminate agents which specifically affect binding of [3H] spiperone to cells expressing human dopamine receptors D2, D3 or D4. Method: Modified from VanTol et al (1991); Nature (Vol 350) Pg 610-613. Frozen pellets containing specific dopamine receptor subtypes stably expressed in clonal cell lines are lysed in 2 ml lysing buffer (lOmM Tris-HCl/5mM Mg, pH 7.4). Pellets obtained after centrifuging these membranes (15' at 24,450 φrn) are resuspended in 50mM Tris-HCl pH 7.4 containing EDTA, MgCl[2], KCl, NaCl, CaCl[2] and ascorbate to give a 1 Mg/mL suspension. The assay is initiated by adding 50-75 μg membranes in a total volume of 500 μl containing 0.2 nM [3H]-spiperone. Non-specific binding is defined using 10 μM apomoφhine. The assay is terminated after a 2 hour incubation at room temperature by rapid filtration over GF/B filters presoaked in 0.3% PEI, using 50mM Tris-HCl pH 7.4. 2. Assay Title: Serotonin 5HTla Objective of the Assay The objective of this assay is to eliminate agents which specifically affect binding to cloned human 5HTla receptor Method; Modified from Schelegel and Peroutka Biochemical Pharmacology 35: 1943-1949 (1986). Mammalian cells expressing cloned human 5HTla receptors are lysed in ice-cold 5 mM Tris-HCl , 2 mM EDTA (pH 7.4) and homogenized with a polytron homogenizer. The homogenate is centrifuged at lOOOXg for 30', and then the supernatant is centrifuged again at 38,OOOXg for 30'. The binding assay contains 0.25 nM [3H]8- OH-DPAT in 50 mM Tris-HCl, 4 mM CaC12 and lmg/ml ascorbate. Non-specific binding is defined using 10 μM propranolol. The assay is terminated after a 1 hour incubation at room temperature by rapid filtration over GF/Cfilters EX AMPLE 14 EXEMPLARY FUNCTIONAL ASSAYS In order to confirm the specificity of compounds for the human alphal C adrenergic receptor and to define the biological activity of the compounds, the following functional tests may be performed: 1. IN VITRO RAT, DOG AND HUMAN PROSTATE AND DOG URETHRA Taconic Farms Sprague-Dawley male rats, weighing 250- 400 grams are sacrificed by cervical dislocation under anesthesia (methohexital; 50 mg/kg, i.p.). An incision is made into the lower abdomen to remove the ventral lobes of the prostate. Each prostate removed from a mongrel dog is cut into 6-8 pieces longitudinally along the urethra opening and stored in ice-cold oxygenated Krebs solution overnight before use if necessary. Dog urethra proximal to prostate is cut into approximately 5 mm rings, the rings are then cut open for contractile measurement of circular muscles. Human prostate chips from transurethral surgery of benign prostate hypeφlasia are also stored overnight in ice-cold Krebs solution if needed. The tissue is placed in a Petri dish containing oxygenated Krebs solution [NaCl, 118 mM; KCl, 4.7 mM; CaCl2, 2.5 mM; KH2PO4, 1.2 mM; MgSθ4, 1.2 mM; NaHC03, 2.0 mM; dextrose, 11 mM] warmed to 37°C. Excess lipid material and connective tissue are carefully removed. Tissue segments are attached to glass tissue holders with 4-0 surgical silk and placed in a 5 ml jacketed tissue bath containing Krebs buffer at 37°C, bubbled with 5% Cθ2/95% 02- The tissues are connected to a Statham-Gould force transducer; 1 gram (rat, human) or 1.5 gram (dog) of tension is applied and the tissues are allowed to equilibrate for one hour. Contractions are recorded on a Hewlett-Packard 7700 series strip chart recorder. After a single priming dose of 3 μM (for rat), 10 μM (for dog) and 20 μM (for human) of phenylephrine, a cumulative concentration response curve to an agonist is generated; the tissues are washed every 10 minutes for one hour. Vehicle or antagonist is added to the bath and allowed to incubate for one hour, then another cumulative concentration response curve to the agonist is generated. EC50 values are calculated for each group using GraphPad Inplot software. pA2 (-log Kb) values were obtained from Schild plot when three or more concentrations were tested. When less than three concentrations of antagonist are tested, Kb values are calculated according to the following formula Kb = 1B1. x-1 where x is the ratio of EC50 of agonist in the presence and absence of antagonist and [B] is the antagonist concentration. 2. MEASUREMENT OE TNTR A -URETH AL PRESSURE TN ANESTHETIZED DOGS PURPOSE: Benign prostatic hypeφlasia causes decreased urine flow rate that may be produced by both passive physical obstruction of the prostatic urethra from increased prostate mass as well as active obstruction due to prostatic contraction. Alpha adrenergic receptor antagonists such as prazosin and terazosin prevent active prostatic contraction, thus improve urine flow rate and provide symptomatic relief in man. However, these are non-selective alpha- 1 receptor antagonists which also have pronounced vascular effects. Because we have identified the alpha- IC receptor subtype as the predominent subtype in the human prostate, it is now possible to specifically target this receptor to inhibit prostatic contraction without concomitant changes in the vasculature. The following model is used to measure adrenergically mediated changes in intra-urethral pressure and arterial pressure in anesthetized dogs in order to evaluate the efficacy and potency of selective alpha adrenergic receptor antagonists. The goals are to: 1) identify the alpha- 1 receptor subtypes responsible for prostatic/urethral contraction and vascular responses, and 2) use this model to evaluate novel selective alpha adrenergic antagonists. Novel and standard alpha adrenergic antagonists may be evaluated in this manner. METHODS: Male mongrel dogs (7-12 kg) are used in this study. The dogs are anesthetized with pentobarbital sodium (35 mg/kg, i.v. plus 4 mg/kg/hr iv infusion). An endotracheal tube is inserted and the animal ventilated with room air using a Harvard instruments positive displacement large animal ventilator. Catheters (PE 240 or 260) are placed in the aorta via the femoral artery and vena cava via the femoral veins (2 catheters, one in each vein) for the measurement of arterial pressure and the administration of drugs, respectively. A supra-pubic incision -1/2 inch lateral to the penis is made to expose the urethers, bladder and urethra. The urethers are ligated and cannulated so that urine flows freely into beakers. The dome of the bladder is retracted to facilitate dissection of the proximal and distal urethra. Umbilical tape is passed beneath the urethra at the bladder neck and another piece of umbilical tape is placed under the distal urethra approximately 1 -2 cm distal to the prostate. The bladder is incised and a Millar micro-tip pressure transducer is advanced into the urethra. The bladder incision is sutured with 2-0 or 3-0 silk (purse-string suture) to hold the transducer. The tip of the transducer is placed in the prostatic urethra and the position of the Millar catheter is verified by gently squeezing the prostate and noting the large change in urethral pressure. Phenylephrine, an alpha- 1 adrenergic agonist, is administered (0.1-100 ug/kg, iv; 0.05 ml/kg volume) in order to construct dose response curves for changes in intra-urethral and arterial pressure. Following administration of increasing doses of an alpha adrenergic antagonist (or vehicle), the effects of phenylephrine on arterial pressure and intra-urethral pressure are re-evaluated. Four or five phenylephrine dose-response curves are generated in each animal (one control, three or four doses of antagonist or vehicle). The relative antagonist potency on phenylephrine induced changes in arterial and intra-urethral pressure are determined by Schild analysis. The family of averaged curves are fit simultaneously (using ALLFTT software package) with a four paramenter logistic equation constraining the slope, minimum response, and maximum response to be constant among curves. The dose ratios for the antagonist doses (rightward shift in the dose-response curves from control) are calculated as the ratio of the ED50's for the respective curves. These dose-ratios are then used to construct a Schild plot and the Kb (expressed as ug kg, iv) determined. The Kb (dose of antagonist causing a 2-fold rightward shift of the phenylephrine dose-response curve) is used to compare the relative potency of the antagonists on inhibiting phenylephrine responses for intra-urethral and arterial pressure. The relative selectivity is calculated as the ratio of arterial pressure and intra-urethral pressure Kb's. Effects of the alpha- 1 antagonists on baseline arterial pressure are also monitored. Comparison of the relative antagonist potency on changes in arterial pressure and intra-urethral pressure provide insight as to whether the alpha receptor subtype responsible for increasing intra-urethral pressure is also present in the systemic vasculature. According to this method, one is able to confirm the selectivity of alphal C adrenergic receptor antagonists that prevent the increase in intra-urethral pressure to phenylephrine without any activity at the vasculature. At the end of the experiment, the dogs are killed via an overdose of intravenously administered pentobarbital or saturated KCl. EXAMPLE 15 l,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazo!inyl)-piperidin-l - yl)-butyl)-l,2-benzisothiazol-3(2H)-one Step 1: A mixture of 15.4 g 4-piperidone hydrochloride hydrate, 200 mL ether, 100 mL saturated aqueous Na2C03 solution and 21.8 g di-t- butyldicarbonate was vigorously stirred for 48 h. The layers were separated and the organic layer was washed with two 150 mL portions of 10% aqueous citric acid, dried over MgS04. Removal of solvents under jeduced pressure gave 18.9 g (95%) N-t-butyloxycarbonyl-4- piperidone as a white solid. Step 2: A mixture of 6.0 g N-t-butyloxycarbonyl-4-piperidone, 3.3 g of 2-aminophenol, 25 mL of 1,2-dichloroethane, 25 mL of glacial acetic acid, and 500 mg powdered 4A molecular sieves was stirred under inert atmosphere. After 30 min, 6.4 g sodium triacetoxyborohydride was added stirring was continued for 38 h. The reaction mixture was poured into 400 mL ethyl acetate and 200 mL saturated aqueous NaHCθ3 and the layers separated. The organic layer was washed with brine (2 x 100 mL), dried over MgS04, filtered and concentrated under reduced pressure. Chromatography of the crude product on silica gel, eluting with a gradient of 1-3% methanol/methylene chloride containing 0.5% concentrated NH4OH gave 6.95 g (79%)l-t-butyloxycarbonyl-4-(2- hydroxyphenylamino)piperidine as an orange foam. Step 3: To a stirred solution of 6.95 g l-t-butyloxycarbonyl-4-(2- hydroxyphenylamino)piperidine and 6.2 mL diisopropylethylamine in 120 mL tetrahydrofuran cooled to 0 β C was added 3.0 g triphosgene. The reaction was stirred 30 min at 0°C and then at room temperature 2 h. The precipitate was removed by filtration, the filtrate concentrated at reduced pressure and partitioned between 250 mL ethyl acetate and 100 mL saturated aqueous Na2C03. The layers were separated, the organic layer washed with 100 mL of saturated aqueous Na2C03, 100 mL of water, 100 mL of brine , dried over MgS04, and concentrated under reduced pressure. Chromatography of the crude product on silica gel, eluting with a gradient of 40-50% ethyl acetate- hexanes gave 6.0 g (79%) l-((l-t-butyloxycarbonyl)piperidin-4-yl)-3- benzoxazolin-2-one as a yellow foam. Step 4: A stirred solution of 6.0 g (19 mmol) l-((l-t- butyloxycarbonyl)piperidin-4-yl)-3-benzoxazolin-2-one in 120 mL ethyl acetate was cooled to -78°C and a stream of hydrogen chloride gas was introduced with a fritted dispersion tube for 15 min. The mixture was allowed to warm to 0°C for 1 h, then room temperature for 2 h. The resulting precipitate was collected by filtration. Drying at reduced pressure for 8 h gave 4.2 g (16.5 mmol, 88%) of the hydrochloride salt of l-(4-piperidinyl)-3-benzoxazolin-2-one as an off-white solid. Step 5: A mixture of 430 mg (1.7 mmol) of the hydrochloride salt of l-(4-piperidinyl)-3-benzoxazolin-2-one and 588 mg (1.9 mmol) of 2- (4-bromobutyl)-l,l-dioxido-l,2-benzothiazol-3(2H)-one, 20 mL dry dimethylformamide and 0.6 mL (3.5 mmol) diisopropylethylamine was warmed to 80°C for 3 h. The solvents were removed under reduced pressure and the crude oily product dissolved in 100 mL ethyl acetate, washed with saturated aqueous NaHC03 (3 x 30 mL), brine (1 x 30 mL), dried over Na2S04 and concentrated at reduced pressure. Chromatography of the crude product on silica gel, eluting with a gradient of 10% methanol in methylene chloride and recrystallization from ethyl acetate gave 300 mg (40%) of l ,l-dioxido-2-(4-(4-(2-oxo- 3-benzoxazolinyl)-piperidin-l-yl)-butyl)-l,2-benzisothiazol-3(2H)-one as an off-white crystalline solid. Analysis calculated for C23H25N3O5S C: 60.64, H: 5.53, N: 9.22 found C: 60.04, H: 5.50, N: 9.29. iH NMR (300 MHz, CDCI3) 8.07 (dd, J = 6.54, 2.2 Hz, IH), 7.93 (m, IH), 7.85 (m, 2H), 7.18 (m, 4H), 4.21 (tt, J = 12.4, 4.34 Hz, IH), 3.85 (t, J = 7.27 Hz, 2H), 3.07 (d, J = 11.67 Hz, 2H), 2.45 (t, J = 7.57 Hz, 2H), 2.35 (dt, J = 12.45, 3.71 Hz, 2H), 2.11 (dt, J = 12.1 , 1.84 Hz, 2H), 1.90 (m, 4H), 1.64 (m, 2H). EXAMPLE lfi l,l-Dioxido-2-(4-(4-(3,4-dihydro-2-oxo-(l#)-quinolin-l-yl)- piperidin-l-yl)-butyl)-l,2-benzisothiazol-3(2H)-one From the hydrochloride salt of 3,4-dihydro-l-(4-piperidyl)-2(l/ )- quinolinone prepared according to H. Ogawa et. al. J. Med. Chem. 1993, 36, 2011-2017, and 2-(4-bromobutyl)-l,l-dioxido-l ,2- benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained l,l-dioxido-2-(4-(4-(3,4-dihydro-2-oxo-(lH)- quinolin-1 -yl)-piperidin-l-yl)-butyl)-l ,2-benzisothiazol-3(2H)-one as a white solid: iH NMR (300 MHz, CDCI3) 8.07 (dd, J = 6.5, 2.3 Hz, IH), 7.92 (t, J = 6.73 Hz, IH), 7.84 (m, 2H), 7.21 (t, J = 8.73 Hz, 2H), 7.19 (m, IH), 6.99 (t, J = 7.13 Hz, IH), 4.35 (tt, J = 12.2, 4.2 Hz, IH), 3.83 (t, J = 7.32 Hz, 2H), 3.04 (d, J = 11.42 Hz, 2H), 2.81 (t, J = 6.59 Hz, 2H), 2.61 (m, 3H), 2.43 (t, J = 7.19 Hz, 2H), 2.09 (t, J = 11.71 Hz, 2H), 1.88 (m, 2H), 1.69 (m, 5H). EXAMPLE 17 l ,l-Dioxido-2-(4-(4-(l,2-dihydro-4(H)-2-oxo-3,l - benzoxazinyl)-piperidin-l - l)-butyI)-l,2-benzisothiazoI- 3(2H)-one Stepl : A mixture of 20 g of N-t-butyloxycarbonyl-4-piperidinone, 13 g of 2-aminobenzyl alcohol 14 mL of acetic acid and 500 mL of toluene was refluxed under inert atmosphere with azeotropic removal of water for 16 h. After cooling to ambient temperature, 14 g of sodium cyanoborohydride and 200 mL tetrahydrofuran were added and the mixture was stirred at ambient temperature for 24 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 750 mL of ethyl acetate and washed with saturated aqueous NaHC03 (4x 500 mL) and brine (250 mL). The organic layer was dried over MgSθ4, and the solvent was removed under reduced pressure. Chromatography of the crude product on silica gel, eluting with a gradient of 15-30% ethyl acetate-hexanes gave 24 g (78%) of 1- t-butyloxycarbonyl-4-((2-hydroxymethyl)phenylamino)piperidine as a gum . Step 2. To a stirred mixture of 24 g of l-t-butyloxycarbonyl-4-((2- hydroxymethyl)-phenylamino)piperidine, 250 mL of tetrahydrofuran, 41 mL of diisopropylethylamine cooled to 0°C was added 8.54 g of triphosgene. The reaction was stirred at 0°C for lh, and then at ambient temperature for 72 h. Ether (250 mL) was added, the mixture was cooled to 0°C for 3 h, the precipitate removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in 750 mL of ethyl acetate, washed with 5% aqueous citric acid (2x 500 mL), water (250 mL), saturated aqueous NaHC03 (2x 500 mL), dried over MgSθ4 and concentrated under reduced pressure. The residue was boiled in ether (ca. 200 mL) until the solid had dissolved. Cooling overnight gave 19 g of l-((l-t- buty loxycarbonyl)piperidin-4-y 1)- 1 ,2-dihydro-4(H)-3 , 1 -benzoxazin-2- one as off-white crystals (75% yield). Step 4. A stream of hydrogen chloride gas was dispersed through a stirred, ice cold solution of 19 g of l-((l-t-butyloxycarbonyl)- piperidin-4-yl)-l,2-dihydro-4(H)-3,l-benzoxazin-2-one in 500 mL of ethyl acetate for 30 min. Stirring was continued at 0°C for 1 h, then at ambient temperature for 1 h. The suspension was diluted with 250 mL of ether, aged for 1 h at 0°C, and the solid product was collected by filtration. Drying under reduced pressure for 18 h, gave 14 g of the hydrochloride salt of l-(4-piperidinyl)-l,2-dihydro-4(H)-3,l - benzoxazin-2-one as an off-white solid (91 %) Step 5: From the hydrochloride salt of l-(4-piperidinyl)-l ,2-dihydro- 4(H)-3,l-benzoxazin-2-one, and 2-(4-bromobutyl)-l,l-dioxido-l,2- benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid, HCl salt: iH NMR (400 MHz, CD3OD) 8.10 (t, J = 7.33 Hz, IH), 7.99 (m, 3H), 7.42 (t, J = 7.14 Hz, IH), 7.27 (t, J = 7.51 Hz, 2H), 7.16 (t, J = 7.69 Hz, IH), 5.17 (s, 2H), 4.27 (t, J = 12.08 Hz, IH), 3.87 (t, J = 6.22 ppm, 2H), 3.67 (m, 3H), 3.19 (m, 3H), 2.98 (m, 2H), 2.16 (d, J = 12.5 Hz, 2H), 1.92 (m, 4H). EXAMPLE 18 l,l-Dioxido-2-(4-(4-(2-oxo-(lH)-quinolin-l-yl)-piperidin-l- yl)-butyI)-l,2-benzisothiazol-3(2H)-one From the hydrochloride salt of l-(4-piperidyl)-2(l/ )-quinolinone was prepared according to H. Ogawa et. al. J. Med. Chem. 1993, 36, 2011-2017, and 2-(4-bromobutyl)-l ,l-dioxido-l,2-benzothiazol- 3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: iH NMR (300 MHz, CDCI3) 8.08 (d, J = 6.73 Hz, IH), 7.90 (m, 3H), 7.7 (d, J = 9.5 Hz, IH), 7.6 (d, J = 9.2 Hz, IH), 7.56 (d, J = 7.62 Hz, IH), 7.26 (m, 2H), 6.71 (d, J = 9.47 Hz, IH), 3.85 (br m, 3H), 3.45 (br m, IH), 3.25 (br m, 3H), 3.14 (br m, 6H), 1.95 (br s, 4H). EXAMPLE 19 l,l-Dioxido-2-(4-(4-(2-oxo-(lH)-quinoIin-l -yI)-piperidin-l - yI)-butyI)-5-nitro-l,2-benzisothiazol-3(2H)-one From the hydrochloride salt of l-(4-piperidyl)-2(l/ )-quinolinone prepared according to H. Ogawa et. al. J. Med. Chem. 1993, 36, 201 1-2017, and 2-(4-bromobutyl)-5-nitro-l,l-dioxido-l ,2- benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: iH NMR (300 MHz, CDCI3) 8.88 (d, J = 1.9 Hz, IH), 8.73 (dd, J = 8.36, 1.71 Hz, IH), 8.15 (d, J = 8.36 Hz, IH), 7.79 (br m, IH), 7.62 (d, J = 3.47 Hz, IH), 7.51 (m, 2H), 7.20 (m, 2H), 6.66 (d, J = 9.33 Hz, IH), 3.91 (t, J = 7.33 Hz, 2H), 2.85 (br m, 2H), 2.48 (t, J = 8.27 Hz, 2H), 2.21 (t, J = 10.65 Hz, 2H). EX AMPLE 20 6-Chloro-l ,l-dioxido-2-(4-(4-(2-oxo-(lH)-quinolin-l -yl)- piperidin-l -yl)-butyl)-l,2-benzisothiazol-3(2H)-one From the hydrochloride salt of l-(4-piperidyl)-2(l/ )-quinolinone prepared according to H. Ogawa et. al. J. Med. Chem. 1993, 36, 2011-2017, and 2-(4-bromobutyl)-6-chloro-l,l-dioxido-l,2- benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid, HCl salt: iH NMR (300MHz, CD3OD) 8.25 (d, J = 1.66 Hz, IH), 8.08 (d, J = 8.17 Hz, IH), 7.98 (dd, J = 8.24, 1.71 Hz, IH), 7.89 (d, J = 9.52 Hz, IH), 7.85 (d, J = 8.55 Hz, IH), 7.71 (d, J = 7.68 Hz, IH), 7.68 (t, J = 7.57 Hz, 1H), 7.33 (t, J = 7.65 Hz, IH), 6.59 (d, J = 9.52 Hz, IH), 5.06 (br m, IH), 3.88 (t, J = 6.3 Hz, 2H), 3.69 (d, J = 9.87 Hz, 2H), 3.26 (m, 6H), 1.94 (m, 6H). EXAMPLE 21 5-ChIoro-l ,l-dioxido-2-(4-(4-(2-oxo-(lH)-quinolin-l -yI)- piperidin-l -yl)-butyl)-l,2-benzisothiazol-3(2H)-one From the hydrochloride salt of l-(4-piperidinyl)-3-benzoxazolin-2- one and 2-(4-bromobutyl)-6-chloro-l ,l-dioxido-l,2-benzothiazol- 3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid, HCl salt: iH NMR (300 MHz, CD3OD) 8.11 (d, J = 7.81 Hz, IH), 8.13 (s, IH), 8.02 (dd, J = 8.3, 1.7 Hz, IH), 7.90 (d, J = 9.52 Hz, IH), 7.85 (d, J = 8.85 Hz, IH), 7.71 (d, J = 7.57 Hz, IH), 7.67 (t, J = 8.97 Hz, IH), 7.33 (t, J = 7.32 Hz, IH), 6.59 (d, J = 9.47 Hz, IH), 5.08 (br m, IH), 3.89 (t, J = 6.11 Hz, 2H), 3.71 (d, J = 8.74 Hz, 2H), 3.30 (br m, 6H), 2.0-1.9 (m, 6H). EXAMPLE 2? l,l-Dioxido-2-(4-(4-(2-oxo-(lH)-quinolin-l -yl)-piperidin-l- yl)-butyI)-7-nitro-l,2-benzisothiazoI-3(2H)-one From the hydrochloride salt of l-(4-piperidinyl)-3-benzoxazolin-2- one and 2-(4-bromobutyl)-6-nitro-l,l-dioxido-l,2-benzothiazol- 3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: iH NMR (300 MHz, CDCI3) 8.65 (d, J = 8.19 Hz, IH), 8.44 (d, J = 7.63 Hz, IH), 8.10 (t, J = 8.11 Hz, IH), 7.81 (br s, IH), 7.61 (d, J = 9.34 Hz, IH), 7.52 (m, 2H), 7.19 (t, J = 7.33 Hz, IH), 6.67 (d, J = 9.28 Hz, IH), 3.95 (t, J = 7.38 Hz, 2H), 3.10 (d, J = 10.37 Hz, 2H), 2.86 (br s, 2H), 2.49 (t, J = 6.95 Hz, 2H), 2.22 (t, J = 10.74 Hz, 2H), 1.98 (m, 2H), 1.70 (br m, 5H). EXAMPLE 23 l,l -Dioxido-2-(4-(4-(2-oxo-(lH)-quinolin-l-yl)-piperidin- l-yl)-butyl)-4-methoxy-l,2-benzisothiazol-3(2H)-one From the hydrochloride salt of l-(4-piperidyl)-2(l/ )-quinolinone prepared according to H. Ogawa et. al. J. Med. Chem. 1993, 36, 2011-2017, and 2-(4-bromobutyl)-4-methoxy-l ,l-dioxido-l,2- benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: iH NMR (300 MHz, CDC13) 7.80 (t, J = 8.1 Hz, 2H), 7.60 (d, J = 9.33 Hz, 2H), 7.51 (m, 2H), 7.25 (m, 3H), 6.66 (d, J = 9.27 Hz, IH), 4.06 (s, 2H), 3.80 (t, J = 6.9 Hz, 2H), 3.09 (dd, J = 9.8, 1.8 Hz, 2H), 2.84 (m, 2H), 2.46 (t, J = 7.2 Hz, 2H), 2.19 (t, J = 11.6 Hz, 2H), 1.89 (br m, 2H), 1.69 (br m, 3H), 1.58 (s, 3H). EXAMPLE 24 l,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l - yl)-butyl)-5-nitro-l,2-benzisothiazol-3(2H)-one From the hydrochloride salt of l-(4-piperidinyl)-3-benzoxazolin-2- one and 2-(4-bromobutyl)-5-nitro-l ,l-dioxido-l,2-benzothiazol- 3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid, HCl salt: iH NMR (300 MHz, CD3OD) 8.82 (m, 2H), 8.39 (d, J = 8.98 Hz, IH), 7.25 (m, 4H), 4.50 (tt, J = 8.01, 3.96 Hz, IH), 3.93 (t, J = 6.05 Hz, 2H), 3.74 (d, J = 12.94 Hz, 2H), 3.26 (m, 4H), 2.73 (m, 2H), 2.17 (d, J = 13.9 Hz, 2H), 1.93 (br m, 4H). EXAMPLE 25 6-Chloro-l,l -dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)- piperidin-l -yl)-butyl)-l,2-benzisothiazol-3(2H)-one From the hydrochloride salt of l-(4-piperidinyl)-3-benzoxazolin-2- one and 2-(4-bromobutyl)-6-chloro-l ,l-dioxido-l,2-benzothiazol- 3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid, HCl salt: J H NMR (300 MHz, CD3OD) 8.22 (d, J = 1.41 Hz, IH), 8.07 (dd, J = 8.3, 2.63 Hz, IH), 7.96 (dd, J = 8.19, 1.65 Hz), 7.33 (d, J = 7.13 Hz, IH), 7.23 (m, 2H), 4.49 (tt, J = 12.21 , 4.21 Hz, IH), 3.88 (t, J = 5.86 Hz, 2H), 3.74 (d, J = 11.72 Hz, 2H), 3.23 (br m, 4H), 2.73 (m, 2H), 2.17 (d, J = 13.43 Hz, 2H), 1.9 (br m, 4H). EXAMPLE 2$ 5-Chloro-l,l -dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)- piperidin-l -yI)-butyl)-l,2-benzisothiazol-3(2H )-one From the hydrochloride salt of l-(4-piperidinyl)-3-benzoxazolin-2- one and 2-(4-bromobutyl)-5-chloro-l,l-dioxido-l,2-benzothiazol- 3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid, HCl salt: H NMR (300 MHz, CD3OD) 8.10 (d, J = 6.59 Hz, IH), 8.11 (s, IH), 7.29 (m, 2H), 7.21 (m, 2H), 4.49 (tt, J = 12.21, 4.21 Hz, IH), 3.88 (t, J = 5.86 Hz, 2H), 3.74 (d, J = 11.72 Hz, 2H), 3.23 (br m, 4H), 2.73 (m, 2H), 2.17 (br d, 2H), 1.9 (br m, 4H). EXAMPLE 27 l,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazo!inyI)-piperidin-l - yl)-butyl)-7-nitro-l,2-benzisothiazol-3(2H)-one From the hydrochloride salt of l-(4-piperidinyl)-3-benzoxazolin-2- one and 2-(4-bromobutyl)-7-nitro-l,l-dioxido-l,2-benzothiazol- 3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid, HCl salt: J H NMR (300 MHz, CD3OD) 8.76 (d, J = 8.25 Hz, IH), 8.50 (d, J = 7.76 Hz, IH), 8.22 (t, J = 7.76 Hz), 7.24 (m, 4H), 4.49 (tt, J = 12.21, 4.21 Hz, IH), 3.96 (t, J = 6.01 Hz, 2H), 3.76 (d, J = 11.7 Hz, 2H), 3.23 (m, 4H), 2.73 (m, 2H), 2.17 (dd, J = 14.5, 2.2 Hz, 2H), 1.9 (m, 4H). EXAMPLE 2S l,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyI)-piperidin-l - yl)-butyl)-4-methoxy-l,2-benzisothiazoI-3(2H)-one From the hydrochloride salt of l-(4-piperidinyl)-3-benzoxazolin-2- one and 2-(4-bromobutyl)-4-methoxy-l,l-dioxido-l,2-benzothiazol- 3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: iH NMR (400 MHz, CDCI3) 7.83 (t, J = 8.06 Hz, IH), 7.49 (d, J = 7.69 Hz, IH), 7.46 (d, J = 7.51 Hz, IH), 7.30 (d, J = 8.6 Hz, IH), 7.17 (m, 3H), 4.56 (dt, J = 11.72, 4.21 Hz, IH), 4.07 (s, 3H) 3.79 (m, 4H), 3.16 (m, 2H), 2.88 (m, 4H), 2.07 (d, J = 13.0 Hz, 2H), 1.96 (m, 4H). EXAMPLE 29 l,l-Dioxido-2-(4-(4-(5-chloro-2-oxo-3-benzoxazolin I)- piperidin-l -yl)-butyl)-l,2-benzisothiazol-3(2H)-one From the hydrochloride salt of 5-chloro-l-(4-piperidinyl)-3- benzoxazolin-2-one and 2-(4-bromobutyl)-l,l-dioxido-l,2- benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid, HCl salt: iH NMR (400 MHz, CD3OD) 8.10 (td, J = 6.0, 1.2 Hz, 2H), 8.02-7.94 (overlapping dt, 2H), 7.43 (d, J = 1.8 Hz, IH), 7.24 (d, J = 8.4 Hz, IH), 7.16 (dd, J = 8.6, 2.0 Hz, IH), 4.43 (tt, J = 12.4, 4.4, IH), 3.88 (t, J = 6.4, 2H), 3.66 (d, J = 11.5, 2H), 3.16-3.05 (m, 4H), 2.66 (qd, J = 13.0, 3.7, 2H), 2.13 (d, J = 13.4, 2H), 2.01-1.88 (m, 4H). EX AMPLE 30 l ,l -Dioxido-2-(4-(4-(3a-(fl)-8a-(S)-2-oxo-3,3a,8,8a- tetrahydro-2H-indeno[l,2-d]oxazolinyl)-piperidin-l-yl)- butyl)-l,2-benzisothiazol-3(2H)-one From the hydrochloride salt of 4-(3a-(R)-8a-(S)-2-oxo-3,3a,8,8a- tetrahydro-2H-indeno[l,2-d]oxazolinyl)-piperidine and 2-(4- bromobutyl)-l ,l-dioxido-l,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid, HCl salt: iH NMR (400 MHz, CD3OD) 8.10-8.07 (m, IH), 8.02-7.94 (m, 2H), 7.59 (d, J = 7.1 Hz, IH), 7.32-7.31 (m, 4H), 5.37-5.30 (m, 2H), 3.86 (m, 3H), 3.55-3.41 (m, 4H), 3.25-2.98 (m, 5H), 2.55 (m, 2H), 2.14 (m, IH), 1.94-1.77 (m, 4H), EXAMPLE 31 l ,l-Dioxido-2-(4-(4-(2-oxonaphth[2,3-d]oxazolinyl)- piperidin-l-yl)-butyI)-l,2-benzisothiazol-3(2H)-one From the hydrochloride salt of 4-(2-oxonaphth[2,3-d]oxazolinyl)- piperidine and 2-(4-bromobutyl)-l,l-dioxido-l ,2-benzothiazol-3(2H)- one using the procedure described for Example 15, Step 5 there was obtained a white solid, HCl salt: iH NMR (400 MHz, CD3OD) 8.11 (td, J = 6.5, 0.9 Hz, 2H), 8.02-7.94 (m, 2H), 7.89 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 5.3 Hz, 2H), 7.50-7.42 (m, 2H), 4.58 (tt, J = 12.3, 4.0 Hz, IH), 3.90 (t, J = 6.4 Hz, 2H), 3.72 (d, J = 13.0 Hz, 2H), 3.22-3.15 (m, 4H), 2.80 (qd, J = 12.8, 3.0 Hz, 2H), 2.21 (d, J = 13.7 Hz, 2H), 2.00- 1.92 (m, 4H). EX AMPLE 32 l,l-Dioxido-2-(4-(4-(6-methyI-2-oxo-3-benzoxazolinyl)- piperidin-l-yl)-butyI)-l,2-benzisothiazoI-3(2H)-one From the hydrochloride salt of 4-(6-methyl-2-oxo-3-benzoxazolinyl)- piperidine and 2-(4-bromobutyl)-l,l-dioxido-l ,2-benzothiazol-3(2H)- one using the procedure described for Example 15, Step 5 there was obtained a white solid, HCl salt: J H NMR (400 MHz, CD3OD) 8.09 (td, J = 5.7, 1.5 Hz, 2H), 8.03-7.94 (m, 2H), 7.21 (d, J = 8.1 Hz, IH), 7.11 (s, IH), 7.06 (d, J = 8.0 Hz, IH), 4.46 (tt, J = 12.2, 4.0 Hz, IH), 3.88 (t, J = 6.4 Hz, 2H), 3.71 (d, J = 12.5 Hz, 2H), 3.26-3.16 (m, 4H), 2.71 (qd, J = 13.5, 3.5 Hz, 2H), 2.38 (s, 3H), 2.14 (d, J = 14.1 Hz, 2H), 1.97-1.91 (m, 4H). EXAMPLE 33 l,l -Dioxido-2-(4-(4-(2-oxo-5-phenyI-3-benzoxazolinyl)- piperidin-l -yl)-butyl)-l,2-benzisothiazol-3(2H )-one From the hydrochloride salt of 4-(2-oxo-5-phenyl-3-benzoxazolinyl)- piperidine and 2-(4-bromobutyl)-l ,l-dioxido-l ,2-benzothiazol-3(2H)- one using the procedure described for Example 15, Step 5 there was obtained a white solid, HCl salt: iH NMR (400 MHz, CD3OD) 8.11- 8.07 (overlapping t, 2H), 8.02-7.94 (m, 2H), 7.64 (d, J = 7.1 Hz, 2H), 7.58 (d, J = 1.5 Hz, IH), 7.47-7.41 (m, 3H), 7.38-7.33 (m, 2H), 4.57 (tt J = 12.4, 4.2 Hz, IH), 3.88 (t, J = 6.4 Hz, 2H), 3.71 (d, J = 12.1 Hz, 2H), 3.23-3.13 (m, 4H), 2.77 (qd, J = 14.0, 3.0 Hz, 2H), 2.18 (d, J = 13.9, 2H), 1.97-1.90 (m, 4H). EX AMPLE 34 l,l-Dioxido-2-(4-(4-(6-methoxy-2-oxo-3-benzoxazolinyl)- piperidin-l-yl)-butyl)-l,2-benzisothiazol-3(2H)-one From the hydrochloride salt of 4-(6-methoxy-2-oxo-3- benzoxazolinyl)-piperidine and 2-(4-bromobutyl)-l ,l-dioxido-l ,2- benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid, HCl salt: iH NMR (400 MHz, CD3OD) 8.14 (td, J = 6.4, 1.4 Hz, 2H), 8.05-8.00 (overlapping td, 2H), 7.26 (d, J = 8.6 Hz, IH), 6.99 (d, J = 2.4 Hz, IH), 6.86 (dd, J = 8.8, 2.4 Hz, IH), 4.48 (tt, J = 12.1 , 4.2 Hz, IH), 3.92 (t, J = 6.2 Hz, 2H), 3.83 (s, 3H), 3.75 (d, J = 12.1, 2H), 3.34-3.22 (m, 4H), 2.74 (qd, J = 12.6, 3.6 Hz, 2H), 2.19 (d, J = 13.5 Hz, 2H), 2.00-1.95 (m, 4H). EX AMPLE 35 l,l -Dioxido-2-(4-(4-(6-carbomethoxy-2-oxo-3- benzoxazoIinyI )-piperidin-l -yl)-butyl )-l,2-benzisothiazol- 3(2H)-one From the hydrochloride salt of 4-(6-carbomethoxy-2-oxo-3- benzoxazolinyi)-piperidine and 2-(4-bromobutyl)-l ,l-dioxido-l,2- benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid, HCl salt: iH NMR (400 MHz, CD3OD) 8.01 (t, J = 6.8 Hz, 2H), 7.94-7.86 (m, 3H), 7.78 (d, J = 1.5 Hz, IH), 7.31 (d, J = 8.4, IH), 4.40 (m, IH), 3.83 (s, 3H), 3.79 (t, J = 6.6, 2H), 3.72 (d, J = 7.1, 2H), 3..05 (m, 2H), 2.97 (m, 2H), 2.60 (m, 2H), 2.05 (d, J = 12.5, 2H), 1.89-1.79 (m, 4H). EXAMPLE 3fi l,l-Dioxido-2-(4-(4-(5-ethylsulfonyl-2-oxo-3- benzoxazolinyl)-piperidin-l -yI)-butyl)-l,2-benzisothiazol- 3(2H)-one From the hydrochloride salt of 4-(5-ethylsulfonyl-2-oxo-3- benzoxazolinyl)-piperidine and 2-(4-bromobutyl)-l,l-dioxido-l,2- benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid, HCl salt: J H NMR (400 MHz, CD3OD) 8.01 (t, J = 6.0 Hz, 2H), 7.93-7.87 (m, 2H), 7.77 (s, IH), 7.67 (d, J = 7.1 Hz, IH), 7.42 (d, J = 8.2 Hz, IH), 4 T 48 (m, IH), 3.79 (m, 2H), 3.60 (d, J = 11.2 Hz, 2H), 3.14-3.06 (overlapping q & m, 6H), 2.61 (br q, J = 12.5 Hz, 2H), 2.10 (d, J = 13.4 Hz, 2H), 1.85 (m, 4H), 1.15 (t, J = 6.2 Hz, 3H), EXAMPLE 37 l,l-Dioxido-2-(4-(4-(2-oxo-3-oxazolo[4,5-b]pyridyI)- piperidin-l-yl)-butyl)-l,2-benzisothiazol-3(2H)-one From the hydrochloride salt of 4-(2-oxo-3-oxazolo[4,5-b]pyridyl)- piperidine and 2-(4-bromobutyl)-l,l-dioxido-l,2-benzothiazol-3(2H)- one using the procedure described for Example 15, Step 5 there was obtained a white solid, HCl salt: iH NMR (400 MHz, CD3OD) 8.03- 7.99 (m, 3H), 7.94-7.85 (2 overlapping td, 2H), 7.49 (dd, J = 8.0, 1.2 Hz, IH), 7.07 (dd, J = 8.0, 5.0 Hz, IH), 4.56 (tt, J = 12.1, 4.1 Hz, IH), 3.79 (t, J = 6.4 Hz, 2H), 3.63 (t, J = 12.8 Hz, 2H), 3.20-3.09 (m, 4H), 2.82 (qd, J = 13.3, 3.5 Hz, 2H), 2.09 (d, J = 13.4, 2H), 1.88-1.78 (m, 4H). EXAMPLE 38 l,l -Dioxido-2-(4-(4-(7-carbethoxy-2-oxo-3-benzoxazoIin I)- piperidin-l -yl)-butyI)-l,2-benzisothiazol-3(2H)-one From the hydrochloride salt of 4-(7-carbethoxy-2-oxo-3- benzoxazoliny -piperidine and 2-(4-bromobutyl)- 1 , 1 -dioxido- 1 ,2- benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid, HCl salt: iH NMR (400 MHz, CD3OD) 8.01 (td, J = 6.4, 1.5 Hz, 2H), 7.94-7.86 (m, 2H), 7.63 (dd, J = 8.1, 1.1 Hz, IH), 7.47 (dd, J = 7.9, 1.1 Hz, IH), 7.26 (t, J = 8.1 Hz, IH), 4.42 (tt, J = 12.1 , 4.0 Hz, IH), 3.87 (s, 3H), 3.80 (t, J = 6.2, 2H), 3.63 (d, J = 12.8 Hz, 2H), 3.16-3.06 (m, 4H), 2.65 (qd, J = 13.0, 4.0 Hz, 2H), 2.09 (d, J = 13.5 Hz, 2H), 1.89-1.83 (m, 4H). EXAMPLE 39 l,l -D . oxido-2-(4-(4-(5-terf-butyl-2-oxo-3-benzoxazolinyl)- piperidin-l -yl)-butyl)-l,2-benzisothiazol-3(2H)-one From the hydrochloride salt of 4-(5-tert-butyl-2-oxo-3- benzoxazolinyl)-piperidine and 2-(4-bromobutyl)- 1,1 -dioxido- 1,2- benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: J H NMR (300 MHz, CDCI3) 8.07 (dd, J = 6.6, 2.25 Hz, IH), 7.88 (m, 3H), 7.19 (s, IH), 7.11 (s, 2H), 4.17 (tt, J = 12.21, 3.66 Hz, IH), 3.85 (t, J = 7.14 Hz, 2H), 3.09 (d, J = 10.85 Hz, 2H), 2.46 (t, J = 7.38 Hz, 2H), 2.36 (dt, J 12.15, 3.5 Hz, 2H), 2.13 (dt, J = 10.89, 1.27 Hz, 2H), 1.91 (m, 4H), 1.66 (m, 2H), 1.342 (s, 9H). EXAMPLE 40 l,l-Dioxido-2-(4-(4-(5,7-dimethyl-2-oxo-3-benzoxazolinyl)- piperidin-l -yl)-butyl)-l,2-benzisothiazol-3(2H)-one From the hydrochloride salt of 4-(5,7-dimethyl-2-oxo-3- benzoxazolinyl)-piperidine and 2-(4-bromobutyl)- 1 ,1 -dioxido- 1,2- benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: iH NMR (300 MHz, CDC13) 8.08 (d, J = 7.27 Hz, IH), 7.90 (m, 3H), 7.65 (br m, IH), 6.752 (s, IH), 4.55 (br m, IH), 3.85 (br t, 2H), 3.70 (br m, 2H), 3.32 (br m, 2H), 3.10 (br m, 2H), 2.87 (br m, 2H), 2.413 (s, 3H), 2.318 (s, 3H), 2.06 (br m, 6H). EXAMPLE 41 2-(4-Bromobut l)-l,l-dioxido-l,2-benzothiazol-3(2H)-one The general procedure of J. D. Commerford and H. B. Donahue J. Org. Chem. 1956, 21 , 583-4 was modified: A mixture of 6 g of sodium saccharin, 100 mL of 1 ,4-dibromobutane, and 5 mL of N,N- dimethylformamide was heated at 50°C overnight. After cooling to ambient temperature, the mixture was diluted with 250 mL of ether and 50 mL of water. The aqueous layer was extracted with two additional 50 mL portions of ether and the combined organic extracts were dried over MgSθ4 and concentrated under reduced pressure. The excess 1 ,4-dibromobutane was removed by short path vacuum distillation and the oily residue purified by crystallization from ether- hexane, mp 71-2°C. EXAMPLE 42 2-(4-Bromobutyl)-l,l-dioxido-5-methoxy-l,2-benzothiazol- 3(2H)-one The general procedure of J. D. Commerford and H. B. Donahue J. Org. Chem. 1956, 21, 583-4 was modified: A mixture of 0.5 g of 3,3-dioxido-5-methoxy-l,2-benzothiazol-3(2H)-one prepared as described by J. G. Lombardino, J. Org. Chem. 1971, 36, 1843-5, 1 mL of N,N-dimethylformamide and 0.1 g of sodium hydride 60% oil dispersion was stirred at ambient temperature for 15 min, and 1.4 mL of 1 ,4-dibromobutane was added. After stirring at ambient temperature overnight, the mixture was diluted with 25 mL of ethyl acetate, washed with 25 mL of sat'd NaHCθ3, 25 mL of sat'd brine and dried over MgSθ4. Removal of solvents under reduced pressure and vacuum distillation gave 0.8 g of crude product as a viscous oil which was free of 1 ,4-dibromobutane by J H-NMR and was used without further purification. EXAMPLE 43 2-(4-Bromobutyl)-l,l -dioxido-5-nitro-l,2-benzothiazol- 3(2H)-one The general procedure of J. D. Commerford and H. B. Donahue J. Org. Chem. 1956, 21, 583-4 was modified: A stirred mixture of 1.0 g of 3,3-dioxido-5-nitro-l ,2-benzothiazol-3(2H)-one prepared as described by W. S. Saari and J. E. Schwering, J. Heterocyclic Chem. 1986, 23, 1253, and 6 mL of IN NaOH was warmed to dissolution and allowed to cool to ambient temperature for 15 min. The mixture was concentrated to dryness under reduced pressure and the white solid azeotropically dried with 20 mL of toluene. The resulting sodium salt was dissolved in 3 mL of N,N-dimethylformamide and 2.6 mL of 1 ,4-dibromobutane was added. After stirring at ambient temperature overnight, the mixture was diluted with 25 mL of ethyl acetate, washed with 25 mL of sat'd NaHCθ3, 25 mL of sat'd brine and dried over MgSθ4. Removal of solvents under reduced pressure and vacuum distillation gave 1.1 g of crude product as a solid which was free of 1,4-dibromobutane by iH¬ NMR and was used without further purification: iH NMR (300 MHz, CDC13): 8.87 (d, J = 0.5 Hz, IH), 8.74 (dd, J = 8.38, 2.03 Hz, IH), 8.15 (dd, J = 8.41 , 2.0 Hz, IH), 3.88 (t, J = 6.8 Hz, 2H), 3.47 (t, J = 6.3 Hz, 2H), 2.02 (m, 4H). EXAMPLE 44 l ,l -Dioxido-2-(4-(spiro-l,3-dihydro-l -oxo-2H-indenyI)-2,4'- piperidin-l'-yl)butyl)-l,2-benzisothiazol-3(2H)-one Step 1 : To a ice cold, stirred mixture of 55 g of ethyl isonipecotate, 200 mL of ether, 200 mL of saturated sodium carbonate and 200 mL of water was added dropwise 40 mL of benzoyl chloride. The resulting mixture was allowed to warm and stir overnight, diluted with 200 mL of ethyl acetate and separated. The organic layer was washed with 200 mL of IN hydrochloric acid, dried over MgS04, and concentrated. Drying the residue under vacuum gave 83.3 g (92%) of ethyl 1 - benzoyl-4-piperidinecarboxylate as a white solid. Step 2: A stirred solution of 176 mL of commercial IM lithium bistrimethylsilylamide in tetrahydrofuran was diluted with 100 mL of tetrahydrofuran and cooled to -78°C under inert atmosphere. A solution of 44 g of ethyl l-benzoyl-4-piperidinecarboxylate in 200 mL of tetrahydrofuran was added dropwise keeping the temperature below -60°C, followed by 21 mL of benzyl bromide. The resulting mixture was allowed to warm and stir overnight, diluted with 200 mL of IN hydrochloric acid, 200 mL of ethyl acetate and separated. The organic layer was washed with 200 mL of IN hydrochloric acid, dried over MgSθ4, and concentrated. The residue was dissolved in 300 mL of toluene, filtered and concentrated under reduced pressure. Drying under reduced pressure gave 56.3 g of ethyl l-benzoyl-4- (phenylmethyl)-4-piperidinecarboxylate as a viscous oil homogeneous by thin layer chromatography, eluting with 1:1 ethyl acetate: hexane, iH NMR (300 MHz, CDCI3) 1.20 (t, 3H), 1.40 (m, IH), 1.60 (m, IH), 2.07 (m, IH), 2.22 (m, IH), 2.85 (d, 2H), 3.08 (m, IH), 3.65 (m, IH), 4.12 (q, 2H), 4.65 (m, IH), 7.04 (m, 2H), 7.24 (m, 3H), 7.38 (m, 5H). Step 2: A mixture of 65 g of ethyl l-benzoyl-4-(phenylmethyl)-4- piperidinecarboxylate, 300 g of polyphosphoric acid and 500 mL of xylene was heated at reflux overnight. The xylene layer was decanted off and the residue washed with two additional 100 mL portions of xylene. The residue was dissolved in 1L of water and 1L of ethyl acetate and separated. The aqueous was extracted with two additional 200 mL portions of ethyl acetate and the combined organic extracts were washed with 500 mL of sat'd Na2C03, water and dried over MgS04. Removal of solvents under reduced pressure gave 27 g of 1 '- benzoyl-l,3-dihydro-l-oxo-spiro(2H-indenyl-2,4'-piperidine) as crystalline solid, mp 149-154< C; iH NMR (300 MHz, CDCI3) 1.50 (m, 2H), 2.00 (m, 2H), 3.12 (m, 2H), 3.25 (ddd, 2H), 3.90 (m, IH), 4.62 (m, IH), 7.43 (m, IH), 7.63 (dd, IH), 7.79 (d, IH). Step 3: A mixture of 27 g of 1 '-benzoyl- 1,3-dihydro-l -oxo-spiro(2H- indenyl-2,4'-piperidine) 400 mL of ethanol and 100 mL of cone, hydrochloric acid was heated at reflux for 48 hrs. The mixture was concentrated to remove ethanol, diluted 200 mL with water and extracted with two additional portions of ethyl acetate. The aqueous layer was basified with 20% NaOH and extracted with three 200 mL portions of ethyl acetate. The combined organic extracts were washed with 50 mL of water and dried over MgSθ4. Removal of solvents under reduced pressure gave 18 g of l ,3-dihydro-l-oxo-spiro(2H- indene-2,4'-piperidine) as brown solid product: iH NMR (300 MHz, CDCI3) 1.35 (dd, 2H), 1.62 (br s, IH), 1.88 (ddd, 2H), 2.81 (ddd, 2H), 3.10 (s, 2H), 3.17 (m, 2H), 7.38 (t, IH), 7.46 (d, IH), 7.60 (t, IH), 7.77 (d, IH). Step 4: From l,3-dihydro-l-oxo-spiro(2H-indenyl-2,4'-piperidine), and 2-(4-bromobutyl)-l,l-dioxido-l,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained 1,1- dioxido-2-(4-(spiro(l ,3-dihydro-l -oxo-2H-indene-2,4'-piperidin-l '- yl)butyl)-l ,2-benzisothiazol-3(2H)-one as a white solid: J H NMR (400 MHz, CDCI3): 8.06 (d, J=6.8 Hz, IH), 7.92 (d, J=6.6 Hz, IH), 7.89-7.83 (m, 2H), 7.75 (d, J=7.7 Hz, IH), 7.59 (t, J=7.4 Hz, IH), 7.44 (d, J=6.96 Hz, IH), 7.37 (t, J=7.4 Hz, IH), 3.83 (t, J=7.4 Hz, 2H), 3.02 (s, 2H), 2.95 (t, J=11.36 Hz, 2H), 2.45 (t, J=7.4 Hz, 2H), 2.17-2.01 (m, 4H), 1.94-1.90 (m, 2H), 1.67-1.64 (m, 2H), 1.38 (br d, J=12 Hz, 2H). EXAMPLE 45 l,l-Dioxido-2-(4-(4*-(3,4-dihydro-l -oxonapththalene)-2(lH)- spiropiperidin-l '-yl)butyl)-l,2-benzisothiazol-3(2H)-one From 4'-(3,4-dihydro-l -oxonapththalene)-2(lH)-spiropiperidine, prepared as described by P. J. Gilligan, et al., J. Med. Chem. 1994, 37, 364-370, and 2-(4-bromobutyl)-l ,1 -dioxido- 1 ,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: mp 226-8°C. EXAMPLE 4$ 4-(3,4-Dihydro-6-methyl-spiro[2H-l-benzopyran-2, 4' -piperidine 4(3H)-one]-l '-yl)-butylphthaIimide From 3,4-dihydro-6-methyl-spiro[2H-l -benzopyran-2,4'-piperidine, and 2-(4-bromobutyl)-phthalimide using the procedure described for Example 15, Step 5 there was obtained a white solid:mp>275°C dec. EXAMPLE 47 4-(Spiro(piperidine-4,6 , -[6H]thieno[2,3-b]thiopyran-4'(5Η)-one- l '-yD-butylphthalimide From 4-(spiro(piperidine-4,6'-[6H]thieno[2,3-b]thiopyran-4'(5'H)-one, and 2-(4-bromobutyl)-phthalimide using the procedure described for Example 15, Step 5 there was obtained a white solid:mp 261-3°C dec. EXAMPLE 48 4-(Spiro[benzothiazol-2(3H),4'-piperidin-l '-yl)-butylphthalimide Step 1 : A solution of 4-piperidone hydrochloride hydrate (2 gram, 13 mmol), bromobutylphthalimide (3.67 gram, 13 mmol) and triethylamine (3.4 ml, 26 mmol) in Chloroform (25 ml) was refluxed overnight. The reaction mixture was washed with sat. NaHCθ3 and was dried over Na2Sθ4. Purification using flash chromatography gave 4- (4'-ketopiperidinyl)butylphthalimide (0.85 gram). Step 2: A solution of 4-(4'-ketopiperidinyl)butylphthalimide (200 mg, 0.67 mmol), 2-aminothiophenol (125ml, 0.73mmol) and tosic acid (30 mg) in benzene (25 ml) was refluxed overnight. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and sat. NaHC03. The organic layer was dried over Na2Sθ4. Chromatography gave a white solid: J H NMR (300 MHz, CDCI3): 8.01-7.95 (m, 2H), 7.88-7.82 (m, 2H), 7.17 (d, J=7.57 Hz, IH), 7.04 (t, IH), 6.86 (t, J=3.76 Hz, IH), 6.78 (d, J=7.63 Hz, IH), 4.14 (br s, IH), 3.85 (t, J=7.04 Hz, 2H), 2.89-2.06 (m, 2H), 2.54-2.30 (m, 6H), 2.18- 2.06 (m, 2H), 1.90-1.72 (m, 2H), 1.69-1.37 (m, 2H). EXAMPLE 49 4-(3,4-Dihydro-6-methoxy-spiro[2H-l-benzopyran-2,4' -piperidi 4(3H)-one]-r-yl)-butylphthalimide From 3,4-dihydro-6-methoxy-spiro[2H-l-benzopyran-2,4'-piperidine- 4(3H)-one and 2-(4-bromobutyl)-phthalimide using the procedure described for Example 15, Step 5 there was obtained a white solid:mp 11-113°C. EXAMPLE 50 4-(3,4-Dihydro-6-methanesulfonylamidyI-spiro[2H-l-benzopyran 2,4'-piperidine-4(3H)-one]-l '-yl)-butylphthalimide From 3,4-dihydro-6-methanesulfonylamidyl-spiro[2H-l -benzopyran- 2,4'-piperidine-4(3H)-one and 2-(4-bromobutyl)-phthalimide using the procedure described for Example 15, Step 5 there was obtained a white solid: mp 89-90°C. EXAMPLE 51 l,l-Dioxido-2-(4-(spiro[benzothiazol-2(3H),4 , -piperidin-l » - yI)-butyl)-l,2-benzisothiazol-3(2H)-one From 2-(4-bromobutyl)-l ,l-dioxido-l,2-benzothiazol-3(2H)-one, 4- piperidone and 2-aminothiophenol using the procedure described for Example 48 there was obtained a white solid: mp 178-80°C. EXAMPLE 52 4-(6-TrifIuoromethyl-spiro[benzothiazol-2(3H),4'-piperidin-l '-yl butylphthalimide From 4-(4'-ketopiperidinyl)butylphthalimide and 2-amino-5- trifluoromethylthiophenol using the procedure described for Example 48, Step 2 there was obtained a white solid: mp 157-8°C. EXAMPLE 53 l,l-Dioxido-2-(4-(spiro[benzofuran-2(3H),4'-piperidin]-l '- yl)-butyl)-l,2-benzisothiazol-3(2H)-one From spiro[benzofuran-2(3H),4'-piperidine] prepared as described by R. C. Effland, et al. J. Heterocyclic Chem. 1981, 18, 811, and 2-(4- bromobutyl)- 1,1 -dioxido- l,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: mp 98-100oC. EXAMPLE 54 4-(Spiro[benzofuran-2(3H),4'-piperidin]-l'-yl)-butylphthalimide From spiro[benzofuran-2(3H),4'-piperidine] prepared as described by R. C. Effland, et al. J. Heterocyclic Chem. 1981, 75, 811, and 2-(4- bromobutyl)-phthalimide using the procedure described for Example 15, Step 5 there was obtained a white solid: mp 255-7°C. EXAMPLF 55 4-(Spiro[2H-l,3-benzoxazine-2,4'-piperidin]-l '-yl)- butylphthalimide From spiro[2H-l ,3-benzoxazine-2,4'-piperidine] and 2-(4-bromobutyl)- phthalimide using the procedure described for Example 15, Step 5 there was obtained a white solid: mp 165-7°C. EXAMPLE gfi 3,3-Dioxido-l,2-dehydro-2-(4-(spiro[2H-inden l-2,4'-piperidin l (3H)-one]-l '-yl)-butyl)-naphth[l,2-d]isothiazol-l -one From l,3-dihydro-l -oxo-spiro(2H-indenyl-2,4'-piperidine) and 2-(4- bromobutyl)-3,3-dioxido-l ,2-dehydronaphth[l,2-d]isothiazol-l-one using the procedure described for Example 15, Step 5 there was obtained a white solid: iH NMR (300 MHz, CDCI3): 9.27 (d, J=8.4 Hz, IH), 8.30 (d, J=8.5 Hz, IH), 8.00 (d, J=7.6 Hz, IH), 7.88 (d, J=8.5 Hz, IH), 7.82-7.73 (m, 3H), 7.56 (t, IH), 7.43 (d, J=7.6 Hz, IH), 7.36 (t, 3H), 3.85 (t, J=7.4 Hz, 2H), 3.01 (s, 2H), 2.97 (br d, 2H), 2.14-2.0 (m, 4H), 1.90 (m, 8H), 1.69 (m, 2H), 1.38 (br d, J=12 Hz, 2H); mp (HCl salt) 243-5°C. EXAMPLE 57 l,l-Dioxido-2-(4-(spiro[2H-indenyl-2,4'-piperidine-l(3H)-one]- yl)-butyl)-4-methoxy-l,2-benzisothiazol-3(2H)-one From l,3-dihydro-l-oxo-spiro(2H-indenyl-2,4'-piperidine) and 1 ,1- dioxido-2-(4-bromobutyl)-4-methoxy-l ,2-benzisothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: iH NMR (300 MHz, CDCI3): 7.83-7.74 (m, 2H), 7.61 (t, J=7.4 Hz, IH), 7.56 (m, 2H), 7.34 (t, J=7.7 Hz, IH), 7.29 (m, IH), 4.05 (s, 3H), 3.78 (t, J=7.3 Hz, 2H), 3.02 (s, 2H), 2.96 (br d, J=l l Hz, 2H), 2.43 (t, J=7.6 Hz, 2H), 2.17-2.0 (m, 4H), 1.87 (m, 2H), 1.65 (m, 2H), 1.31 (br d, J=12 Hz, 2H). EXAMPLE 58 l,l-Dioxido-2-(4-(spiro[2H-indenyl-2,4'-piperidine-l(3H)- onel-l'-yI)-butyl)-7-methoxy-l,2-benzisothiazoI-3(2H)-one From l,3-dihydro-l-oxo-spiro(2H-indenyl-2,4'-piperidine) and 1,1- dioxido-2-(4-bromobutyl)-7-methoxy-l,2-benzisothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: J H NMR (300 MHz, CDC1 3 ): 7.77-7.72 (m, 2H), 7.61-56 (m, 2H), 7.44 (d, J=7.6 Hz, IH), 7.37 (t, IH), 7.28 (d, IH), 4.05 (s, 3H), 3.80 (t, J=7.3 Hz, 2H), 3.02 (s, 2H), 2.96 (m, 2H), 2.44 (t, J=7.5 Hz, 2H), 2.13-2.03 (m, 4H), 1.89 (m, 2H), 1.65 (m, 2H), 1.39 (br d, J=12 Hz, 2H); mp (HCl salt) 130°C (dec). EXAMPLE 59 l,l -Dioxido-2-(4-(spiro(l,3-dihydro-l-oxo-2H-indenyl-2,4'- piperidin-l '-yl)butyl)-5-methoxy-l,2-benzisothiazol-3(2H)- one From l,3-dihydro-l-oxo-spiro(2H-indenyl-2,4'-piperidine) and 1,1- dioxido-2-(4-bromobutyl)-5-methoxy-l,2-benzisothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: iH NMR (400 MHz, CDCI 3 ): 7.80 (d, J=8.6 Hz, IH), 7.75 (d, J=7.6 Hz, IH), 7.6 (d, J=7.6 Hz, IH), 7.59 (t, IH), 7.48- 7.37 (m, 2H), 7.32 (t, J=7.8 Hz, IH), 7.29 (d, IH), 3.95 (s, 3H), 3.81 (t, J=7.4 Hz, 2H), 3.02 (s, 2H), 2.95 (br d, J=l 1 Hz, 2H), 2.44 (t, J=7.4 Hz, 2H), 2.14-2.0 (m, 4H), 1.90 (m, 2H), 1.65 (m, 2H), 1.38 (br d, J=12 Hz, 2H); mp (HCl salt) 205-7°C. EXAMPLE 60 l,l-Dioxido-2-(4-(spiro(l,3-dihydro-l-oxo-2H-indenyI-2,4'- piperidin-l '-yl)butyl)-6-methoxy-l,2-benzisothiazol-3(2H)- one From l,3-dihydro-l-oxo-spiro(2H-indenyl-2,4'-piperidine) and 1,1- dioxido-2-(4-bromobutyl)-6-methoxy-l,2-benzisothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid:rom spiro[2H-indene-2,4'-piperidine and 2-(4- bromobutyl)-5-methoxy-l,2-benzisothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: iH NMR (400 MHz, CDCI3): 7.94 (d, J=8.6 Hz, IH), 7.75 (d, J=7.6 Hz, IH), 7.6 (t, IH), 7.44 (d, J=7.6 Hz, IH), 7.39-7.34 (m, 2H), 7.27-7.25 (m, IH), 3.97 (s, 3H), 3.79 (t, J=7.3 Hz, 2H), 3.02 (s, 2H), 2.96 (m, 2H), 2.44 (br t, 2H), 2.14-2.0 (m, 4H), 1.89 (m, 2H), 1.65 (m, 2H), 1.38 (br d, 2H); mp (HCl salt) 229-31 0 Q EXAMPLE 6 l,l-Dioxido-2-(4-(spiro(l,3-dihydro-l-oxo-2H-indeny 1-2,4' - piperidin-r-yl)butyl)-5-meth l-l,2-benzisothiazol-3(2H)-one From l,3-dihydro-l-oxo-spiro(2H-indenyl-2,4'-piperidine) and 1 ,1- dioxido-2-(4-bromobutyl)-5-methyl-l,2-benzisothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: iH NMR (300 MHz, CDCI3): 7.86-7.76 (m, 3H), 7.68-7.58 (m, 2H), 7.46 (d, J= 6.8 Hz, IH), 7.39 (t, J=7.4 Hz, IH), 3.83 (t, J=6.8 Hz, 2H), 3.03 (s, 2H), 2.98 (br d, J=10.6 Hz, 2H), 2.57 (s, 3H), 2.46 (t, J=7.4 Hz, 2H), 2.19-2.05 (m, 4H), 1.92 (m, 2H), 1.66 (m,2H), 1.40 (br d, 11.6 Hz, 2H); mp (HCl salt) 230- 1 °C. EXAMPLE 62 l,l-Dioxido-2-(4-(spiro(l,3-dihydro-l-oxo-2H-indenyl-2,4'- piperidin-l '-yl)butyI)-5-chloro-l,2-benzisothiazol-3(2H)-one From l,3-dihydro-l-oxo-spiro(2H-indenyl-2,4'-piperidine) and 1,1- dioxido-2-(4-bromobutyl)-5-chloro-l,2-benzisothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: iH NMR (400 MHz, CDCI3): 8.02 (s, IH), 7.87-7.80 (m, 2H), 7.75 (d, J=7.6 Hz, IH), 7.59 (t, J=7.6 Hz, IH), 7.44 (d, J=7 Hz, IH), 7.37 (t, J=7.5 Hz, IH), 3.82 (t, J=7.4 Hz, 2H), 3.02 (s, 2H), 2.95 (br d, J=11.5 Hz, 2H), 2.44 (t, 2H), 2.16-2.0 (m, 4H), 1.90 (m, 2H), 1.64 (m, 2H), 1.38 (br d, J=11.5 Hz, 2H); mp (HCl salt) 235-7°C. EXAMPLE 63 l,l-Dioxido-2-(4-(spiro(l,3-dihydro-l-oxo-2H-indene-2,4'- piperidin-l '-yI)butyl)-5-fluoro-l,2-benzisothiazol-3(2H)-one From l,3-dihydro-l-oxo-spiro(2H-indenyl-2,4'-piperidine) and 1,1- dioxido-2-(4-bromobutyl)-5-fluoro-l,2-benzisothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: iH NMR (400 MHz, CDCI3): 7.93 (m, IH), 7.76-7.71 (m, 2H), 7.61-7.45 (m, 2H), 7.44 (d, J=7.7 Hz, IH), 7.37 (t, J=7.4 Hz, IH), 3.82 (t, J=7.4 Hz, 2H), 3.02 (s, 2H), 2.97 (br d, J=11.5 Hz, 2H), 2.45 (t, J=7.4 Hz, 2H), 2.16 (m, 2H), 2.05 (m, 2H), 1.95-1.87 (m, 2H), 1.7- 1.6 (m, 2H), 1.38 (br d, J=12.5 Hz, 2H); mp (HCl salt) 238-40 O C. EXAMPLE 64 l,l-Dioxido-2-(4-(spiro(l,3-dihydro-l-oxo-2H-indenyl-2,4'- piperidin-l '-yl)butyl)-5-nitro-l,2-benzisothiazol-3(2H)-one From l,3-dihydro-l-oxo-spiro(2H-indenyl-2,4'-piperidine) and 1,1- dioxido-2-(4-brόmobutyl)-5-nitro-l,2-benzisothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid:lH NMR (400 MHz, CDCI 3 ): 8.84 (s, IH), 8.70 (d, J=6.38 Hz, IH), 8.11 (d, J=8.4 Hz, IH), 7.73 (d, J=7.6 Hz, IH), 7.56 (d, J=8.4 Hz, IH), 7.43 (d, J=7.7 Hz, IH), 7.35 (t, IH), 3.86 (t, J=7.4 Hz, 2H), 3.00 (s, 2H), 2.95 (br d, 2H), 2.42 (t, J=7.4 Hz, 2H), 2.14 (m, 2H), 2.04 (m, 2H), 1.94 (m, 2H), 1.63 (m, 2H), 1.37 (br d, J=12.5 Hz, 2H); mp (HCl salt) 241 -3<>C. E AMPLE 65 l,l-Dioxido-2-(4-(spiro(l,3-dihydro-l -oxo-2H-indeny 1-2,4' - piperidin-l '-yl)butyl)-6-nitro-l,2-benzisothiazol-3(2H)-one From l ,3-dihydro-l-oxo-spiro(2H-indenyl-2,4'-piperidine) and 1 ,1- dioxido-2-(4-bromobutyl)-6-nitro- 1 ,2-benzisothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: iH NMR (300 MHz, CDCI3): 8.75 (s, IH), 8.68 (dd, J= 2, 6.4 Hz, IH), 8.26 (d, J=8.3 Hz, IH), 7.75 (d, J= 7.5 Hz, IH), 7.59 (t, IH), 4.25 (br d, J=12.5 Hz, 2H), 3.88 (t, J=7.4 Hz, 2H), 3.02 (s, 2H), 2.96 (br d, 2H), 2.44 (t, J=7.4 Hz, 2H), 2.13-1.91 (m, 6H), 1.63 (m, 2H); mp (HCl salt) 231-4°C. EXAMPLE 66 l,l-Dioxido-2-(4-(spiro(l,3-dihydro-l-oxo-2H-indeny 1-2,4' - piperidin-l '-yl)butyl)-isothiazoIo[5,4-c]pyridin-3(2H)-one Step 1 : A solution of 16 g of pyridine-3-sulfonyl chloride prepared as described by B. I. Alo, O. B. Familoni, F. Marsais and G. Queguiner, J. Heterocyclic Chem. 1992, 29, 61-4 in 250 mL of chloroform was added to a solution of 8 g of 4-amino-l-butanol and 40 mL of triethylamine in 250 mL of chloroform at 0°C. The mixture was stirred overnight while warming to ambient temperature, the concentrated under reduced pressure to dryness. The residue was stirred with 500 mL of ethyl acetate, filtered and concentrated to dryness. To a solution of the crude N-(4-hydroxybutyl)pyridine-3- sulfonamide (28 g) in 200 mL of dichloromethane was added 30 mL of 3,4-dihydro-2H-pyran and 3 g of p-toluenesulfonic acid monohydrate. The reaction was stirred overnight, shaken with 100 mL of saturated sodium bicarbonate, dried over MgS04, and concentrated to dryness. Chromatography of the residue over silica gel, eluting with ethyl acetate gave 20 g of N-(4-(2- tetrahydropyranyloxy)butyl)pyridine-3-sulfonamide as a thich amber oil. Step 2: To a stirred solution of 54 mL of dry diisopropylamine in 200 mL of dry tetrahydrofuran cooled to -78°C was added 205 mL of commercial 1.6M n-butyllithium in hexane keeping the temperature below -30°C. After aging for 30 min -30°C, the solution was cooled to -78°C a solution of 23.3 g of N-(4-(2-tetrahydropyranyloxy)butyl) pyridine-3-sulfonamide in 150 mL of dry tetrahydrofuran was added dropwise keeping the internal temperature below -70°C (ca. 30 min). The resulting solution was aged at -78°C for 2.5 h and the deep red solution quenched by a stream of carbon dioxide gas with a fritted glass dispersion tube. During the addition, the color dissipated and the temperature rose to -40°C. After 15 min below -40°C, the bath was removed and the solution allowed to warm to room temprature over 1 h under a gentle stream of carbon dioxide. The mixture was partitioned between 400 mL of water and 500 mL of ether. The ether extracts contained unreacted N-(4-(2-tetrahydropyranyloxy)butyl) pyridine-3-sulfonamide. The aqueous layer was carefully acidified to pH=3 with concentrated HCl, and extracted with five 200 mL portions of chloroform. The combined organic extracts were dried over MgSθ4 and concentrated under reduced pressure. Drying under vacuum gave 19 g of N-(4-(2-tetrahydropyranyloxy)butyl) 4- carboxypyridine-3-sulfonamide as a amber solid. Step 3: To a stirred solution of 19 g of N-(4-(2- tetrahydropyranyloxy)butyl) 4-carboxypyridine-3-sulfonamide and 16 mL of triethylamine in 300 mL of dichloromethane at 0°C was added 6.5 mL of methyl chloroformate dropwise. After 30 min, the mixture was shaken with 100 mL of saturated sodium bicarbonate, dried over MgSθ4 and concentrated under reduced pressure. Chromatography of the dark brown oil over silica gel, eluting with 1 :1 ethyl acetate: hexane gave 16 g of homogeneous l,l-dioxido-2-(4-(2- tetrahydropyranyloxy) butyl)-isothiazolo[5,4-c]pyridin-3(2H)-one as an amber oil. Step 4: A solution of 1 g of 2-(4-(2-tetrahydropyranyloxy)butyl)- isothiazolo[5,4-c]pyridin-3(2H)-one and 0.1 g of p-toluenesulfonic acid monohydrate in 50 mL of methanol was stirred overnight at ambient temperature and concentrated to dryness under reduced pressure. The residue was dissolved in 200 mL of ethyl acetate, washed with 4 mL of saturated sodium bicarbonate, dried over MgS04 and concentrated under reduced pressure. Drying under vacuum overnight gave 0.73 g (78%) of 2-(4-hydroxybutyl)-isothiazolo[5,4-c]pyridin-3(2H)-one as an oil: iH NMR (400 MHz, CDCI3): 9.28 (s, IH), 9.15 (d, J=5 Hz, IH), 7.98 (d, J=5Hz, IH), 3.86 (t, J= 7.5 Hz, 2H), 3.71 (t, J= 6.4 Hz, 2H), 2.36 (br s, IH), 1.98 (m, 2H), 1.27 (m, 2H). Step 4: To a stirred solution of 0.73 g of 2-(4-hydroxybutyl)- isothiazolo[5,4-c]pyridin-3(2H)-one and 0.8 mL of triethylamine in 50 mL of dry tetrahydrofuran at 0°C was added 0.63 g of technical grade 4-nitrobenzenesulfonyl chloride. After 4 h, the solution was filtered and concentrated to dryness under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate, washed with 10 mL of saturated sodium carbonate and dried over MgSO Concentration under reduced pressure gave 1.4 g of crude 2-(4-(4- nitrobenzenesulfonyloxy)butyl)-isothiazolo[5,4-c]pyridin-3(2H)-one as an oil. The crude product was a mixture of 4-nitrobenzenesulfonate contaminated with a small amount of chloride by NMR, and was used in the next step without further purification. Step 6: A mixture of 0.60 g of 1 ,3-dihydro- l-oxo-spiro(2H-indenyl- 2,4'-piperidine) and 1.4 g of l,l-dioxido-2-(4-(4- nitrobenzenesulfonyloxy)butyl)-isothiazolo[5,4-c]pyridin-3(2H)-one in 20 mL of anhydrous acetonitrile were allowed to stir overnight at ambient temperature then concentrated to dryness under reduced pressure. The solid mass was partitioned between 200 mL of ethyl acetate and 20 mL of saturated sodium carbonate. The organic extract was dried over MgS04 and concentrated under reduced pressure. Chromatography of the residue on silica gel, eluting with 10% methanol in ethyl acetate gave 0.5 g of a white solid: iH NMR (400 MHz, CDCI3): 9.26 (s, IH), 9.15 (m, IH), 7.95 (d, J=4.9 Hz, IH), 7.75 (d, J= 7.5 Hz, IH), 7.59 (t, J=8.1 Hz, IH), 7.44 (d, J=7.7 Hz, IH), 3.85 (t, J=7.4 Hz, 2H), 3.02 (s, 2H), 2.95 (br d, J=12 Hz, 2H), 2.44 (t, J=7.4 Hz, 2H), 2.17-2.03 (m, 4H), 1.92 (m, 2H), 1.64 (m, 2H), 1.4 (br d, J=12 Hz, 2H); mp (HCl salt) 228-30°C. EXAMPLE 67 l,l-Dioxido-2-(4-(spiro(l,3-dihydro-l -oxo-2H-indenyl-2,4'- piperidin-l '-yl)butyI)-isothiazolo[5,4-b]pyridin-3(2H)-one Step 1 : Chlorine gas was dispersed through a mixture of 4.3 g of methyl 2-mercaptonicotinate, prepared as described by L. Katz, W. Schroeder and M. Cohen, J. Org. Chem. 1954, 19, 711-17, 10 mL of dichloromethane, 60 mL of glacial acetic acid and 150 mL of water at 0-3°C for 1.5 h. The resulting solution was extracted with four 200 mL portions of chloroform and the combined extracts dried over MgSθ4 and concentrated under reduced pressure in a fume hood. The oily methyl 2-chlorosulfonylnicotinate, 3.5 g, was dissolved in 20 mL of dichloromethane and added to a solution of 2 g of 4-amino-l- butanol and 3 mL of triethylamine in 200 mL of dichloromethane at 0°C. The mixture was stirred overnight while warming to ambient temperature, the decanted and the residue extracted with three 100 mL portions of dichloromethane. The combined extracts were concentrated under reduced pressure to dryness. To a solution of the resulting crude N-(4-hydroxybutyl) 3-methoxycarbonylpyridine-2- sulfonamide (5 g) in 100 mL of dichloromethane was added 10 mL of 3,4-dihydro-2H-pyran and 1 g of p-toluenesulfonic acid monohydrate. The reaction was stirred overnight, shaken with 50 mL of saturated sodium bicarbonate, dried over MgSθ4, and concentrated to dryness. To a stirred solution of the resulting crude N-(4-(2- tetrahydropyranyloxy)butyl) 3-methoxycarbonylpyridine-2- sulfonamide (7 g) in 100 mL of 100 mL of methanol and 30 mL of water was added 2 g of lithium hydroxide monohydrate. The reaction mixture was stirred overnight at ambient temperature, concentrated to dryness under reduced pressure to remove methanol, acidified to ρH=3 with concentrated HCl and extracted with five 50 mL portions of chloroform. The combined extracts were dried over MgS04 and concentrated to dryness. The residue, N-(4-(2- tetrahydropyranyloxy)butyl) 3-carboxycarbonylpyridine-2- sulfonamide weighed 5 g and was used without further purification. Step 2: To a stirred solution of 3 g of N-(4-(2- tetrahydropyranyloxy)butyl) 3-carboxycarbonylpyridine-2- sulfonamide and 2.3 mL of triethylamine in 100 mL of dichloromethane at 0°C was added 0.8 mL of methyl chloroformate dropwise. After 2 h, the mixture was shaken with 10 mL of saturated sodium bicarbonate, dried over MgS04 and concentrated under reduced pressure. Chromatography of the dark brown oil over silica gel, eluting with 1 :1 ethyl acetate: hexane gave 3 g of homogeneous l ,l-dioxido-2-(4-(2-tetrahydropyranyloxy)butyl)-isothiazolo[5,4- b]pyridin-3(2H)-one as an amber oil. Step 3: A solution of 1 g of 2-(4-(2-tetrahydropyranyloxy)butyl)- isothiazolo[5,4-b]pyridin-3(2H)-one and 0.1 g of p-toluenesulfonic acid monohydrate in 50 mL of methanol was stirred overnight at ambient temperature and concentrated to dryness under reduced pressure. The residue was dissolved in 200 mL of ethyl acetate, washed with 4 mL of saturated sodium bicarbonate, dried over MgS04 and concentrated under reduced pressure. Drying under vacuum overnight gave 0.73 g of l ,l-dioxido-2-(4-hydroxybutyl)- isothiazolo[5,4-b]pyridin-3(2H)-one as an oil: iH NMR (400 MHz, CDCI3): 9.00 (d, J=1.5 Hz, IH), 8.40 (d, J= 7.7 Hz, IH), 7.80 (dd, J=1.5, 7.7 Hz, IH), 3.86 (t, J= 7.5 Hz, 2H), 3.71 (t, J= 6.4 Hz, 2H), 2.31 (br s, IH), 1.98 (m, 2H), 1.26 (m, 2H). Step 4: To a stirred solution of 0.73 g of l,l-dioxido-2-(4- hydroxybutyl)-isothiazolo[5,4-b]pyridin-3(2H)-one and 0.8 mL of triethylamine in 50 mL of dry tetrahydrofuran at 0°C was added 0.63 g of technical grade 4-nitrobenzenesulfonyl chloride. After 4 h, the solution was filtered and concentrated to dryness under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate, washed with 10 mL of saturated sodium carbonate and dried over MgS04. Concentration under reduced pressure gave 1.4 g of crude 1 , 1 -dioxido-2-(4-(4-nitrobenzenesulfonyloxy )butyl)-isothiazolo[5,4- b]pyridin-3(2H)-one as an oil. The crude product was a mixture of 4- nitrobenzenesulfonate contaminated with a small amount of chloride by NMR, and was used in the next step without further purification. Step 5: A mixture of 0.60 g of 1 ,3-dihydro- l-oxo-spiro(2H-indenyl- 2,4'-piperidine) and 1.4 g of l,l-dioxido-2-(4-(4- nitrobenzenesulfonyloxy)butyl)-isothiazolo[5,4-b]pyridin-3(2H)-one in 20 mL of anhydrous acetonitrile were allowed to stir overnight at ambient temperature then concentrated to dryness under reduced pressure. The solid mass was partitioned between 200 mL of ethyl acetate and 20 mL of saturated sodium carbonate. The organic extract was dried over MgS04 and concentrated under reduced pressure. Chromatography of the residue on silica gel, eluting with 10% methanol in ethyl acetate gave 0.5 g of a white solid: iH NMR (400 MHz, CDCI3): 9.00(d, J=4.8 Hz, IH), 8.38 (d, J=7.7 Hz, IH), 7.81-7.74 (m, 2H), 7.59 (t, J= 7.4 Hz, IH), 7.45 (d, J=7 Hz, IH), 7.37 (t, J=7.4 Hz, IH), 3.87 (t, J=7.23 Hz, IH), 3.02 (s, 2H), 2.97 (br d, J=l 1.35 Hz, 2H), 2.46 (t, J=7.33 Hz, 2H), 2.20-2.03 (m, 4H), 2.07-2.20 (m, 2H), 1.97- 1.90 (m, 2H), 1.70-1.61 (m, 2H), 1.61 (br d, J=12.08 Hz, 2H). EXAMPLE 68 l,l -Dioxido-2-(4-(4-(6-methyl-2-oxo-3-benzoxazolinyl)- piperidin-l-yl)-butyl)-5-nitro-l,2-benzisothiazoI-3(2H)-one From 4-(6-methyl-2-oxo-3-benzoxazolinyl)-piperidine and 2-(4- bromobutyl)-l,l-dioxido-5 -nitro- 1 ,2-benzisothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid:lH NMR, HCl salt, (400 MHz, CDCI3): 8.87 (d, J = 2.0 Hz, IH), 8.74 (d, J = 2.18 Hz, IH), 8.72 (d, J = 1.8 Hz, IH), 8.14 (d, J = 8.4 Hz, IH), 7.11 (d, J = 6.54 Hz, IH), 7.03 (s, IH), 6.94 (d, J = 8.06 Hz, IH), 4.18 (m, IH), 3.89 (t, J = 7.39 Hz, 2H), 3.06 (d, J = 10.07 Hz, 2H), 2.46 (m, 2H), 2.38 (s, 3H), 2.34 (m, 2H), 2.14 (t, J = 11.5 Hz, 2H), 1.94 (m, 2H), 1.85 (d, J = 11.4 Hz, 2H), 1.65 (m, 2H). EXAMPLE 69 2-(4-(Spiro(l,3-dihydro-l -oxo-2H-inden l-2,4'-piperidin-l '- yl)butyl)-pyrrolo[3,4b]pyridin-5,7(lH)-dione From l ,3-dihydro-l-oxo-spiro(2H-indenyl-2,4'-piperidine) and 2-(4- bromobutyl)-pyrrolo[3,4b]pyridin-5,7(lH)-dione using the procedure described for Example 15, Step 5 there was obtained a white solid: iH NMR, (400 MHz, CDCI3): 9.15 (s, IH), 9.06 (s, IH), 9.06 (d, J=4.76 Hz, IH), 7.75 (d, J=4.76 Hz, IH), 7.59 (t, J=7.42 Hz, IH), 7.44 (d, J=8.0Hz, IH), 7.37 (t, J=7.33 Hz, IH), 3.76 (t, J=7.14 Hz, 2H), 3.02 (s, 2H), 2.41 (br t, J=7.33 Hz, 2H), 2.12-1.99 (m, 4H), 1.77-1.72 (m, 2H), 1.56 (br m, 2H), 1.38 (m, 2H). EXAMPLE 70 l,l -Dioxido-2,3-dihydro-2-(4-(spiro[2H-indeny 1-2, 4' -piperidine- l (3H)-one]-l '-yI)-butyl)-naphth[l,8-de]isothiazin-3-one From l ,3-dihydro-l-oxo-spiro(2H-indenyl-2,4'-piperidine) and 2-(4- bromobutyl)- 1 , 1 -dioxido-2,3-dihydronaphth[ 1 ,8-de]isothiazin-3-one using the procedure described for Example 15, Step 5 there was obtained a white solid: iH NMR (300 MHz, CDCI3): 8.37 (d, J=7.92 Hz, IH), 8.26 (d, IH), 8.08 (m, 2H), 7.86-7.74 (m, 3H), 7.58 (t, IH), 7.44 (d, J=7.7 Hz, IH), 7.38 (t, IH), 3.90 (t, J=7.3 Hz, 2H), 3.02 (s, 2H), 2.98 (br d, 2H), 2.46 (t, J=7.4 Hz, 2H), 2.14-1.94 (m, 6H), 1.69 (m, 2H), 1.40 (br d, 2H); mp (HCl salt) 248-50°C. EXAMPLE 71 2-(4-Bromobutyl)-l,l-dioxido-4-methoxy-l,2-benzothiazol- 3(2H)-one The general procedure of J. D. Commerford and H. B. Donahue J. Org. Chem. 1956, 21, 583-4 was modified: A mixture of 0.5 g of 3,3-dioxido-4-methoxy-l,2-benzothiazol-3(2H)-one prepared as described by D. J. Hlasta, J. J. Court and R. C. Desai, Tetrahedron Lett. 1991, 32, 7179-82, 1 mL of N,N-dimethylformamide and 0.1 g of sodium hydride 60% oil dispersion was stirred at ambient temperature for 15 min, and 1.4 mL of 1 ,4-dibromobutane was added. After stirring at ambient temperature overnight, the mixture was diluted with 25 mL of ethyl acetate, washed with 25 mL of sat'd NaHCθ3, 25 mL of sat'd brine and dried over MgS04. Removal of solvents under reduced pressure and vacuum distillation gave a crude product as a viscous oil which was free of 1,4-dibromobutane by 1 H- NMR and was used without further purification. EXAMPLE 72 2-(4-Bromobutyl)-l,l-dioxido-6-methoxy-l,2-benzothiazol- 3(2H)-one The general procedure of J. D. Commerford and H. B. Donahue J. Org. Chem. 1956, 21, 583-4 was modified: A mixture of 0.5 g of 3,3-dioxido-6-methoxy-l ,2-benzothiazol-3(2H)-one prepared from N,N-diethyl-4-methoxybenzamide using the general procedure described by D. J. Hlasta, J. J. Court and R. C. Desai, Tetrahedron Lett. 1991, 32, 7179-82, 1 mL of N,N-dimethylformamide and 0.1 g of sodium hydride 60% oil dispersion was stirred at ambient temperanire for 15 min, and 1.4 mL of 1,4-dibromobutane was added. After stirring at ambient temperature overnight, the mixture was diluted with 25 mL of ethyl acetate, washed with 25 mL of sat'd NaHCθ3, 25 mL of sat'd brine and dried over MgSθ4- Removal of solvents under reduced pressure and vacuum distillation gave a crude product as a viscous oil which was free of 1,4-dibromobutane by iH¬ NMR and was used without further purification. EXAMPLE 73 2-(4-Bromobutyl)-l,l-dioxido-7-methoxy-l,2-benzothiazol- 3(2H)-one The general procedure of J. D. Commerford and H. B. Donahue J. Org. Chem. 1956, 21, 583-4 was modified: A mixture of 0.5 g of 3,3-dioxido-7-methoxy-l,2-benzothiazol-3(2H)-one prepared from N,N-diethyl-3-methoxybenzamide using the general procedure described by D. J. Hlasta, J. J. Court and R. C. Desai, Tetrahedron Lett. 1991, 32, 7179-82, 1 mL of N,N-dimethylformamide and 0.1 g of sodium hydride 60% oil dispersion was stirred at ambient temperature for 15 min, and 1.4 mL of 1,4-dibromobutane was added. After stirring at ambient temperature overnight, the mixture was diluted with 25 mL of ethyl acetate, washed with 25 mL of sat'd NaHCθ3, 25 mL of sat'd brine and dried over MgSO Removal of solvents under reduced pressure and vacuum distillation gave a crude product as a viscous oil which was free of 1,4-dibromobutane by iH¬ NMR and was used without further purification. EXAMPLE 74 2-(4-Bromobutyl)-l,l-dioxido-5-meth l-l,2-benzothiazoI- 3(2H)-one The general procedure of J. D. Commerford and H. B. Donahue J. Org. Chem. 1956, 27, 583-4 was modified: A mixture of 0.5 g of 3,3-dioxido-5-methyl-l,2-benzothiazol-3(2H)-one prepared as described by J. G. Lombardino, J. Org. Chem. 1971, 36, 1843-5, 1 mL of N,N-dimethylformamide and 0.1 g of sodium hydride 60% oil dispersion was stirred at ambient temperature for 15 min, and 1.4 mL of 1 ,4-dibromobutane was added. After stirring at ambient temperature overnight, the mixture was diluted with 25 mL of ethyl acetate, washed with 25 mL of sat'd NaHC03, 25 mL of sat'd brine and dried over MgSθ4. Removal of solvents under reduced pressure and vacuum distillation gave a crude product as a viscous oil which was free of 1 ,4-dibromobutane by iH-NMR and was used without further purification. EX AMPLE 75 2-(4-Bromobutyl)-l,l-dioxido-5-fluoro-l,2-benzothiazol- 3(2H)-one The general procedure of J. D. Commerford and H. B. Donahue J. Org. Chem. 1956, 27, 583-4 was modified: A mixture of 0.5 g of 3,3-dioxido-5-fluoro-l ,2-benzothiazol-3(2H)-one prepared as described by J. G. Lombardino, J. Org. Chem. 1971, 36, 1843-5, 1 mL of N,N-dimethylformamide and 0.1 g of sodium hydride 60% oil dispersion was stirred at ambient temperature for 15 min, and 1.4 mL of 1 ,4-dibromobutane was added. After stirring at ambient temperature overnight, the mixture was diluted with 25 mL of ethyl acetate, washed with 25 mL of sat'd NaHCθ3, 25 mL of sat'd brine and dried over MgSO Removal of solvents under reduced pressure and vacuum distillation gave a crude product as a viscous oil which was free of 1,4-dibromobutane by iH-NMR and was used without further purification. EXAMPLE 76 2-(4-Bromobutyl)-l,l-dioxido-5-chIoro-l,2-benzothiazol- 3(2H)-one The general procedure of J. D. Commerford and H. B. Donahue J. Org. Chem. 1956, 27, 583-4 was modified: A mixture of 0.5 g of 3,3-dioxido-5-chloro-l,2-benzothiazol-3(2H)-one prepared as described by J. G. Lombardino, J. Org. Chem. 1971, 36, 1843-5, 1 mL of N,N-dimethylformamide and 0.1 g of sodium hydride 60% oil dispersion was stirred at ambient temperature for 15 min, and 1.4 mL of 1 ,4-dibromobutane was added. After stirring at ambient temperature overnight, the mixture was diluted with 25 mL of ethyl acetate, washed with 25 mL of sat'd NaHCθ3, 25 mL of sat'd brine and dried over MgSθ4. Removal of solvents under reduced pressure and vacuum distillation gave a crude product as a viscous oil which was free of 1 ,4-dibromobutane by J H-NMR and was used without further purification. EXAMPLE 77 2-(4-Bromobutyl)-l,l-dioxido-6-nitro-l,2-benzothiazoI- 3(2H)-one The general procedure of J. D. Commerford and H. B. Donahue J. Org. Chem. 1956, 27, 583-4 was modified: A stirred mixture of 1.0 g of 3,3-dioxido-6-nitro-l ,2-benzothiazol-3(2H)-one prepared as described by H. Kamogawa, S. Yamamoto and M. Nanasawa, Bull. Chem. Soc. Japan ,1982, 55, 3824-7, and 6 mL of IN NaOH was warmed to dissolution and allowed to cool to ambient temperature for 15 min. The mixture was concentrated to dryness under reduced pressure and the white solid azeotropically dried with 20 mL of toluene. The resulting sodium salt was dissolved in 3 mL of N,N- dimethylformamide and 2.6 mL of 1,4-dibromobutane was added. After stirring at ambient temperature overnight, the mixture was diluted with 25 mL of ethyl acetate, washed with 25 mL of sat'd NaHCθ3, 25 mL of sat'd brine and dried over MgSθ4. Removal of solvents under reduced pressure and vacuum distillation gave a crude product as a solid which was free of 1,4-dibromobutane by iH-NMR and was used without further purification. EXAMPLE 7ft 2-(4-Bromobutyl)-l,l-dioxido-2,3-dihydronaphth[l,8-de] isothiazin-3-one The general procedure of J. D. Commerford and H. B. Donahue J. Org. Chem. 1956, 27, 583-4 was modified: A mixture of 0.5 g of 1 , 1 -dioxido-2,3-dihydronaphth[ 1 ,8-de]isothiazin-3-one prepared as described by J. G. Lombardino, J. Org. Chem. 1971, 36, 1843-5, 1 mL of N,N-dimethylformamide and 0.1 g of sodium hydride 60% oil dispersion was stirred at ambient temperature for 15 min, and 1.4 mL of 1 ,4-dibromobutane was added. After stirring at ambient temperature overnight, the mixture was diluted with 25 mL of ethyl acetate, washed with 25 mL of sat'd NaHC03, 25 mL of sat'd brine and dried over MgSθ4. Removal of solvents under reduced pressure and vacuum distillation gave a crude product as a viscous oil which was free of 1 ,4-dibromobutane by iH-NMR and was used without further purification. EXAMPLE 79 2-(4-Bromobutyl)-3,3-dioxido-l,2-dehydronaphth[l,2-d] isothiazol-1 -one The general procedure of J. D. Commerford and H. B. Donahue J. Org. Chem. 1956, 27, 583-4 was modified: A mixture of 0.5 g of 3,3-dioxido-l,2-dehydronaphth[l,2-d]isothiazol-l-one prepared as described by J. G. Lombardino, /. Org. Chem. 1971, 36, 1843-5, 1 mL of N,N-dimethylformamide and 0.1 g of sodium hydride 60% oil dispersion was stirred at ambient temperature for 15 min, and 1.4 mL of 1 ,4-dibromobutane was added. After stirring at ambient temperature overnight, the mixture was diluted with 25 mL of ethyl acetate, washed with 25 mL of sat'd NaHC03, 25 mL of sat'd brine and dried over MgS04. Removal of solvents under reduced pressure and vacuum distillation gave a crude product as a viscous oil which was free of 1,4-dibromobutane by *H-NMR and was used without further purification. EXAMPLE SO 2-(4-Bromobutyl)-pyrrolo[3,4b]pyridin-5,7(lH)-dione The general procedure of J. D. Commerford and H. B. Donahue J. Org. Chem. 1956, 27, 583-4 was modified: A mixture of 0.5 g of commercial pyrrolo[3,4b]pyridin-5,7(lH)-dione (Aldrich Chemical Co.), 1 mL of N,N-dimethylformamide and 0.1 g of sodium hydride 60% oil dispersion was stirred at ambient temperature for 15 min, and 1.4 mL of 1 ,4-dibromobutane was added. After stirring at ambient temperature overnight, the mixture was diluted with 25 mL of ethyl acetate, washed with 25 mL of sat'd NaHCθ3, 25 mL of sat'd brine and dried over MgSO Removal of solvents under reduced pressure and vacuum distillation gave a crude product as a viscous oil which was free of 1 ,4-dibromobutane by JH-NMR and was used without further purification. EXAMPLE S l,l-Dioxido-2-(4-(spiro[3-oxo-phthalan-l,4'-piperidin-l '- yl)butyl)-l,2-benzisothiazol-3(2H)-one From spiro[phthalan-l ,4'-piperidine]-3-one, prepared as described in US Patent 3,686,186, and 2-(4-bromobutyl)- 1,1 -dioxido- 1,2- benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: mp 226-8°C. EXAMPLE S2 5-chloro-l-(4-piperidinyl)-3-benzoxazolin-2-one From the reaction of 2-amino-4-chlorophenol and N-t- butyloxycarbonyl-4-piperidone according to Example 15 Steps 2-4 was obtained a white solid. EXAMPLE 83 4-(3a-(R)-8a-(S)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[l,2- d]oxazolin l)-piperidine From the reaction of (-)-l(S)-amino-2(R)-hydroxyindan, prepared according to W. J. Thompson et. al. J. Med. Chem. 1992, 35, 1685- 1701 , and N-t-butyloxycarbonyl-4-piperidone according to Example 15 Steps 2-4 was obtained a white solid. EXAMPLE 84 4-(2-oxonaphth[2,3-d]oxazolinyI)-piperidine From the reaction of 3-amino-2-naphthol and N-t-butyloxycarbonyl-4- piperidone according to Example 15 Steps 2-4 was obtained a white solid. EXAMPLE S5 4-(6-methyl-2-oxo-3-benzoxazolinyl)-piperidine From the reaction of 6-amino-m-cresol and N-t-butyloxycarbonyl-4- piperidone according to Example 15 Steps 2-4 was obtained a white solid. EXAMPLE 86 4-(2-oxo-5-phenyl-3-benzoxazolinyl)-piperidine From the reaction of 2-amino-4-phenylphenol and N-t- butyloxycarbonyl-4-piperidone according to Example 15 Steps 2-4 was obtained a white solid. EXAMPLE 37 4-(6-methoxy-2-oxo-3-benzoxazoIinyl)-piperidine From the reaction of 2-amino-5-methoxyphenol and N-t- butyloxycarbonyl-4-piperidone according to Example 15 Steps 2-4 was obtained a white solid. EXAMPLE SS 4-(6-carbomethoxy-2-oxo-3-benzoxazolinyI)-piperidine From the reaction of methyl 4-amino-3-hydroxybenzoate and N-t- butyloxycarbonyl-4-piperidone according to Example 15 Steps 2-4 was obtained a white solid. EX AMPLE S9 4-(5-ethyIsuIfonyl-2-oxo-3-benzoxazolinyl)-piperidine From the reaction of 2-amino-4-(ethylsulfonyl)phenol and N-t- butyloxycarbonyl-4-piperidone according to Example 15 Steps 2-4 was obtained a white solid. EXAMPLE 90 4-(2-oxo-3-oxazolo[4,5-b]pyridyl)-piperidine From the reaction of 2-amino-3-hydroxypyridine and N-t- butyloxycarbonyl-4-piperidone according to Example 15 Steps 2-4 was obtained a white solid. EXAMPLE 91 4-(7-carbethoxy-2-oxo-3-benzoxazolinyl)-piperidine From the reaction of methyl 3-amino-2-hydroxybenzoate and N-t- butyloxycarbonyl-4-piperidone according to Example 15 Steps 2-4 was obtained a white solid. EXAMPLE 92 4-(5-tert-butyl-2-oxo-3-benzoxazoIinyI)-piperidine From the reaction of 2-amino-4-tert-butylphenol and N-t- butyloxycarbonyl-4-piperidone according to Example 15 Steps 2-4 was obtained a white solid. EXAMPLE 93 4-(5,7-dimethyl-2-oxo-3-benzoxazolinyl)-piperidine From the reaction of 6-amino-2,4-dimethylphenol and N-t- butyloxycarbonyl-4-piperidone according to Example 15 Steps 2-4 was obtained a white solid. EXAMPLE 94 l,l-Dioxido-2-(4-(4-(l,3-dihydro-2-oxo-2H-benzimidazolin- l-yI)-piperidin-l-yl)-butyl)-l,2-benzisothiazol-3(2H)-one From l,3-dihydro-l-(4-piperidinyl)-2H-benzimidazol-2-one and 2-(4- bromobutyl)-l,l-dioxido-l,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: mp 193-5°C; Analysis calculated for C23H26N4O4S • 0.5 CHCI3 C: 54.89 H: 5.19, N: 10.90 found C: 54.60, H: 5.24, N: 10.84. iH NMR (300 MHz, CDCI3) 10.0 (s, IH), 8.2 (d, IH), 8.1-7.9 (m, 3H), 7.4 (dd, IH), 7.25 (m, IH), 7.18 (m, 3H), 4.5 (m, IH), 3.95 (t, 2H), 3.2 (d, J = 12 Hz, 2H), 2.6 (m, 4H), 2.3 (t, J = 12 Hz, 2H), 2.1 (m, 4H), 1.95 (m, 2H), 1.8(m, 2H). EXAMPLE 9^ l,l-Dioxido-2-(4-(4-(l,3-dihydro-2-oxo-3-methyl-2H- benzimidazolin-l-yI)-piperidin-l-yl)-butyl)-l,2- benzisothiazol-3(2H)-one Step 1: A mixture of 1 g of 1 ,3-dihydro- l-(4-piperidinyl)-2H- benzimidazol-2-one, 25 mL of tetrahydrofuran, 10 mL of saturated Na2C03, 20 mL of water and 1.05 g of di-tert-butyl-dicarbonate was stirred for 6 h. The mixture was extracted with 100 mL of chloroform and the organic extracts concentrated to dryness under reduced pressure. Drying under vacuum gave 1.6 g of 1,3-dihydro-l- (l-tert-butyloxycarbonylρiperidm-4-yl)-2H-benzimidazol-2-one as a white crystalline solid. Step 2: A mixture of 0.060 g of sodium hydride, 60% oil dispersion, 10 mL of DMF, 0.086 mL of iodomethane, and 0.4 g of 1,3-dihydro- 1 -(1 -tert-butyloxycarbonylpiperidin-4-yl)-2H-benzimidazol-2-one was stirred for 12 h, then partitioned between 100 mL of chloroform and 50 mL of water. The chloroform extracts dried over MgS04, and concentrated under reduced pressure. Trituration with hexane gave 0.38 g of l,3-dihydro-l-(l-tert-butyloxycarbonylpiperidin-4-yl)-3- methyl-2H-benzimidazol-2-one as a crystalline solid: iH NMR (300 MHz, CDC13) 7.13-7.03 (m, 3H), 6.98 (d, IH), 4.5 (m, IH), 4.3 (br m, 2H), 3.4 (s, 3H), 2.85 (m, 4H), 2.3 (m, 2H), 1.8 (d, 2H), 1.5 (s, 9H). Step 3: A stream of hydrogen chloride gas was dispersed through a stirred, ice cold solution of 0.383 g of 1 ,3-dihydro- l-(l-tert- butyloxycarbonylpiperidin-4-yl)-3-methyl-2H-benzimidazol-2-one in 500 mL of ethyl acetate for 30 min. Stirring was continued at 0°C for 1 h, then at ambient temperature for 1 h. The suspension was partitioned between 250 mL of chloroform and 50 mL of saturated Na2Cθ3. Drying under reduced pressure gave 0.296 of 1 ,3-dihydro- 1 -(4-piperidinyl)-2H-benzimidazol-2-one as an off-white solid. Step 4: From 1 ,3-dihydro- l-(4-piperidinyl)-3-methyl-2H- benzimidazol-2-one and 2-(4-bromobutyl)- 1 ,1 -dioxido- 1 ,2- benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: mp 161-163°C. Analysis calculated for C24H28N4O4S C: 61.52, H: 6.02, N: 11.96 found C: 61.44, H: 6.06, N: 11.84. iH NMR (300 MHz, CDCI3) 8.2 (d, IH), 8.1-7.9 (m, 3H), 7.13-7.03 (m, 3H), 6.98 (d, IH), 4.5 (m, IH), 3.95 (t, 2H), 3.4 (s, 3H), 3.2 (d, J = 12 Hz, 2H), 2.6 (m, 4H), 2.3 (t, J = 12 Hz, 2H), 2.1 (m, 4H), 1.95 (m, 2H), 1.8(m, 2H). EXAMPLE 96 l,l -Dioxido-2-(4-(4-(l,3-dihydro-2-oxo-5-methyI-2H- benzirnidazolin-l-yT)-piperidin-l -yT)-butyI)-l,2- benzisothiazoI-3(2H)-one Step 1 : A mixture of 69 g of 4-chloro-3-nitro-toluene, 50 g of ethyl 4- amino-1-piperidinecarboxylate, 24 g of sodium carbonate, 0.1 g of sodium iodide and 120 mL of cyclohexanol was heated to 150°C for 72 h. After cooling the cyclohexanol was distilled off under reduced pressure and the residue partitioned between 1 L of ethyl acetate and 1 L of water. The organic extract was dried over MgS04 and concentrated under reduced pressure. Chromatography over silica gel, eluting with 20% ethyl acetate in cyclohexane gave 38.5 g (42.3%) of ethyl 4-(4-methyl-2-nitroanilino)-l-piperidinecarboxylate as an orange crystalline solid. iH NMR (400 MHz, CDC13) 8.0 (s, IH), 7.27 (t, J = 9 Hz, IH), 6.8 (d, J = 9 Hz, IH), 4.15 (q, J = 7 Hz, 2H), 4.05 (br m, 2H), 3.67 (br m, IH), 3.10 (br t, J = 11 Hz, 2H), 2.27 (s, 3H), 2.06 (br d, J = 11 Hz, 2H), 1.6 (m, 2H), 1.27 (t, J = 7 Hz, 4H). Step 2: A mixture of 8.23 g of ethyl 4-(4-methyl-2-nitroanilino)-l- piperidinecarboxylate, 200 mL of tetrahydrofuran , 225 mL of ethanol and 2 g of 5% platinum on carbon was stirred under an atmosphere of hydrogen for 7 h. The catalyst was filtered off and the filtrate concentrated to to a thick oil. To an ice cold, vigorously stirred solution of the resulting crude ethyl 4-(4-methyl-2-aminoanilino)-l - piperidinecarboxylate in 500 mL of ethyl acetate was added 500 mL of saturated sodium carbonate followed by 20 mL of 1.9 M phosgene in toluene dropwise over 30 min. After stirring overnight at room temperature, the layers were separated and the organic layer dried over MgS04 and concentrated to dryness. Trituration of the residue with ether-hexane gave 8 g of ethyl 4-(5-methyl-2-oxo-l- benzimidazolinyl)piperidine-l -carboxylate as a white crystalline solid. Step 3: A mixture of 5 g of ethyl 4-(5-methyl-2-oxo-l- benzimidazolinyl)piperidine-l -carboxylate and 20 mL of 2N NaOH was heated under reflux for 12 h. The resulting solution is cooled and stirred for for 30 minutes with 5 g of ammonium chloride and extracted with three 200 mL portions of chloroform. The combined organic extracts were dried over MgS04, concentrated under reduced pressure and triturated with ether. The solid product 1 ,3-dihydro- 1 -(4- piperidinyl)-5-methyl-2H-benzimidazol-2-one weighed 3.5 g after drying. Step 4: From l,3-dihydro-l-(4-piperidinyl)-5-methyl-2H- benzimidazol-2-one and 2-(4-bromobutyl)- 1 ,1 -dioxido- 1 ,2- benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: mp 104-6°C; Analysis calculated for C24H28N4O4S-0.35 CH3OHO.35 CH2CI2 C: 58.22, H: 5.95, N: 11.00 found C: 58.43, H: 5.91 , N: 10.60. EXAMPLE 97 l,l-Dioxido-2-(4-(4-(l,3-dihydro-2-oxo-4-methyI-2H- benzimidazolin-l -yI)-piperidin-l -yl)-butyl )-l,2- benzisothiazol-3(2H)-one From 1 ,3-dihydro- 1 -(4-piperidinyl)-4-methyl-2H-benzimidazol-2-one and 2-(4-bromobutyl)-l ,l-dioxido-l,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: mp 90-2°C; Analysis calculated for C24H28N4θ4S«0.5 CH2CI2 C: 57.58, H: 5.72, N: 10.96 found C: 57.41, H: 5.74, N: 10.96. EXAMPLE 98 l,l -Dioxido-2-(4-(4-(l,3-dihydro-2-oxo-5-methoxy-2H- benzimidazolin-l -yI)-piperidin-l -yl)-butyI)-l,2- benzisothiazol-3(2H)-one From 4-chloro-3-nitro-anisole using the procedures described for Example 96, Steps 1 through 4, there was obtained a white solid: mp 162-4°C; Analysis calculated for C24H28N4O5S-0.5 CH3OH C: 58.78, H: 6.04, N: 11.19 found C: 58.99, H: 5.88, N: 10.87. EXAMPLE 99 l,l-Dioxido-2-(4-(4-(l,3-dihydro-2-oxo-5-chloro-2H- benzimidazolin-l-yl)-piperidin-l -yl)-butyl)-l,2- benzisothiazol-3(2H)-one From 2,5-dichloronitrobenzene using the procedures described for Example 96, Steps 1 through 4, there was obtained a white solid: mp 206-8°C; Analysis calculated for C23H25C1N4O4S-0.8 CH2CI2 C: 54.46, H: 5.11, N: 10.68 found C: 54.34, H: 4.87, N: 10.81. EXAMPLE 100 l,l-Dioxido-2-(4-(4-(l,3-dihydro-2-oxo-5-fIuoro-2H- benzimidazolin-l -yl)-piperidin-l -yl)-butyl)-5-chloro-l,2- benzisothiazol-3(2H)-one From 2-chloro-5-fluoronitrobenzene using the procedures described for Example 96, Steps 1 through 4, and 2-(4-bromobutyl)-l,l-dioxido- 5-chloro-l,2-benzisothiazol-3(2H)-one there was obtained a white solid: mp 259-61°C; Analysis calculated for C23H24FCIN4O4S • HCl C: 50.83, H: 4.64, N: 10.31 found C: 50.74, H: 4.60, N: 10.18. EXAMPLE 101 l,l-Dioxido-2-(4-(4-(l,3-dihydro-2-oxo-5-methyl-2H- benzimidazolin-l-yl)-piperidin-l-yl)-butyl)-5-chloro-l,2- benzisothiazol-3(2H)-one From 1 ,3-dihydro- 1 -(4-piperidinyl)-5-methyl-2H-benzimidazol-2-one and 2-(4-bromobutyl)- 1 , 1 -dioxido-5-chloro- 1 ,2-benzisothiazol-3(2H)- one using the procedure described for Example 15, Step 5 there was obtained a white solid: mp 258-60°C; Analysis calculated for C23H27CIN4O4S • HCl • 0.4 H2θ C: 52.72, H: 5.31, N: 10.25 found C: 52.75, H: 5.23, N: 10.25. EXAMPLE 102 l,l-Dioxido-2-(4-(4-(l,3-dihydro-2-oxo-6-methyI-2H- benzimidazolin-l-yl)-piperidin-l-yI)-butyl)-5-chIoro-l,2- benzisothiazoI-3(2H)-one From 1 ,3-dihydro- 1 -(4-piperidinyl)-5-methyl-2H-benzimidazol-2-one and 2-(4-bromobutyl)-l ,1 -dioxido-5-chloro-l ,2-benzisothiazol-3(2H)- one using the procedure described for Example 15, Step 5 there was obtained a white solid: mp 273-75°C; Analysis calculated for C23H27CIN4O4S • HCl • 0.5 H2θ C: 52.55, H: 5.33, N: 10.22 found C: 52.52, H: 5.05, N: 10.16. EX AMPLE 103 1, 1 -Dioxido -2-(4-(4-(5-methy l-2-oxo-3-benzoxazoliny 1) - piperidin-l-yl)-butyl)-5,6-dihydro-[l,4]dioxino[2,3- e]benzisothiazol-3(2H )-one From 4-(5-methyl-2-oxo-3-benzoxazolinyl)-piperidine and 2-(4- hydroxybutyl)-l,l-dioxido-5,6-dihydro-[l ,4]dioxino[2,3- d]benzisothiazol-3(2H)-one using the procedure described for Example 66, Steps 4-6 there was obtained a white solid: mp 98-101 °C Analysis calculated for C26H29N3O7S • 0.3 CHCI3 C: 56.06, H: 5.24, N: 7.46 found C: 56.11, H: 5.30, N: 7.45. J H NMR (300 MHz, CDCI3) 7.4 (d, H), 7.27 (d, IH), 7.18 (d, IH), 7.05 (s, IH), 6.95 (d, IH), 4.5 (m, 2H), 4.4 (m, 2H), 4.2 (m, IH), 3.8 (t, 2H), 3.08 (d, 2H), 2.44 (t, 2H), 2.39 (s, 3H), 2.1 (t, 2H), 1.85 (m, 4H), 1.71 (m, 2H), 1.65 (m, 2H). EX AMPLE 104 l,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l - yl)-butyl)-5,6-dihydro-[l,4]dioxino[2,3-e]benzisothiazol- 3(2H)-one From 4-(2-oxo-3-benzoxazolinyl)-piperidine and 2-(4-hydroxybutyl)- 1.1 -dioxido-5,6-dihydro-[ 1 ,4]dioxino[2,3-d]benzisothiazol-3(2H)-one using the procedure described for Example 66, Steps 4-6 there was obtained a white solid: mp 79-82 °C iH NMR (400 MHz, CDCI3) 7.4 (d, IH), 7.3 (m, 2H), 7.2-7.0 (br m, 3H), 4.5 (m, 2H), 4.4 (m, 2H), 4.2 (m, IH), 3.8 (m, 2H), 3.1 (br d, 2H), 2.5-2.4 (br m, 2H), 2.2 (m, 2H), 2.0-1.85 (br m, 4H), 1.80 (m, 2H), 1.7 (m, 2H) Analysis calculated for C25H27N3O7S • 0.3 CHCI3 C: 55.31 , H: 5.01 , N: 7.65 found C: 55.20, H: 5.08, N: 7.39. EXAMPLE 105 l,l -Dioxido-2-(4-(4-(spiro-l,3-dihydro-l -oxo-2H-indenyl)- 2,4'-piperidin-l '-yI)-butyl)-5,6-dihydro-[l,4]dioxino[2,3- e]benzisothiazol-3(2H)-one From l,3-dihydro-l-oxo-spiro(2H-indenyl-2,4'-piperidine) and 2-(4- hydroxybutyl)-l,l-dioxido-5,6-dihydro-[l ,4]dioxino[2,3- d]benzisothiazol-3(2H)-one using the procedure described for Example 66, Steps 4-6 there was obtained a white solid: Analysis calculated for C26H298N206S • 0.4 CHCI3 C: 58.25, H: 5.26, N: 5.15 found C: 58.36, H: 5.40, N: 5.20. EXAMPLE 106 l,l-Dioxido-2-(4-(4-(l,3-dihydro-2-oxo-lH-3,4- dihydroquinazolin-l-yl)-piperidin-l-yI)-butyl)-l,2- benzisothiazoI-3(2H)-one Step 1 : A mixture of 45 g of 2-aminomethylaniline, 60 g of άi-tert -butyldicarbonate, 1000 mL of dichloromethane was stirred for 18 h and washed with 500 mL of 2N NaOH. The organic extract was dried over MgSθ4 and concentrated under reduced pressure. Drying under vacuum gave 47 g of 2-(tert -butoxycarbonylaminomethyl)aniline as a white crystalline solid. iH NMR (400 MHz, CDCI3) 7.1 (t, IH), 7.05 (d, IH), 6.65 (dd, 2H), 4.8 (br s, IH), 4.2 (br m, 4H), 1.44 (s, 9H). Step 2: A mixture of 15.5 g of 2-{tert -butoxycarbonyl aminomethyl)aniline, 15 g of N-t-butyloxycarbonyl-4-piperidone, 250 mL of 1 ,2-dichloroethane, 4.2 mL of glacial acetic acid and 25 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 500 mL chloroform and 500 mL saturated aqueous Na2C03 and the layers separated. The aqueous layer was extracted with 2 X 250 mL of chloroform and the combined organic layers dried over MgS04 and concentrated under reduced pressure. Drying overnight under vacuum gave 30.1 g of ten -butyl (2- (tert -butoxycarbonyl aminomethyl)anilino)piperidine carboxylate as a solid: iH NMR (400 MHz, CDCI3) 7.19 (t, IH), 7.0 (d, IH), 6.6 (dd, 2H), 4.94 (br s, IH), 4.75 (br s, IH), 4.23 (br m, 2H), 4.0 (br m, 2H), 3.45 (br m, IH), 3.0 (br m, 2H), 2.0 (br m, 2H), 1.82 (br m, IH), 1.46 (s, 9H), 1.44 (s, 9H). Step 3: To a stirred solution of 27.1 g of tert -butyl 4-(2-tert -butoxycarbonylaminomethylanilino)-l-piperidinecarboxylate and 30 mL of triethylamine in 400 mL of dichloromethane was added dropwise 60 mL of a 1.93 M solution of phosgene in toluene. After stirring for 12 h, 200 mL of IN NaOH was added. The mixture was shaken, and the organic layer separated, dried over MgSθ4 and concentrated under reduced pressure. Chromatography on silica gel, eluting with 25% ethyl acetate in hexane gave, after drying overnight under vacuum, 25 g of 1 ,3-dihydro- 1 -[ 1 -tert -butoxycarbonylpiperidin-4-yl]-3- rt -butoxycarbonyl- lH-3,4-dihydroquinazolin-2-one carboxylate as a clear glass:lH NMR (400 MHz, CDCI3) 7.52 (d, IH), 7.45 (t, IH), 7.36 (m, IH), 7.10 (d, IH), 4.2-4.0 (br m, 5H), 3.65-3.25 (br m, 2H), 2.75 (br m, 2H), 2.28 (br d, IH), 1.8 (br d, IH), 1.5 (s, 9H), 1.49 (s, 9H). Step 4: A stirred solution of 25 g of 1, 3 -dihydro-l-[l -ter -butoxycarbonylpiperidin-4-yl]-3-terr -butoxycarbonyl- 1H-3 ,4- dihydroquinazolin-2-one carboxylate in 1 L of ethyl acetate cooled to -50°C was saturated with hydrogen chloride gas for 15 min. The resulting mixture was allowed to warm to room temperature and stir for 4 h. The white solid precipitate was collected by filtration. Drying under vacuum gave 13.1 of 1 ,3-dihydro- l-[piperidin-4-yl]-3-terr -butoxycarbonyl- lH-3,4-dihydroquinazolin-2-one hydrochloride salt as a white solid. The salt (0.8 g) was converted to the free base by partitioning between chloroform and saturated sodium carbonate. Drying under vacuum gave 0.68 g of 1 ,3-dihydro- l-[piperidin-4-yl]- lH-3,4-dihydroquinazolin-2-one as a white solid: iH NMR (400 MHz, CDC13) 7.25 (dd, IH), 7.12 (d, IH), 7.06 (d, IH), 6.98 (t, IH), 5.2 (br s, IH), 4.28 (s, 2H), 4.10 (m, IH), 3.22 (d, 2H), 2.73 (m, 2H), 2.59 (m, 2H), 2.05 (br s, IH), 1.82 (br d, 2H). Step 5: From l,3-dihydro-l-[piperidin-4-yl]-lH-3,4-dihydroquinazolin- 2-one and 2-(4-bromobutyl)-l,l-dioxido-l,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: Analysis calculated for C24H28N4O4S • 0.35 CHCI3 • 0.45 H20 C: 52.70 H: 5.49, N: 10.10 found C: 52.71, H: 5.49, N: 10.33. EXAMPLE 107 2-(4-Hydroxybutyl)-l,l-dioxido-5,6-dihydro- [l,4]dioxino[2,3-d]benzisothiazol-3(2H)-one Step 1 : To a stirred solution of 12 g of 1,4-benzodioxane in 40 mL of chloroform cooled to -10C under calcium sulfate drying tube was added dropwise over 15 min, 6 mL of chlorosulfonic acid. The mixture was allowed to warm to 20C over 15 min, poured onto 400 mL of ice and extracted into 1 L of chloroform. Drying over MgS04 and concentration under reduced pressure gave 21.5 g of 1,4-benzodioxane- 6-sulfonylchloride as a white crystalline solid. Step 2: To an ice cold, stirred solution of 10 g of 4-aminobutanol and 25 mL of triethylamine in 250 mL of dichloromethane was added a solution of 21.5 g of l,4-benzodioxane-6-sulfonylchloride in 100 mL of chloroform over 30 min. The mixture was allowed to warm and stir overnight, washed with 100 mL of 6N HCl and dried over MgS04. To this solution was added 300 mL of dichloromethane, 20 mL of dihydropyran and 100 mg of p-toluenesulfonic acid monohydrate. After stirring for 12 h, the mixture was washed with 100 mL of saturated Na2Cθ3, dried over MgS04 and concentrated under reduced pressure. Chromatography on silica gel, eluting with 30% ethyl acetate in hexane gave, after drying overnight under vacuum, 13 g of N-(4-(2- tetrahydropyranyloxy)butyl)-l,4-benzodioxane-6-sulfonamide as a resin. Step 3: To a stirred solution of 13 g of N-(4-(2- tetrahydropyranyloxy)butyl)-l,4-benzodioxane-6-sulfonamide in 250 mL of dry tetrahydrofuran cooled to -78°C was added 50 mL of commercial 1.6M n-butyllithium in hexane over 10 min. After aging for 60 min with warming to 0°C, the solution was cooled to -78°C and quenched by a stream of carbon dioxide gas with a fritted glass dispersion tube, keepiing the temperature below -40°C for 30 min. The solution was allowed to warm to room temprature over 1 h and partitioned between 200 mL of water, 200 mL of saturated Na2C03 and3 x 200 mL of ether. The aqueous layer was carefully acidified to pH=3 with concentrated HCl, and extracted with 3 x 200 mL portions of ether. The combined organic extracts were dried over MgS04 and concentrated under reduced pressure. Drying under vacuum gave 10.1 g of N-(4-(2-tetrahydropyranyloxy)butyl) 5 -carboxy- 1 ,4- benzodioxane-6-sulfonamide as a foam. Step 4: To a stirred solution of 10 g of N-(4-(2- tetrahydropyranyloxy)butyl) 5-carboxy-l ,4-benzodioxane-6- sulfonamide and 7 mL of triethylamine in 200 mL of dichloromethane cooled to 0°C was added 2 mL of methyl chloroformate dropwise. After 3 h at 20°C, the mixture was shaken with 50 mL of saturated sodium carbonate, dried over MgS04 and concentrated under reduced pressure. The residue was disolved in 200 mL of methanol containing 1 g of p-toluenesulfonic acid monohydrate, stirred overnight at ambient temperature, and concentrated to dryness under reduced pressure. The residue was dissolved in 200 mL of ethyl acetate, washed with 5 mL of saturated sodium carbonate, dried over MgS04 and concentrated under reduced pressure. Trituration with ether gave 4 g of 2-(4-hydroxybutyl)-l,l-dioxido-5,6-dihydro-[l,4]dioxino[2,3- d]benzisothiazol-3(2H)-one as a white crystalline solid: mp °C; iH NMR (400 MHz, CDCI3): 7.4 (d, IH), 7.25 (d, IH), 4.5 (m, 2H), 4.4 (m, 2H), 3.8 (t, 2H), 3.7 (t, 2H), 1.95 (m, 2H), 1.7 (m, 2H), 1.55 (br s, IH). EXAMPLE IPS 2-(4-HydroxybutyI)-l,l-dioxido-5-ethoxy-l,2-benzothiazol- 3(2H)-one From ethoxybenzene using the procedures described for Example 107, Steps 1-4 there was obtained a thick oil. EX A MPT. E 109 2-(4-Hydroxybutyl)-l,l-dioxido-5-eth l-l,2-benzothiazol- 3(2H)-one From 4-ethylbenzenesulfonylchloride using the procedures described for Example 107, Steps 2-4 there was obtained a thick oil. EXAMPLE 110 2-(4-Hydroxybutyl)-l,l-dioxido-5-isopropy 1-1,2- benzothiazol-3(2H)-one From 4-isopropylbenzenesulfonylchloride using the procedures described for Example 107, Steps 2-4 there was obtained a thick oil. EXAMPLE 111 l,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l- yl)-butyl)-5-ethoxy-l,2-benzothiazol-3(2H)-one From 4-(2-oxo-3-benzoxazolinyl)-piperidine and 2-(4-hydroxybutyl)- l,l-dioxido-5-ethoxy-l,2-benzothiazol-3(2H)-one using the procedure described for Example 66, Steps 4-6 there was obtained a white solid: iH NMR ( 400 MHz, CDCI3) 7.79 (d, J = 8.57 Hz, IH), 7.44 (s, IH), 7.29-7.26 (m, 2H), 7.21 (d, J = 6.89 Hz, IH), 7.16-7.06 (m, 2H), 4.24- 4.11 (m, IH), 3.81 (t, J = 7.3 Hz, 2H), 3.06 (br d, J = 1 1.76 Hz, 2H), 2.45 (t, J = 7.39 Hz, 2H), 2.36 (m, 2H), 2.11 (bt, J = 11.08 Hz, 2H), 1.93-1.80 (br m, 6H), 1.65 (br m, 2H), 1.48 (t, J = 6.97, 3H) Analysis calculated for C25H30N3O6S • HCl • 1.2 H2O C: 53.75, H: 6.03, N: 7.52 found C: 53.72, H: 5.65 N: 7.52. EX AMPLE 112 l,l-Dioxido-2-(4-(4-(spiro-l,3-dihydro-l -oxo-2H-indenyl)- 2,4'-piperidin-r-yl)-butyl)-5-ethoxy-l,2-benzothiazol- 3(2H)-one From l,3-dihydro-l-oxo-spiro(2H-indenyl-2,4'-piperidine) and 2-(4- hydroxybutyl)-l,l-dioxido-5-ethoxy-l,2-benzothiazol-3(2H)-one using the procedure described for Example 66, Steps 4-6 there was obtained a white solid: Analysis calculated for C26H30N2O5S • HCl • 0.45 H2O • 0.3 CHCI3 C: 56.11, H: 5.77, N: 4.98 found C: 56.14, H: 5.74, N: 5.18. EXAMPLE 113 l,l-Dioxido-2-(4-(4-(spiro-l,3-dihydro-l-oxo-2H-indenyl)- 2,4'-piperidin-l , -yl)-butyl)-5-ethyl-l,2-benzothiazol-3(2H)- one From l,3-dihydro-l-oxo-spiro(2H-indenyl-2,4'-piperidine) and 2-(4- hydroxybutyl)-l,l-dioxido-5-ethyl-l,2-benzothiazol-3(2H)-one using the procedure described for Example 66, Steps 4-6 there was obtained a white solid: Analysis calculated for C26H30N2O4S • HCl • 0.2 CHCI3 C: 59.71 , H: 5.97, N: 5.32 found C: 59.66, H: 6.16, N: 5.35. EXAMPLE 114 l,l -Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l - yl)-butyl)-5-ethyl-l,2-benzothiazol-3(2H)-one From 4-(2-oxo-3-benzoxazolinyl)-piperidine and 2-(4-hydroxybutyl)- l,l-dioxido-5-ethyl-l,2-benzothiazol-3(2H)-one using the procedure described for Example 66, Steps 4-6 there was obtained a white solid: mp 165-168 °C iH NMR (400 MHz, CDCI3) 7.9 (s, IH), 7.8 (m, IH), 7.66 (m, IH), 7.3 (m, IH), 7.2-7.05 (m, 3H), 4.2 (m, IH), 3.8 (m, 2H), 3.1 (m, 2H), 2.82 (m, 2H), 2.4 (m, 2H), 2.1 (m, 2H), 2.0-1.8 (br m, 4H), 1.8-1.6 (br m, 4H), 1.3 (t, 3H) Analysis calculated for C25H30N3O6S • HCl • 1.4 H2O C: 55.66, H: 6.06, N: 7.01 found C: 55.82, H: 5.81, N: 6.91. EXAMPLE 115 l,l -Dioxido-2-(4-(4-(spiro-l,3-dihydro-l -oxo-2H-indenyl)- 2,4' -piperidin-l '-yl)-butyl)-5-(2-propyl)-l,2-benzothiazol- 3(2H)-one From l,3-dihydro-l-oxo-spiro(2H-indenyl-2,4'-piperidine) and 2-(4- hydroxybutyl)-l ,1 -dioxido-5-(2-propyl)-l ,2-benzothiazol-3(2H)-one using the procedure described for Example 66, Steps 4-6 there was obtained a white solid: Analysis calculated for C27H32N2O4S • HCl • 1.00 H2θ C: 60.60, H: 6.59, N: 5.24 found C: 60.62, H: 6.36, N: 5.28. EXAMPLE 116 l,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazo!inyl)-piperidin-l - yI)-butyl)-5-(2-propyl)-l,2-benzothiazol-3(2H)-one From 4-(2-oxo-3-benzoxazolinyl)-piperidine and 2-(4-hydroxybutyl)- l,l-dioxido-5-(2-propyl)-l,2-benzothiazol-3(2H)-one using the procedure described for Example 66, Steps 4-6 there was obtained a white solid: iH NMR (400 MHz, CDCI3) 7.9 (s, IH), 7.8 (d, IH), 7.7 (d, IH), 7.3 (m, IH), 7.2-7.0 (br m, 3H), 4.2 (m, IH), 3.8 (m, 2H), 3.1 (m, 3H), 2.7-2.5 (br m, 2H), 2.1 (m, 2H), 2.0 - 1.8 (br m, 4H), 1.7-1.6 (m, 4H), 1.35 (d, 6H) Analysis calculated for C25H30N3O6S • HCl • 1.6 CH3CO2CH2CH3 C: 57.64, H: 6.69, N: 6.23 found C: 57.06, H: 6.12, N: 6.56. The following Examples 117-144 were made in the same manner as described in detail above using readily available starting materials. EXAMPLE 117 l,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyI)-piperidin-l - yl)-butyl)-6-nitro-l,2-benzisothiazol-3(2H)-one iH NMR (400 MHz, CDCI3) 8.78 (d, J = 1.46 Hz, IH), 8.70 (dd, J = 8.39 Hz, 2.01 Hz, IH), 8.29 (dd, J = 8.39 Hz, 0.4 Hz, IH), 7.26-7.08 (m, 4H), 4.21 (dt, J = 12.43 Hz, 4.2 Hz, IH), 3.91 (t, J = 7.40 Hz, 2H), 3.08 (d, J = 11.58 Hz, 2H), 2.47 (t, J = 7.22 Hz, 2H), 2.39 (dq, J = 12.43 Hz, 3.80 Hz, 2H), 2.12 (t, J = 10.24 Hz, 2H), 1.95 (q, J = 7.56 Hz, 2H), 1.87 (dd, J = 11.92 Hz, 2.01 Hz, 2H), 1.65 (q, J = 7.89 Hz, 2H). EXAMPLE US l,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l - yI)-butyl)-5-fluoro-l,2-benzisothiazol-3(2H)-one iH NMR (400 MHz, CDCI3) 7.95 (dd, J = 4.37 Hz, 4.20 Hz, IH), 7.73 (dd, J = 7.05 Hz, 2.35 Hz, IH), 7.56 (dt, J = 8.39 Hz, 2.52 Hz, IH), 7.25 (s, IH), 7.20 (d, J = 7.89 Hz, IH), 7.14 (dt, J = 7.55 Hz, 1.18 Hz, IH), 7.09 (dq, J = 7.72 Hz, 1.18 Hz, IH), 4.22 (tt, J = 12.42 Hz, 4.2 Hz, IH), 3.84 (t, J = 7.39 Hz, 2H), 3.07 (d, J = 11.75 Hz, 2H), 2.45 (t, J = 7.22 Hz, 2H), 2.38 (dq, J = 8.70 Hz, 3.90 Hz, 2H), 2.12 (dt, J = 11.75 Hz, 1.51 Hz, 2H), 1.82 - 1.60 (m, 4H), 1.64 (q, J = 7.56 Hz, 2H). EX AMPLE 119 l,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyI)-piperidin-l - yI)-butyl)-5-methyl-l,2-benzisothiazol-3(2H)-one iH NMR (400 MHz, CDCI3) 7.86 (s, IH), 7.81 (d, J = 7.89 Hz, IH), 7.66 (d, J = 8.06 Hz, IH), 7.21 (d, J = 7.55 Hz, IH), 7.15 (t, J = 6.21 Hz, 1.51 Hz, IH), 4.2 (m, IH), 3.83 (t, J = 7.39 Hz, 2H), 3.08 (d, J = 11.75 Hz, 2H), 2.56 (s, 3H), 2.45 (t, J = 6.88 Hz, 2H), 2.37 (dt, J = 8.22 Hz, 3.86 Hz, 2H), 2.11 (t, J = 12.26 Hz, 2H), 1.94 - 1.85 (m, 4H), 1.63 (m, 2H). EXAMPLE 120 l,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazo!inyl)-piperidin-l - yl)-butyl)-5-bromo-l,2-benzisothiazol-3(2H)-one mp 158-162 °C iH NMR (400 MHz, CDCI3) 8.20 (m, IH), 7.99 (dd, IH), 7.79 (d, IH), 7.22 - 7.06 (m, 4H), 4.21 (m, IH), 3.83 (t, 2H), 3.07 (d, 2H), 2.55 (t, 2H), 2.42-2.30 (m, 2H), 2.10 (t, 2H), 1.94-1.82 (m, 4H), 1.61 (m, 2H). EXAMPLE 121 l,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l - yl)-butyl)-5-trifluorometh l-l,2-benzisothiazol-3(2H)-one mp 177-179 °C iH NMR (400 MHz, CDCI3) 8.38 (s, IH), 8.18 (d, IH), 8.10 (d, IH), 7.25 (m, IH), 7.2 (d, IH), 7.1-7.2 (m, 2H), 4.2 (m, IH), 3.88 (m, 2H), 3.05 (br d, 2H), 2.45 (m, 2H), 2.4 (m, 2H), 2.1 (m, 2H), 1.82-2.0 (br m, 4H), 1.75-1.6 (m, 2H). EXAMPLE 122 l ,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l - yl)-butyl)-5-trifluoromethoxy-l,2-benzisothiazol-3(2H)-one mp 230-233 °C iH NMR (400 MHz, CDCI3) 8.0 (d, IH), 7.9 (s, IH), 7.68 (d, IH), 7.25 (d, IH), 7.20 (d, IH), 7.1-7.19 (m, 2H), 4.2 (m, IH), 3.83 (m, 2H), 3.05 (br d, 2H), 2.42 (m, 2H), 2.4 (m, 2H), 2.1 (m, 2H), 2.8-1.8 (br m, 4H), 1.6 (m, 2H). EXAMPLE 123 l,l -Dioxido-2-(4-(4-(2-oxo-l-naphth [l,2-d]oxazolinyl)- piperidin-l-yl)-butyl)-l,2-benzisothiazol-3(2H)-one iH NMR (400 MHz, CD3OD) 7.46 (d, J = 8.61 Hz, IH), 7.24 (dd, J = 6.77, 0.73 Hz, IH), 7.21 (d, J = 7.32 Hz, IH), 7.16-7.09 (m, 3H), 6.90 (d, J = 8.79 Hz, IH), 6.79 (t, J = 7.30 Hz, IH), 6.66 (t, J = 7.51 Hz, IH), 6.64 (d, J = 8.79 Hz, IH), 4.35 (m, IH), 3.03 (t, J = 6.22 Hz, 2H), 2.89 (d, J = 12.63 Hz, 2H), 2.63 (q, J = 6.96 Hz, IH), 2.53 (br t, J = 12.45 Hz, IH), 2.41 (br m, 2H), 2.17 (br m, 2H), 1.48 (br d, J = 13.55 Hz, 2H), 1.10 (br m, 4H). EXAMPLE 124 l,l-Dioxido-2-(4-(4-(5,6,7,8-tetrahydro-2-oxo-3-naphth[2,3- d]oxazoIinyl)-piperidin-l-yl)-butyl)-l,2-benzisothiazol- 3(2H)-one H NMR (300 MHz, CD3OD) 8.09 (m, 2H), 7.98 (m, 2H), 7.08 (s, IH), 6.93 (s, IH), 3.87 (m, 2H), 3.74 (d, J = 12.21 Hz, 2H), 3.24 (br m, 4H), 2.79 (br m, 6H), 2.13 (br d, J = 13.54 Hz, 2H), 1.95 (br d, J = 3.47 Hz, 4H), 1.89 (s, 4H). EX AMPLE 125 l,l-Dioxido-2-(4-(4-(5-methyI-2-oxo-3-benzoxazolinyl)- piperidin-l -yl)-butyl)-l,2-benzisothiazol-3(2H)-one H NMR (400 MHz, CDCI3) 8.08 (d, J = 7.05 Hz, IH), 7.95-7.85 (m, 4H), 7.06 (d, J = 8.23 Hz, IH), 6.92 (d, J = 8.22 Hz, IH), 4.58 (br t, J = 11.92 Hz, IH), 3.86 (t, J = 6.55 Hz, 2H), 3.72 (d, J = 10.58 Hz, 2H), 3.34 (q, J = 11.25 Hz, 2H), 3.13 (br m, 2H), 2.93 (br m, 2H), 2.45 (s, 3H), 2.11 - 1.99 (m, 6H). EXAMPLE 126 l,l -Dioxido-2-(4-(4-(5-carbomethoxy-2-oxo-3- benzoxazolinyl)-piperidin-l -yI)-butyl)-l,2-benzisothiazoI- 3(2H)-one iH NMR (400 MHz, CDCI3) 8.63 (s, IH), 8.09 (d, J = 7.05 Hz, lH),7.96-7.86 (m, 5H), 4.61 (br t, J = 13.09 Hz, IH), 4.00 (s, 3H), 3.87 (t, J = 6.72 Hz, 2H), 3.75 (d, J = 10.91, 2H), 3.41 (q, J = 12.26, 2H), 3.13 (m, 2H), 2.93 (m, 2H), 2.13-2.00 (m, 6H). EXAMPLE 127 l,l-Dioxido-2-(4-(4-(6-fluoro-2-oxo-3-benzoxazolinyl)- piperidin-l-yl)-butyl)-l,2-benzisothiazol-3(2H)-one mp 154-155 °C iH NMR (400 MHz, CDCI3) 8.06 (dd, IH), 7.96-7.82 (m, 3H), 7.18 (br q, IH), 6.99 (dd, IH), 6.88 (td, IH), 4.19 (m, IH), 3.84 (t, 2H), 3.06 (d, 2H), 2.44 (t, 2H), 2.40-2.25 (m, 2H), 2.10 (t, 2H), 1.96-1.81 (m, 4H), 1.61 (bs, 2H). EX AMPLE 12S l,l -Dioxido-2-(4-(4-(4-methyI-2-oxo-3-benzoxazoIinyI)- piperidin-l -yl)-butyl)-l,2-benzisothiazol-3(2H)-one iH NMR (400 MHz, CDCI3) 8.07 (dd, J = 6.72, 1.52 Hz, IH), 7.93 (d, J = 6.55 Hz, IH), 7.85 (m, 2H), 7.03 (d, J = 7.05 Hz, IH), 6.97 (t, J = 7.72 Hz, IH), 6.89 (d, J = 7.72 Hz, IH), 4.21 (dt, J = 8.23, 3.86 Hz, IH), 3.86 (t, J = 7.21 Hz, 2H), 3.09 (d, J = 11.92 Hz, 2H), 2.71 (dq, J = 8.72, 3.7 Hz, 2H), 2.55 (s, 3H), 2.43 (t, J = 7.56 Hz, 2H), 2.03 (t, J = 12.08 Hz, 2H), 1.91 (m, 2H), 1.65 (d, J = 7.72 Hz, 2H), 1.63-1.59 (m, 2H). EXAMPLE 129 1, 1 -Dioxido -2-(4-(4-(4-meth oxy -2-oxo-3-benzoxazol inyl) - piperidin-l -yl)-butyl)-l,2-benzisothiazol-3(2H)-one iH NMR (400 MHz, CDCI3) 8.07 (dd, J = 5.37, 1.01 Hz, IH), 7.94-7.82 (m, 3H), 7.04 (t, J = 8.22 Hz, IH), 6.85 (dd, J = 7.21, 0.84 Hz, IH), 6.73 (d, J = 8.56 Hz, IH), 4.45 (tt, J = 12.25, 4.2 Hz, IH), 3.94 (s, 3H), 3.84 (t, J = 7.39 Hz, 2H), 3.04 (br d, J = 11.58 Hz, 2H), 2.54 (qd, J = 8.73, 3.69 Hz, 2H), 2.43 (t, J = 7.22, 2H), 2.07 (dt, J = 10.24, 1.68 Hz, 2H), 1.93 (m, 2H), 1.77 (br d, J = 9.74 Hz, 2H), 1.63 (m, 2H). EXAMPLE 130 5-Chloro-l,l-dioxido-2-(4-(4-(6-methyI-2-oxo-3- benzoxazolinyl)-piperidin-l-yl)-butyT)-l,2-benzisothiazol- 3(2H)-one iH NMR (400 MHz, CDCI3) 8.04 (d, J = 1.68 Hz, IH), 7.85 (overlapping t and dt, 2H), 7.13 (d, J = 8.05 Hz, IH), 7.04 (s, IH), 6.95 (d, J = 8.05 Hz, IH), 4.19 (dt, J = 12.42, 4.02 Hz, IH), 3.84 (t, J = 7.39 Hz, 2H), 3.07 (d, J = 11.59 Hz, 2H), 2.45 (t, J = 7.39 Hz, 2H), 2.38 (s, 3H), 2.33 (dq, J = 12.25, 3.52 Hz, 2H), 2.11 (t, J = 11.58 Hz, 2H), 1.95- 1.84 (m, 4H), 1.63 (m, 2H). EX AMPLE 131 5-Methylthio-l,l -dioxido-2-(4-(4-(6-methyl-2-oxo-3- benzoxazolinyl)-piperidin-l -yl)-butyl )-l ,2-benzisothiazol- 3(2H)-one iH NMR (400 MHz, CDCI3) 7.78 (t, J = 1.68 Hz, IH), 7.75 (s, IH), 7.62 (dd, J= 8.23, 1.85 Hz, IH), 7.15 (br d, J = 7.39 Hz, IH), 7.02 (s, IH), 6.94 (d, J = 8.06 Hz, IH), 4.19 (m, IH), 3.82 (t, J = 7.22 Hz, 2H), 3.08 (br d, J = 9.56 Hz, 2H), 2.60 (s, 3H), 2.46 (br m, 2H), 2.37 (s, 3H), 2.42-2.37 (br m, 2H), 2.15-2.11 (br m, 2H), 1.94-1.83 (br m, 4H), 1.66-1.64 (br m, 2H). EXAMPLE 132 5-Ethoxy-l,l-dioxido-2-(4-(4-(6-methyl-2-oxo-3- benzoxazolinyl)-piperidin-l -yl)-butyl)-l,2-benzisothiazol- 3(2H)-qne iH NMR (400 MHz, CDCI3) 7.79 (dd, J = 8.56, 3.53 Hz, IH), 7.44 (dd, J = 4.36, 2.35 Hz, IH), 7.29 (m, IH), 7.14 (d, J = 8.06 Hz, IH), 7.02 (s, IH), 6.94 (br d, J = 7.22 Hz, IH), 4.18 (m, 3H), 3.81 (t, J = 7.38 Hz, 2H), 3.71 (t, J = 6.38 Hz, IH), 3.06 (d, J = 11.75 Hz, 2H), 2.44 (t, J = . 7.38 Hz, 2H), 2.37 (s, 3H), 2.31 (dt, J = 12.26, 3.53 Hz, IH), 2.10 (dt, J = 11.92, 2.02 Hz, 2H), 1.97-1.82 (m, 4H), 1.73-1.61 (m, 2H), 1.48 (dt, J = 7.06, 1.18 Hz, 3H). EXAMPLE 133 5-Chloro-l,l -dioxido-2-(4-(4-(6-fluoro-2-oxo-3- benzoxazolinyl)-piperidin-l-yl)-butyl)-l,2-benzisothiazol- 3(2H)-one mp 155-156 °C iH NMR (400 MHz, CDCI3) 8.04 (dd, IH), 7.89 - 7.82 (m, 2H), 7.18 (q, IH), 7.00 (dd, IH), 6.89 (td, IH), 4.19 (m, IH), 3.82 (t, 2H), 3.07 (d, 2H), 2.45 (t, 2H), 2.40-2.27 (m, 2H), 2.11 (td, 2H), 1.97-1.82 (m, 4H), 1.64 (m, 2H). EXAMPLE 134 4-Methy 1-1,1 -dioxido-2-(4-(4-(2-oxo-3-benzoxazoliny 1)- piperidin-l -yI)-butyl)-l,2-benzisothiazol-3(2H)-one mp 137-138 °C iH NMR (400 MHz, CDCI3) 7.78-7.69 (m, 2H), 7.58 (d, J = 7.5 Hz, IH), 7.27 (d, J = 4.7 Hz, IH), 7.20 (dd, J = 6.9 Hz, 1.4 Hz, IH), 7.17-7.06 (m, 2H), 4.21 (m, IH), 3.81 (t, J = 14.8 Hz, 2H), 3.07 (d, J = 11.6 Hz, 2H), 2.79 (s, 3H), 2.46 (t, J = 14.8 Hz, 2H), 2.41 - 2.31 (m, 2H), 2.12 (t, J = 23.8 Hz, 2H), 1.97-1.81 (m, 4H), 1.69-1.59 (m, 2H). EXAMPLE 135 4-Chloro-l,l -dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)- piperidin-l -yl)-butyI)-l,2-benzisothiazol-3(2H)-one mp 178-180 °C iH NMR (400 MHz, CDCI3) 7.88-7.84 (m, IH), 7.82- 7.76 (m, 2H), 7.31-7.26 (m, IH), 7.24-7.08 (m, 3H), 4.21 (m, IH), 3.84 ( t, J = 14.6 Hz, 2H), 3.09 (d, J = 9.6 Hz, 2H), 2.46 ( t, J = 14.5 Hz, 2H), 2.43-2.33 (m, 2H), 2.12 (t, J = 23.8 Hz, 2H), 1.99-1.83 (m, 4H), 1.71-1.59 (m, 2H). EXAMPLE 136 4-Ethoxy-l,l-dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)- piperidin-l-yl)-butyl)-l,2-benzisothiazol-3(2H)-one iH NMR (400 MHz, CDCI3), 7.77 (t, J = 7.6 Hz, IH), 7.45 (d, J = 8.0 Hz, IH), 7.28-7.27 (m, 2H), 7.19 (d, J = 7.6 Hz, IH), 7.15 (t, J = 7.6 Hz, IH), 7.08 (td, J = 7.6, 1.4 Hz, IH), 4.28 (q, J = 7.0 Hz, 2H), 4.26 (tt, J = 12.6, 4.2 Hz, IH), 3.78 (t, J = 7.4 Hz, 2H), 3.07 (d, J = 11.6 Hz, 2H), 2.44 (t, J = 7.2 Hz, 2H), 2.36 (td, J = 12.5, 3.7 Hz, 2H), 2.11 (td, J = 12.0, 1.6 Hz, 2H), 1.93-1.83 (m, 4H), 1.63 (qn, J = 7.6 Hz, 2H), 1.55 (t, J = 7.0 Hz, 3H). EXAMPLE 137 4-(2-Propyloxy)-l ,l-dioxido-2-(4-(4-(2-oxo-3- benzoxazolinyI)-piperidin-l-yl)-butyI)-l,2-benzisothiazol- 3(2H)-one iH NMR (400 MHz, CDCI3) 7.75 (dd, J = 8.4, 7.7 Hz, IH), 7.43 (d, J = 7.5 Hz, IH), 7.27 (d, J = 7.9 Hz, IH), 7.26 (d, J = 8.6 Hz, IH), 7.19 (dd, J = 7.8, 1.2 Hz, IH), 7.14 (td, J = 7.7, 1.3 Hz, IH), 7.08 (td, J = 7.8, 1.2 Hz, IH), 4.77 (sept., J = 6.0 Hz, IH), 4.21 (tt, J = 12.5, 4.3 Hz, IH), 3.77 (t, J = 7.4 Hz, 2H), 3.07 (d, J = 11.7 Hz, 2H), 2.44 (t , J = 7.3 Hz, 2H), 2.36 (td, J = 12.6, 3.8 Hz, 2H), 2.11 (td, J = 11.9, 1.8 Hz, 2H), 1.94-1.83 (m, 4H), 1.63 (qn, J = 7.5 Hz, 2H), 1.47 (d, J = 6.0 Hz, 6H). EXAMPLE 133 5-Methoxy-l,l-dioxido-2-(4-(4-(6-methy I-2-OXO-3- benzoxazolinyI)-piperidin-l -yl)-butyl)-l,2-benzisothiazol- 3(2H)-one iH NMR (400 MHz, CDCI3) 7.81 (d, J = 8.6 Hz, IH), 7.77 (d, J = 8.1 Hz, IH), 7.48 (d, J = 2.2 Hz, IH), 7.33 (dd, J = 8.6, 2.4 Hz, IH), 7.07 (d, J = 7.9 Hz, IH), 7.03 (s, IH), 4.56 (t, J = 12.6 Hz, IH), 3.97 (s, 3H), 3.83 (t, J = 6.6 Hz, 2H), 3.72 (d, J = 11.0 Hz, 2H), 3.25 (m, 2H), 3.11 (m, 2H), 2.90 (m, 2H), 2.37 (s, 3H), 2.09-1.96 (m, 6H). EXAMPLE 139 l,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l- yl)-butyl)-6-methylsulfon l-l,2-benzisothiazol-3(2H)-one iH NMR (400 MHz, CDCI3) 8.51 (s, IH), 8.40 (d, J = 9.57 Hz, IH), 8.27 (d, J = 7.89 Hz, IH), 7.20 (d, J = 7.73 Hz, IH), 7.16-7.08 (m, 3H), 4.21 (m, IH), 3.89 (t, J = 7.39 Hz, 2H), 3.17 (s, 3H), 3.12 (bd, 2H), 2.40 (s, 2H), 2.37 (d, 2H), 1.93 (t, J = 7.73 Hz, 2H), 1.87 (bd, 2H), 1.60 (bm, 4H). EXAMPLE 140 5-Methoxy-l,l-dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)- piperidin-l-yI)-butyI)-l,2-benzisothiazol-3(2H)-one iH NMR (400 MHz, CDC13) 7.93 (d, J = 7.87 Hz, IH), 7.82 (d, J = 8.60 Hz, IH), 7.48 (d, J = 2.38 Hz, IH), 7.34 (dd, J = 6.22, 2.38 Hz, IH), 7.27 (m, IH), 7.20 (d, J = 7.14, IH), 7.13 (t, J = 7.69 Hz, IH), 4.60 (tt, J = 12.81, 4.03 Hz, IH), 3.97 (s, 3H), 3.83 (t, J = 6.59 Hz, 2H), 3.74 (d, J = 12.09 Hz, 2H), 3.32 (dq, J = 12.82, 4.03 Hz, 2H), 3.12 (br t, J = 4.58 Hz, 2H), 2.92 (br q, J = 10.07 Hz, 2H), 2.14-1.95 (m, 6H). EXAMPLE 141 l,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l- yI)-butyl)-5-methylsulfon l-l,2-benzisothiazol-3(2H)-one iH NMR (400 MHz, DMS0-d6) 8.67 (d, J = 8.06 Hz, IH), 8.57 (dd, J = 8.06, 1.51 Hz, IH), 8.54 (s, IH), 7.39 (m, 2H), 7.26 (t, J = 7.88 Hz, IH), 7.17 (t, J = 7.72 Hz, IH), 4.49 (dt, J = 11.92, 4.01 Hz, IH), 3.85 (bm, 2H), 3.64 (br d, J = 11.92 Hz, 2H), 3.44 (s, 3H), 3.20-3.10 (m, 2H), 2.54 (m, 2H), 2.08 (br d, J = 12.59 Hz, 2H). EXAMPLE 142 5-Methylthio-l,l-dioxido-2-(4-(4-(2-oxo-3-benzoxazoIinyI)- piperidin-l-yl)-butyl)-l,2-benzisothiazol-3(2H)-one iH NMR (400 MHz, CDCI3) 7.93 (d, J = 7.87 Hz, IH), 7.77 (m, 2H), 7.63 (dd, J = 8.24, 1.83 Hz, IH), 7.27 (m, IH), 7.20 (dd, J = 8.05, 1.10 Hz, IH), 7.13 (t, J = 8.42, 0.92 Hz, IH), 4.60 (dt, J = 12.81, 4.22 Hz, IH), 3.84 (t, J = 6.59 Hz, 2H), 3.74 (br d, J = 11.54 Hz, 2H), 3.33 (dq, J = 13.55, 3.84 Hz, 2H), 3.13 (m, 2H), 2.93 (q, J = 10.07 Hz, 2H), 2.60 (s, 3H), 2.14-1.93 (m, 6H). EXAMPLE 143 5-Methylsulfonyl-l,l-dioxido-2-(4-(4-(6-methyl-2-oxo-3- benzoxazolinyl)-piperidin-l -yO-butyl)-l,2-benzisothiazol- 3(2H)-one iH NMR (400 MHz, CDCI3) 8.63 (s, IH), 8.46 (dd, J = 8.05, 1.65 Hz, IH), 8.15 (dd, J = 8.05, 0.55 Hz, IH), 7.13 (d, J = 8.06 Hz, IH), 7.03 (s, IH), 6.95 (d, J = 8.05 Hz, IH), 4.18 (dt, J = 12.01 , 4.21 Hz, IH), 3.89 (t, J = 7.33 Hz, 2H), 3.16 (s, 3H), 3.07 (br d, J = 10.99 Hz, 2H), 2.46 (t, J = 7.14 Hz, 2H), 2.38 (s, 3H), 2.34 (m, 2H), 2.11 (t, J = 11.17 Hz, 2H), 1.97-1.84 (m, 6H). EXAMPLE 144 l,l -Dioxido-2-(4-(4-(2-oxo-l-oxazolo[5,4-b]pyridyl)- piperidin-l-yl)-butyl)-l,2-benzisothiazoI-3(2H)-one H NMR (400 MHz, CDCI3) 8.38 (d, J = 7.51 Hz, IH), 8.07 (m, 2H), .7.91 (m, 3H), 7.25 (m, IH), 4.64 (m, IH), 3.86 (t, J = 3.20 Hz, 2H), 3.74 (br d, J = 10.99 Hz, 2H), 3.29 (m, 2H), 3.13 (bs, 2H), 2.92 (m, 2H), 2.18-1.99 (m, 6H). SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: Thompson, Wayne J. Huff, Joel R. Nerenberg, Jennie B. Lee, Hee-Yoon Bell, Ian M. (ii) TITLE OF INVENTION: ALPHAIC ADRENERGIC RECEPTOR ANTAGONISTS (iii) NUMBER OF SEQUENCES: 35 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: Merck & Co. , Inc. (B) STREET: 126 Lincoln Avenue (C) CITY: Rahway (D) STATE: New Jersey (E) COUNTRY: United States of America (F) ZIP: 07065 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Patentln Release #1.0, Version #1.25 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: (B) FILING DATE: (C) CLASSIFICATION: (vii) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: 08/229,276 (B) FILING DATE: 14-APR-1995 (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: Appollina, Mary A. (B) REGISTRATION NUMBER: 34,087 (C) REFERENCE/DOCKET NUMBER: 19169Y (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: (908)594-3462 (B) TELEFAX: (908)594-4720 (C) TELEX: 138825 (2) INFORMATION FOR SEQ ID NO:1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 28 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: both (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID Nθ:l: TTTTCTAGAT TRTTNARRTA NCCNAGCC 28 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 26 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: TTTACTAGTA TCSTNGTNAT GTAYTG 26 (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 26 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3 : TTTTCTAGAG AARAANGGNA RCCARC 26 (2) INFORMATION FOR SEQ ID NO: : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 235 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: both (D) TOPOLOGY: both (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: : GCCGCGTCTA CGTGGTGGCC AAGAGGGAGA GCCGGGGCCT CAAGTCTGGC CTCAAGACCG 60 ACAAGTCGGA CTCGGAGCAA GTGACGCTCC GCATCCATCG GAAAAACGCC CCGGCAGGAG 120 GCAGCGGGAT GGCCAGCGCC AAGACCAAGA CGCACTTCTC AGTGAGGCTC CTCAAGTTCT 180 CCCGGGAGAA GAAAGCGGCC AAAACGCTGG GCATCGTGGT CGGCTGCTTC GTCCT 235 (2) INFORMATION FOR SEQ ID NO: 5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 78 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (v) FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: Arg Val Tyr Val Val Ala Lys Arg Glu Ser Arg Gly Leu Lys Ser Gly 1 5 10 15 Leu Lys Thr Asp Lys Ser Asp Ser Glu Gin Val Thr Leu Arg lie His 20 25 30 Arg Lys Asn Ala Pro Ala Gly Gly Ser Gly Met Ala Ser Ala Lys Thr 35 40 45 Lys Thr His Phe Ser Val Arg Leu Leu Lys Phe Ser Arg Glu Lys Lys 50 55 60 Ala Ala Lys Thr Leu Gly He Val Val Gly Cys Phe Val Leu 65 70 75 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 93 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (v) FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: Leu Val Met Tyr Cys Arg Val Tyr Val Val Ala Lys Arg Glu Ser Arg 1 5 10 15 Gly Leu Lys Ser Gly Leu Lys Thr Asp Lys Ser Asp Ser Glu Gin Val 20 25 30 Thr Leu Arg He His Arg Lys Asn Ala Gin Val Gly Gly Ser Gly Val 35 40 45 Thr Ser Ala Lys Asn Lys Thr His Phe Ser Val Arg Leu Leu Lys Phe 50 55 60 Ser Arg Glu Lys Lys Ala Ala Lys Thr Leu Gly He Val Val Gly Cys 65 70 75 80 Phe Val Leu Cys Trp Leu Pro Phe Phe Leu Val Met Pro 85 90 (2) INFORMATION FOR SEQ ID NO:7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1601 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: both (D) TOPOLOGY: both (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID N0:7: GAATTCCCTC CTAGAAGCTG GAGAGAGCAG GAGCCTTCGG TGGGGCAGCT CAAAATGTAG 60 GTAACTGCGG GCCAGGAGCA GCGCCCAGAT GCCATCGGTC CCTGCCTTTG AGCGTCGACG 120 GCTGATCTTT TGGTTTGAGG GAGAGACTGG CGCTGGAGTT TTGAATTCCG AATCATGTGC 180 AGAATCGTGA ATCTTCCCCC AGCCAGGACG AATAAGACAG CGCGGAAAAG CAGATTCTCG 240 TAATTCTGGA ATTGCATGTT GCAAGGAGTC TCCTGGATCT TCGCACCCAG CTTCGGGTAC 300 GGGAGGGAGT CCGGGTCCCG GCTAGGCCAG CCCGCAGGTG GAGAGGGTCC CCGGCAGCCC 360 CGCGCGCCCC TGGCCATGTC TTTAATGCCC TGCCCCTTCA TGTGGCCTTC TGAGGGTTCC 420 CAGGGCTGGC CAGGGTTGTC TCCCACCCGC GCGCGCCGTC TCACCCCCAG CCAAACCCAC 480 CTGGCAGGGC TCCCTCCAGA AGAGACCTTT TGATTCCCGG CTCCCGCGCT CCCGCCTCCG 540 CGCCAGCCCG GGAGGTGGCC CTGGACAGCC GGACCTCGCC CGGCCCCGGC TGGGACCATG 600 GTGTTTCTCT CGGGAAATGC TTCCGACAGC TCCAACTGCA CCCAACCGCC GGCACCGGTG 660 AACATTTCCA AGGCCATTCT GCTCGGGGTG ATCTTGGGGG GCCTCATTCT TTTCGGGGTG 720 CTGGGTAACA TCCTAGTGAT CCTCTCCGTA GCCTGTCACC GACACCTGCA CTCAGTCACG 780 CACTACTACA TCGTCAACCT GGCGGTGGCC GACCTCCTGC TCACCTCCAC GGTGCTGCCC 840 TTCTCCGCCA TCTTCGAGGT CCTAGGCTAC TGGGCCTTCG GCAGGGTCTT CTGCAACATC 900 TGGGCGGCAG TGGATGTGCT GTGCTGCACC GCGTCCATCA TGGGCCTCTG CATCATCTCC 960 ATCGACCGCT ACATCGGCGT GAGCTACCCG CTGCGCTACC CAACCATCGT CACCCAGAGG 1020 AGGGGTCTCA TGGCTCTGCT CTGCGTCTGG GCACTCTCCC TGGTCATATC CATTGGACCC 1080 CTCTTCGGCT GGAGGCAGCC GGCCCCCGAG GACGAGACCA TCTGCCAGAT CAACGAGGAG 1140 CCGGGCTACG TGCTCTTCTC GGCTCTGGGC TCCTTCTACC TGCCTCTGGC CATCATCCTG 1200 GTCATGTACT GCCGCGTCTA CGTGGTGGCC AAGAGGGAGA GCCGGGGCCT CAAGTCTGGC 1260 CTCAAGACCG ACAAGTCGGA CTCGGAGCAA GTGACGCTCC GCATCCATCG GAAAAACGCC 1320 CCGGCAGGAG GCAGCGGGAT GGCCAGCGCC AAGACCAAGA CGCACTTCTC AGTGAGGCTC 1380 CTCAAGTTCT CCCGGGAGAA GAAAGCGGCC AAAACGCTGG GCATCGTGGT CGGCTGCTTC 1440 GTCCTCTGCT GGCTGCCTTT TTTCTTAGTC ATGCCCATTG GGTCTTTCTT CCCTGATTTC 1500 AAGCCCTCTG AAACAGTTTT TAAAATAGTA TTTTGGCTCG GATATCTAAA CAGCTGCATC 1560 AACCCCATCA TATACCCATG CTCCAGCCAA GAGGGAATTC C 1601 (2) INFORMATION FOR SEQ ID NO:8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 26 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: TTTGAATTCT GATTTCAAGC CCTCTG 26 (2) INFORMATION FOR SEQ ID NO:9 : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 30 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: TTTGAATTCT TANACYTCYT CNCCRTTYTC 30 (2) INFORMATION FOR SEQ ID NO:10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 512 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: both (D) TOPOLOGY: both (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10: CTGATTTCAA GCCCTCTGAA ACAGTTTTTA AAATAGTATT TTGGCTCGGA TATCTAAACA 60 GCTGCATCAA CCCCATCATA TACCCATGCT CCAGCCAAGA GTTCAAAAAG GCCTTTCAGA 120 ATGTCTTGAG AATCCAGTGT CTCCGCAGAA AGCAGTCTTC CAAACATGCC CTGGGCTACA 180 CCCTGCACCC GCCCAGCCAG GCCGTGGAAG GGCAACACAA GGACATGGTG CGCATCCCCG 240 TGGGATCAAG AGAGACCTTC TACAGGATCT CCAAGACGGA TGGCGTTTGT GAATGGAAAT 300 TTTTCTCTTC CATGCCCCGT GGATCTGCCA GGATTACAGT GTCCAAAGAC CAATCCTCCT 360 GTACCACAGC CCGGGTGAGA AGTAAAAGCT TTTTGCAGGT CTGCTGCTGT GTAGGGCCCT 420 CAACCCCCAG CCTTGACAAG AACCATCAAG TTCCAACCAT TAAGGTCCAC ACCATCTCCC 480 TCAGTGAGAA CGGCGAAGAG GTTTAAGAAT TC 512 (2) INFORMATION FOR SEQ ID NO:11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2004 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: both (D) TOPOLOGY: both (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11: GAATTCCCTC CTAGAAGCTG GAGAGAGCAG GAGCCTTCGG TGGGGCAGCT CAAAATGTAG 60 GTAACTGCGG GCCAGGAGCA GCGCCCAGAT GCCATCGGTC CCTGCCTTTG AGCGTCGACG 120 GCTGATCTTT TGGTTTGAGG GAGAGACTGG CGCTGGAGTT TTGAATTCCG AATCATGTGC 180 AGAATCGTGA ATCTTCCCCC AGCCAGGACG AATAAGACAG CGCGGAAAAG CAGATTCTCG 2 0 TAATTCTGGA ATTGCATGTT GCAAGGAGTC TCCTGGATCT TCGCACCCAG CTTCGGGTAC 300 GGGAGGGAGT CCGGGTCCCG GCTAGGCCAG CCCGCAGGTG GAGAGGGTCC CCGGCAGCCC 360 CGCGCGCCCC TGGCCATGTC TTTAATGCCC TGCCCCTTCA TGTGGCCTTC TGAGGGTTCC 420 CAGGGCTGGC CAGGGTTGTC TCCCACCCGC GCGCGCCGTC TCACCCCCAG CCAAACCCAC 480 CTGGCAGGGC TCCCTCCAGA AGAGACCTTT TGATTCCCGG CTCCCGCGCT CCCGCCTCCG 540 CGCCAGCCCG GGAGGTGGCC CTGGACAGCC GGACCTCGCC CGGCCCCGGC TGGGACCATG 600 GTGTTTCTCT CGGGAAATGC TTCCGACAGC TCCAACTGCA CCCAACCGCC GGCACCGGTG 660 AACATTTCCA AGGCCATTCT GCTCGGGGTG ATCTTGGGGG GCCTCATTCT TTTCGGGGTG 720 CTGGGTAACA TCCTAGTGAT CCTCTCCGTA GCCTGTCACC GACACCTGCA CTCAGTCACG 780 CACTACTACA TCGTCAACCT GGCGGTGGCC GACCTCCTGC TCACCTCCAC GGTGCTGCCC 8 0 TTCTCCGCCA TCTTCGAGGT CCTAGGCTAC TGGGCCTTCG GCAGGGTCTT CTGCAACATC 900 TGGGCGGCAG TGGATGTGCT GTGCTGCACC GCGTCCATCA TGGGCCTCTG CATCATCTCC 960 ATCGACCGCT ACATCGGCGT GAGCTACCCG CTGCGCTACC CAACCATCGT CACCCAGAGG 1020 AGGGGTCTCA TGGCTCTGCT CTGCGTCTGG GCACTCTCCC TGGTCATATC CATTGGACCC 1080 CTCTTCGGCT GGAGGCAGCC GGCCCCCGAG GACGAGACCA TCTGCCAGAT CAACGAGGAG 1140 CCGGGCTACG TGCTCTTCTC GGCTCTGGGC TCCTTCTACC TGCCTCTGGC CATCATCCTG 1200 GTCATGTACT GCCGCGTCTA CGTGGTGGCC AAGAGGGAGA GCCGGGGCCT CAAGTCTGGC 1260 CTCAAGACCG ACAAGTCGGA CTCGGAGCAA GTGACGCTCC GCATCCATCG GAAAAACGCC 1320 CCGGCAGGAG GCAGCGGGAT GGCCAGCGCC AAGACCAAGA CGCACTTCTC AGTGAGGCTC 1380 CTCAAGTTCT CCCGGGAGAA GAAAGCGGCC AAAACGCTGG GCATCGTGGT CGGCTGCTTC 1440 GTCCTCTGCT GGCTGCCTTT TTTCTTAGTC ATGCCCATTG GGTCTTTCTT CCCTGATTTC 1500 AAGCCCTCTG AAACAGTTTT TAAAATAGTA TTTTGGCTCG GATATCTAAA CAGCTGCATC 1560 AACCCCATCA TATACCCATG CTCCAGCCAA GAGTTCAAAA AGGCCTTTCA GAATGTCTTG 1620 AGAATCCAGT GTCTCCGCAG AAAGCAGTCT TCCAAACATG CCCTGGGCTA CACCCTGCAC 1680 CCGCCCAGCC AGGCCGTGGA AGGGCAACAC AAGGACATGG TGCGCATCCC CGTGGGATCA 1740 AGAGAGACCT TCTACAGGAT CTCCAAGACG GATGGCGTTT GTGAATGGAA ATTTTTCTCT 1800 TCCATGCCCC GTGGATCTGC CAGGATTACA GTGTCCAAAG ACCAATCCTC CTGTACCACA 1860 GCCCGGGTGA GAAGTAAAAG CTTTTTGCAG GTCTGCTGCT GTGTAGGGCC CTCAACCCCC 1920 AGCCTTGACA AGAACCATCA AGTTCCAACC ATTAAGGTCC ACACCATCTC CCTCAGTGAG 1980 AACGGCGAAG AGGTTTAAGA ATTC 2004 (2) INFORMATION FOR SEQ ID NO:12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 466 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (v) FRAGMENT TYPE: N-terminal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: Met Val Phe Leu Ser Gly Asn Ala Ser Asp Ser Ser Asn Cys Thr Gin 1 5 10 15 Pro Pro Ala Pro Val Asn He Ser Lys Ala He Leu Leu Gly Val He 20 25 30 Leu Gly Gly Leu He Leu Phe Gly Val Leu Gly Asn He Leu Val He 35 40 45 Leu Ser Val Ala Cys His Arg His Leu His Ser Val Thr His Tyr Tyr 50 55 60 He Val Asn Leu Ala Val Ala Asp Leu Leu Leu Thr Ser Thr Val Leu 65 70 75 80 Pro Phe Ser Ala He Phe Glu Val Leu Gly Tyr Trp Ala Phe Gly Arg 85 90 95 Val Phe Cys Asn He Trp Ala Ala Val Asp Val Leu Cys Cys Thr Ala 100 105 110 Ser He Met Gly Leu Cys He He Ser He Asp Arg Tyr He Gly Val . 115 120 125 Ser Tyr Pro Leu Arg Tyr Pro Thr He Val Thr Gin Arg Arg Gly Leu 130 135 140 Met Ala Leu Leu Cys Val Trp Ala Leu Ser Leu Val He Ser He Gly 145 150 155 160 Pro Leu Phe Gly Trp Arg Gin Pro Ala Pro Glu Asp Glu Thr He Cys 165 170 175 Gin He Asn Glu Glu Pro Gly Tyr Val Leu Phe Ser Ala Leu Gly Ser 180 185 190 Phe Tyr Leu Pro Leu Ala He He Leu Val Met Tyr Cys Arg Val Tyr 195 200 205 Val Val Ala Lys Arg Glu Ser Arg Gly Leu Lys Ser Gly Leu Lys Thr 210 215 220 Asp Lys Ser Asp Ser Glu Gin Val Thr Leu Arg He His Arg Lys Asn 225 230 235 240 Ala Pro Ala Gly Gly Ser Gly Met Ala Ser Ala Lys Thr Lys Thr His 245 250 255 Phe Ser Val Arg Leu Leu Lys Phe Ser Arg Glu Lys Lys Ala Ala Lys 260 265 270 Thr Leu Gly He Val Val Gly Cys Phe Val Leu Cys ' Trp Leu Pro Phe 275 280 285 Phe Leu Val Met Pro He Gly Ser Phe Phe Pro Asp Phe Lys Pro Ser 290 295 300 Glu Thr Val Phe Lys He Val Phe Trp Leu Gly Tyr Leu Asn Ser Cys 305 310 315 320 He Asn Pro He He Tyr Pro Cys Ser Ser Gin Glu Phe Lys Lys Ala 325 330 335 Phe Gin Asn Val Leu Arg He Gin Cys Leu Arg Arg Lys Gin Ser Ser 340 345 350 Lys His Ala Leu Gly Tyr Thr Leu His Pro Pro Ser Gin Ala Val Glu 355 360 365 Gly Gin His Lys Asp Met Val Arg He Pro Val Gly Ser Arg Glu Thr 370 375 380 Phe Tyr Arg He Ser Lys Thr Asp Gly Val Cys Glu Trp Lys Phe Phe 385 390 395 400 Ser Ser Met Pro Arg Gly Ser Ala Arg He Thr Val Ser Lys Asp Gin 405 410 415 Ser Ser Cys Thr Thr Ala Arg Val Arg Ser Lys Ser Phe Leu Gin Val 420 425 430 Cys Cys Cys Val Gly Pro Ser Thr Pro Ser Leu Asp Lys Asn His Gin 435 440 445 Val Pro Thr He Lys Val His Thr He Ser Leu Ser Glu Asn Gly Glu 450 455 460 Glu Val 465 (2) INFORMATION FOR SEQ ID NO:13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1621 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: both (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: CCCGTGCAGG GGCCCTACGG ACACCACCAG GGCTACGACC CAGAGCAGGG CCAGGATGGC 60 GGCCGCCTTG CGCTCGGTCA TGATGGCTGG GTACTTGAGT GAGTGGCGCA CGCCCACGTA 120 CCGGTCCACG GAGATGGTGC AGAGGCTGAG GATGGAGGCC GTGCAGCACA GCACGTCCAC 180 GGCGGCCGTC GGGGGACTGG TGGTGAGCGC GCAGGGCGTG GGCGTGGGCG TCTTCCTGGC 240 AGCCTTCATC CTTATGGCCG TGGCAGGTAA CCTGCTTGTC ATCCTCTCAG TGGCCTGCAA 300 CCGCCACCTG CAGACCGTCA CCAACTATTT CATCGTGAAC CTGGCCGTGG CCGACCTGCT 360 GCTGAGCGCC ACCGTACTGC CCTTCTCGGC CACCATGGAG GTTCTGGGCT TCTGGGCCTT 420 TGGCCGCGCC TTCTGCGACG TATGGGCCGC CGTGGACGTG CTGTGCTGCA CGGCCTCCAT 480 CCTCAGCCTC TGCACCATCT CCGTGGACCG GTACGTGGGC GTGCGCCACT CACTCAAGTA 540 CCCAGCCATC ATGACCGAGC GCAAGGCGGC CGCCATCCTG GCCCTGCTCT GGGTCGTAGC 600 CCTGGTGGTG TCCGTAGGGC CCCTGCTGGG CTGGAAGGAG CCCGTGCCCC CTGACGAGCG 660 CTTCTGCGGT ATCACCGAGG AGGCGGGCTA CGCTGTCTTC TCCTCCGTGT GCTCCTTCTA 720 CCTGCCCATG GCGGTCATCG TGGTCATGTA CTGCCGCGTG TACGTGGTCG CGCGCAGCAC 780 CACGCGCAGC CTCGAGGCAG GCGTCAAGCG CGAGCGAGGC AAGGCCTCCG AGGTGGTGCT 8 0 GCGCATCCAC TGTCGCGGCG CGGCCACGGG CGCCGACGGG GCGCACGGCA TGCGCAGCGC 900 CAAGGGCCAC ACCTTCCGCA GCTCGCTCTC CGTGCGCCTG CTCAAGTTCT CCCGTGAGAA 960 GAAAGCGGCC AAGACTCTGG CCATCGTCGT GGGTGTCTTC GTCCTCTGCT GGTTCCCTTT 1020 CTTCTTTGTC CTGCCGCTCG GCTCCTTGTT CCCGCAGCTG AAGCCATCGG AGGGCGTCTT 1080 CAAGGTCATC TTCTGGCTCG GCTACTTCAA CAGCTGCGTG AACCCGCTCA TCTACCCCTG 1140 TTCCAGCCGC GAGTTCAAGC GCGCCTTCCT CCGTCTCCTG CGCTGCCAGT GCCGTCGTCG 1200 CCGGCGCCGC CGCCCTCTCT GGCGTGTCTA CGGCCACCAC TGGCGGGCCT CCACCAGCGG 1260 CCTGCGCCAG GACTGCGCCC CGAGTTCGGG CGACGCGCCC CCCGGAGCGC CGCTGGCCCT 1320 CACCGCGCTC CCCGACCCCG ACCCCGAACC CCCAGGCACG CCCGAGATGC AGGCTCCGGT 1380 CGCCAGCCGT CGAAGCCACC CAGCGCCTTC CGCGAGTGGA GGCTGCTGGG GCCGTTCCGG 1440 AGACCCACGA CCCAGCTGCG CGCCAAAGTC GCCAGCCTGT CGCACAAGAT CGCCGCCGGG 1500 GGCGCGCAGC GCGCAGAGGC AGCGTGCGCC CAGCGCTCAG AGGTGGAGGC TGTGTCCCTA 1560 GGCGTCCCAC ACGAGGTGGC CGAGGGCGCC ACCTGCCAGG CCTACGAATT GGCCGACTAC 1620 A 1621 (2) INFORMATION FOR SEQ ID NO:14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 501 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (v) FRAGMENT TYPE: N-terminal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: Met Ala Ala Ala Leu Arg Ser Val Met Met Ala Gly Tyr Leu Ser Glu 1 5 10 15 Trp Arg Thr Pro Thr Tyr Arg Ser Thr Glu Met Val Gin Arg Leu Arg 20 25 30 Met Glu Ala Val Gin His Ser Thr Ser Thr Ala Ala Val Gly Gly Leu 35 40 45 Val Val Ser Ala Gin Gly Val Gly Val Gly Val Phe Leu Ala Ala Phe 50 55 60 He Leu Met Ala Val Ala Gly Asn Leu Leu Val He Leu Ser Val Ala 65 70 75 80 Cys Asn Arg His Leu Gin Thr Val Thr Asn Tyr Phe He Val Asn Leu 85 90 95 Ala Val Ala Asp Leu Leu Leu Ser Ala Thr Val Leu Pro Phe Ser Ala 100 105 110 Thr Met Glu Val Leu Gly Phe Trp Ala Phe Gly Arg Ala Phe Cys Asp 115 120 125 Val Trp Ala Ala Val Asp Val Leu Cys Cys Thr Ala Ser He Leu Ser 130 135 140 Leu Cys Thr He Ser Val Asp Arg Tyr Val Gly Val Arg His Ser Leu 145 150 155 160 Lys Tyr Pro Ala He Met Thr Glu Arg Lys Ala Ala Ala He Leu Ala 165 170 175 Leu Leu Trp Val Val Ala Leu Val Val Ser Val Gly Pro Leu Leu Gly 180 185 190 Trp Lys Glu Pro Val Pro Pro Asp Glu Arg Phe Cys Gly He Thr Glu 195 200 205 Glu Ala Gly Tyr Ala Val Phe Ser Ser Val Cys Ser Phe Tyr Leu Pro 210 215 220 Met Ala Val He Val Val Met Tyr Cys Arg Val Tyr Val Val Ala Arg 225 230 235 240 Ser Thr Thr Arg Ser Leu Glu Ala Gly Val Lys Arg Glu Arg Gly Lys 245 250 255 Ala Ser Glu Val Val Leu Arg He His Cys Arg Gly Ala Ala Thr Gly 260 265 270 Ala Asp Gly Ala His Gly Met Arg Ser Ala Lys Gly His Thr Phe Arg 275 280 285 Ser Ser Leu Ser Val Arg Leu Leu Lys Phe Ser Arg Glu Lys Lys Ala 290 295 300 Ala Lys Thr Leu Ala He Val Val Gly Val Phe Val Leu Cys Trp Phe 305 310 315 320 Pro Phe Phe Phe Val Leu Pro Leu Gly Ser Leu Phe Pro Gin Leu Lys 325 330 335 Pro Ser Glu Gly Val Phe Lys Val He Phe Trp Leu Gly Tyr Phe Asn 340 345 350 Ser Cys Val Asn Pro Leu He Tyr Pro Cys Ser Ser Arg Glu Phe Lys 355 360 365 Arg Ala Phe Leu Arg Leu Leu Arg Cys Gin Cys Arg Arg Arg Arg Arg 370 375 380 Arg Arg Pro Leu Trp Arg Val Tyr Gly His His Trp Arg Ala Ser Thr 385 390 395 400 Ser Gly Leu Arg Gin Asp Cys Ala Pro Ser Ser Gly Asp Ala Pro Pro 405 410 415 Gly Ala Pro Leu Ala Leu Thr Ala Leu Pro Asp Pro Asp Pro Glu Pro 420 425 430 Pro Gly Thr Pro Glu Met Gin Ala Pro Val Ala Ser Arg Arg Ser His 435 440 445 Pro Ala Pro Ser Ala Ser Gly Gly Cys Trp Gly Arg Ser Gly Asp Pro 450 455 460 Arg Pro Ser Cys Ala Pro Lys Ser Pro Ala Cys Arg Thr Arg Ser Pro 465 470 475 480 Pro Gly Ala Arg Ser Ala Gin Arg Gin Arg Ala Pro Ser Ala Gin Arg 485 490 495 Trp Arg Leu Cys Pro 500 (2) INFORMATION FOR SEQ ID NO:15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 24 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15: TCTAGACCAT GAAYCCNGAY CTGG 24 (2) INFORMATION FOR SEQ ID NO:16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16: TTTGAATTCA CATWCCGACY ACAATGCCC 29 (2) INFORMATION FOR SEQ ID NO:17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 921 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: both (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17: TCTAGACCAT GAATCCCGAC CTGGACACCG GCCACAACAC ATCAGCACCT GCCCACTGGG 60 GAGAGTTGAA AAATGCCAAC TTCACTGGCC CCAACCAGAC CTCGAGCAAC TCCACACTGC 120 CCCAGCTGGA CATCACCAGG GCCATCTCTG TGGGCCTGGT GCTGGGCGCC TTCATCCTCT 180 TTGCCATCGT GGGCAACATC CTAGTCATCT TGTCTGTGGC CTGCAACCGG CACCTGCGGA 240 CGCCCACCAA CTACTTCATT GTCAACCTGG CCATGGCCGA CCTGCTGTTG AGCTTCACCG 300 TCCTGCCCTT CTCAGCGGCC CTAGAGGTGC TCGGCTACTG GGTGCTGGGG CGGATCTTCT 360 GTGACATCTG GGCAGCCGTG GATGTCCTGT GCTGCACAGC GTCCATTCTG AGCCTGTGCG 420 CCATCTCCAT CGATCGCTAC ATCGGGGTGC GCTACTCTCT GCAGTATCCC ACGCTGGTCA 480 CCCGGAGGAA GGCCATCTTG GCCCTGCTCA GTGTCTGGGT CTTGTCCACC GTCATCTCCA 540 TCGGGCCTCT CCTTGGGTGG AAGGAGCCGG CACCCAACGA TGACAAGGAG TGCGGGGTCA 600 CCGAAGAACC CTTCTATGCC CTCTTCTCCT CTCTGGGCTC CTTCTACATC CCTCTGGCGG 660 TCATTCTAGT CATGTACTGC CGTGTCTATA TAGTGGCCAA GAGAACCACC AAGAACCTAG 720 AGGCAGGAGT CATGAAGGAG ATGTCCAACT CCAAGGAGCT GACCCTGAGG ATCCATTCCA 780 AGAACTTTCA CGAGGACACC CTTAGCAGTA CCAAGGCCAA GGGCCACAAC CCCAGGAGTT 840 CCATAGCTGT CAAACTTTTT AAGTTCTCCA GGGAAAAGAA AGCAGCTAAG ACGTTGGGCA 900 TTGTGGTCGG TATGTGAATT C 921 (2) INFORMATION FOR SEQ ID NO:18: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18: GAAGGCGCGC TTGAACTC 18 (2) INFORMATION FOR SEQ ID NO:19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: " NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: AGAGAACCAC CAAGAACC 18 (2) INFORMATION FOR SEQ ID NO:20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 389 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: both (D) TOPOLOGY: both (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20: AAGAGAACCA CCAAGAACCT AGAGGCAGGA GTCATGAAGG AGATGTCCAA CTCCAAGGAG 60 CTGACCCTGA GGATCCATTC CAAGAACTTT CACGAGGACA CCCTTAGCAG TACCAAGGCC 120 AAGGGCCACA ACCCCAGGAG TTCCATAGCT GTCAAACTTT TTAAGTTCTC CAGGGAAAAG 180 AAAGCAGCTA AGACGTTGGG CATTGTGGTC GGTATGTTCA TCTTGTGCTG GCTACCCTTC 240 TTCATCGCTC TACCGCTTGG CTCCTTGTTC TCCACCCTGA AGCCCCCCGA CGCCGTGTTC 300 AAGGTGGTGT TCTGGCTGGG CTACTTCAAC AGCTGCCTCA ACCCCATCAT CTACCCATGC 360 TCCAGCAAGG AGTTCAAGCG CGCTTTCGT 389 (2) INFORMATION FOR SEQ ID NO:21: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 27 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21: TTTGAATTCA TGTTCAAGGT GGTGTTC 27 (2) INFORMATION FOR SEQ ID NO:22: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 35 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: TTTGAATTCT AAAASTGNCC NGGNSCCAGN GGCAT 35 (2) INFORMATION FOR SEQ ID NO:23: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 582 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: both (D) TOPOLOGY: both (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: GAATTCATGA TTCAAGGTGG TGTTCTGGCT GGGCTACTTC AACAGCTGCC TCAATCCCAT 60 CATCTACCCG TGCTCCAGCA AGGAGTTCAA GCGCGCCTTC ATGCGTATCC TTGGGTGCCA 120 GTGCCGCGGT GGCCGCCGCC GCCGCCGCCG TCGCCGTCTA GGCGCGTGCG CTTACACCTA 180 CCGGCCGTGG ACCCGCGGCG GCTCGCTGGA GAGATCACAG TCGCGGAAGG ACTCTCTGGA 240 TGACAGCGGC AGCTGCATGA GCGGCCAGAA GAGGACCCTG CCCTCGGCGT CGCCCAGCCC 300 GGGCTACCTG GGTCGAGGAA CGCAGCCACC CGTGGAGCTG TGCGCCTTCC CCGAGTGGAA 360 ACCCGGGGCG CTGCTCAGCT TGCCAGAGCC TCCTGGCCGC CGCGGCCGTC TCGACTCTGG 420 GCCACTCTTC ACCTTCAAGC TCCTGGGCGA TCCTGAGAGC CCGGGAACCG AAGCGACAGC 480 CAGCAACGGG GGCTGCGACA CCACGACCGA CCTGGCCAAC GGGCAGCCCG GCTTCAAGAG 540 CAACATGCCC CTGGGCCCGG GCCACTTTTA AAAGCCGAAT TC 582 (2) INFORMATION FOR SEQ ID NO:24: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1567 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: both (D) TOPOLOGY: both (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24: TCTAGACCAT GAATCCCGAC CTGGACACCG GCCACAACAC ATCAGCACCT GCCCACTGGG 60 GAGAGTTGAA AAATGCCAAC TTCACTGGCC CCAACCAGAC CTCGAGCAAC TCCACACTGC 120 CCCAGCTGGA CATCACCAGG GCCATCTCTG TGGGCCTGGT GCTGGGCGCC TTCATCCTCT 180 TTGCCATCGT GGGCAACATC CTAGTCATCT TGTCTGTGGC CTGCAACCGG CACCTGCGGA 240 CGCCCACCAA CTACTTCATT GTCAACCTGG CCATGGCCGA CCTGCTGTTG AGCTTCACCG 300 TCCTGCCCTT CTCAGCGGCC CTAGAGGTGC TCGGCTACTG GGTGCTGGGG CGGATCTTCT 360 GTGACATCTG GGCAGCCGTG GATGTCCTGT GCTGCACAGC GTCCATTCTG AGCCTGTGCG 420 CCATCTCCAT CGATCGCTAC ATCGGGGTGC GCTACTCTCT GCAGTATCCC ACGCTGGTCA 480 CCCGGAGGAA GGCCATCTTG GCCCTGCTCA GTGTCTGGGT CTTGTCCACC GTCATCTCCA 540 TCGGGCCTCT CCTTGGGTGG AAGGAGCCGG CACCCAACGA TGACAAGGAG TGCGGGGTCA 600 CCGAAGAACC CTTCTATGCC CTCTTCTCCT CTCTGGGCTC CTTCTACATC CCTCTGGCGG 660 TCATTCTAGT CATGTACTGC CGTGTCTATA TAGTGGCCAA GAGAACCACC AAGAACCTAG 720 AGGCAGGAGT CATGAAGGAG ATGTCCAACT CCAAGGAGCT GACCCTGAGG ATCCATTCCA 780 AGAACTTTCA CGAGGACACC CTTAGCAGTA CCAAGGCCAA GGGCCACAAC CCCAGGAGTT 840 CCATAGCTGT CAAACTTTTT AAGTTCTCCA GGGAAAAGAA AGCAGCTAAG ACGTTGGGCA 900 TTGTGGTCGG TATGTTCATC TTGTGCTGGC TACCCTTCTT CATCGCTCTA CCGCTTGGCT 960 CCTTGTTCTC CACCCTGAAG CCCCCCGACG CCGTGTTCAA GGTGGTGTTC TGGCTGGGCT 1020 ACTTCAACAG CTGCCTCAAC CCCATCATCT ACCCATGCTC CAGCAAGGAG TTCAAGCGCG 1080 CCTTCATGCG TATCCTTGGG TGCCAGTGCC GCGGTGGCCG CCGCCGCCGC CGCCGTCGCC 1140 GTCTAGGCGC GTGCGCTTAC ACCTACCGGC CGTGGACCCG CGGCGGCTCG CTGGAGAGAT 1200 CACAGTCGCG GAAGGACTCT CTGGATGACA GCGGCAGCTG CATGAGCGGC CAGAAGAGGA 1260 CCCTGCCCTC GGCGTCGCCC AGCCCGGGCT ACCTGGGTCG AGGAACGCAG CCACCCGTGG 1320 AGCTGTGCGC CTTCCCCGAG TGGAAACCCG GGGCGCTGCT CAGCTTGCCA GAGCCTCCTG 1380 GCCGCCGCGG CCGTCTCGAC TCTGGGCCAC TCTTCACCTT CAAGCTCCTG GGCGATCCTG 1440 AGAGCCCGGG AACCGAAGCG ACAGCCAGCA ACGGGGGCTG CGACACCACG ACCGACCTGG 1500 CCAACGGGCA GCCCGGCTTC AAGAGCAACA TGCCCCTGGG CCCGGGCCAC TTTTAAAAGC 1560 CGAATTC 1567 (2) INFORMATION FOR SEQ ID NO:25: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 515 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (v) FRAGMENT TYPE: N-terminal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25: Met Asn Pro Asp Leu Asp Thr Gly His Asn Thr Ser Ala Pro Ala His 1 5 10 15 Trp Gly Glu Leu Lys Asn Ala Asn Phe Thr Gly Pro Asn Gin Thr Ser 20 25 30 Ser Asn Ser Thr Leu Pro Gin Leu Asp He Thr Arg Ala He Ser Val 35 40 45 Gly Leu Val Leu Gly Ala Phe He Leu Phe Ala He Val Gly Asn He 50 55 60 Leu Val He Leu Ser Val Ala Cys Asn Arg His Leu Arg Thr Pro Thr 65 70 75 80 Asn Tyr Phe He Val Asn Leu Ala Met Ala Asp Leu Leu Leu Ser Phe 85 90 95 Thr Val Leu Pro Phe Ser Ala Ala Leu Glu Val Leu Gly Tyr Trp Val 100 105 110 Leu Gly Arg He Phe Cys Asp He Trp Ala Ala Val Asp Val Leu Cys 115 120 125 Cys Thr Ala Ser He Leu Ser Leu Cys Ala He Ser He Asp Arg Tyr 130 135 140 He Gly Val Arg Tyr Ser Leu Gin Tyr Pro Thr Leu Val Thr Arg Arg 145 150 155 160 Lys Ala He Leu Ala Leu Leu Ser Val Trp Val Leu Ser Thr Val He 165 170 175 Ser He Gly Pro Leu Leu Gly Trp Lys Glu Pro Ala Pro Asn Asp Asp 180 185 190 Lys Glu Cys Gly Val Thr Glu Glu Pro Phe Tyr Ala Leu Phe Ser Ser 195 200 205 Leu Gly Ser Phe Tyr He Pro Leu Ala Val He Leu Val Met Tyr Cys 210 215 220 Arg Val Tyr He Val Ala Lys Arg Thr Thr Lys Asn Leu Glu Ala Gly 225 230 235 240 Val Met Lys Glu Met Ser Asn Ser Lys Glu Leu Thr Leu Arg He His 245 250 255 Ser Lys Asn Phe His Glu Asp Thr Leu Ser Ser Thr Lys Ala Lys Gly 260 265 270 His Asn Pro Arg Ser Ser He Ala Val Lys Leu Phe Lys Phe Ser Arg 275 280 285 Glu Lys Lys Ala Ala Lys Thr Leu Gly He Val Val Gly Met Phe He 290 295 300 Leu Cys Trp Leu Pro Phe Phe He Ala Leu Pro Leu Gly Ser Leu Phe 305 310 315 320 Ser Thr Leu Lys Pro Pro Asp Ala Val Phe Lys Val Val Phe Trp Leu 325 330 335 Gly Tyr Phe Asn Ser Cys Leu Asn Pro He He Tyr Pro Cys Ser Ser 340 345 350 ' Lys Glu Phe Lys Arg Ala Phe Met Arg He Leu Gly Cys Gin Cys Arg 355 360 365 Gly Gly Arg Arg Arg Arg Arg Arg Arg Arg Leu Gly Ala Cys Ala Tyr 370 375 380 Thr Tyr Arg Pro Trp Thr Arg Gly Gly Ser Leu Glu Arg Ser Gin Ser 385 390 395 400 Arg Lys Asp Ser Leu Asp Asp Ser Gly Ser Cys Met Ser Gly Gin Lys 405 410 415 Arg Thr Leu Pro Ser Ala Ser Pro Ser Pro Gly Tyr Leu Gly Arg Gly 420 425 430 Thr Gin Pro Pro Val Glu Leu Cys Ala Phe Pro Glu Trp Lys Pro Gly 435 440 445 Ala Leu Leu Ser Leu Pro Glu Pro Pro Gly Arg Arg Gly Arg Leu Asp 450 455 460 Ser Gly Pro Leu Phe Thr Phe Lys Leu Leu Gly Asp Pro Glu Ser Pro 465 470 475 480 Gly Thr Glu Ala Thr Ala Ser Asn Gly Gly Cys Asp Thr Thr Thr Asp 485 490 495 Leu Ala Asn Gly Gin Pro Gly Phe Lys Ser Asn Met Pro Leu Gly Pro 500 505 510 Gly His Phe 515 (2) INFORMATION FOR SEQ ID NO:26: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1987 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: both (D) TOPOLOGY: both (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26: GAATTCCCTC CTAGAAGCTG GAGAGAGCAG GAGCCTTCGG TGGGGCAGCT CAAAATGTAG 60 GTAACTGCGG GCCAGGAGCA GCGCCCAGAT GCCATCGGTC CCTGCCTTTG AGCGTCGACG 120 GCTGATCTTT TGGTTTGAGG GAGAGACTGG CGCTGGAGTT TTGAATTCCG AATCATGTGC 180 AGAATCGTGA ATCTTCCCCC AGCCAGGACG AATAAGACAG CGCGGAAAAG CAGATTCTCG 240 TAATTCTGGA ATTGCATGTT GCAAGGAGTC TCCTGGATCT TCGCACCCAG CTTCGGGTAC 300 GGGAGGGAGT CCGGGTCCCG GCTAGGCCAG CCCGCAGGTG GAGAGGGTCC CCGGCAGCCC 360 CGCGCGCCCC TGGCCATGTC TTTAATGCCC TGCCCCTTCA TGTGGCCTTC TGAGGGTTCC 420 CAGGGCTGGC CAGGGTTGTC TCCCACCCGC GCGCGCCGTC TCACCCCCAG CCAAACCCAC 480 CTGGCAGGGC TCCCTCCAGA AGAGACCTTT TGATTCCCGG CTCCCGCGCT CCCGCCTCCG 540 CGCCAGCCCG GGAGGTGGCC CTGGACAGCC GGACCTCGCC CGGCCCCGGC TGGGACCATG 600 GTGTTTCTCT CGGGAAATGC TTCCGACAGC TCCAACTGCA CCCAACCGCC GGCACCGGTG 660 AACATTTCCA AGGCCATTCT GCTCGGGGTG ATCTTGGGGG GCCTCATTCT TTTCGGGGTG 720 CTGGGTAACA TCCTAGTGAT CCTCTCCGTA GCCTGTCACC GACACCTGCA CTCAGTCACG 780 CACTACTACA TCGTCAACCG CTAGTGGCGG TGGCCGACCT CCTGCTCACC TCCACGGTGC 840 TGCCCTTCTC CGCCATCTTC GAGGTCCTAG GCTACTGGGC CTTCGGCAGG GTCTTCTGCA 900 ACATCTGGGC GGCAGTGGAT GTGCTGTGCT GCACCGCGTC CATCATGGGC CTCTGCATCA 960 TCTCCATCGA CCGCTACATC GGCGTGAGCT ACCCGCTGCG CTACCCAACC ATCGTCACCC 1020 AGAGGAGGGG TCTCATGGCT CTGCTCTGCG TCTGGGCACT CTCCCTGGTC ATATCCATTG 1080 GACCCCTCTT CGGCTGGAGG CAGCCGGCCC CCGAGGACGA GACCATCTGC CAGATCAACG 1140 AGGAGCCGGG CTACGTGCTC TTCTCGGCTC TGGGCTCCTT CTACCTGCCT CTGGCCATCA 1200 TCCTGGTCAT GTACTGCCGC GTCTACGTGG TGGCCAAGAG GGAGAGCCGG GGCCTCAAGT 1260 CTGGCCTCAA GACCGACAAG TCGGACTCGG AGCAAGTGAC GCTCCGCATC CATCGGAAAA 1320 ACGCCCCGGC AGGAGGCAGC GGGATGGCCA GCGCCAAGAC CAAGACGCAC TTCTCAGTGA 1380 GGCTCCTCAA GTTCTCCCGG GAGAAGAAAG CGGCCAAAAC GCTGGGCATC GTGGTCGGCT 1440 GCTTCGTCCT CTGCTGGCTG CCTTTTTTCT TAGTCATGCC CATTGGGTCT TTCTTCCCTG 1500 ATTTCAAGCC CTCTGAAACA GTTTTTAAAA TAGTATTTTG GCTCGGATAT CTAAACAGCT 1560 GCATCAACCC CATCATATAC CCATGCTCCA GCCAAGAGTT CAAAAAGGCC TTTCAGAATG 1620 TCTTGAGAAT CCAGTGTCTC CGCAGAAAGC AGTCGCTAGT TCCAAACATG CCCTGGGCTA 1680 CACCCTGCAC CCGCCCAGCC AGGCCGTGGA AGGGCAACAC AAGGACATGG TGCGCATCCC 1740 CGTGGGATCA AGAGAGACCT TCTACAGGAT CTCCAAGACG GATGGCGTTT GTGAATGGAA 1800 ATTTTTCTCT TCCATGCCCC GTGGATCTGC CAGGATTACA GTGTCCAAAG ACCAATCCTC 1860 CTGTACCACA GCCCGGGTGA GAAGTAAAAG CTTTTTGCAG GTCTGCTGCT GTGTAGGGCC 1920 CTCAACCCCC AGCCTTGACA AGAACCATCA AGTTCCAACC ATTAAGGTCC ACACCATCTC 1980 CCTCAGT 1987 (2) INFORMATION FOR SEQ ID NO:27: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1997 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: both (D) TOPOLOGY: both (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27: AATTCCCTCC TAGAAGCTGG AGAGAGCAGG AGCCTTCGGT GGGGCAGCTC AAAATGTAGG 60 TAACTGCGGG CCAGGAGCAG CGCCCAGATG CCATCGGTCC CTGCCTTTGA GCGTCGACGG 120 CTGATCTTTT GGTTTGAGGG AGAGACTGGC GCTGGAGTTT TGAATTCCGA ATCATGTGCA 180 GAATCGTGAA TCTTCCCCCA GCCAGGACGA ATAAGACAGC GCGGAAAAGC AGATTCTCGT 240 AATTCTGGAA TTGCATGTTG CAAGGAGTCT CCTGGATCTT CGCACCCAGC TTCGGGTACG 300 GGAGGGAGTC CGGGTCCCGG CTAGGCCAGC CCGCAGGTGG AGAGGGTCCC CGGCAGCCCC 360 GCGCGCCCCT GGCCATGTCT TTAATGCCCT GCCCCTTCAT GTGGCCTTCT GAGGGTTCCC 420 AGGGCTGGCC AGGGTTGTCT CCCACCCGCG CGCGCCGTCT CACCCCCAGC CAAACCCACC 480 TGGCAGGGCT CCCTCCAGAA GAGACCTTTT GATTCCCGGC TCCCGCGCTC CCGCCTCCGC 540 GCCAGCCCGG GAGGTGGCCC TGGACAGCCG GACCTCGCCC GGCCCCGGCT GGGACCATGG 600 TGTTTCTCTC GGGAAATGCT TCCGACAGCT CCAACTGCAC CCAACCGCCG GCACCGGTGA 660 ACATTTCCAA GGCCATTCTG CTCGGGGTGA TCTTGGGGGG CCTCATTCTT TTCGGGGTGC 720 TGGGTAACAT CCTAGTGATC CTCTCCGTAG CCTGTCACCG ACACCTGCAC TCAGTCACGC 780 ACTACTACAT CGTCAACCTG GCGGTGGCCG ACCTCCTGCT CACCTCCACG GTGCTGCCCT 840 TCTCCGCCAT CTTCGAGGTC CTAGGCTACT GGGCCTTCGG CAGGGTCTTC TGCAACATCT 900 GGGCGGCAGT GGATGTGCTG TGCTGCACCG CGTCCATCAT GGGCCTCTGC ATCATCTCCA 960 TCGACCGCTA CATCGGCGTG AGCTACCCGC TGCGCTACCC AACCATCGTC ACCCAGAGGA 1020 GGGGTCTCAT GGCTCTGCTC TGCGTCTGGG CACTCTCCCT GGTCATATCC ATTGGACCCC 1080 TCTTCGGCTG GAGGCAGCCG GCCCCCGAGG ACGAGACCAT CTGCCAGATC AACGAGGAGC 1140 CGGGCTACGT GCTCTTCTCG GCTCTGGGCT CCTTCTACCT GCCTCTGGCC ATCATCCTGG 1200 TCATGTACTG CCGCGTCTAC GTGGTGGCCA AGAGGGAGAG CCGGGGCCTC AAGTCTGGCC 1260 TCAAGACCGA CAAGTCGGAC TCGGAGCAAG TGACGCTCCG CATCCATCGG AAAAACGCCC 1320 CGGCAGGAGG CAGCGGGATG GCCAGCGCCA AGACCAAGAC GCACTTCTCA GTGAGGCTCC 1380 TCAAGTTCTC CCGGGAGAAG AAAGCGGCCA AAACGCTGGG CATCGTGGTC GGCTGCTTCG 1440 TCCTCTGCTG GCTGCCTTTT TTCTTAGTCA TGCCCATTGG GTCTTTCTTC CCTGATTTCA 1500 AGCCCTCTGA AACAGTTTTT AAAATAGTAT TTTGGCTCGG ATATCTAAAC AGCTGCATCA 1560 ACCCCATCAT ATACCCATGC TCCAGCCAAG AGTTCAAAAA GGCCTTTCAG AATGTCTTGA 1620 GAATCCAGTG TCTCTGCAGA AAGCAGTCTT CCAAACATGC CCTGGGCTAC ACCCTGCACC 1680 CGCCCAGCCA GGCCGTGGAA GGGCAACACA AGGACATGGT GCGCATCCCC GTGGGATCAA 1740 GAGAGACCTT CTACAGGATC TCCAAGACGG ATGGCGTTTG TGAATGGAAA TTTTTCTCTT 1800 CCATGCCCCG TGGATCTGCC AGGATTACAG TGTCCAAAGA CCAATCCTCC TGTACCACAG 1860 CCCGGGTGAG AAGTAAAAGC TTTTTGCAGG TCTGCTGCTG TGTAGGGCCC TCAACCCCCA 1920 GCCTTGACAA GAACCATCAA GTTCCAACCA TTAAGGTCCA CACCATCTCC CTCAGTGAGA 1980 ACGGGGAGGA AGTCTAG 1997 (2) INFORMATION FOR SEQ ID NO:28: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 466 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (v) FRAGMENT TYPE: N-terminal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28: Met Val Phe Leu Ser Gly Asn Ala Ser Asp Ser Ser Asn Cys Thr Gin 1 5 10 15 Pro Pro Ala Pro Val Asn He Ser Lys Ala He Leu Leu Gly Val He 20 25 30 Leu Gly Gly Leu He Leu Phe Gly Val Leu Gly Asn He Leu Val He 35 40 45 Leu Ser Val Ala Cys His Arg His Leu His Ser Val Thr His Tyr Tyr 50 55 60 He Val Asn Leu Ala Val Ala Asp Leu Leu Leu Thr Ser Thr Val Leu 65 70 75 80 Pro Phe Ser Ala He Phe Glu Val Leu Gly Tyr Trp Ala Phe Gly Arg 85 90 95 Val Phe Cys Asn He Trp Ala Ala Val Asp Val Leu Cys Cys Thr Ala 100 105 110 Ser He Met Gly Leu Cys He He Ser He Asp Arg Tyr He Gly Val 115 120 125 Ser Tyr Pro Leu Arg Tyr Pro Thr He Val Thr Gin Arg Arg Gly Leu 130 135 140 Met Ala Leu Leu Cys Val Trp Ala Leu Ser Leu Val He Ser He Gly 145 150 155 160 Pro Leu Phe Gly Trp Arg Gin Pro Ala Pro Glu Asp Glu Thr He Cys 165 170 175 Gin He Asn Glu Glu Pro Gly Tyr Val Leu Phe Ser Ala Leu Gly Ser 180 185 190 Phe Tyr Leu Pro Leu Ala He He Leu Val Met Tyr Cys Arg Val Tyr 195 200 205 Val Val Ala Lys Arg Glu Ser Arg Gly Leu Lys Ser Gly Leu Lys Thr 210 215 220 Asp Lys Ser Asp Ser Glu Gin Val Thr Leu Arg He His Arg Lys Asn 225 230 235 240 Ala Pro Ala Gly Gly Ser Gly Met Ala Ser Ala Lys Thr Lys Thr His 245 250 255 Phe Ser Val Arg Leu Leu Lys Phe Ser Arg Glu Lys Lys Ala Ala Lys 260 265 270 Thr Leu Gly He Val Val Gly Cys Phe Val Leu Cys Trp Leu Pro Phe 275 280 285 Phe Leu Val Met Pro He Gly Ser Phe Phe Pro Asp Phe Lys Pro Ser 290 295 300 Glu Thr Val Phe Lys He Val Phe Trp Leu Gly Tyr Leu Asn Ser Cys 305 310 315 320 He Asn Pro He He Tyr Pro Cys Ser Ser Gin Glu Phe Lys Lys Ala 325 330 335 Phe Gin Asn Val Leu Arg He Gin Cys Leu Cys Arg Lys Gin Ser Ser 340 345 350 Lys His Ala Leu Gly Tyr Thr Leu His Pro Pro Ser Gin Ala Val Glu 355 360 365 Gly Gin His Lys Asp Met Val Arg He Pro Val Gly Ser Arg Glu Thr 370 375 380 Phe Tyr Arg He Ser Lys Thr Asp Gly Val Cys Glu Trp Lys Phe Phe 385 390 395 400 Ser Ser Met Pro Arg Gly Ser Ala Arg He Thr Val Ser Lys Asp Gin 405 410 415 Ser Ser Cys Thr Thr Ala Arg Val Arg Ser Lys Ser Phe Leu Gin Val 420 425 430 Cys Cys Cys Val Gly Pro Ser Thr Pro Ser Leu Asp Lys Asn His Gin 435 440 445 Val Pro Thr He Lys Val His Thr He Ser Leu Ser Glu Asn Gly Glu 450 455 460 Glu Val 465 (2) INFORMATION FOR SEQ ID NO:29: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1776 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: both (D) TOPOLOGY: both (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: CTCCCTGCCG GCCGCTCGTT CTGTGCCCCG GCCCGGCCAC CGACGGCCGG CGTTGAGATG 60 ACTTTCCGCG ATCTCCTGAG CGTCAGTTTC GAGGGACCCC GCCCGGACAG CAGCGCAGGG 120 GGCTCCAGCG CGGGCGGCGG CGGGGGCGGC GCGGGCGGCG CGGCCCCCTC GGAGGGCCCG 180 GCGGTGGGCG GCGTGCCGGG GGGCGCGGGC GGCGGCGGCG GCGTGGTGGG CGCAGGCAGC 240 GGCGAGGACA ACCGGAGCTC CGCGGGGGAG CCGGGGAGCG CGGGCGCGGG CGGCGACGTG 300 AATGGCACGG CGGCCGTCGG GGGACTGGTG GTGAGCGCGC AGGGCGTGGG CGTGGGCGTC 360 TTCCTGGCAG CCTTCATCCT TATGGCCGTG GCAGGTAACC TGCTTGTCAT CCTCTCAGTG 420 GCCTGCAACC GCCACCTGCA GACCGTCACC AACTATTTCA TCGTGAACCT GGCCGTGGCC 480 GACCTGCTGC TGAGCGCCAC CGTACTGCCC TTCTCGGCCA CCATGGAGGT TCTGGGCTTC 540 TGGGCCTTTG GCCGCGCCTT CTGCGACGTA TGGGCCGCCG TGGACGTGCT GTGCTGCACG 600 GCCTCCATCC TCAGCCTCTG CACCATCTCC GTGGACCGGT ACGTGGGCGT GCGCCACTCA 660 CTCAAGTACC CAGCCATCAT GACCGAGCGC AAGGCGGCCG CCATCCTGGC CCTGCTCTGG 720 GTCGTAGCCC TGGTGGTGTC CGTAGGGCCC CTGCTGGGCT GGAAGGAGCC CGTGCCCCCT 780 GACGAGCGCT TCTGCGGTAT CACCGAGGAG GCGGGCTACG CTGTCTTCTC CTCCGTGTGC 840 TCCTTCTACC TGCCCATGGC GGTCATCGTG GTCATGTACT GCCGCGTGTA CGTGGTCGCG 900 CGCAGCACCA CGCGCAGCCT CGAGGCGGGC GTCAAGCGCG AGCGAGGCAA GGCCTCCGAG 960 GTGGTGCTGC GCATCCACTG TCGCGGCGCG GCCACGGGCG CCGACGGGGC GCACGGCATG 1020 CGCAGCGCCA AGGGCCACAC CTTCCGCAGC TCGCTCTCCG TGCGCCTGCT CAAGTTCTCC 1080 CGTGAGAAGA AAGCGGCCAA GACTCTGGCC ATCGTCGTGG GTGTCTTCGT GCTCTGCTGG 1140 TTCCCTTTCT TCTTTGTCCT GCCGCTCGGC TCCTTGTTCC CGCAGCTGAA GCCATCGGAG 1200 GGCGTCTTCA AGGTCATCTT CTGGCTCGGC TACTTCAACA GCTGCGTGAA CCCGCTCATC 1260 TACCCCTGTT CCAGCCGCGA GTTCAAGCGC GCCTTCCTCC GTCTCCTGCG CTGCCAGTGC 1320 CGTCGTCGCC GGCGCCGCCG CCCTCTCTGG CGTGTCTACG GCCACCACTG GCGGGCCTCC 1380 ACCAGCGGCC TGCGCCAGGA CTGCGCCCCG AGTTCGGGCG ACGCGCCCCC CGGAGCGCCG 1440 CTGGCCCTCA CCGCGCTCCC CGACCCCGAC CCCGAACCCC CAGGCACGCC CGAGATGCAG 1500 GCTCCGGTCG CCAGCCGTCG AAAGCCACCC AGCGCCTTCC GCGAGTGGAG GCTGCTGGGG 1560 CCGTTCCGGA GACCCACGAC CCAGCTGCGC GCCAAAGTCT CCAGCCTGTC GCACAAGATC 1620 CGCGCCGGGG GCGCGCAGCG CGCAGAGGCA GCGTGCGCCC AGCGCTCAGA GGTGGAGGCT 1680 GTGTCCCTAG GCGTCCCACA CGAGGTGGCC GAGGGCGCCA CCTGCCAGGC CTACGAATTG 1740 GCCGACTACA GCAACCTACG GGAGACCGAT ATTTAA 1776 (2) INFORMATION FOR SEQ ID NO:30: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 572 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (v) FRAGMENT TYPE: N-terminal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30: Met Thr Phe Arg Asp Leu Leu Ser Val Ser Phe Glu Gly Pro Arg Pro 1 5 10 15 Asp Ser Ser Ala Gly Gly Ser Ser Ala Gly Gly Gly Gly Gly Gly Ala 20 25 30 Gly Gly Ala Ala Pro Ser Glu Gly Pro Ala Val Gly Gly Val Pro Gly 35 40 45 Gly Ala Gly Gly Gly Gly Gly Val Val Gly Ala Gly Ser Gly Glu Asp 50 55 60 Asn Arg Ser Ser Ala Gly Glu Pro Gly Ser Ala Gly Ala Gly Gly Asp 65 70 75 80 Val Asn Gly Thr Ala Ala Val Gly Gly Leu Val Val Ser Ala Gin Gly 85 90 95 Val Gly Val Gly Val Phe Leu Ala Ala Phe He Leu Met Ala Val Ala 100 105 110 Gly Asn Leu Leu Val He Leu Ser Val Ala Cys Asn Arg His Leu Gin 115 120 125 Thr Val Thr Asn Tyr Phe He Val Asn Leu Ala Val Ala Asp Leu Leu 130 135 140 Leu Ser Ala Thr Val Leu Pro Phe Ser Ala Thr Met Glu Val Leu Gly 145 150 155 160 Phe Trp Ala Phe Gly Arg Ala Phe Cys Asp Val Trp Ala Ala Val Asp 165 170 175 Val Leu Cys Cys Thr Ala Ser He Leu Ser Leu Cys Thr He Ser Val 180 185 190 Asp Arg Tyr Val Gly Val Arg His Ser Leu Lys Tyr Pro Ala He Met 195 200 205 Thr Glu Arg Lys Ala Ala Ala He Leu Ala Leu Leu Trp Val Val Ala 210 215 220 Leu Val Val Ser Val Gly Pro Leu Leu Gly Trp Lys Glu Pro Val Pro 225 230 235 240 Pro Asp Glu Arg Phe Cys Gly He Thr Glu Glu Ala Gly Tyr Ala Val 245 250 255 Phe Ser Ser Val Cys Ser Phe Tyr Leu Pro Met Ala Val He Val Val 260 265 270 Met Tyr Cys Arg Val Tyr Val Val Ala Arg Ser Thr Thr Arg Ser Leu 275 280 285 Glu Ala Gly Val Lys Arg Glu Arg Gly Lys Ala Ser Glu Val Val Leu 290 295 300 Arg He His Cys Arg Gly Ala Ala Thr Gly Ala Asp Gly Ala His Gly 305 310 315 320 Met Arg Ser Ala Lys Gly His Thr Phe Arg Ser Ser Leu Ser Val Arg 325 330 335 Leu Leu Lys Phe Ser Arg Glu Lys Lys Ala Ala Lys Thr Leu Ala He 340 345 350 Val Val Gly Val Phe Val Leu Cys Trp Phe Pro Phe Phe Phe Val Leu 355 360 365 Pro Leu Gly Ser Leu Phe Pro Gin Leu Lys Pro Ser Glu Gly Val Phe 370 375 380 Lys Val He Phe Trp Leu Gly Tyr Phe Asn Ser Cys Val Asn Pro Leu 385 390 395 400 He Tyr Pro Cys Ser Ser Arg Glu Phe Lys Arg Ala Phe Leu Arg Leu 405 410 415 Leu Arg Cys Gin Cys Arg Arg Arg Arg Arg Arg Arg Pro Leu Trp Arg 420 425 430 Val Tyr Gly His His Trp Arg Ala Ser Thr Ser Gly Leu Arg Gin Asp 435 440 445 Cys Ala Pro Ser Ser Gly Asp Ala Pro Pro Gly Ala Pro Leu Ala Leu 450 455 460 Thr Ala Leu Pro Asp Pro Asp Pro Glu Pro Pro Gly Thr Pro Glu Met 465 470 475 480 Gin Ala Pro Val Ala Ser Arg Arg Lys Pro Pro Ser Ala Phe Arg Glu 485 490 495 Trp Arg Leu Leu Gly Pro Phe Arg Arg Pro Thr Thr Gin Leu Arg Ala 500 505 510 Lys Val Ser Ser Leu Ser His Lys He Arg Ala Gly Gly Ala Gin Arg 515 520 525 Ala Glu Ala Ala Cys Ala Gin Arg Ser Glu Val Glu Ala Val Ser Leu 530 535 540 Gly Val Pro His Glu Val Ala Glu Gly Ala Thr Cys Gin Ala Tyr Glu 545 550 555 560 Leu Ala Asp Tyr Ser Asn Leu Arg Glu Thr Asp He 565 570 (2) INFORMATION FOR SEQ ID NO:31: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 16 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: both (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31: GAATCCCGAC CTGGAC 16 (2) INFORMATION FOR SEQ ID NO:32: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: both (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (Xi) SEQUENCE DESCRIPTION: SEQ ID NO:32: GGATCCTCAG GGTC 14 (2) INFORMATION FOR SEQ ID NO:33: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 19 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: both (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33: CCATGGTGTT TCTCTCGGG 19 (2) INFORMATION FOR SEQ ID NO:34: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: both (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO ( i) SEQUENCE DESCRIPTION: SEQ ID NO:34: GACGCGGCAG TACATGAC 18 (2) INFORMATION FOR SEQ ID NO:35: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 21 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: both (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35: GTCATGATGG CTGGGTACTT G 21

Claims: WHAT IS CLAIMED IS: A compound having the formula: and a pharmaceutically acceptable salt, prodrug, polymorph, or metabolite thereof wherein: n is an integer from 3 to 5; Y represents carbonyl, sulphonyl, -CO-CH2-, or -CO-NR 2-; R 2 is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted phenyl; E is carbonyl or sulphonyl; A, B, G, D are independently carbon or nitrogen; R -R4 are independently selected from the group consisting of hydrogen; halogen; nitro; amino; substituted or unsubstituted lower alkyl; perhalogenated lower alkyl; substituted or unsubstituted lower alkoxy; sulfonyl alkyl; and substituted or unsubstituted aryl or heteroaryl, with the proviso that if any of A, B, G, or D is a nitrogen, then the substituent R group is not present; Q is, independently, (-CH2-)r, -NH-, S, or O; r is 0-3; and X is a ) or b) T is nitrogen, carbon, lower alkylene of one to three carbons or lower alkenylene of one to three carbons; R7-R10 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, and lower alkoxy; and Z is O, S, CH2, CH20, OCH2, SCH2, lower alkylene, lower alkenylene, NH, or NMe. 2. The compound of Claim 1 having the structure: and a pharmaceutically acceptable salt, prodrug, polymorph, or metabolite thereof wherein all substituents are as defined in Claim 1. 3. The compound of Claim 2 which is a benzoxazolinyl piperidine substituted butyl saccharine or a spiro 1 -oxo-2H-indeneny 1 piperidine substituted butyl saccharine. 4. The compound of Claim 3 selected from: and wherein all substituents are as defined in Claim 1. 5. A compound selected from: 1 , 1 -Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin- 1 -yl)-butyl)- 1 ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(3,4-dihydro-2-oxo-(l/ )-quinolin-l-yl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(4-(2-oxo-3,l ,4-benzoxazinyl)-piperidin-l -yl)-butyl)- 1 ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(2-oxo-(lH)-quinolin-l-yl)-piperidin-l-yl)-butyl)- 1 ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxo-( 1 H)-quinolin- 1 -yl)-piperidin- 1 -yl)- butyl)-5-nitro- 1 ,2-benzisothiazol-3(2H)-one; 6-Chloro- 1 , 1 -dioxido-2-(4-(4-(2-oxo-( 1 H)-quinolin- 1 -yl)-piperidin- 1 - yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 5-Chloro-l,l-dioxido-2-(4-(4-(2-oxo-(lH)-quinolin-l-yl)-piperidin-l- yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxo-(l H)-quinolin- 1 -yl)-piperidin- 1 -yl)- butyl)-7-nitro- 1 ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxo-(l H)-quinolin- 1 -yl)-piperidin-l -yl)-butyl)- 4-methoxy- 1 ,2-benzisothiazol-3 (2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxo-3-benzoxazoliny l)-piperidin- 1 -yl)-buty 1)- 5-nitro-l ,2-benzisothiazol-3(2H)-one; 6-Chloro-l ,l-dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l - yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 5-Chloro-l ,1 -dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l - yl)-butyl)-l,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l -yl)-butyl)- 7-nitro-l ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin- 1 -yl)-butyl)-4- methoxy-l,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(5-chloro-2-oxo-3-benzoxazolinyl)-piperidin-l-yl)- butyl)- 1 ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(3a-(R)-8a-(S)-2-oxo-3,3a,8,8a-tetrahydro-2H- indenofl ,2-d]oxazolinyl)-piperidin-l -yl)-butyl)-l ,2-benzisothiazol- 3(2H)-one; l ,l-Dioxido-2-(4-(4-(2-oxonaphth[2,3-d]oxazolinyl)-piperidin-l-yl)- butyl)- 1 ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(6-methy l-2-oxo-3-benzoxazoliny l)-piperidin- 1 - yl)-butyl)-l,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(2-oxo-5-phenyl-3-benzoxazolinyl)-piperidin-l- yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(4-(6-methoxy-2-oxo-3-benzoxazolinyl)-piperidin-l - yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(6-carbomethoxy-2-oxo-3-benzoxazolinyl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(5-ethy lsulfonyl-2-oxo-3-benzoxazolinyl)- piperidin-1 -yl)-butyl)- 1 ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(2-oxo-3-oxazolo[4,5-b]pyridyl)-piperidin-l -yl)- butyl)-l,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(7-carbethoxy-2-oxo-3-benzoxazolinyl)-piperidin- 1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(5-/erf-butyl-2-oxo-3-benzoxazoliny l)-piperidin- 1 - yl)-butyl)-l,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(5,7-dimethyl-2-oxo-3-benzoxazolinyl)-piperidin- 1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(spiro( 1 ,3-dihydro- 1 -oxo-2H-indene-2,4'-piperidin- 1 '-yl)butyl)-l ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4'-(3 ,4-dihydro- 1 -oxonapththalene)-2( 1 H)- spiropiperidin-r-yl)butyl)-l ,2-benzisothiazol-3(2H)-one; 4-(3,4-Dihydro-6-methyl-spiro[2H-l-benzopyran-2,4'-piperidine-4(3H)- one]-l '-yl)-butylphthalimide; 4-(Spiro(piperidine-4,6'-[6H]thieno[2,3-b]thiopyran-4'(5'H)-one-l '-yl)- butylphthalimide; 4-(Spiro[benzothiazol-2(3H),4'-piperidin-l '-yl)-butylphthalimide; 4-(3,4-Dihydro-6-methoxy-spiro[2H-l-benzopyran-2,4'-piperidine- 4(3H)-one]-l '-yl)-butylphthalimide; 4-(3,4-Dihydro-6-methanesulfonylamidyl-spiro[2H-l-benzopyran-2,4'- piperidine-4(3H)-one]- 1 '-yl)-butylphthalimide; l ,l-Dioxido-2-(4-(spiro[benzothiazol-2(3H),4'-piperidin- -yl)-butyl)- 1 ,2-benzisothiazol-3(2H)-one; 4-(6-Trifluoromethyl-spiro[benzothiazol-2(3H),4'-piperidin- -yl)- butylphthalimide; l ,l-Dioxido-2-(4-(spiro[benzofuran-2(3H),4 , -piperidin]- -yl)-butyl)- 1 ,2-benzisothiazol-3(2H)-one; 4-(Spiro[benzofuran-2(3H),4'-piperidin]-r-yl)-butylphthalimide; 4-(Spiro[2H-l,3-benzoxazine-2,4'-piperidin]- -yl)-butylphthalimide; 3,3-Dioxido-l ,2-dehydro-2-(4-(spiro[2H-indene-2,4'-piperidine-l(3H)- one]-r-yl)-butyl)-naphth[l,2-d]isothiazol-l-one; 1 , 1 -Dioxido-2-(4-(spiro[2H-indene-2,4'-piperidine- 1 (3H)-one] - 1 '-yl)- butyl)-4-methoxy- 1 ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(spiro[2H-indene-2,4'-piperidine-l(3H)-one]-l '-yl)- butyl)-7-methoxy- 1 ,2-benzisothiazol-3 (2H)-one; l ,l-Dioxido-2-(4-(spiro(l ,3-dihydro-l-oxo-2H-indene-2,4'-piperidin- 1 '-y l)buty l)-5-methoxy- 1 ,2-benzisothiazol-3 (2H)-one; 1 , 1 -Dioxido-2-(4-(spiro(l ,3-dihydro- 1 -oxo-2H-indene-2,4'-piperidin- 1 '-yl)butyl)-6-methoxy-l ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(spiro(l ,3-dihydro- 1 -oxo-2H-indene-2,4'-piperidin- 1 '-yl)butyl)-5 -methyl- 1 ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(spiro(l ,3-dihydro-l-oxo-2H-indene-2,4'-piperidin- 1 '-yl)butyl)-5-chloro-l ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(spiro(l ,3-dihydro-l-oxo-2H-indene-2,4'-piperidin- 1 '-yl)butyl)-5-fluoro- 1 ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(spiro( 1 ,3-dihydro- 1 -oxo-2H-indene-2,4'-piperidin- 1 '-yl)butyl)-5-nitro-l ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(spiro(l ,3-dihydro-l-oxo-2H-indene-2,4'-piperidin- 1 '-yl)butyl)-6-nitro-l ,2-benzisothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(spiro(l ,3-dihydro- l-oxo-2H-indene-2,4'-piperidin- r-yl)butyl)-isothiazolo[5,4-c]pyridin-3(2H)-one; 1 ,1 -Dioxido-2-(4-(spiro(l ,3-dihydro- l-oxo-2H -indene-2,4'-piperidin- 1 '-yl)butyl)-isothiazolo[5,4-b]pyridin-3(2H)-one ; 1 , 1 -Dioxido-2-(4-(4-(6-methyl-2-oxo-3-benzoxazolinyl)-piperidin- 1 - y l)-buty l)-5-nitro- 1 ,2-benzisothiazol-3(2H)-one; 2-(4-(Spiro(l ,3-dihydro-l -oxo-2H-indene-2,4'-piperidin-l '-yl)butyl)- pyrrolo[3,4b]pyridin-5,7(lH)-dione; 1 ,1 -Dioxido-2,3-dihydro-2-(4-(spiro[2H-indene-2,4'-piperidine-l (3H)- one]- 1 '-yl)-butyl)-naphth[ 1 ,8-de]isothiazin-3-one; and l ,l-Dioxido-2-(4-(spiro[3-oxo-phthalan-l,4'-piperidin- -yl)butyl)-l,2- benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-2H-benzimidazolin-l-yl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-3-methyl-2H-benzimidazolin- 1 -yl)-piperidin-l-yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-5-methyl-2H-benzimidazolin- l-yl)-piperidin-l-yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-4-methyl-2H-benzimidazolin- 1 -yl)-piperidin- 1 -yl)-butyl)- 1 ,2-benzisothiazol-3 (2H)-one; l ,l-Dioxido-2-(4-(4-(l,3-dihydro-2-oxo-5-methoxy-2H-benzimidazo- lin- 1 -yl)-piperidin- 1 -yl)-buty 1)- 1 ,2-benzisothiazol-3 (2H)-one; l ,l-Dioxido-2-(4-(4-(l,3-dihydro-2-oxo-5-chloro-2H-benzimidazolin- 1 -y l)-piperidin- 1 -y l)-buty 1)- 1 ,2-benzisothiazol-3 (2H)-one; 1 ,1 -Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-5-fluoro-2H-benzimidazolin- 1 -yl)-piperidin-l -yl)-butyl)-5-chloro-l ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-5-methyl-2H-benzimidazolin- l -yl)-piperidin-l-yl)-butyl)-5-chloro-l ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-6-methyl-2H-benzimidazolin- l -yl)-piperidin-l-yl)-butyl)-5-chloro-l ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(5-methyl-2-oxo-3-benzoxazolinyl)-piperidin-l - yl)-butyl)-5,6-dihydro-[l ,4]dioxino[2,3-e]benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin- 1 -yl)-buty 1)- 5,6-dihydro-[l,4]dioxino[2,3-e]benzisothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(4-(spiro-l ,3-dihydro- 1 -oxo-2H-indenyl)-2,4'- piperidin-r-yl)-butyl)-5,6-dihydro-[l ,4]dioxino[2,3-e]benzisothiazol- 3(2H)-one; l ,l-Dioxido-2-(4-(4-(l,3-dihydro-2-oxo-lH-3,4-dihydroquinazolin-l- yl)-piperidin-l-yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 2-(4-Hydroxybutyl)-l,l-dioxido-5,6-dihydro-[l,4]dioxino[2,3- d]benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l-yl)-butyl)- 5-ethoxy- 1 ,2-benzothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(spiro-l ,3-dihydro-l-oxo-2H-indenyl)-2,4'- piperidin-r-yl)-butyl)-5-ethoxy-l ,2-benzothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(4-(spiro-l ,3-dihydro- 1 -oxo-2H-indenyl)-2,4'- piperidin-r-yl)-butyl)-5-ethyl-l,2-benzothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l -yl)-butyl)- 5-ethyl- 1 ,2-benzothiazol-3(2H)-one; l ,l -Dioxido-2-(4-(4-(spiro-l ,3-dihydro-l-oxo-2H-indenyl)-2,4'- piperidin- -yl)-butyl)-5-(2-propyl)-l ,2-benzothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin- 1 -yl)-buty 1)- 5-(2-ρropyl)-l,2-benzothiazol-3(2H)-one; l,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l-yl)-butyl)-6- nitro-l ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l-yl)-butyl)-5- fluoro-l,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin- 1 -yl)-buty l)-5- l o methyl- 1 ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin- 1 -yl)-buty l)-5- bromo-l ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l-yl)-butyl)-5- trifluoromethyl-l,2-benzisothiazol-3(2H)-one; is l ,l-Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l-yl)-butyl)-5- trifluoromethoxy- 1 ,2-benzisothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(4-(2-oxo-l -naphth[ 1 ,2-d]oxazolinyl)-piperidin-l -yl)- butyl)- 1 ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(5,6,7,8-tetrahydro-2-oxo-3-naphth[2,3- 20 d]oxazolinyl)-piperidin-l-yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(4-(5-methyl-2-oxo-3-benzoxazolinyl)-piperidin-l - yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(5-carbomethoxy-2-oxo-3-benzoxazolinyl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 25 1 ,1 -Dioxido-2-(4-(4-(6-fluoro-2-oxo-3-benzoxazolinyl)-piperidin-l -yl)- butyl)- 1 ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(4-methyl-2-oxo-3-benzoxazolinyl)-piperidin- 1 - yl)-butyl)-l,2-benzisothiazol-3(2H)-one; l,l-Dioxido-2-(4-(4-(4-methoxy-2-oxo-3-benzoxazolinyl)-piperidin-l- 3 o yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 5-Chloro-l ,l-dioxido-2-(4-(4-(6-methyl-2-oxo-3-benzoxazolinyl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 5-Methylthio-l ,l-dioxido-2-(4-(4-(6-methyl-2-oxo-3-benzoxazolinyl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 5-Ethoxy-l ,l-dioxido-2-(4-(4-(6-methyl-2-oxo-3-benzoxazolinyl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 5-Chloro-l ,l -dioxido-2-(4-(4-(6-fluoro-2-oxo-3-benzoxazolinyl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 4-Methyl- 1 , 1 -dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin- 1 -yl)- butyl)-l,2-benzisothiazol-3(2H)-one; 4-Chloro- 1 , 1 -dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin- 1 -yl)- butyl)-l,2-benzisothiazol-3(2H)-one; 4-Ethoxy-l ,l -dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l- yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 4-(2-Propyloxy)-l ,l-dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 5-Methoxy-l ,l-dioxido-2-(4-(4-(6-methyl-2-oxo-3-benzoxazolinyl)- piperidin-1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin- 1 -yl)-buty l)-6- methylsulfonyl- 1 ,2-benzisothiazol-3(2H)-one; 5-Methoxy-l ,l-dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l - yl)-butyl)-l,2-benzisothiazol-3(2H)-one; 1 ,1 -Dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin-l -yl)-butyl)-5- methylsulfonyl- 1 ,2-benzisothiazol-3(2H)-one; 5-Methylthio-l,l-dioxido-2-(4-(4-(2-oxo-3-benzoxazolinyl)-piperidin- 1 -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 5-Methylsulfonyl-l,l-dioxido-2-(4-(4-(6-methyl-2-oxo-3- benzoxazolinyl)-piperidin-l-yl)-butyl)-l,2-benzisothiazol-3(2H)-one; or 1 ,1 -Dioxido-2-(4-(4-(2-oxo-l -oxazolo[5,4-b]pyridyl)-piperidin-l -yl)- butyl)- 1 ,2-benzisothiazol-3(2H)-one; and a pharmaceutically acceptable salt, prodrug, polymorph, or metabolite thereof. 6. The compound of Claim 5 selected from: 1 , 1 -Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-2H-benzimidazolin- 1 -yl)- piperidin-1 -yl)-butyl)- 1 ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-3-methyl-2H-benzimidazolin- 1 -yl)-piperidin-l -yl)-butyl)-l ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-( 1 ,3-dihydro-2-oxo-5-methyl-2H-benzimidazolin- 1 -y l)-piperidin- 1 -yl)-butyl)- 1 ,2-benzisothiazol-3 (2H)-one; l ,l-Dioxido-2-(4-(4-(l,3-dihydro-2-oxo-5-chloro-2H-benzimidazolin- 1 -y l)-piperidin- 1 -y l)-buty 1)- 1 ,2-benzisothiazol-3 (2H)-one; 1 ,1 -Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-5-fluoro-2H-benzimidazolin- 1 -yl)-piperidin- 1 -yl)-butyl)-5-chloro-l ,2-benzisothiazol-3(2H)-one; l ,l-Dioxido-2-(4-(4-(l ,3-dihydro-2-oxo-5-methyl-2H-benzimidazolin- 1 -yl)-piperidin-l -yl)-butyl)-5-chloro-l ,2-benzisothiazol-3(2H)-one; 1 , 1 -Dioxido-2-(4-(4-( 1 ,3-dihydro-2-oxo-6-methyl-2H-benzimidazolin- 1 -yl)-piperidin-l -yl)-butyl)-5-chloro-l ,2-benzisothiazol-3(2H)-one; or l ,l-Dioxido-2-(4-(4-(5-methyl-2-oxo-3-benzoxazolinyl)-piperidin-l - yl)-butyl)-5,6-dihydro-[l ,4]dioxino[2,3-e]benzisothiazol-3(2H)-one; and a pharmaceutically acceptable salt, prodrug, polymorph, or metabolite thereof. 7. A pharmaceutical composition comprising a therapeutically effective amount of the compound of Claim 1 and a pharmaceutically acceptable carrier. 8. The composition of Claim 7 which further comprises a therapeutically effective amount of a testosterone 5-alpha reductase inhibitor. 9. The composition of Claim 8, wherein the testosterone 5- alpha reductase inhibitor is a type 1, a type 2, a type 1 and a type 2 or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor. 10. The composition of Claim 9, wherein the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor. 11. The composition of Claim 10, wherein the testosterone 5-alpha reductase inhibitor is finasteride. 12. A method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound of Claim 1. 13. The method of Claim 12 wherein the compound is administered in combination with a therapeutically effective amount of a testosterone 5-alpha reductase inhibitor. 14. The method of Claim 13, wherein the testosterone 5- alpha reductase inhibitor is finasteride. 15. The method of Claim 12, wherein the compound additionally does not cause a fall in blood pressure at dosages effective for treating benign prostatic hyperplasia. 16. A method of treating benign prostatic hyperplasia which comprises administering a therapeutically effective amount of the composition of claim 7. 17 A method of inhibiting contraction of prostate tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound of Claim 1. 18. The method of Claim 17 wherein the compound is administered in combination with a therapeutically effective amount of a testosterone 5-alpha reductase inhibitor. 19. The method of Claim 18, wherein the testosterone 5- alpha reductase inhibitor is finasteride. 20. The method of Claim 17, wherein the compound additionally does not cause a fall in blood pressure at dosages effective for treating benign prostatic hyperplasia. 21. A method of using the compound of Claim 1 to selectively antagonize the human alpha IC adrenergic receptor which comprises exposing the human alpha IC adrenergic receptor to an antagonistically effective amount of said compound. 22. A method of preparing an antagonist of the human alpha IC adrenergic receptor which comprises alkylating a halogenated butyl saccharine with a deprotected spiropiperidine or a deprotected benzoxazolinyl piperidine 23. The use of the compound of Claim 1 in the preparation of a medicament for the treatment of benign prostatic hypeφlasia. 24. The use of the compound of Claim 1 in the preparation of a medicament for inhibiting contraction of prostate tissue. 25. A drug which is useful for treating benign prostatic hypeφlasia, the effective ingredient of the said drug being a compound as claimed in Claim 1. 26. A drug which is useful for inhibiting contraction of prostate tissue, the effective ingredient of the said drug being a compound as claimed in Claim 1.

Inventors: HUFF JOEL R, LEE HEE-YOON, NERENBERG JENNIE B, THOMPSON WAYNE J, HUFF, JOEL, R., LEE, HEE-YOON, NERENBERG, JENNIE, B., THOMPSON, WAYNE, J.
Applicants: HUFF JOEL R, LEE HEE YOON, MERCK & CO INC, NERENBERG JENNIE B, THOMPSON WAYNE J, HUFF, JOEL, R., LEE, HEE-YOON, MERCK & CO., INC., NERENBERG, JENNIE, B., THOMPSON, WAYNE, J.
Application year: 1995
Main classification: C07D401
IPC codes: A61K31, A61P13, A61P15, A61P17, A61P43, C07D417, C07D471, C07D491, C07D495, C07D498, C07D513