USE OF SUBSTITUTED ARYL-MORPHOLINO-, THIOMORPHOLINO- OR PIPERAZINO-PROPANONES FOR THE TREATEMENT OF PREVENTION OF ALZHEIMER'DISEASE

Abstract: Disclosed are compounds of formula (I), wherein X is selected from oxygen, sulfur and NR; wherein R is selected from hydrogen, lower alkyl and CH2CH2COAr1; and Z is hydrogen; straight or branched chain alkyl having 1-6 carbon atoms; or Z and R1, R2 or R3 together represent CH2; CH2CH2; CH2O; or CH2S forming a five or six membered ring and such ring may be optionally substituted with lower alkyl or phenyl; R24 is hydrogen; lower alkyl, or optionally substituted phenyl; each R10 is selected from hydrogen and lower alkyl; and Ar1 represents an aryl group or optionally substituted phenyl, thienyl or optionally substituted thienyl; or the pharmaceutically acceptable salts thereof, useful for preventing or decreasing the production of abnormally phosphorylated paired helical filament (PHF) epitopes associated with Alzheimer's Disease and, therefore, useful for treating Alzheimer's Disease.

Description: USE OF SUBSTITUTED ARYL-MORPHOLINO- , THIOMORPHOLINO- OR PIPERAZIN O-PROPANONES FOR THE TREATEMENT OF PREVENTION OF ALZHEIMER'S DISEASE BACKGROUND OF THE INVENTION 1 . Field of the Invention This invention relates to the use of certain l-aιyl-3-(4 -alkyl- l'-piperizinyl)-; l-aryl-3-(4- morpholinyl)-; and l-aryl-3-(4'-thiomo holinyl)-l-propanones in the treatment of Alzheimer's Disease. 2. Description of the Related Art Alzheimer's Disease is a progressive neurodegenerative disorder affecting 7% of the population over 65 years of age and characterized clinically by progressive loss of intellectual function. This impairment of function is caused by me presence of neuritic plaques in the neσcoπex and the loss of presynaptic markers of cholinergic neurons. Neuritic plaques are composed of degenerating axons and nerve teπninals, often surrounding an amyloid core and usually containing reactive glial elements. Another characteristic pathologic feature of Alzheimer's Disease is the neurofibrillary tangle, which is an intraneuronal mass which corresponds to an accumulation of abnormally phosphorylated tau protein polymerized into Ωbrillar structures termed paired helical filaments. In addition, the neurofibrillary tangle also contains highly phosphoiylated neurofilament proteins. Even the earliest papers on Alzheimer s Disease were clear that both "senile" plaques and neurofibrillary tangles had to be present in abundance to allow a post-mortem diagnosis of the disease. Before any understanding of the molecular nature of these structures was obtained, efforts were being made to understand die relationship between the numbers of these lesions and the progression or severity of the dementia experienced by the patienL The limitations of silver staining were such that early workers in this field were unable to appreciate the complexity of these abnormal structures (Ball, MI, Neurobiol. of Aging, 8: 564-565, 1987). Although early attempts to correlate pathologic lesion counts with clinical symptoms generally yielded poor results, it was clear that the incidence of large numbers of both type lesions were invariably associated with dementia (Perry et al, J. Neural Transmission, 24: 131-136, 1987; Alafuzoff, I., Acta Neuropath, 74: 209-225, 1987; Whitehouse et al, Prog. Clin. Biol. Res., 317: 131-142, 1989; Tomlinson, Neuropathol. Appl. Neurobiol, 15: 491-512, 1989). More recent work has allowed a clearer definition of the nature of the lesions stained by silver salts. "Senile" plaques are actually two distinct types of structures, the classical plaques described by Alzheimer being composed of degenerating neuronal elements (neurites) surrounding a central core of amyloid, while the other so-called "diffuse" or "primitive" plaque is usually a deposit of amyloid without a halo of degenerating neurites (Tagliavini, , et al, Neurosci. Lett., 93, 191-196, 1988; Dickson, DW, et al, Am. J. Path., 132, 86-101, 1988). These structures are difficult to distinguish from each other with silver stains or with the widely used fluorescent dye, thioflavin S. Early attempts, using silver staining, at correlations between plaque number and extent of dementia, as well as some more recent studies using thioflavin S, were flawed by this inability to define what type of plaque was being counted (Hansen, LA, et al, Neurology, 38, 48-54, 1988; Katzman, R, et al, Ann. Neurol., 23, 138-144, 1988). This becomes very obvious in recent studies, which have consistendy reported that amyloid plaques can be found in large numbers in the brains of the majority of the very elderly (over 80 years), and are only rarely associated with dementia when present without evidence of degenerating neurites (Davies, L, et al, Neurology, 38, 1688-1693, 1988; Delaere, P, et al, Neurosci. Lett., 116, 87-93, 1990; Dickson, DW, et al, Neurobiol. Aging, 13, 179-189, 1991). The counting of neurofibrillary tangles also fails to give an accurate picture of the extent of neurofibrillary degeneration. Again, the presence of large numbers of tangles is invariably associated with a profound dementia, and some index of disease severity can be gained from tangle counts (Tomlinson, BE, Neuropathol. Appl. Neurobiol., 15, 491-512, 1989; Delaere, P, et al, Acta Neuropath., 77, 645-653, 1989). Electron microscopy first revealed that tangles were composed of masses of paired helical filaments (PHF) filling the cytoplasm of neurons (Terry, RD, et al, pages 145-155, In CIBA Foundation Symposium on Alzheimer's Disease and Related Conditions. Ed. by Wolstenholme, GEW, O'Conner, M, J and A Churchill, London, 1970). These studies also clearly showed that degenerating neurites also contained PHF, a fact only widely appreciated much later, when the use of antibodies to PHF became common (Wolozin, BL, et al, Science, 232, 648-650, 1986). Thus, both the plaques and the tangles of Alzheimer's -2- snεsmuπ SHEET RQU 2β Disease contain PHF. The use of antibodies to PHF also revealed the widespread presence of these paired helical filaments in neuronal processes (Brun, A, Prog. Clin. Biol. Res., 317, 285- 293, 1989). Thus, the presence of PHF is much more widespread than was first suspected, and is today considered to be an indication of a widespread neuronal disease, of which the neuritic plaque and d e neurofibrillary tangle are only the most obvious signs (McKee, AC, et al, Ann. Neurol., 30, 156-165, 1991). It has been estimated mat as much as 90% of die PHF in die cortex of the average Alzheimer case is present in neuronal processes rather than in the plaque or tangle (Wolozin, BL, Ann. Neural., 22, 521-526, 1987). Much of the early and indeed the present confusion with regard to diagnosis and severity of Alzheimer's Disease comes from the failure to appreciate the complexity of the pathology in this disease, although the occurrence of significant amounts of PHF in the brain is always associated with severe dementia (Hyman, BT, Current Opinions in Neurology and Neurosurgery, 5, 88-93, 1992). These results suggest that good correlations can be obtained between the concentration of PHF proteins (sometimes referred to as Alzheimer's Disease Associated Proteins or ADAP) in the cerebral cortex and the degree of dementia measured prior to the death of the patient (Ghanbari, HA, et al, JAMA, 263, 2907- 2910, 1990). It is noted that d e terminology used to describe the abnormal protein complexes composing the fibrillar pathology in Alzheimer's Disease can be confusing. PHF is a morphological designation, describing abnormal filaments found in neurofibrillary tangles. An abnormal protein species migrating at 68 kDa, electrophoretically, and observed on immunoblots of tissue from AD brains was termed A68 (Wolozin, B, et al, Science, 232, 648-650, 1986). A protein complex shown to be specific for AD by immunochemical analyses was designated Alzheimer's Disease Associated Protein or by the acronym, ADAP (Ghanbari, HA, et al, JAMA, 263, 2907-2910, 1990). It is now known that A68 and ADAP, when viewed by the electron microscope, are PHFs. These PHFs have been further shown to contain, primarily, the microtubule-associated protein, tau. Hence, the terms A68, ADAP, PHF and PHF-tau are often used interchangeably. Thus, they are meant to be interchangable herein. A series of important studies have suggested that die progression of Alzheimer's Disease can be defined padiologically by careful neuroanatomic studies of large numbers of brains from -3- MEr Riaf» elderly humans, (Braak, H, et al, Neurosci. Lett., 103, 24-28, 1989; Braak, H, et al. Neuropath, and Applied Neurobiol., 15, 13-26, 1989; Braak, H, et al, Acta Neuropadi., 82, 239-259, 1991; Braak, H, et al, European Neurology, 33, 403-408, 1993). The Break's focus is almost entirely on the development of neurofibrillary pathology, which begins in the entσrhinal cortex perhaps years before the clinical signs of the disease are apparent. The progression of Alzheimer's Disease is thought to be somewhat unusual, in the sense that the disease progresses by the involvement of more and more neurons in the formation of PHF, in an anatomic sequence which is to some extent predictable. In die initial stages, only those neurons of the entorhinal cortex contain PHF, in later stages, neurons of the CA1 and CA2 pyramidal layer of die hippocampus contain these structures, and still later, neurons of the association cortex begin to show evidence of PHF formation. Clearly, prevention of PHF formation even after die process is underway in die hippocampus could limit the disease to this brain region, at which point clinical problems are confined to some loss of short term memory. Patients first seek help at a stage when PHF pathology is largely limited to d e hippocampus (Berg, L, et al, pages 9-25, in Alzheimer's Disease, Eds., Terry, RD; Katzman, R; Bick, KL. Raven Press, New York, 1994). To prevent the progression of Alzheimer's Disease at this point would clearly be a major benefit to the patient (Davies, P, pages 327-334, in Alzheimer's Disease, Eds., Terry, RD; Katzman, R; Bick, KL. Raven Press, New York, 1994; Khachaturian ZS, et al, pages 445-454, in Alzheimer's Disease, Eds., Terry, RD; Katzman, R; Bick, KL. Raven Press, New York, 1994). Attempts to determine die molecular nature of the PHF were hampered at first by an approach which attempted to purify PHF from isolated neurofibrillary tangles. Once incorporated into the macromolecular complex that is the tangle, PHFs become extremely difficult to solubilize for protein analysis. The microtubule-associated protein tau appears to be a major antigenic component of PHF. The repeat region of microtubule-associated protein tau forms part of the core of the paired helical filament of Alzheimer's Disease (Goedert, M, et al, Proc. Nat'l. Acad. Sci., 85, 4051-4055, 1988; Wischik, CM, et al, Proc. Nat'l. Acad. Sci., 85, 4506-4510, 1988). The involvement of protein phosphσrylation in die formation of PHF has been suggested by a variety of studies which have shown diat tau in PHF is hyperphosphorylated (Kosik, KS, et -4- al, Ann. Med., 21, 109-112, 1989; Goedert, M, Trends in Neurosciences, 16, 460-465, 1993; Iqbal, K, et al, Act Neurobiologiae Experimentalis, 53, 325-335, 1993). There is suggestive evidence that several other proteins, especially neurofilaments and otiier microtubule associated proteins (MAPs) are also hyperphosphσrylated in the brains of patients with Alzheimer's Disease (Lovestone, S, et al, Current Opinions in Neurology and Neurosurgery, 5, 883-888, 1992). In 1985, a monoclonal antibody ALZ50 was raised (produced by hybridoma cell line ATCC No. HB9205) that recognized a 68 kDa polypeptide (termed A68) in immunoblots of die vulnerable brain regions in AD, but not in control brains, (Wolozin, B, et al, Science, 232, 648- 650, 1986). Immunohistochemical analysis with this antibody indicated an intense reaction widi neurofibrillary tangles and, in later experiments, with the PHF's, as well. The discovery of A68 was die first report of a biochemically determined abnormal protein species associated with the fibrillar pathology in AD. In other laboratories in 1986, monoclonal and polyclonal antibodies recognizing the microtubule-associated protein, tau, were shown to react with neurofibrillary tangles, and subsequendy, with PHFs (Grundke-Iqbal, I, et al, Proc. Nat'l,. Acad. Sci., 83, 4913-4917, 1986; Kosik, KS, et al, Proc. Nat'l. Acad. Sci., 83, 4044-4048, 1986). Furthermore, biochemical analyses of the protease-resistant "core" of the PHF demonstrated die presence of peptides containing the tau sequence, (Goedert, M, et al, Proc. Nat'l. Acad. Sci., 85, 4051- 4055, 1988; Wischik, CM, et al, Proc. Nat'l. Acad. Sci., 85, 4506-4510, 1988). Additionally, monoclonal antibodies, whose epitopes spanned the tau molecule, all were shown to react with neurofibrillary tangles in AD brain (Kosik, KS, et al, Neuron, 1, 817-825, 1988). Much later, it was determined diat die ALZ50 antibody reacts with the extreme amino terminus of the tau molecule, (Goedert, M, et al, Neuroscience Letters, 126, 149-154, 1991). In 1990, in an attempt to purify A68, a more readily soluble preparation of PHFs was isolated (Greenberg, S and Davies, P, Proc. Nat'l. Acad. Sci., 87, 5827-5831, 1990). Immunoblots of these structures indicated diat three closely migrating electrophoreric species, the slowest migrating of which was ca. 68 kDa in size, all reacted with ALZ50 and tau antibodies (Lee, V, et al, Science, 251, 675-678, 1991). This indicated diat the A68 complex of proteins -5- SUBSTITUTE SHEET (RULE 26 is, to a large extent, composed of die tau protein. This polymerized form of tau was shown over the years to be in a hyperphosphorylated state. Other monoclonal antibodies raised against human PHF preparations are die antibodies PHF-1 and TG3. While these antibodies display robust affinity for paired helical filament preparations, they only have trace reactivity towards normal adult tau. Further studies revealed diat d e monoclonal antibody PHF-1 has a reduced affinity for PHF which has been treated with alkaline phosphatase or hydrofluoric acid, thereby suggesting that this antibody recognized a phosphorylated epitope(s) in paired helical filaments. These phosphorylated epitopes (recognized by PHF-1) reside within die C-terminal fragment of the tau protein, at serine 396 and 404 (Trojanowski, J.Q., et al, Clin. Neurosci., 1, 184-191, 1993). The epitope(s) recognized by TG3 has not been mapped yet To date, it has not been possible to consistendy induce die formation of Alzheimer-like epitopes either in vivo or in vitro. Hence, there is a need for an assay for the determination of tau protein, paired helical filaments and mechanisms involved witii Alzheimer's Disease. There is further a need for an assay suitable for screening for drugs which may prevent or decrease Alzheimer's Disease activity. SUSST-TUTE SHEET (RtR£ 26 SUMMARY OF THE INVENTION The compounds of this invention and an antipyschotic agent, chlorproma-rine, are active in an assay indicative of the potential of certain drugs to inhibit a hallmark trait of Alzheimer's Disease. Further, chlσrpromazine is shown herein to be capable of treating and/or preventing Alzheimer's Disease. Consequendy, the compounds of this invention are useful for treating and/or preventing die disease. The human neuroblastoma MSNla cell line expresses the proteins known to be involved in PHF formation (including tau, other MAPs and neurofilament proteins, and tiius is a cell line in which Alzheimer's Disease epitopes can be expressed. (Arias et al, J. Neurochem., 61: 673- 682, 1993; Vincent et al, J. Neurochem., 62: 715-723, 1994). Immunohistochemical staining of brains from normal and Alzheimer's Disease (AD) patients using the monoclonal antibodies PHF-1 and TG3 indicates diat these monoclonal antibodies specifically stain elements of AD brain, but not normal brain (Figure 1). Conditions were established which led to hyperphosphorylation of the proteins known to be involved in PHF formation. Using monoclonal antibodies PHF-1 and TG 3 generated to human PHF preparations, die effects of a variety of manipulations of die phosphorylation state of these proteins were tested. These tests required diat most of the abnormal epitopes recognized by these monoclonal antibodies in the human Alzheimer brain should be generated in die MSNla cells. The treatment of MSNla cells with okadaic acid and other selected inhibitors of protein phosphatases has been found to generate the epitopes associated with these Alzheimer brain specific monoclonal antibodies, thereby meeting die requirements described above. These epitopes are either absent or present at a very low level in untreated MSNla cells. The AD specificity of the PHF-1 and TG3 antibodies was also demonstrated using an ELISA assay. Shown in Figure 2A are bar graphs (percent of AD) of the ELISA immunoreactivity of brain preparations (AD or normal) to either PHF-1 or TG3. Shown in Figure 2B are bar graphs (percent of MSN+) of the ELISA immunoreactivity of MSNla cell preparations (minus or plus okadaic acid) to eitiier PHF-1 or TG3. The MSNla cell preparations plus vs minus okadaic acid closely parallel the AD vs normal brain preparations. This clearly shows the relationship between disease padiology (i.e. AD brain) and what is recognized by the -7- 6 antibodies in die MSNla in vitro cell culture assay. The cell culture system according to die invention in which epitopes characteristic of PHF can be readily generated and subsequendy recognized by die specific Alzheimer brain specific antibodies provides an assay suitable for screening compounds for their ability to block the production of these phosphorylated epitopes. PHF tau protein has lower affinity for microtubules as compared to normal tau protein, which is likely the result of the abnormal phosphorylation (Lindwall et al, J. Biol. Chem., 259: 5301-5305, 1984). As a consequence, microtubule destabilization occurs which interferes with important neuronal processes such as rapid axonal transport and, subsequently, this process leads to die formation of PHF and die neurofibrillary tangles (Bancher, et al, Brain Res., 477, 90-99, 1989). Thus, inhibition of the production of die abnormal phosphorylated PHF epitopes will interfere with and/or prevent the formation of PHF. Since PHF formation is a major feature of Alzheimer pathology, the development of compounds mat interfere with all or pan of this process inhibit or prevent the progression of this disease. The invention provides compounds of formula I: I or the pharmaceutically acceptable salts thereof wherein X is selected from oxygen, sulfur and NR, wherein R is selected from hydrogen, loweralkyl and CH2CH2COArι ; and Z is hydrogen, straight or branched chain alkyl having 1-6 carbon atoms, or Z and a substituent on the aryl group together represent CH2, CH2CH2, CH2O, or CH2S to form a five or six membered ring where the ring is optionally substituted widi loweralkyl or phenyl; R24 is hydrogen, loweralkyl, or optionally substituted phenyl; each Rio is selected from hydrogen and loweralkyl; and -8- Ari represents an aryl group or optionally substituted phenyl. These compounds are useful for treating Alzheimer's Disease. The compounds of this invention, by preventing or decreasing the production of abnormally phosphorylated paired helical filament epitopes associated with die production of die neurofibrillary tangles, a characteristic pathological feature of Alzheimer's Disease, are useful in the treatment of this neurodegenerative disorder. The compounds of formula I inhibit and/or prevent the formation of abnormally phosphorylated epitopes on PHF tau. Through inhibitory interactions of die phosphorylation events associated with the formation of PHF tau, and otiier proteins involved in PHF formation, one can modulate die assembly of microtubules, thereby affecting neuronal processes such a rapid axonal transport, thus preventing the formation of PHF and die production of the neurofibrillary tangles. Thus, the compounds of the present invention are therapeutically useful in various neurodegenerative disorders such as Alzheimer's Disease. Thus, the invention provides methods of preventing and or treating Alzheimer's Disease in a patient comprising administering to the patient a compound of formula I in an amount effective to inhibit formation of abnormally phosphorylated paired helical filament epitopes. -9- BRIEF DESCRIPTION OF THE DRAWINGS Figures 1 A- ID are images produced by light microscopy showing immunohistochemical staining of brain tissue from normal Alzheimer's Disease patients witii monoclonal antibodies PHF-l and TG3. Figure 2A is a graphic comparison of normal (Norm) and Alzheimer's Disease (AD) brain homogenate immunoreactivity toward PHF-1 and TG3 antibodies expressed as a percent of total AD immuonreactivity. Figure 2B is a graphic comparison of MSNla cell lysate (minus or plus okadaic acid) immunoreactivity toward PHF-1 and TG3 antibodies expressed as a percent of total immuonreactivity in lysates of MSN+ okadaic acid. Figure 3 is a western blot showing PHF-1 immunoreactivity in lysates from control and chlorpromazine treated MSN cells treated witii okadaic acid. Figure 4A is a chart showing relative ADAP concentrations in Brodman Area 10 in Alzheimer's Disease patients, normal controls and patients treated with chloropromazine (Rx). Figure 4B is a chart showing relative ADAP concentrations in Brodman Area 38 in Alzheimer's Disease patients, normal controls and patients treated with chloropromazine (Rx). -10- DETAILED DESCRIPTION OF THE INVENTION The invention provides compounds of formula I or the pharmaceutically acceptable salts thereof wherein X represents oxygen, sulfur and NR, wherein R is selected from hydrogen, loweralkyl and CH2CH2COArι; Z is hydrogen; straight or branched chain alkyl having 1-6 carbon atoms; or Z and R] , R2 or R3 together represent CH2, C(R24)2CH2, C(R24)2θ, or C(R24)2S to form a five or six membered ring; each Rio independendy represents hydrogen or loweralkyl; and Ari is a group of the formula: wherein Rl, R2 and R3 independently represent hydrogen, halogen, nitro, cyano, alkoxy, phenoxy, benzoyloxy, benzyloxy, alkylsulfonylamino, trifluoromethyl, trifluoroalkoxy, thioloweralkoxy, thienyl, furyl, methylsulfinyl, phenyl, loweralkyl; or Ari is a group of the formula: *< whe χ rein t ; J ocf Y is oxygen or sulfur Zi is oxygen or methylene R4 and R5 are independendy selected from hydrogen, halogen, loweralkoxy, hydroxy; and -11- R6, R7, R8. and R9 are independendy selected from hydrogen, halogen, nitro, cyano, loweralkyl, phenyl, optionally substituted phenyl, diienyl or optionally substituted diienyl. R24 is hydrogen, loweralkyl, or optionally substituted phenyl. The invention further encompasses compounds of formula π wherein: Rl is hydrogen, loweralkyl of 1 to 4 carbons, benzyl, phenyl or 2-, 3-, or 4-pyridyl; R2 and R3 independently represent C1-C8 alkyl, C2-C8 alkenyl or C3-C8 cycloalkyl, phenyl, halogenated-phenyl or loweralkoxyphenyl; R4 is hydrogen or C1-C4 alkyl attached to carbon atom 6 or 7 of the indole nucleus; X and Y are lower alkyl, hydroxy lower alkyl, lower acyloxy alkyl, carbamoyloxy lower alkyl and phenyl lower alkyl; or NXY represents a heterocyclic ring having a maximum of 8 members. A preferred compound of formula II is 3-etiιyl-4,5,6,7-tetrahydro-2-methyl-5- mσrpholinomethyl-4-oxoindole. Methods for preparing the compound of formula II are described in U.S. Patent No. 3,491 ,093. The invention further encompasses compounds of formula ID: ■12- S8ESTITUTESHET(RiaE26) πi wherein Rl , R2 and R3 independently represent hydrogen, thioloweralkyl, nitro, halogen, trifluoromethyl, trifluoromethoxy, loweralkoxy, alkylsulfonylamido, methylsulfinyl, loweralkyl, phenyl, thienyl, or phenoxy. The invention also encompasses compounds of formula IV: IV wherein R and Rio are independendy selected from hydrogen or loweralkyl; and Rl , R2 and R3 independently represent hydrogen, thioloweralkyl, nitro, halogen, trifluoromethoxy, trifluoromethyl, loweralkoxy, alkylsulfonylamido, methylsulfinyl, loweralkyl, phenyl, thienyl, or phenoxy. The invention also encompasses compounds of formula V: V wherein Rl is nitro or halogen. The invention also encompasses compounds of formula VI -13- VI wherein Rl and R2 are independendy selected from hydrogen, loweralkyl or halogen. The invention also encompasses compounds of formula VII vπ wherein R is CH2CH2COAri; and Ari is a group of the formula:. wherein Rl, R2 and R3 independendy represent hydrogen, thioloweralkyl, nitro, halogen, trifluoromethyl, trifluoromethoxy, loweralkoxy, alkylsulfonylamido, metiiylsulfinyl, loweralkyl, phenyl, thienyl, or phenoxy. The invention also encompasses compounds of formula VHI 28 vm wherein Z is oxygen, sulfur, methylene or a chemical bond; and Rl is loweralkyl, hydrogen or halo. The instant invention includes optically active compounds as well as racemic mixtures of such compounds. The invention further includes die pharmaceutically acceptable salts of such compounds or racemic mixtures. The invention still further includes pharmaceutical compositions comprising such compounds, salts thereof, or racemic mixtures thereof. The numbering system used for the oxoindole rings of the invention is as follows: As used herein, the term "loweralkyl" means straight or branched chain saturated hydrocarbon radicals having 1 to 4 carbon atoms, such as methyl, ethyl, π-propyl, t-butyl, and the like. As used herein, the term "thioloweralkoxy" refers to -SRi l, wherein Rl l is loweralkyl. As used herein, the term "halo or halogen" refers to fluorine, chlorine, bromine, or iodine. As used herein, the term "alkylsulfonylamino" means Rl2S(O)2NRl3 - wherein R12 is loweralkyl, phenyl, or substituted phenyl, and R13 is hydrogen, loweralkyl or -SO2R12- As used herein, the term "trifluoroalkoxy" refers to -R14CF3, wherein denotes a loweralkoxy group as defined above, attached to the parent molecular moiety through the oxygen atom. Representatives of such R14 groups include, for example, methleneoxy, ethyleneoxy and die like. As used herein, the term "Ar" or "aryl" refers to systems characterized by 4n+2 π electrons, i.e., aromatic carbocyclic groups having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4- tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which can optionally be unsubstituted or -15- substituted witii e.g., halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, and heteroaryl. As used herein, die term "heteroaryl" means 5, 6, or 7 membered aromatic ring systems having at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur. Examples of heteroaryl groups are pyridyl, pyrimidinyl, pyrrolo, pyrazolo, pyrazinyl, pyridazinyl, oxazolo, furanyl, quinoline, isoquinoline, thiazole, thiadiazole, isoxazole, and diienyl, which can optionally be unsubstituted or substituted with, e.g., halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, cyano, nitro, aryl, and heteroaryl. As used herein, the term "optionally substituted phenyl" refers to a phenyl ring having from zero to three substituents independently selected from loweralkyl, halogen, hydroxy, loweralkoxy, amino, thioloweralkoxy, nitro and cyano. As used herein, the term "optionally substituted diienyl" refers to a thiophene ring with from zero to three substituents independendy selected from loweralkyl, halo, phenyl, cyano and nitro. As used herein, the term "optionally substituted phenoxy" refers to the phenoxy ring substituted as defined for optionally substituted phenyl. The term "pharmaceutically acceptable salts" refers to the pharmaceutically acceptable, relatively non-toxic, inorganic, or organic acid addition salts of die compounds of this invention. These salts can be prepared in situ during the final isolation and purification of die compounds or by separately reacting die free base with a suitable organic or inorganic acid. Representative salts include d e hydrochloride, hydrobromide, sulfate, phosphate, nitrate, bisulfate, acetate, oxalate, valerate, oleate, palmitrate, methanesulfonate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napsylate, lactobionate, and die like. It will be apparent to those skilled in the art that, depending upon the number of available amino groups for salt formation, the salt of this invention can be per N-salts. The present invention also provides pharmaceutical compositions which comprise one or more of die compounds of formula I above formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specifically -16- formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectaly, parenterally (i.e. intravenously, intramuscularly, or sub- cutaneously), intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), transdermally, bucally, or as an oral or nasal spray. Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and die like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in die case of dispersions, and by die use of surfactants. These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of die action of microorganisms may be ensured by d e inclusion of various antibacterial and antifungal agents, for example, para ben, chlorobutanol, phenol sorbic acid, and die like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. If desired, and for more effective distribution, die compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in die form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use. -17- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alingnates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, die dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and die like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to die active compounds, die -18- SrømiTESJHT RUlI26 liquid dosage forms may contain inen diluents commonly used in the an such as, for example, water or otiier solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ediyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimediyl for amide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inen diluents, d e oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention widi suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which arc solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve die desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and die condition and prior medical history of the patient being treated. However, it is within the skill of the an to start doses of the compound at levels lower tiian required for to achieve the desired -19- therapeutic effect and to gradually increase the dosage until the desired effect is achieved. Generally dosage levels of about 0.1 to about 200, more preferably of about 0.5 to about 150, and most preferably about 1 to about 125 mg of active compound per kilogram of body weight per day are administered orally to a mammalian patient suffering from Alzheimer's Disease. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day. All documents e.g., patents and journal articles, cited above or below are hereby incorporated by reference in their entirety. One skilled in the art will recognize that modifications may be made in the present invention without deviating from the spirit or scope of the invention. The invention is illustrated further by the following examples which are not to be construed as limiting the invention or scope of the specific procedures described herein. GENERAL PROCEDURE As is more fully explained in die following scheme and examples, die compounds of die invention may be prepared by adding an appropriate secondary amine (1 mole) to a solution of concentrated hydrochloric acid (2-5 moles) in sufficient isopropanol to achieve an amine concentration of about 0.1 Λ/-0.4 M. To the solution of amine hydrochloride salt which has been formed in situ is added paraformaldehyde (1-2.2 moles) followed by the desired aryl or heteroarylketone (1.1-2 moles), and the resulting reaction mixture is then refiuxed for about 12- 72 hours. The reaction is cooled and die resulting solid is filtered and recrystallized from methanol or triturated with methanol or ethanol to afford the desired product. The compounds of die invention may be prepared according to die reactions set forth in d e following reaction scheme. -20- π 10 where Ari, Z, X, and Rio are as defined above for formula I. Using the above-described procedure, the compounds described in the following examples were prepared. -21- Example 1 1 -Phenyl- 3-(4'-methyl- 1 '-piperazinyl)- 1 -propanone dihydrochloride: A mixture of acetophenone (1.56 g, 12.98 mmol), 1-methylpiperazine (1.00 g, 9.98 mmol), parafoπnaldehyde (0.39 g, 12.98 mmol), and concentrated hydroclonc acid (4.16 mL, 0.05 mol) in 25 mL isopropanol were refiuxed for 16 h. The reaction was cooled, filtered and the filter cake was basified (NH4OH), extracted witii dicholormethane (2 x 75 mL), and purified via flash chromatography (silica; 8:2 EtOAC MeOH). The free amine was converted to its dihydrochloride salt by the addition of dry ether/HCl to give 0.40 g (13%) of the desired product: mp 194-196 β C; 1H NMR of the free base (300 MHz, CDCI3) δ 7.95 (d, 2 H), 7.6-7.35 (m, 3 H), 3.2 (t, 2 H), 2.85 (t, 2 H), 2.7- 2.35 (brm, 8 H), 2.3 (s, 3 H). Example 2 l-( -Methylphenyl)-3-(4'-methyl-l '-piperazinyl)- 1 -propanone dihydrochloride: mp 188"C (dec.); 1H NMR of the free base (300 MHz, CDCI3) δ 7.7 (m, 2 H), 7.35 (m, 2 H), 3.18 (t, 2 H), 2.85 (t, 2 H), 2.7-2.15 (brm, 14 H). Example 3 l-(p-Phenoxyphenyl)-3-(4'-methyl- 1 '-piperazinyl)- 1 -propanone dihydrochloride: mp 225°C (dec); 1H NMR of the free base (300 MHz, CDCI3) δ 7.95 (d, 2 H), 7.40 (t, 2 H), 7.2 (t, 1 H), 7.15-6.95 (m, 4 H), 3.15 (t, 2 H), 2.85 (t, 2 H), 2.7-2.35 (brm, 8 H), 2.3 (s, 3 H). -22- Example 4 l-Phenyl-3-(4'-n-propyl-l'-piperazinyl)-l -propanone dihydrochloride: mp 200 * C (dec); -H NMR of the free base (300 MHz, CDQ 3 ) δ 7.95 (d, 2 H), 7.64-7.35 (m, 3 H), 3.2 (t, 2 H), 2.85 (t, 2 H), 2.7-2.15 (m, 10 H), 1.5 (septet, 2 H), 0.9 (t, 3 H). Example 5 l-(/π-Methylphenyl)-3-(4'-propyl-l '-piperazinyl)- 1 -propanone dihydrochloride: mp 198 β C (dec); IH NMR of the free base (300 MHz, CDC1 3 ) δ 7.75 (m, 2 H), 7.35 (m, 2 H), 3.2 (t, 2 H), 2.85 (t, 2 H), 2.7-2.2 (m, 13 H), 1.5 (septet, 2 H), 0.90 (t, 3 H). Example 6 l-(p-Phenoxyphenyl)-3-(4'-«-propyl- 1 '-piperazinyl)- 1 -propanone: mp 64-65'C; IH NMR (300 MHz, CDCI3) δ 7.95 (d, 2 H), 7.4 (t, 2 H), 7.2 (t, 1 H), 7.15-6.90 (m, 4 H), 3.15 (t, 2 H), 2.85 (t, 2 H), 2.7-2.2 (m, 10 H), 1.5 (septet, 2 H), 0.90 (t, 3 H). Example 7 l-(3",4"-Dichlorophenyl)-3-(4'-methyl-l '-piperazinyl)- 1 -propanone hydrochloride: mp 205- 207 β C; IH NMR of the free base (300 MHz, CDCI3) δ 8.05 (s, 1 H), 7.77 (d, 1 H), 7.55 (d, 1 H), 3.12 (t, 2 H), 2.82 (t, 2 H), 2.7-2.2 (m, 11 H). Example 8 1 -(p-Chlorophenyl)-3-(4'-methyl- 1 '-piperazinyl)- 1 -propanone hydrochloride: mp 217-220 β C; IH NMR (300 MHz, DMSO-d 6 ) δ 11.7 (brs, 2 H), 8.0 (d, 2 H), 7.7 (d, 2 H), 4.1-3.2 (brm, 12 H), 2.8 (s, 3 H). -23- SUBSTITUTE SHEET R f 2 Example 9 l-(m-Medιylphenyl)-3-(4'-mo holinyl)-l-propanone hydrochloride: A mixture of m- methylacetophenone (2.00 g, 0.015 mol), morpholine (1.00 g, 0.011 mol), paraformaldehyde (0.45 g, 0.015 mol), and concentrated hydrochloric acid (2.75 mL, 0.033 mol) in 25 mL isopropanol were refiuxed for 3 h. The reaction was cooled, diluted witii acetone (10 mL) and crystallized to give 1.90 g (64%) of die desired product: mp 176-179'C; *H NMR of the free base (300 MHz, CDC1 3 ) δ 7.77 (m, 2 H), 7.38 (m, 2 H), 3.7 ( , 4 H), 3.18 (t, 2 H), 2.82 (t. 2 H), 2.5 (m, 4 H), 2.4 (s, 3 H). Example 10 l-(/π-Methylphenyl)-3-(l * -piperidyl)-l-propanone hydrochloride: mp 154-158 β C; iH NMRof the free base (300 MHz, CDCI3) δ 7.77 (m, 2 H), 7.36 (m, 2 H), 3.2 (t, 2 H), 2.8 (t, 2 H), 2.6-2.3 (m, 7 H), 1.7-1.35 (m, 6 H). Example 11 l-(p-Phenoxyphenyl)-3-(4'-morpholinyl)-l -propanone hydrochloride: mp 165-170°C; IH NMR of the free base (300 MHz, CDCI3) δ 7.95 (d, 2 H), 7.4 (t, 2 H), 7.2 (t, 1 H), 7.15-6.95 (m, 4 H), 3.72 ( , 4 H), 3.15 (t, 2 H), 2.83 (t, 2 H), 2.5 (m, 4 H). Example 12 l-(p-Fluorophenyl)-3-(4'-morpholinyl)-l -propanone hydrochloride: mp 202 β C (dec); J H NMR (300 MHz, DMSO-d6) δ 10.1 (brs, 1 H), 8.1 (m, 2 H), 7.4 (m, 2 H), 4.0 (m, 2 H), 3.8-3.3 (m, 10 H). -24- Example 13 l-(o-Methoxyphenyl)-3-(4'-morpholinyl)-l -propanone hydrochloride: mp 161-163 β C; IH NMR of the free base (300 MHz, CD0 3 ) δ 7.68 (dd, 1 H), 7.45 (m, 1 H), 6.99 (m, 2 H), 3.9 (s, 3 H), 3.7 (m, 4 H), 3.2 (t, 2 H), 2.78 (t, 2 H), 2.48 (m, 4 H). Example 14 l-( -Methoxyphenyl)-3-(4'-morpholinyl)-l -propanone hydrochloride: mp 165-167 * 0; IH NMR of the free base (300 MHz, CD0 3 ) δ 7.52 (m, 2 H), 7.4 (t, 1 H), 7.12 (m, 1 H), 3.87 (s, 3 H), 3.7 (m, 4 H), 3.2 (t, 2 H), 2.83 (t, 2 H), 2.5 (m, 4 H). Example 15 l-(p-Methanesulfonamidophenyl)-3-(4'-morpholinyl)-l -propanone hydrochloride: mp 215- 218 * C; IH NMR (300 MHz, DMSO-d^) δ 11.1 (brs 1 H), 10.45 (s, 1 H), 8.0 (d, 2 H), 7.35 (d, 2 H), 4.1-3.2 (brm 12 H), 3.1 (s, 3 H). Example 16 l-(3",4"-Dichlorophenyl)-3-(4'-morpholinyl)-l -propanone hydrochloride: mp 190-191°C; IH NMR (300 MHz, DMSO-dό) δ 10.6 (brs 1, H), 8.25 (dd, 1 H), 7.9 ( , 2 H), 4.0 (m, 2 H), 3.85-3.0 (brm, 10 H). Example 17 l-(2",5"-Dichlorophenyl)-3-(4'-morpholinyl)-l-propanone hydrochloride: mp 163°C (dec); *H NMR of the free base (300 MHz, CDO3) δ 7.5-7.3 (m, 3 H), 3.68 ( , 4 H), 3.12 (t, 2 H), 2.75 (t, 2 H), 2.44 (m, 4 H). Example 18 l-(p-Chlorophenyl)-3-(4'-mo holinyl)-l -propanone: mp 90-91 β C; IH NMR (300 MHz, CDCI3) δ 7.9 (d, 2 H), 7.45 (d, 2 H), 3.71 (m, 4 H), 3.16 (t, 2 H), 2.84 (t, 2 H), 2.5 (m, 4 H). Example 19 1 -(3 "-Thienyl)-3-(4'-moτphohnyl)-l -propanone hydrochloride: mp 192-194°C; >H NMR (300 MHz, D 2 O) δ 8.3 (s, 1 H), 7.43 (m, 2 H), 3.85 (brs, 4 H), 3.55-3.1 (brm, 8 H). Example 20 l-(p-Nitrophenyl)-3-(4'-dιiomorpholinyl)-l -propanone hydrochloride: mp 203-205'C; IH NMR (300 MHz, D 2 O) δ 8.23 (d, 2 H), 8.05 (d, 2 H), 3.18-3.15 (brm, 8 H), 3.1-2.6 (brs, 4 H). Example 21 l-(m-Nitrophenyl)-3-(4'-methyl-l '-piperazinyl)- 1 -propanone dihydrochloride: mp 210-212'C; I H NMR (300 MHz, DMSO-dό) δ 12.00-11.40 (brs, 2 H), 8.70 (s, 1 H), 8.55 (d, 1 H), 8.40 (d, 1 H), 7.90 (dd, 1 H), 4.00-3.20 (m, 12 H), 2.85 (s, 3 H). -26- SUESTΠUΪE SHEET (Mill 26) Example 22 l-(p-Methylphenyl)-3-(4'-methyl-l'-piperazinyl)-l-propanone dihydrochloride: mp 199-200 * 0; IH NMR (300 MHz, DMSO-dβ) δ 12.15-7.5 (brs, 2 H), 7.90 (d, 2 H), 7.35 (d, 2 H), 4.05- 3.15 (m, 12 H), 2.85 (s, 3 H), 2.35 (s, 3 H). Example 23 l-(o-Fluorophenyl)-3-(4'-methyl- -piperazinyl)-l -propanone dihydrochloride: mp 198-200 * 0; IH NMR (300 MHz, DMSO-dβ) δ 11.90-11.50 (brs, 2 H), 8.00-6.5 (m, 2 H), 7.50-7.30 (m, 2 H), 3.90-3.15 (m, 12 H), 2.80 (s, 3 H). Example 24 l-( -Nitrophenyl)-3-(4'-/ι-propyl- -piperazinyl)-l -propanone dihydrochloride: mp 200-203'C; IH NMR (300 MHz, DMSO-d6) δ 12.20-11.50 (brs, 2 H), 8.75 (s, 1 H), 8.55 (d, 1 H), 8.40 (d, 1 H), 7.90 (dd, 1 H), 4.00-2.90 (m, 14 H), 1.72 (m, 2 H), 0.93 (t, 3 H). Example 25 l-(/n-Benzoyloxyphenyl)-3-(4'-n propyl-1 '-piperazinyl)- 1 -propanone dihydrochloride: mp 215-218°C; IH NMR (300 MHz, DMSO-dό) δ 12.00-11.30 (brs, 2 H), 8.12 (d, 2 H), 8.00-7.50 ( , 7 H), 4.00-2.90 (M, 14 H), 1.85-1.75 (m, 2 H), 0.91 (t, 3 H). -27- HEET BULE 26 Example 26 l-(m-Nitrophenyl)-3-(2',6'-dimethyl-4'-piperazinyl)-l -propanone dihydrochloride: mp 210 * C (dec); IH NMR (300 MHz, DMSO-dβ) δ 12.30-12.00 (brs, 1 H), 10.20-10.00 (brs, 1 H), 10.00-9.70 (brs, 1 H), 8.70 (s, 1 H), 8.54 (d, 1 H), 8.43 (d, 1 H), 7.90 (dd, 1 H), 4.10-2.90 (m, 10 H), 1.30 (d, 6 H). Example 27 l-(o-Fluorophenyl)-3-(2',6'-dimethyl-4'-piperazinyl)-l-propanone dihydrochloride: mp 215'C (dec); IH NMR (300 MHz, DMSO-dβ) δ 12.15 (brs, 1 H), 10.05-9.75 (brs, 1 H), 10.25- 10.05 (brs, 1 H), 7.95-7.65 (m, 2 H), 7.50-7.30 (m, 2 H), 3.90-2.95 (m, 10 H), 1.30 (d, 6 H). Example 28 1 -(/n-Chlorophenyl)-3-(4'-methyl- 1 '-piperazinyl)- 1 -propanone dihydrochloride : mp 200-205 °C; IH NMR (300 MHz, DMSO-dβ) δ 12.30-11.60 (brs, 2 H), 8.04 (s, 1 H), 7.95 (d, 1 H), 7.75 (d, 1 H), 7.60 (dd, 1 H), 4.00-3.10 (m, 12), 2.80 (s, 3 H). Example 29 l-(p-Bromophenyl)-3-(4'-methyl-l '-piperazinyl)- 1 -propanone dihydrochloride: mp 216-220°C; IH NMR (300 MHz, DMSO-dβ) δ 12.35-11.73 (brs, 2 H), 7.90 (d, 2 H), 7.79 (d, 2 H), 6.00- 3.05 (m, 12 H), 2.80 (s, 3 H). -28- Example 30 l-(m-Nitrophenyl)-3-(4'-morpholinyl)-l -propanone hydrochloride: mp 194-195"C; !H NMR (300 MHz, DMS dβ) δ 11.25-11.50 (brs, 1 H), 8.75 (s, 1 H), 8.55 (d, 1 H), 8.42 (d, 1 H), 7.90 (dd, 1 H), 4.10-3.40 (m, 10 H), 3.25-3.00 (m, 2 H). Example 31 l-(p-Metiιylphenyl)-3-(4'-morpholinyl)-l-propanone hydrochloride: mp 202-204'C; *H NMR (300 MHz, DMSO-dβ) δ 11.60-11.30 (brs, 1 H), 7.82 (d, 2 H), 7.35 (d, 2 H), 4.11-3.00 (m, 12 H), 2.40 (s, 3 H). Example 32 l-(ø-Fluorophenyl)-3-(4'-moτpholinyl)-l -propanone hydrochloride: mp 185-187'C; IH NMR (300 MHz, DMSO-dβ) δ 11.55-11.30 (brs, 1 H), 7.88-7.55 (m, 2 H), 7.50-7.22 (m, 2 H), 4.10-3.32 (m, 10 H), 3.25-3.00 (m, 2 H). Example 33 l-(m-Methanesulfonamidophenyl)-3-(4'-morpholinyl)-l -propanone hydrochloride: mp 209- 210 * C; IH NMR (300 MHz, DMSO-dβ) δ 11.35-11.17 (brs, 1 H), 10.15 (s, 1 H), 7.90-7.70 (m, 2 H), 7.60-7.40 (m, 2 H), 4.10-3.20 (m, 10 H), 3.20-3.00 (m, 2 H), 3.00 (s, 3 H). -29- Example 34 l-[m-(N-Methyl-/V-memylsdfonylamino)phenyl]-3-(4'-morpholinyl)-l-propanone hydrochloride: mp 174-175 * C; IH ΝMR (300 MHz, DMSO-d6) δ 11.25-11.05 (brs, 1 H), 8.10-7.90 (m, 2 H), 7.75 (d, 1 H), 7.65 (dd, 1 H), 4.10-3.40 (m, 10 H), 3.30 (s, 3 H), 3.23- 3.05 (m, 2 H), 3.00 (s, 3 H). Example 35 l-(p-Methyldιiophenyl)-3-(4'-morpholinyl)-l -propanone hydrochloride: A mixture of p- methyldiioacetophenone (1.10 g, 7.46 mmol), morpholine (0.50 g, 5.74 mmol, 0.05 ml), paraformaldehyde (0.34 g, 11.33 mmol) and concentrated hydrochloric acid (1.43 ml) in 30 ml. isopropanol were refiuxed for 48 h. The reaction was cooled, filtered and die filter cake was triturated with acetone to give 1.10 g (~ 64%) of the desired product: mp 200-202°C; 'H ΝMR (300 MHz, DMSO-d6) δ 11.40-11.05 (brs 1 H), 7.93 (d, 2 H), 7.40 (d, 2 H), 4.10-3.32 (m, 10 H), 3.20-3.00 (m, 2 H), 2.55 (s, 3 H). Example 36 l-(p-Methoxyphenyl)-3-(4'-morpholinyl)-l -propanone hydrochloride: mp 207-210°C; Η ΝMR (300 MHz, DMSO-d6) δ 11.30-11.10 (brs, 1 H), 8.00 (d, 2 H), 7.10 (d, 2 H), 4.10-3.05 (m, 12 H), 3.85 (s, 3 H). -30- Example 37 l-(4"-Fluoronaphth-l"-yl)-3-(4'-morpholinyl)-l-propanone hydrochloride: mp 180-182'C; *H NMR (300 MHz, DMSO-dβ) δ 11.00-10.95 (brs, 1 H), 8.75 (d, 1 H), 8.40-8.25 (m, 1 H), 8.15 (d, 1 H), 7.70 (m, 2 H), 7.60-7.50 (m, 1 H), 4.00-3.10 (m, 12 H). Example 38 l-( -Chlorophenyl)-3-(4'-morpholinyl)-l -propanone hydrochloride: mp 188-190 * 0; IH NMR (300 MHz, DMSO-d6) δ 11.25-11.00 (brs, 1 H), 8.05 (s, 1 H), 7.95 (d, 1 H), 7.75 (d, 1 H), 7.65 (dd, 1 H), 4.10-3.05 (m, 12 H). Example 39 1 -( 1 ",2",3",4"-Tetrahydronaphth-6"-yl)-3-(4'-morpholinyl)- 1 -propanone hydrochloride: mp 190 * 0; IH NMR (300 MHz, CDC1 3 ) δ 13.40-13.10 (brs, 1 H), 7.80-7.60 (m, 2 H), 7.16 (d, 1 H), 4.30 (t, 2 H), 4.10-3.90 (m, 2 H), 3.76 (t, 2 H), 3.60-3.30 (m, 4 H), 3.10-2.70 (m, 6 H), 1.90-1.70 (brs, 4 H). Example 40 l-(p-Trifiuoromethoxyphenyl)-3-(4'-moφholinyl)-l -propanone hydrochloride: mp 175-178 * 0; IH NMR (300 MHz, DMSO-dβ) δ 11.15-10.90 (brs 1 H), 8.15 (d, 2 H), 7.55 (d, 2 H), 4.08- 3.40 (m, 10 H), 3.25-3.00 (m, 2 H). -31- Example 41 l-(2",3"-Dihydro-l",4"-benzodioxan-6"-yl)-3-(4'-morpholinyl)-l-propanone hydrochloride: mp 223-225 * 0; IH NMR (300 MHz, DMSO-dβ) δ 11.25-11.50 (brs, 1 H), 7.65-7.40 (m, 2 H), 7.05 (d, 1 H), 4.50-4.15 (m, 4 H), 4.05-3.30 (m, 10 H), 3.20-3.00 (m, 2 H). Example 42 l-(p-Bromophenyl)-3-(4'-moφholinyl)-l-propanone hydrochloride: mp 209-212 * 0; IH NMR (300 MHz, DMSO-dβ) 11.55-11.30 (brs, 1 H), 7.95 (d, 2 H), 7.75 (d, 2 H), 4.10-3.35 (m, 10 H), 3.25-3.00 (m, 2 H). Example 43 l-(p-Ethylphcnyl)-3-(4'-morpholinyl)-l -propanone hydrochloride: mp 202-205'C; - NMR (300 MHz, DMSO-dβ) 11.65-11.35 (brs, 1 H), 7.95 (d, 2 H), 7.40 (d, 2 H), 4.08-3.30 (m, 10 H), 3.25-3.00 (m, 2 H), 2.70 (q, 2 H), 1.20 (t, 3 H). 1 ,4-Bis-(3'-Phenylpropane-3'-one-l '-yl)-piperazine dihydrochloride: A mixture of acetophenone (3.49 g, 0.029 mol), piperazine (1.00 g, 0.012 mol), paraformaldehyde (0.87 g, 0.029 mol), and concentrated hydrochloric acid (5.00 mL, 0.06 mol) were refiuxed for 24 h. The reaction was cooled, filtered and the filter cake was triturated widi methanol to give 3.5 g (83%) of the desired product: mp 230 * C (dec); IH NMR of the free base (300 MHz, 0DO3) δ 7.96 (d, 4 H), 7.51 (m, 6 H), 3.19 (t, 4 H), 2.85 (t, 4 H), 2.58 (brs, 8 H). -32- SUBSTITUTE SHEET RILE 25 Example 45 l,4-Bis-(3'-Phenylpropane-3'-one-r-yl)-2,5-dimethylpiperazine dihydrochloride: mp 250 * 0; IH NMR of the free base (300 MHz, 0DO 3 ) δ 7.98 (d, 4 H), 7.51 (m, 6 H), 3.21 (m, 6 H), 2.82 (m, 4 H), 2.49 (m, 2 H), 2.14 (t, 2 H), 1.08 (d, 6 H). Example 46 l,4-Bis-(3'-p-fluorophenylpropane-3'-one-l'-yl)-piperazine: mp 170-173 * C; IH NMR (300 MHz, CDC1 3 ) δ 7.98 (m, 4 H), 7.13 (m, 4 H), 3.18 (t, 4 H), 2.86 (t, 4 H), 2.59 (brs, 8 H). Example 47 l,4-Bis-[3'-(3",4"-dichlorophenyl)-propane-3'-one- -yl]-piperazine dihydrochloride: mp > 230 * 0; IH NMR of the free base (300 MHz, 0DO ) δ 8.03 (d, 2 H), 7.78 (dd, 2 H), 7.55 (d, 2 H), 3.14 (t, 4 H), 2.82 (t, 4 H), 2.56 (brs, 8 H). Example 48 l,4-Bis-(3'-/7-chlorophenylpropane-3'-one- -yl)-piperazine dihydrochloride: mp > 230 * C; J H NMR of the free base (300 MHz, CDCI 3 ) δ 7.9 (d, 4 H), 7.43 (d, 4 H), 3.15 (t, 4 H), 2.84 (t, 4 H), 2.56 (brs, 8 H). -33- Example 49 l,4-Bis-(3'-m-chlσrophenylpropane-3'-one-l'-yl) piperazine: mp 121-122 * 0; IH NMR (300 MHz, 0DO 3 ) δ 7.95 (s, 2 H), 7.82 (d, 2 H), 7.55 (d, 2 H), 7.40 (t, 2 H), 3.15 (t, 4 H), 2.85 (t, 4 H), 2.70-2.40 (brs, 8 H). Example 50 l,4-Bis-(3'-p-bromophenylpropane-3'-one-l'-yl) piperazine: mp 158-160 * C; IH NMR (300 MHz, 0DO3) δ 7.85 (d, 4 H), 7.60 (d, 4 H), 3.15 (t, 4 H), 2.85 (t, 4 H), 2.65-2.40 (brs, 8 H). Example 51 l,4-Bis-(3'-p-medιylphenylpropane-3'-one-l'-yl) piperazine: mp 229-231 * C; *H NMR (300 MHz, 0DO 3 ) δ 7.86 (d, 4 HO, 7.26 (d, 4 H), 3.17 (t, 4 H), 2.83 (t, 4 H), 2.67-2.45 (brs, 8 H), 2.40 (s, 6 H). Example 52 l,4-Bis-(3'-o-fluorophenylpropane-3'-one-l'-yl) piperazine: >H NMR (300 MHz, DMSO-dβ) δ 7.85-7.55 (m, 4 H), 7.40-7.20 (m, 4 H), 3.10 (t, 4 H), 2.62 (t, 4 H), 2.43-2.20 (brs, 8 H). Example 53 l,4-Bis-(3'-m-nitrophenylpropane-3'-one- -yl) piperazine: mp 154-155 * 0; Η NMR (300 MHz, CDC1 3 ) δ 8.80 (s, 2 H), 8.42 (d, 2 H), 8.27 (d, 2 H), 7.69 (t, 2 H), 3.21 (t, 4 H), 2.56 (t, 4 H), 2.70-2.40 (brs 8 H). -34- SUBSTITUTE SHEET (PULE 26. Example 54 1 -(/?-NitrophenyI)-3-(4'-methyl- 1 '-piperazinyl)- 1 -propanone dihydrochloride: mp 225-226 * C; IH NMR (300 MHz, DMSO-dβ) δ 12.1 (s, 2 H), 8.4 (d, 2 H), 8.2 (d, 2 H), 4.25-3.18 (m, 12 H), 2.85 (s, 3H). Example 55 l-(p-Nitrophenyl)-3-(2',6'-dimethyl-4'-piperazinyl)-l -propanone dihydrochloride: mp > 260 * 0; IH NMR (300 MHz, D2O) δ 7.95 (d, 2 H), 7.78 (d, 2 H), 3.58 (m, 2 H), 3.39 (m, 6 H), 2.83 (t, 2 H). Example 56 l-(p-Nitrophenyl)-3-(4'-morpholinyl)-l -propanone hydrochloride: mp 214-216'C; IH NMR (300 MHz, D O) δ 8.2 (d, 2 H), 8.02 (d, 2 H), 4.1-3.0 (m, 12 H). Example 57 l-(p-Iodophenyl)-3-(4'-methyl- -piperazinyl)-l-propanone dihydrochloride: mp 224-225'C; IH NMR (300 MHz, DMSO-dβ) δ 11.94 (brs, 2 H), 7.99 (d, 2 H), 7.87 (d,. 2 H), 4.18-3.05 (brm, 12 H), 2.81 (s, 3 H). Example 58 l-(p-Iodophenyl)-3-(4'-morpholinyl)-l -propanone hydrochloride: mp 224-225°C; IH NMR (300 MHz, DMSO-dβ) δ 11.09 (s, 1 H), 8.02 (d, 2 H), 7.89 (d, 2 H), 4.10-2.95 (m, 12 H). Example 59 l-(m-Fluorophenyl)-3-(4'methyl- -piperazinyl)-l -propanone dihydrochloride: mp 189-190 * C; IH NMR (300 MHz, DMSO-dβ) δ 11.95 (s, 2 H), 4.0-3.1 (m, 12 H), 2.8 (s, 3 H). -35- Example 60 l-(m-Ruorophenyl)-3-(4'-morpholinyl)-l -propanone hydrochloride: mp 185-186 * 0; J H NMR of the free base (300 MHz, CDθ3) δ 7.75 (m, 1 H), 7.64 (m, 1 H), 7.46 (m, 1 H), 7.28 (m, 1 H), 3.7 (m, 4 H), 3.18 (t, 2 H), 2.83 (t, 2 H), 2.51 ( , 4 H). Example 61 l-p-Biphenyl-3-(4'-mσrpholinyl)-l -propanone hydrochloride: mp 192- 194° C; IH NMR of the free base (300 MHz, CDθ3) δ 8.05 (d, 2 H), 7.67 (dd, 4 H), 7.45 (m, 3 H), 7.73 ( , 4 H), 3.22 (t, 2 H), 2.86 (t, 2 H), 2.53 (m, 4 H). Example 62 l-p-Biphenyl-3-(4'-methyl- -piperazinyl)-l-propanone: The solid was basified widi NH4OH, extracted widi dichloromediane and evaporated and dried: mp 103-104°C; *H NMR (300 MHz, CDCI3) δ 8.03 (d, 2 H), 7.67 (dd, 4 H), 7.44 (m, 2 H), 3.23 (t, 2 H), 2.9 (t, 2 H), 2.54 (m, 8 H), 2.31 (s, 3 H). Example 63 1 -(p-Methylsulfonamidophcnyl)-3-(4'-methyl- 1 -piperazinyl)- 1 -propanone dihydrochloride: mp 199-200" C; IH NMR (300 MHz, 0DO 3 ) δ 11.9 (s, 2 H), 10.28 (s, 1 H), 8.0 (d, 2 H), 7.25 (d, 2 H), 4.8-2.6 (m, 18 H). Example 64 l-(m-Fluorophenyl)-3-(2',6'-dimethyl-4'-piperazinyl)-l -propanone dihydrochloride: mp > 235°C (dec); IH NMR (300 MHz, DMSO-dβ) δ 9.88 (m, 2 H), 7.8 (dd, 2 H), 7.6 (m, 2 H), 4.08-2.9 (m, 10 H), 1.31 (d, 6 H). Example 65 l,4-Bis-(3'- -fluorophenylpropane-3'-one- -yl) piperazine: The solid was basified widi NH4OH, extracted with dichloromethane, dried and filtered: mp 111-112 * C; IH NMR (300 MHz, CD0 3 ) δ 7.72 (d, 2 H), 7.63 (m, 2 H), 7.45 (m, 2 H), 7.28 (m, 2 H), 3.18 (t, 4 H), 2.86 (t, 2 H), 2.57 (brm, 8 H). Example 66 l,4-Bis-(3'-p-Nitrophenylpropane-3'-one-l'-yl) piperazine: The solid was basified widi NH4OH, extracted with dichloromediane and purified via flash chromatography (Silica, 9:1 EtOA MeOH): mp 185-186'C (dec); IH NMR (300 MHz, CDCI3) δ 8.32 (d, 4 H), 8.11 (d, 4 H), 3.23 (t, 4 H), 2.86 (t, 4 H), 2.57 (brs, 8 H). Example 67 Effect of Chlorpromazine on Paired Helical Filament Levels in Human Brain Tissue The in vitro analyses described herein to investigate die activity of the compounds of tiiis invention can also be used to determine the nature of abnormally phosphorylated paired helical filament epitopes involved in Alzheimer's Disease, the regulatory mechanisms involved with Alzheimer's Disease and modifications of the protein tau and other polypeptides associated with PHFs and involved in Alzheimer's Disease. Certain phenothiazines, for example, chlorpromazine, can markedly inhibit die expression of PHF epitopes (as determined by loss of immunoreactivity widi Alzheimer's Disease specific antibodies) upon treatment of MSNla cells with okadaic acid (cf. Figure 3). These compounds are effective at micromolar concentrations, with increased potency being evident when cells are treated prior to the addition of okadaic acid. The effective concentrations appear to be in the range at which these drugs are present in the brain following chronic treatment of psychiatric patients (Svendsen, CN, Psychopharmacology, 90, 316-321, 1986). These results indicate diat patients who were chronically treated with phenothiazines would be protected from the -37- development of PHF, and thus would have a low probability of development of Alzheimer's Disease. Frontal and cortical brain tissue specimens obtained at autopsy from patients chronically treated widi chlorpromazine were analyzed using the ALZ-EIA method previously described (Ghanbari, HA, et al, JAMA, 263, 2907, 1990). The results are shown in Figures 4A and 4B frontal (Broadman area 10) and temporal (Broadman area 38) regions, respectively. The brain tissue (post-mortem) from approximately the same number of (age matched) normal controls and Alzheimer's Disease patients were also analyzed and are presented in these figures as negative and positive controls (for normal and AD, respectively). As the data indicate, the samples from chlorpromazine treated patients (Rx) had low PHF epitope levels similar to normal controls, whereas the PHF epitope levels in the AD group were clearly much higher. Furthermore, tiiese results were consistent with histopathological diagnosis of die brain specimens. Statistically, in the general population, about 20-30% of the individuals in the Rx age group would have developed AD and hence much higher PHF in the brain regions indicated (Katzman, R., Kawas, C. H., pages 105-122, in Alzheimer's Disease, Eds., Teπy, RD; Katzman, R; Bick, KL. Raven Press, New York, 1994). This evidence shows that chronic treatment of patients with chlorpromazine prevents PHF formation and AD. In a subsequent study, 51 additional patients were identified and the analysis was repeated as above using the TG3 antibody in an ELISA format. The results, summarized in Table 1, clearly reproduce and confirm the first retrospective study. Immunohistopathological studies carried out on several brain regions from these patients were consistent with these ELISA results. Taken together, these two studies provide evidence of the therapeutic benefit of chlorpromazine in AD and validate the use of the MSNla model for the identification of dierapeutically useful compounds for the treatment of AD. -38- SUBSTITUTE SHEET (RULE 26 TABLE 1 N MEAN AGE ± SEM SIGNAL* ± SEM Frontal Temporal Normal (12) 79.50 ± 3.33 0.12 1 0.12 0.00 ± 0.00 AD (28) 82.54 ± 1.94 16.54 ± 2.59 17.55 ± 2.82 Rx (51) 76.88 ± 1.55 0.12 1 0.11 0.16 1 0.11 * Signal is calculated by summing the means of duplicate absorbance readings (direct ELISA using TG3 antibody) for 8 dilutions of all lysates prepared by one to two serial dilutions. Efforts to dissect the characteristic lesions of Alzheimer's Disease, namely the neurofibrillary tangles and die neuritic plaques have indicted that aberrant protein phosphorylation is a hallmark of the cytoskeletal abnormalities in AD. Phosphorylated sites on the PHFs found in neurofibrillary tangles and abnormal neurites are detected by AD-specific antibodies, such as TG3 and PHF-1, in the brains of AD patients and not in normal or other neurodegenerative disease controls (cf. Figure 1, 2A). In the MSNla cell culture model (cf. Figure 2B, 3), these aberrandy phosphorylated PHF sites are also detected by these antibodies. Therefore, the therapeutic activity of the compounds of the invention was assessed by die ability of these agents to affect the production of abnormally phosphorylated epitopes pertinent to the production of PHFs of AD, utilizing a human neuroblastoma cell line (MSNla) in the presence of the protein phosphatase inhibitor, okadaic acid (OKA). As described above, chlorpromazine, a clinically used antipyschotic, prevents production of the aberrantly phosphorylated PHF epitopes and, hence, die production of PHFs, thereby preventing AD. As shown in Figures 2B and 3, and in Table 2, chlorpromazine is effective in inhibiting the production of these aberrant phosphorylated epitopes in the MSNla cell culture model as determined by die prevention of the immunoreactivity associated widi PHF antibodies such as TG3 which was utilized in the retrospective clinical analysis. -39- To determine die effect of chlorpromazine on the paired helical filament epitopes associated with AD, MSNla cells expressing paired helical filament epitopes were incubated widi 100 mM chlorpromazine (CPZ) or a 0.2% DMSO vehicle control for 2 hours at 37'C. The cells were isolated by centrifugation, boiled for 10 minutes and 25 mg protein from the resulting heat stable supematants were loaded per lane on an SDS-PAGE gel. The gel was electrophoretically transferred to nitrocellulose membrane and then immunostained with PHF-1. As shown in Figure 3, CPZ gready decreased die production of paired helical filament epitopes by the MSNla cells. In contrast, the control shows diat without the addition of CPZ, there was production of paired helical filament epitopes by the MSNla cells. The use of the MSNla cell culture model for screening of novel compounds for therapeutic activity in AD is, therefore, quite warranted. This assay can thus be used to determine whether a drug is capable of preventing or intervening in AD by attenuating the production of abnormally phosphorylated paired helical filament epitopes associated widi AD. To determine whedier a drug is capable of preventing or intervening in AD activity, the MSNla cells containing tau and associated proteins are treated widi OKA capable of gready increasing immunoreactivity of the MSNla cells with AD specific monoclonal antibodies. Then, either prior to or concomitandy widi OKA treatment, a compound of die present invention is added to the culture. If he compound prevents the induction of the AD epitopes in the MSNla cells treated widi OKA, then it is said to have ami- AD activity. If the AD-specific antibodies are highly reactive with the neuroblastoma cells following OKA treatment in the presence of compound, then the compound is said to be ineffectual against AD. The MSNla human neuroblastoma line was subcloned from a population of MSN cells obtained from the laboratory of Dr. Peter Davies (Albert Einstein College of Medicine, New York, NY). Cells were grown and maintained in flasks in RPMI 1640 medium, supplemented with 15% fetal calf serum, 100 U/ml penicillin, 100 U/ml Streptomycin, 0.5 ug/ml fungizone under 7.5% CO2 at 37'C. Stock solutions of drugs were prepared by dissolving the anhydrous powders to final concentrations of eidier 10 or 20 mM in 50% aqueous or 100% dimethyl sulfoxide (DMSO), respectively. Working solutions of drugs were prepared by dilution of die stock solutions widi Kreb's Ringer in Hepes buffer (KRH) (128 mM NaCl, 5 mM KC1, 2.5 mM CaCl2 1.2 mM -40- W MgSO4, 1 mM Na2HPO4, 10 mM dextrose, 20 mM Hepes, pH 7.4). OKA is maintained as a 1 mM stock solution in DMSO prior to dilution to 4 μM in KRH. MSN cells grown in 225 cm 2 flasks are removed from the incubator, their medium decanted and replaced with 50 ml pre-warmed KRH. The cells are harvested by scraping prior to sedimentation at 1000 rpm for 5 min. The supematants are discarded and the cell pellets are resuspended, die cells counted and diluted to a density of 2 x 104 cells 50 ml. The cells are then plated in a % well plate at 50 μl/well and 25 μl of 4 μM OKA and 25 μl of drug are then added to the appropriate wells; the entire 96 well plate is then incubated for 2 hrs at 37 * 0. Depending on die dilution of drug added, this yields individual wells containing 1 μM OKA, 0-64 μM drug and 2 x 104 cells in 0.26% DMSO in KRH. The incubation is terminated by the addition of 20 μl of 6X extraction buffer and immediate freezing at -80 * C for at least one hr. The 6X extraction buffer contains: 25 mM Tris-HCl, pH 7.6, 150 mM NaCl, 5 mM EDTA, 24 mM β-glycerol phosphate, 10 μg/ml APMSF (4-amidinophenylmethane-sulfonyl flouride), and 2.5 μg ml each of leupeptin, aprotinin, and pepstatin. The plates are thawed in a 37 * 0 water badi and 20 μl of cell lysate is added to a replica well in an ELISA plate that alread contains 80 μl of coating buffer (15 mM Na2CO3 and 35 mM NaHCO3, pH 9.6). The plates are allowed to coat overnight at 4 * 0. The plates are washed four times with deionized water and tiien blocked for 30 min at 37 * 0 with 200 μl/well pre-warmed 1% bovine serum albumin in 10 mM Tris-HCl, pH 7.4, 150 mM NaCl, 3 mM NaN3 (BSA-TBS). After the blocking solution is removed, 100 μl well of an appropriate dilution of pre-warmed primary antibody (eg., TG3 or PHF- 1) in BSA- TBS is added and incubated at 37 * 0 for 30 min. Incubation is terminated by washing four times in deionized water at which time 100 μl of an appropriate dilution of pre-warmed secondary antibody (conjugated to alkaline phosphatase) in BSA-TBS is added to each well in die ELISA plate. Incubation is performed for 30 min at 37 * 0 followed by washing 4 times with deionized water. 100 μl ml of prewarmed chromogenic substrate (1 mg/ml p-nitrophenyl phosphate in 10% dietiianolamine, 3 mM NaN3, 0.5 mM MgCl2, pH 9.8) is added and die plate incubated for 30 min at 37 * C. Absorbance at 405 nm is then determined by reading die plate on a BioRad UV Microplate Reader. -41- Results obtained from the MSNla cell culture model studies utilizing the TG3 antibody are shown in Table 2 for a representative sample of compounds disclosed herein. TABLE 2 IC50 for inhibition of TG3 immunoreactivity in OKA treated MSNla cells Example * IC50 (μM) Chlorpromazine -70.0 1 12.4 5 15.8 9 5.4 13 9.1 17 15.8 23 13.2 26 7.3 30 5.9 34 7.5 38 5.8 42 6.4 45 11.4 As seen in Table 2, the compounds of the present invention are potent inhibitors of the production of die aberrandy phosphorylated epitopes as detected in die MSNla cell culture model system utilizing the antibody TG3. As shown, die compounds of the present invention are more potent than chlorpromazine, which was shown in the retrospective clinical study to both inhibit the production of the AD associated epitopes and prevent AD. The compounds of the present invention are thus useful in the treatment of AD. -42-

Claims: What is claimed is: 1. A method of preventing Alzheimer's Disease comprising administering to a patient susceptible to the disease an amount effective to inhibit formation of abnormal phosphorylated paired helical filament epitopes of a compound of die formula: or the pharmaceutically acceptable salts thereof wherein X represents oxygen, sulfur or NR; wherein R is selected from hydrogen, loweralkyl and CH2CH2COArι; Z is hydrogen; straight or branched chain alkyl having 1 -6 carbon atoms; or Z and R l , R2 or R3 together represent CH2; CH2CH2; CH2O; or CH2S forming a five or six membered ring and such ring may be optionally substituted with loweralkyl or phenyl; R24 is hydrogen; loweralkyl, or optionally substituted phenyl; each Rio independendy represents hydrogen or loweralkyl; and Ari is a group of the formula: wherein R l, R2 and R3 independently represent hydrogen, halogen, nitro, cyano, alkoxy, phenoxy, benzoyloxy, benzyloxy, alkylsulfonylamino, trifluoromethyl, trifluoromethoxy, thioloweralkoxy, thienyl, furyl, mediylsulfinyl, phenyl, loweralkyl; or Ari is a group of the formula: -43- wherein tf Y is oxygen or sulfur Zi is oxygen or methylene R4 and R5 are independendy selected from hydrogen, halogen, loweralkoxy, hydroxy; and R6, R7, R8, and R9 are independendy selected from hydrogen, halogen, nitro, cyano, loweralkyl, phenyl, optionally substituted phenyl, diienyl or optionally substituted thienyl. R24 is hydrogen; loweralkyl, or optionally substituted phenyl. A metiiod according to Claim 1, wherein the compound has the formula: wherein: Rl is hydrogen, loweralkyl of 1 to 4 carbons, benzyl, phenyl or 2-, 3-, or 4-pyridyl; R2 and R3 independendy represent Ci-Cβ alkyl, C2-C8 alkenyl or C3-C8 cycloalkyl, phenyl, halogenated-phenyl or loweralkoxyphenyl; R4 is hydrogen or C1-C4 alkyl attached to carbon atom 6 or 7 of the indole nucleus; X and Y are lower alkyl, hydroxy lower alkyl, lower acyloxy alkyl, carbamoyloxy lower alkyl and phenyl lower alkyl; or NXY represents a heterocyclic ring having a maximum of 8 members. \' 3. A method according to Claim 1 , wherein the compound is selected from the group consisting of: (a) l-Phenyl-3-(4'-methyl-l'-piperazinyl)-l-propanone dihydrochloride; (b) 1 -(m-Methylphenyl)-3-(4'-methyl- 1 '-piperazinyl)- 1 -propanone dihydrochloride; (c) l-(p-Phenoxyphenyl)-3-(4'-methyl-r-piperazinyl)-l-propanone dihydrochloride; (d) l-Phenyl-3-(4'-n-propyl-r-piperazinyl)-l-propanone dihydrochloride; (e) l-( -Methylphenyl)-3-(4 , -propyl- -piperazinyl)-l-propanone dihydrochloride; (f) 1 -(p-Phenoxyphenyl)-3-(4'-/t-propyl- 1 '-piperazinyl)- 1 -propanone; (g) 1 -(3",4"-Dichlorophenyl)-3-(4'-methyl- 1 '-piperazinyl)- 1 -propanone hydrochloride; (h) 1 -(p-Chlorophenyl)-3-(4'-methyl- 1 '-piperazinyl)- 1 -propanone hydrochloride; (i) 1 -( -Nitrophenyl)-3-(4'-methyl- 1 '-piperazinyl)- 1 -propanone dihydrochloride; (j) 1 -(p-Methylphenyl)-3-(4'-methyl- 1 '-piperazinyl)- 1 -propanone dihydrochloride; (k) 1 -( -Chlorophenyl)-3-(4'-methyl- 1 '-piperazinyl)- 1 -propanone dihydrochloride; (1) l-(p-Bromophenyl)-3-(4'-medιyl-l -piperazinyl)- 1 -propanone dihydrochloride; (m) 1 -(p-Iodophenyl)- 3-(4'-methyl- 1 '-piperazinyl)- 1 -propanone dihydrochloride; (n) 1 -(m-Fluorophenyl)-3-(4'methyl- 1 '-piperazinyl)- 1 -propanone dihydrochloride; (0) 1 -p-Biphenyl-3-(4'-methyl- 1 '-piperazinyl)- 1 -propanone; (p) 1 -(p-Methylsulfonamidophenyl)-3-(4'-methyl- 1 '-piperazinyl)- 1 -propanone dihydrochloride; (q) 1 -(p-Nitrophenyl)-3-(4'-methyl- 1 '-piperazinyl)- 1 -propanone dihydrochloride. 4. A method according to Claim 1 , wherein the compound is selected from the group consisting of: (a) 1 -(m-Methylphenyl)-3-(4'-morpholinyl)- 1 -propanone hydrochloride; (b) l-(p-Phenoxyphenyl)-3-(4'-morpholinyl)-l-propanone hydrochloride; (c) 1 -(p-Fluorophenyl)-3-(4'-morpholinyl)- 1 -propanone hydrochloride; (d) 1 -(ø-Methoxyphenyl)-3-(4'-morpholinyl)- 1 -propanone hydrochloride; (e) l-( -Methoxyphenyl)-3-(4'-morpholinyl)-l -propanone hydrochloride; (f) l-(p-Methanesulfonamidophenyl)-3-(4'-morphohnyl)-l -propanone hydrochloride; (g) 1 -(3",4"-Dichlorophenyl)-3-(4'-morpholinyl)- 1 -propanone hydrochloride; (h) 1 -(2",5"-Dichlorophenyl)-3-(4'-morpholinyl)- 1 -propanone hydrochloride; (i) l-(p-Chlorophenyl)-3-(4'-morpholinyl)-l-propanone; (j) l-(-7i-Nitrophenyl)-3-(4'-morpholinyl)-l -propanone hydrochloride; (k) 1 -(p-Methylphenyl)-3-(4'-moτpholinyl)- 1 -propanone hydrochloride; (1) l-(ø-Fluorophenyl)-3-(4'-morpholinyl)-l-propanone hydrochloride; -45- (m) 1 -( -Methanesulfonamidophenyl)-3-(4'-moφholinyl)- 1 -propanone hydrochloride; (n) l-I -(N-Methyl-N-me ykulfonylaιmno)phenyl]-3-(4'-morpholinyl)- 1 - propanone hydrochloride; (o) l-(p-Methoxyphenyl)-3-(4'-moφholinyl)-l-propanone hydrochloride; (p) 1 -(m-ChlGrophenyl)-3-(4'-mσrpholinyl)- 1 -propanone hydrochloride; (q) l-(3"-Thienyl)-3-(4'-morpholinyl)-l-propanone hydrochloride; (r) 1 -(p-Trifluoromethoxyphenyl)-3-(4'-morpholinyl)- 1 -propanone hydrochloride; (s) 1 -(p-Ethylphenyl)-3-(4'-moιpholinyl)- 1 -propanone hydrochloride; (t) l-(p-Iodophenyl)-3-(4'-mσφholinyl)-l -propanone hydrochloride; (u) 1 -(m-Huσrophenyl)-3-(4'-morpholinyl)- 1 -propanone hydrochloride; (v) 1 -/»-Biphenyl-3-(4'-morpholinyl)- 1 -propanone hydrochloride; ( w) 1 -(p-Νitrophenyl)-3-(4'-moτpholinyl)- 1 -propanone hydrochloride. 5. A method according to Claim 1 , wherein the compound is selected from the group consisting of: (a) 1 -(p-Nitrophenyl)-3-(4'-thiomσrpholinyl)- 1 -propanone hydrochloride; (b) 1 -(p-Medιyldιiophenyl)-3-(4'-morpholinyl)- 1 -propanone hydrochloride; (c) 1 -(4"-Fluoronaphth- 1 "-yl)-3-(4'-morpholinyl)- 1 -propanone hydrochloride; (d) 1 -( 1 ",2",3",4"-Tetrahydronaphth-6"-yl)-3-(4'-morpholinyl)- 1 -propanone hydrochloride; (e) 1 -(2",3"-Dihydro- 1 ",4"-benzodioxan-6"-yl)-3-(4'-morpholinyl)- 1 -propanone hydrochloride. 6. A method according to Claim 1 , wherein the compound is selected from the group consisting of: (a) 1 -( -Nitrophenyl)-3-(2',6'-dimethyl-4'-piperazinyl)- 1 -propanone dihydrochloride; (b) 1 -(ø-Fluorophenyl)-3-(2',6'-dimedιyl-4'-piperazinyl)- 1 -propanone dihydrochloride; (c) 1 -(p-Nitrophenyl)-3-(2',6'-dimedιyl-4'-piperazinyl)- 1 -propanone dihydrochloride; (d) 1 -(m-Fluorophenyl)-3-(2',6'-dimedιyl-4'-piperazinyl)- 1 -propanone dihydrochloride. 7. A method according to Claim 1 , wherein the compound is selected from the group consisting of: (a) 1 ,4-Bis-(3'-Phenylpropane-3'-one- 1 '-yl)-piperazine dihydrochloride; -46- (b) 1 ,4-Bis-(3'-Phenylpropane-3'-one- 1 '-yl)-2,5-dimethylpiperazine dihydrochloride; (c) 1 ,4-Bis-(3'-/7-fluorophenylpropane-3'-one- 1 '-yl)-piperazine; (d) 1 ,4-Bis-[3'-(3",4"-dichlσrophenyl)-propane-3'-one- 1 '-yl] -piperazine dihydrochloride; (e) 1 ,4-Bis-(3'-/7-chlorophenylpropane-3'-one- 1 '-yl)-piperazine dihydrochloride; (f) l,4-Bis-(3'-/n-chlorophenylpropane-3'-one-l'-yl) piperazine (g) l,4-Bis-(3'- )-bromophenylpropane-3'-one-r-yl) piperazine; (h) 1 ,4-Bis-(3'-/7-methylphenylpropane-3'-one- 1 -yl) piperazine; (i) l,4-Bis-(3'-ø-fluorophenylpropane-3'-one-l'-yl) piperazine; (j) l,4-Bis-(3'-/n-nitrophenylpropane-3'-one-l'-yl) piperazine; (k) l,4-Bis-(3'- -fluorophenylpropane-3'-one-l'-yl) piperazine; fl) l,4-Bis-(3'-p-Nitrophenylpropane-3'-one- -yl) piperazine; -47-

Inventors: DEBERNARDIS JOHN F, KERKMAN DANIEL J, DEBERNARDIS, JOHN, F., KERKMAN, DANIEL, J.
Applicants: DEBERNARDIS JOHN F, KERKMAN DANIEL J, MOLECULAR GERIATRICS CORP, DEBERNARDIS, JOHN, F., KERKMAN, DANIEL, J., MOLECULAR GERIATRICS CORPORATION
Application year: 1995
Main classification: A61K31
IPC codes: A61K31, C07D279, C07D295, C07D333