WO2004075847A2 - METHODS AND COMPOUNDS FOR THE TREATMENT OF Aß­ ASSOCIATED DISEASES, DISORDERS, AND CONDITIONS - Google Patents

Abstract

The invention features compounds and methods of the treatment of Aß­associated diseases, disorders, or conditions. The compounds are generically represented by the following formulae (I, II, III, IV) and, wherein the substituents are as described in the specification.

Description

METHODS AND COMPOUNDS FOR THE TREATMENT OF AB- ASSOCIATED DISEASES, DISORDERS, OR CONDITIONS

BACKGROUND OF THE INVENTION

The invention relates to the fields of chemical compounds and their therapeutic use for treating Aβ-associated diseases. Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by memory loss, language deterioration, impaired visuospatial skills, poor judgment, indifferent attitude, but preserved motor function. Alzheimer's disease usually begins after age 65, but its onset may occur as early as age 40. This disease is generally diagnosed first from memory decline and, over subsequent years, destroyed cognition, degeneration of personality, and general loss of the ability to function. Confusion and restlessness may also occur. The type, severity, sequence, and progression of changes associated with AD vary widely. The early symptoms of Alzheimer's disease, which include forgetfulness and loss of concentration, can easily be missed because they resemble natural signs of aging. Similar symptoms can also result from fatigue, grief, depression, illness, vision or hearing loss, the use of alcohol or certain medications, or simply the burden of too many details to remember.

At the level of cellular pathology, Alzheimer's disease is characterized by the presence of plaques in the brain. These plaques contain the β-amyloid peptides (e.g., AβX-40 and AβX-42). Aβ peptide is formed during processing of a larger membrane bound protein amyloid precursor protein (APP). Predominant cleavage of the extracellular domain of APP results in the production of soluble APPα (sAPPα). This cleavage occurs in the middle of the Aβ sequence and does not produce Aβ. An alternative cleavage of APP at the N-terminus of the Aβ sequence releases a slightly truncated form of sAPP (sAPPβ). The remaining membrane bound protein is further processed by release of Aβ peptides.

Compounds that reduce the concentration of Aβ by reducing the levels of APP have been studied as potential therapeutic compounds for the treatment of Alzheimer's disease. Altematively, protease inhibitors that inhibit the cleavage events leading to the production of Aβ have been proposed as potential therapeutic compounds. Furthermore, compounds known to affect the processing events through indirect inhibition have also been proposed as potential therapeutics. Despite these approaches a cure or long-term treatment has remained elusive.

In addition to Alzheimer's disease, Aβ appears to be associated with other diseases, disorders, and conditions, e.g., inclusion body myositis. These additional diseases, disorders, or conditions may also be treated by administering compounds that reduce the concentration of Aβ. Thus, there is a need for new compositions and methods of treating such Aβ-associated diseases, disorders, and conditions.

SUMMARY OF THE INVENTION The invention features compositions and methods for the treatment of Aβ-associated diseases, disorders, or conditions, e.g., Alzheimer's disease. These compositions appear to reduce the concentration of Aβ, often without reducing the concentration of sAPPα. Administration of such compounds are useful to treat an individual suffering from, at risk for, or in the process of developing an Aβ-associated disease, disorder, or condition and should ameliorate, delay, or arrest the pathology and symptoms of Aβ-associated diseases.

In one aspect, the invention features a compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein R¹ is H, alkoxy, or halo, R² is alkyl, R³ is H, alkyl, alkaryl, or C(O)R⁷, R⁴ is H, alkyl, alkaryl, or aryl, R⁵ is aryl or alkaryl, R is H, halo, alkyl, or alkoxy, R is H, alkyl, aryl, OR , or NR⁹R¹⁰, and R⁸, R⁹, and R¹⁰ are independently H, alkyl, aryl, or alkaryl, provided that when R¹ is methoxy, R² is methyl, R⁴ and R are H, and R⁵ is phenyl, R³ is not methyl or benzyl. In certain embodiments, R⁶ is H, or R⁴ is H and R⁵ is phenyl or substituted phenyl. Exemplary compounds of formula I include:

10895 10840 10838

10901 10902

In another aspect, the invention features a compound having the formula:

II or a pharmaceutically acceptable salt thereof, wherein R¹ is H, alkoxy, or halo, R² is alkyl, R³ is (CH₂)₂-X-aryl, R⁴ is H, alkyl, or C(0)R⁶, R⁵ is H, halo, alkyl, or alkoxy, R⁶ is H, alkyl, aryl, OR⁷, or NR⁸R⁹, X is O, S, NC(0)R¹⁰, OR¹¹, or NR¹²R¹³, and R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², andR¹³ are independently H, alkyl, aryl, or alkaryl. In one embodiment, R⁵ is H. Exemplary compounds of formula II include:

10830

The invention also features a compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein R¹ is H, alkoxy, or halo, R² is H or alkyl, R³ is alkyl or C(O)OR⁷, R⁴ is H, alkyl, aryl, or alkaryl, R⁵ is aryl or alkaryl, and R⁶ is H, halo, alkyl, or alkoxy, R⁷ is H, alkyl, or aryl, provided that when R¹, is methoxy, R² and R³ are methyl, R⁴ is H, R⁵ is not phenyl. In one embodiment, R⁶ is H. Exemplary compounds of formula III include:

10835 10837

10833

In another aspect, the invention features a compound having the formula:

IV or a pharmaceutically acceptable salt thereof, wherein R¹ is H, alkoxy, or halo, R² is alkyl, aryloxy, or alkaryloxy, R³ is H, alkyl, or alkaryl, R is alkaryl or aryl, and R⁵ is H, halo, alkyl, or alkoxy. In certain embodiments, R⁵ is H, or R⁴ is phenyl and R is H. Exemplary compounds of formula IV include:

10876 10889

The invention furthers features a pharmaceutical composition including any of the above described compounds and a pharmaceutically acceptable carrier. In one aspect, the invention features a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein R¹ is H, alkoxy, or halo, R² is alkyl, R³ is H, alkyl, alkaryl, or C(O)R⁷, R⁴ is H, alkyl, alkaryl, or aryl, R⁵ is aryl or alkaryl, R⁶ is H, halo, alkyl, or alkoxy, R⁷ is H, alkyl, aryl, OR⁸, or NR⁹R¹⁰, and R⁸, R⁹, and R¹⁰ are independently H, alkyl, aryl, or alkaryl. Exemplary compounds for this aspect include:

10895 10840

10838 10901

9203 9237

The invention further features a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the formula:

II or a pharmaceutically acceptable salt thereof, wherein R¹ is H, alkoxy, or halo, R² is alkyl, R³ is (CH₂)₂-X-aryl or benzyl, R⁴ is H, alkyl, or C(0)R⁶, R⁵ is H, halo, alkyl, or alkoxy, R⁶ is H, alkyl, aryl, OR⁷, or NR⁸R⁹, X is O, S,

NC(0)R¹⁰, OR¹¹, or NR¹²R¹³, and R⁷, R⁸, R⁹, R¹⁰, , π L¹², andR¹³ are 4 independently H, alkyl, aryl, or alkaryl, wherein when R is benzyl, R and R^~ are methyl, and R¹ is methoxy. Exemplary compounds for this aspect include:

10830 9276

In another aspect, the invention features a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein R is H, alkoxy, or halo, R² is H or alkyl, R³ is alkyl or C(O)OR⁷, R⁴ is H, alkyl, aryl, or alkaryl, R⁵ is aryl or alkaryl, and R⁶ is H, halo, alkyl, or alkoxy, R⁷ is H, alkyl, or aryl. Exemplary compounds for this aspect include:

10835 10837

The invention further features a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the formula:

IV or a pharmaceutically acceptable salt thereof, wherein R¹ is H, alkoxy, or halo, R² is alkyl, aryloxy, or alkaryloxy, R³ is H, alkyl, or alkaryl, R⁴ is alkaryl or aryl, and R⁵ is H, halo, alkyl, or alkoxy. Exemplary compounds for this aspect include:

10876 10889

10 In various embodiments of the above pharmaceutical compositions, the compound is present in the composition in an amount sufficient to reverse, halt, or slow the progress of the Aβ-associated disease, disorder, or condition. The invention also features a method of treating an Aβ-associated disease, disorder, or condition by administering to a mammal a compound or pharmaceutical composition of the invention. In one embodiment, the compound is administered in an amount sufficient to reverse, halt, or slow the progress of the Aβ-associated disease, disorder, or condition. Exemplary Aβ- associated diseases, disorders, or conditions that are treated by the methods described herein include Alzheimer's disease, inclusion body myositis, congophilic amyloid angiopathy, Down's syndrome, or hereditary cerebral amyloidosis with haemorrhage of the Dutch type.

In various embodiments of any of the above aspects, a compound of the invention reduces the concentration of Aβ by at least 5%, e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50 %, at least 60%, at least 75%, at least 80%, at least 90%, or at least 95%, when administered to an individual. The reduction in concentration may occur, for example, by reducing the production of Aβ or by increasing the degradation of Aβ.

The invention encompasses all enantiomeric and diastereomeric forms of the compounds described herein.

By an "Aβ-associated disease, disorder, or condition" is meant a disease, disorder, or condition that is correlated with an elevated concentration of Aβ. Exemplary Aβ-associated diseases, disorders, or conditions include Alzheimer's disease, inclusion body myositis, congophilic amyloid angiopathy, Down's syndrome, and hereditary cerebral amyloidosis with haemorrhage of the Dutch type.

By "alkyl" is meant a branched or unbranched saturated hydrocarbon group, desirably having from 1 to 20 or 1 to 50 carbon atoms. An alkyl group may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members. The alkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halo, hydroxy, fluoroalkyl, perfluoroalkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, aryl, and carboxyl groups. In various embodiments of the invention the alkyl group is of 1 to 5, 1 to

10, 1 to 15, 1 to 20, 1 to 50, 5 to 10, 5 to 15, 5 to 50, 10 to 15, 10 to 35, or 10 to 50 carbon atoms. Examples of alkyl groups include methyl; ethyl; n-propyl; isopropyl; n-butyl; iso-butyl; sec-butyl; tert-butyl; pentyl; cyclopropyl; cyclobutyl; cyclopentyl; 1-methylbutyl; 2-methylbutyl; 3-methylbutyl; 2,2- dimethylpropyl; 1-ethylρropyl; 1,1-dimethylpropyl; 1,2-dimethylpropyl; 1- methylpentyl; 2-methylρentyl; 3-methylpentyl; 4-methylρentyl; 1,1- dimethylbutyl; 1,2-dimethylbutyl; 1,3-dimethylbutyl; 2,2-dimethylbutyl; 2,3- dimethylbutyl; 3,3-dimethylbutyl; 1-ethylbutyl; 2-ethylbutyl; 1,1,2- trimethylpropyl; 1,2,2-trimethylpropyl; 1 -ethyl- 1-methylpropyl; l-ethyl-2- methylpropyl; hexyl; heptyl; cyclohexyl; cycloheptyl; and cyclooctyl.

By "aryl" is meant an aromatic group having a ring system comprised of carbon atoms or other atoms with conjugated π electrons (e.g., phenyl or imidazole). The ring of the aryl group is desirably 5 to 18 atoms selected from the group consisting of carbon, nitrogen, oxygen, sulfur, and phosphorous. Aryl groups may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The aryl group may be substituted or unsubstituted. Exemplary substituents include alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halo, fluoroalkyl, carboxyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, and quaternary amino groups. Exemplary aryl groups include, without limitation, phenyl, naphthyl, biphenyl, anthranyl, thienyl, furyl, pyridyl, oxazolyl, quinolyl, isoquinolyl, indolyl, triazolyl, isothiazolyl, isoxazolyl, imidizolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl. By "alkaryl" is meant a chemical substituent of the formula -R-R', wherein R is an alkyl group and R' is an aryl group. Exemplary alkaryl groups include, without limitation, benzyl, phenylethyl, pyridylmethyl, benzimidazolylmethyl, and benzthiophenylmethyl.

By "alkoxy" is meant a chemical substituent of the formula -OR, wherein R is an alkyl group. By "aryloxy" is meant a chemical substituent of the formula -OR, wherein R is an aryl group.

By "alkalryloxy" is meant a chemical substituent of the formula -OR, wherein R is an alkaryl group.

By "halo" is meant fluoro, bromo, chloro, or iodo. By "therapeutically effective amount" is meant an amount of a compound sufficient to treat an Aβ-associated disease, disorder, or condition. This amount may vary from compound to compound and may depend on the route of administration, the formulation employed, or the disease being treated. Standard assays known to those skilled in the art may be used to determine the therapeutically effective amount and means of administration of a compound of the invention.

By "treating" is meant the medical management of a patient with the intent that a cure, amelioration, or prevention of a disease, pathological condition, or disorder will result. This term includes active treatment, that is, treatment directed specifically toward improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventive treatment, that is, treatment directed to prevention of the disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the disease, pathological condition, or disorder. The term "treating" also includes symptomatic treatment, that is, treatment directed toward constitutional symptoms of the disease, pathological condition, or disorder.

In one embodiment, compounds of the invention that are useful for treating an Aβ-associated disease, disorder, or condition show at least a 5%, e.g., 10%, reduction in the concentration of Aβ as determined by the assay described in Example 4. A low level of reduction, e.g., at least 5%, may be beneficial in inhibiting the long term development and progression of and Aβ- associated disease. In another embodiment, compounds useful for the treatment of an Aβ-associated disease, disorder, or condition have low toxicity as measured by at least 75% of the control activity in the assay of Example 2 or less than 200% of the control activity in the assay of Example 3. The efficacy of a treatment may be determined by any method known in the art including, without limitation, biochemical assays (e.g., ELISA); biopsy; visualization techniques (e.g., magnetic resonance imaging); cognitive tests, such as the Alzheimer's Disease Assessment Scale, Cognitive Subsection (Rosen et al. "A New Rating Scale for Alzheimer's Disease" American Journal of Psychiatry 1984; 14:1356-64), the Blessed Information-Memory Concentration Test (BIMC) (Blessed et al. "The Association Between Quantitative Measures of Dementia and of Senile Change in the Cerebral Gray Matter of Elderly Subjects" British Journal of Psychiatry 1968; 114:797-811), the Clinical Dementia Rating Scale (CDR) (Hughes et al. "A New Clinical Scale for the Staging of Dementia" British Journal of Psychiatry 1982; 140:566-72), and the Mini-Mental State Examination (MMSE) (Folstein et al. "Mini-Mental State: a Practical Method for Grading the Cognitive State of Patients for the Clinician" Journal of Psychiatric Research 1975; 12:189-98, Cockrel et al. "Mini-Mental State Examination (MMSE)" Psychopharmacology Bulletin 1988; 24:689-92); functional assessments, such as the Functional Assessment Questionnaire (FAQ) (Pfeffer et al. "Measurement of Functional Activities of Older Adults In the Community" Journal of Gerontology 1982; 37:323-9), the Instrumental Activities Of Daily Living (IADL) (Lawton et al. "Assessment of Older People: Self Maintaining and Instrumental Activities of Daily Living" The Gerontologist 1969; 9:179-86); the Physical Self Maintenance Scale (PSMS) (Lawton et al. "Assessment of Older People: Self Maintaining and Instrumental Activities of Daily Living" The Gerontologist 1969; 9:179-86); and the Progressive Deterioration Scale (PDS) (DeJong et al. "Measurement of Quality of Life Changes in Patients with Alzheimer's Disease" Clinical Therapeutics 1989; 11:545-554); global assessments, such as the Clinical Global Impression Of Change (CGIC) (Guy (Ed). ECDEU Assessment Manual for Psychopharmacology, revised (PP. 218-222). Rockville, MD: U.S. Department of Health and Human Service, Alcohol Drug Abuse and Mental Health Administration, NIMH Psychopharmacology Research Branch. 1976), the Clinician Interview-Based Impression (OBI) (Knopman et al. "The Clinician Interview Based Impression (CIBI) - a Clinician Global Change Rating Scale in Alzheimer's Disease" Neurology 1994; 44:2315-21), the Global Deterioration Scale (CDS) (Reisberget al. "The Global Deterioration Scale for Assessment of Primary Degenerative Dementia" American Journal of Psychiatry 1982; 1136- 39); or caregiver-based assessments, such as the Behavioral Pathology In Alzheimer's Disease Rating Scale (BEHAVE- AD) (Reisberg et al. "Behavioral Symptoms in Alzheimer's Disease: Phenomenology and Treatment" Journal of Clinical Psychiatry 1987; 48: s9-sl5) and the Neuropsychiatric Inventory (NPI) (Cummings et al. "The Neuropsychiatric Inventory: Comprehensive Assessment of Psychopathology in Dementia" Neurology 1994; 44:2308-14).

Other features and advantages of the invention will be apparent from the following description and the claims.

DETAILED DESCRIPTION OF THE INVENTION Previous efforts to find potential therapeutic agents for Alzheimer's disease focused on assaying for a reduction in cellular APP or sAPPα concentrations (see, e.g., International Publication No. WO 02/48150). Surprisingly, we have discovered several compounds that reduce the concentration of Aβ, but do not reduce the concentration of APP, as measured by the concentration of sAPPα. These compounds, thus, appear to modulate the concentration of Aβ by a different mechanism, and the compounds, and their derivatives, represent novel classes of candidate compounds for the treatment of Alzheimer's disease and Aβ-associated diseases, disorders, or conditions in general.

The compounds of the invention have the following generic formulas:

wherein R¹ is H, alkoxy, or halo, R² is alkyl, R³ is H, alkyl, alkaryl, or C(0)R⁷, R⁴ is H, alkyl, alkaryl, or aryl, R⁵ is aryl or alkaryl, R⁶ is H, halo, alkyl, or alkoxy, R⁷ is H, alkyl, aryl, OR⁸, or NR⁹R¹⁰, and R⁸, R⁹, and R¹⁰ are independently H, alkyl, aryl, or alkaryl;

II wherein R is H, alkoxy, or halo, R > 2 is alkyl, R is (CH₂)₂-X-aryl, R is H, alkyl, or C(O)R⁶, R⁵ is H, halo, alkyl, or alkoxy, R⁶ is H, alkyl, aryl, OR⁷, or NR⁸R⁹, X is O, S, NC(O)R¹⁰, OR¹¹, or NR¹²R¹³, and R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,

1 andR are independently H, alkyl, aryl, or alkaryl;

III

1 * H A wherein R is H, alkoxy, or halo, R is H or alkyl, R is alkyl or C(O)OR , R is H, alkyl, aryl, or alkaryl, R⁵ is aryl or alkaryl, and R⁶ is H, halo, alkyl, or alkoxy, R is H, alkyl, or aryl; and

IV wherein R is H, alkoxy, or halo, R^" is alkyl, aryloxy, or alkaryloxy, R is H, alkyl, or alkaryl, R⁴ is alkaryl or aryl, and R⁵ is H, halo, alkyl, or alkoxy. Exemplary compounds of the invention are shown in Table 1.

Table 1. Exemplary compounds of the invention.

Table 1 (cont). Exemplary compounds of the invention.

10839 10902 10901

Clinical Applications

Compounds of the invention may be administered by any appropriate route for treatment, stabilization, or prevention of an Aβ-associated disease, disorder, or condition. These compounds may be administered to humans, domestic pets, livestock, or other animals with a pharmaceutically acceptable diluent, carrier, or excipient, in unit dosage form. Administration may be oral, topical, parenteral, intravenous, intra-arterial, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intranasal, aerosol, by suppositories, or by any other suitable route of administration.

Therapeutic formulations may be in the form of liquid solutions or suspensions; for oral administration, formulations may be in the form of tablets or capsules; and for intranasal formulations, in the form of powders, nasal drops, or aerosols.

Methods well known in the art for making formulations are found, for example, in Remington: The Science and Practice of Pharmacy (20th ed., A.R. Gennaro ed., Lippincott: Philadelphia, 2000). Formulations for parenteral administration may, for example, contain excipients, sterile water, saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds.

Nanoparticulate formulations (e.g., biodegradable nanoparticles, solid lipid nanoparticles, liposomes) may be used to control the biodistribution of the compounds. Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel. The concentration of the compound in the formulation will vary depending upon a number of factors, including the dosage of the drug to be administered, and the route of administration.

The compound may be optionally administered as a pharmaceutically acceptable salt, such as a non-toxic acid addition salts or metal complexes that are commonly used in the pharmaceutical industry. Examples of acid addition salts include organic acids such as acetic, lactic, pamoic, maleic, citric, malic, ascorbic, succinic, benzoic, palmitic, suberic, salicylic, tartaric, methanesulfonic, toluenesulfonic, or trifluoroacetic acids or the like; polymeric acids such as tannic acid, carboxymethyl cellulose, or the like; and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or the like. Metal complexes include zinc, iron, and the like. The chemical compounds for use in such therapies may be produced and isolated as described herein or by any standard technique known to those in the field of medicinal chemistry. Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer the identified compound to patients suffering from an Aβ-associated disease, disorder, or condition. Administration may begin before, during, or after the patient is symptomatic.

The formulations can be administered to human patients in therapeutically effective amounts to provide therapy for an Aβ-associated disease, disorder, or condition. Typical dose ranges are from about 0.1 μg/kg to about 1 mg/kg of body weight per day. The exemplary dosage of drug to be administered is likely to depend on such variables as the type and extent of the disorder, the overall health status of the particular patient, the formulation of the compound, and its route of administration. Standard clinical trials maybe used to optimize the dose and dosing frequency for any particular compound.

Representative synthetic schemes

Exemplary schemes for the synthesis of the compounds of the invention are shown below. Scheme 1 shows routes for the synthesis of compounds of formulas I and III. Any related N-unsubstituted indole may be alkaryiated in a similar manner employing the corresponding alkaryl bromide in the presence of sodium hydride. DMSO/H⁺ induced oxidation to the oxindole, followed by base induced all viation with methyl iodide generated the tricyclic precursor. All iation with alternative agents e.g. allyl bromide, benzyl bromide, generates alternative species. Red-Al mediated reduction results in the formation of the tricyclic product.

Example 8 X =

Example 9 X =

Example 10 X = NHC0₂Me,

Example 11 X =

Scheme 1

Scheme 2 shows synthetic routes for compounds of formula II. The tricyciic phenol is treated with an excess of methyliodide, resulting in both O and Nl methylation. Treatment of this quaternary ammonium salt with a primary amine such as benzyl amine results in the expulsion of dimethyl amine and incorporation of the desired amine. This process is applicable to all primary amines. Alternatively, Example 15, where O-methylation previously occurred, may be transformed in the same manner employing an excess of a primary amine.

Example 13 R = l )

Example 14 R = ^O

Scheme 2

Scheme 3 shows synthetic routes for compounds of formula I. Substituted N-alkaryl anilines may be readily converted to the corresponding α-bromoacetamides, and subsequently to the oxindoles by aluminum chloride mediated ring closure. Sequential alleviation with bromoacetonitrile and an alkyl halide such as methyl iodide generated the tricycle precursor. Lithium aluminum hydride mediated reduction lead to the desired Nl -unsubstituted tricycle. Alleviation with an alkyl or alkaryl halide in the presence of sodium hydride allowed for the generation of the Nl -substituted tricylcic species.

Example 20 X = 5-MeO, Ar

H, R= Bz, Ar = Ph 5-MeO, R = Bz, Ar =

*G_CI

Scheme 3

Scheme 4 shows synthetic routes for compounds of formula IV. N- Alkaryl-2-pyrrolidinones, either commercially available or prepared by alkarylation of 2-pyrrolidinone by standard literature means, may be sequentially alkaryiated and alkylated by successive treatment with strong base and the corresponding alkaryl bromides and alkyl iodides.

Example 22 X = 3-MeO Example 23 X = 3-Me

Ar = Ph Ar = Ph

Scheme 4

The following examples are merely to illustrate the invention and are not intended to be limiting in any way.

EXAMPLES

The following examples are merely to illustrate the various embodiments of the invention are not intended to be limiting in any way.

1. Cell culture and compound addition

SK-N-SH cells were harvested from flasks by removing medium (MEME + 10% heat-inactivated FCS). Trypsin was added to promote detachment of the cells and immediately removed. After waiting 5 minutes, new medium was vigorously pipetted over the cells to suspend them. The SK- N-SH cells were plated at a density of 2 x 10⁵ cells/well in 24-well plates in 0.5 ml/well of medium containing 50 ng/ml of recombinant human β-(nerve growth factor) NGF (R&D Systems, Minneapolis, MN). Another plate received medium only. The plates were incubated for 3 days. After replacing the medium with 0.5 ml per well of MEME + 0.5%FCS containing 50 ng/ml βNGF, the plates were further incubated for 24 hours. The medium was replaced with 0.25 ml of the MEME + 0.5%FCS containing 50 ng/ml βNGF. Addition of 12.5 μl of DMSO (control) or 20x compound dilutions in DMSO to duplicate wells was followed by a further 24 hour incubation. The supematants (210 μl per well) were collected into tubes containing 25 μl of RIPA buffer containing 10x protease inhibitors (3 Roche complete protease inhibitor mini-tabs to 3 ml of RIP A) plus 10 mM AEBSF. The resulting supematants were used for secreted sAPPα ELISAs, LDH measurements, and Aβ ELISAs. The remaining cells in the 24 well plates were used for the MTS toxicity procedure. The assays are described in Example 2-5 below.

2. MTS Assay Procedure

The toxicity of the compounds of the invention was determined using the CellTiter 96^® AQ_ueous Non-Radioactive Cell Proliferation Assay (MTS) (Cat. No. G5421, Promega, Madison, WI). MTS (3-(4,5-dimethylthiazol-2-yl)- 5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H- tetrazolium, inner salt) (42 μl per well plus 168 μl of prewarmed medium) was added to each well of the 24 well plates containing cells from Example 1 to assess toxicity of the compound dilutions. Similar preparations of MTS were added to wells containing medium without cells to assess background levels. The mixture was incubated for 1-3 hours. Supernatant (100 μl per well) was transferred to a clear 96 well plate, and the absorbance at 490 nM was read on a Wallac 2 plate reader. Typically, DMSO-treated cells (control) will yield absorbance readings of 0.8-1.5, and medium only wells will yield absorbance readings of 0.1-0.2. Lower absorbance readings will result from wells containing cells treated with toxic concentrations of compounds. Wells showing less than 75% of the absorbance of the control wells would be considered to indicate some degree of toxicity elicited by the treatment compound.

3. Lactate Dehydrogenase (LDH) Assay Procedure The toxicity of the compounds of the invention was also assayed using the CytoTox 96^® Non-Radioactive Cytotoxicity Assay (Cat. No. G1780, Promega). An aliquot of the collected supernatant from Example 1 (40 μl) was added to the wells of a flat bottom MaxiSorp plate (NUNC). Similar preparations of medium from wells cultured without cells were tested to assess background levels. Varying dilutions of LDH positive control were added to separate wells. The Substrate Mix was reconstituted using the kit assay buffer, and 40 μl was added to each well. The plates were covered and incubated for 30 minutes. Stop solution (40 μl) was added to each well. The absorbance was read at 490 nM. Typically, DMSO-treated cells will yield absorbance readings of 0.4-0.5 and medium only wells will yield absorbance readings of 0.1-0.15. Higher absorbance readings will result from wells containing cells treated with toxic concentrations of compounds because of the release of intracellular LDH into the medium. Wells showing greater than 200% of the absorbance of the control wells should be considered to indicate some degree of toxicity elicited by the treatment compound.

4. Aβ ELISA

To determine the concentration of Aβ produced by cells after being treated with a compound of the invention, the supematants from Example 1 were assayed by the Aβ 1 -40 ELIS A colorimetric kit (Cat. No. KHB3481 ,

BioSource International, Camarillo, CA). 150 μl of supernatant per well were added to the plates provided by BioSource that were pre-coated with capture antibody. After incubating overnight in the refrigerator, the plate was washed (4 x 320 μl) with the provided wash buffer. The detection antibody was diluted as directed and added (100 μl) to each well. After incubating for 3 hours at room temperature with shaking, the plate was washed 4 times. The secondary antibody was diluted as directed and added (100 μl) to each well. After incubating for 3 hours at room temperature with shaking, the plate was washed 5 times. The substrate solution was prepared as directed, and added (100 μl) to each well. After a final incubation for 30 minutes, the absorbance was read at 450 nM. All reagents were included in the BioSource kit. Wells showing less than 90% of the absorbance of the control wells would be considered to indicate some degree of efficacy elicited by the treatment compound. 5. Secreted APPα (sAPPα) ELISA Assay

An ELISA for sAPPα was conducted to determine the concentration of sAPPα secreted by the cells treated with a compound of the invention. APP 44-100 antibody (Cat. No. AHB0141; BioSource) was diluted to 2 μg/mL in DPBS without calcium and magnesium, and an aliquot (100 μl) was added to each well of a Maxisorp plate. The plate was incubated overnight at 4°C. After aspirating the coating solution, the wells were blocked with 200 μl ELISA buffer (4 mg/ml BSA, 0.01% Tween 20 in DPBS without calcium and magnesium) for 30-60 minutes. The plates were washed (300 μl of wash buffer (PBS + 0.01 % Tween 20)). ELISA buffer (80 μl) and 0.5% FCS/MEME (10 μl) was added to all wells. Supematants from Example 1 (10 μl) were added to the appropriate wells, and the plate was incubated overnight at 4°C. 6E10- biotin antibody (Signet Pathology, Cat. No. 9340-05) (100 μl/well of 0.3 μg/ml) was add to each well, and the plate incubated at room temp for 2 hours. The plate was washed 3 times and detection antibody (100 μL/well) added to the appropriate wells. After incubating for 30 minutes the plates were washed 3 times. TMB substrate (Moss, Inc) solution (100 μL/well) was added and developed for approximately 20 minutes until blue. The reaction was stopped with 0.18 M sulfuric acid (100 μL/well). The plate was read at 450 nm on a Wallac Victor2 plate reader. Such an assay may also be employed to determine the amount of APP.

The results of the assays of Examples 1-5 are shown in Table 2 where the data for each compound are indicated as a percentage of the control. Table 2. Data on efficacy and toxicity of compounds of the invention.

6. Preparation of N,N-dimethyl-5-Methoxy-l-(2-phenylbenzyl)tryptamine MES 10833: N,N-dimethyl-5-Methoxytryptamine (Aldrich, 218 mg, 1.0 mmol) was dissolved in dry DMSO (5 ml) and to this added sodium hydride (1.05eq of a 60% dispersion in mineral oil, 42 mg). The suspension was stirred under an argon atmosphere for 10 min. 2-Phenylbenzylbromide (1.05eq, 259 mg, 192 ml) was added, and the resulting suspension was stirred for 15 hr at rt. The resulting mixture was partitioned between ethyl acetate (200 ml) and water (200 ml). The aqueous phase was extracted with an additional portion of ethyl acetate (100 ml). The combined organic fractions were washed with water (5x100 ml), brine (50 ml) and dried over sodium sulfate. Chromatography on silica gel eluted with 2 1/2%- 15% MeOH in CH₂C1₂ gave the crude desired product which was further purified by chromatography on silica gel eluted with 1-5% MeOH in CH₂C1₂ to give the desired material as a thick oil (23 mg). 1H NMR (CDC1₃) δ = 7.5-7.2 (m, 8H), 7.08 (d, J=2.3Hz, 1H), 7.05-6.90 (m, 2H), 6.85-6.70(m, 2H), 5.17 (s, 2H), 3.91 (s, 3H), 3.09 (m, 2H), 2.90 (m, 2H), 2.57 (s, 6H) ppm.

7. Preparation of N,N-dimethyl-5-Methoxy-l-(2-naphthyl)tryptamine

MES10835: The title compound was prepared in an analogous manner to Example 6. Chromatography on silica gel eluted with 1-5% MeOH in CH₂C1₂ to give the desired material as a thick oil (75 mg, 21%). 1H NMR (CDC1₃) δ = 7.81-7.76 (m,3H), 7.56 (s, 1H), 7.47 (m,2H), 7.28-7.10 (m, 3H), 6.99 (s, 1H), 6.86(d, J=2.4Hz, 1H), 5.38 (s, 2H), 3.89 (s, 3H), 2.95 (m, 2H), 2.67 (m, 2H), 2.37 (s, 6H) ppm. 8. Preparation of N,N-dimethyl-5-Methoxy-l-(3,5- difluorobenzyl)tryptamine MES 10837: The title compound was prepared in an analogous manner to Example 6. Chromatography on silica gel eluted with 1-10% MeOH in CH₂C1₂ to give the desired material as a thick oil (43 mg). IH NMR (CDC1₃) δ = 7.08 (m,2H), 6.94 (s, IH), 6.87 (m, IH), 6.70 (br t, J = 7Hz, IH) 6.59 (d, J=5.8Hz, 2H), 5.22 (s, 2H), 3.88 (s, 3H), 2.93 (m, 2H), 2.67 (m, 2H), 2.37 (s, 6H) ppm.

9. Preparation of 5-Methoxy-l-(2-phenylbenzyl)tryptamine methyl carbamate MES 10839: The title compound was prepared from 5-

Methoxytryptamine methyl carbamate in a manner analogous to Example 6. 5-Methoxytryptamine N-methylcarbamate (1.50g, 6.05mmol) was dissolved in dry THF (30ml) and to this added sodium hydride (l.Oeq of a 60% dispersion in mineral oil, 242 mg). The suspension was stirred under an argon atmosphere for 15mins. The resulting suspension was cooled to 0°C and 2-

Phenylbenzylbromide (1.05eq, 259 mg, 192mL) was added and the resulting suspension stirred for 20hr at rt. The resulting mixture was partitioned between ethyl acetate (200ml) and water (250ml). The organic fraction were washed with water (3x100ml), brine (100ml) and dried over sodium sulfate. Cliromatography on silica gel eluted with hexanes/ethyl acetate (4: 1-5:2) gave the desired product as a thick oil which slowly crystallized on standing (1.50g). IH NMR (CDC1₃) δ - 7.55-7.25 (m, 8H), 7.02 (s, IH), 6.94 (m, 2H), 6.79(m, IH), 6.73 (s, IH), 5.18 (s, 2H), 4.72 (br s, IH), 3.86 (s, 3H), 3.68 (s, 3H), 3.47 (m, 2H), 2.91 (m, 2H) ppm.

10. Preparation of 3-(2-Aminoethyl)-5-methoxy-l-(2-phenylbenzyl)-2- oxindole methyl carbamate: 5-Methoxy-l-(2-phenylbenzyl)tryptamine methyl carbamate (414 mg, 1.0 mmol) was dissolved in DMSO (5ml) and to this solution added cone, hydrochloric acid (3ml). The resulting suspension was vigorously stirred for 24hr. The reaction mixture was partitioned between ethyl acetate (200ml) and water (200ml). The organic phase was washed with water (3 x 200ml) and brine (100ml) and dried over sodium sulfate. The sample was absorbed on silica gel and chromatography on silica eluted with hexanes: ethyl acetate (2:1-1:2) to give the desired product as an oil (59 mg, 40%), and recovered stating material (270 mg). IH NMR (CDC13) δ = 7.51- 7.16 (m, 10H), 6.90 (br s, IH), 6.59 (dd, J=2.6, 8.7Hz, IH), 6.18 (d, J=8.5Hz, IH), 5.30 (br s, IH), 4.93 (d, J= 15.9Hz, IH), 4.83 (d, J=16.2Hz, IH), 3.75 (s, 3H), 3.67 (s, 3H), 3.46 (m, 3H), 2.24 (m, IH), 2.19 (m, IH) ppm.

11. Preparation of 3-(2-Aminoethyl)-5-methoxy-3-methyl-l-(2- phenylbenzyι)-2-oxindole methyl carbamate : 3-(2-Aminoethyl)-5-methoxy- l-(2-phenylbenzyl)-2-oxindole methyl carbamate (59 mg, 0.14mmol) was dissolved in methylene chloride (2ml) and to this added 20% aqueous sodium hydroxide (500μl), trimethylbenzylammonium bromide (6 mg), and methyl iodide (82 mg, 0.56mmol, 4eq). After stirring at rt for 5.5 hr the reaction mixture was diluted with methylene chloride (25ml) and washed with water (2 x 20ml), brine (20ml) and dried over sodium sulfate. The crude product was absorbed on to silica gel and chromatography on silica eluted with hexanes: ethyl acetate (2:2-4:3) to give the desired product as an oil (52 mg, 84%). IH NMR (CDC13) δ = 7.53-7.12 (m, 10H), 6.90 (d, J=2.5₅ IH), 6.60 (dd, J=2.5, 8.5Hz, IH), 6.22 (d, J=8.5Hz, IH), 4.96 (d, J= 18.9Hz, IH), 4.78 (d, J=16.9Hz, IH), 4.77 (br s, IH), 3.76 (s, 3H), 3.57 (s, 3H), 3.01 (m, 2H), 2.17 (m, IH), 2.06 (m, IH) 1.55 (s,3H)ppm.

12. Preparation of l,3a-Dimethyl-5-methoxy-8-(2-plιenylbenzyl) hexahydropyrrolo[2,3-b] indole MES 10840: 3-(2-Aminoethyl)-5-methoxy-3- methyl-l-(2-phenylbenzyl)-2-oxindole methyl carbamate (40 mg, 0.09mmol) was dissolved in toluene (500μl) and to this added a solution of Red-Al (4eq of a 65% solution in toluene, 112 mg). The reaction mixture was stirred at rt for 22hr. After quenching with 10% aqueous sulfuric acid (1.4ml), the reaction mixture was diluted with water (5ml) and extracted with ethyl acetate (10ml). The organic phase was washed with water (10ml), brine (10ml). The aqueous acid phase was neutralized to pH7 with IN aqueous sodium hydroxide and extracted with ethyl acetate (20ml). The organic phase was washed with water (10ml) and brine (10ml). The combined organic phases were dried over sodium sulfate, absorbed on to silica gel and purified by chromatography on silica gel eluted with hexanes ethyl acetate (1 : 1-1 :2) to give the desired product (11 mg). IH NMR (CDC1₃) δ = 7.62-7.20 (m, 9H), 6.65 (d, J= 2.5Hz, IH), 6.57 (dd, J = 2.6, 8.5Hz, IH), 6.14 9d, J= 8.5Hz, IH), 4.32 (s, 2H), 4.15 (s, IH), 3.75 (s, 3H), 2.71 (m, 2H), 2.27 (s, 3H), 1.97 (m, 2H), 1.40 (s, 3H)ppm.

13. Preparation of 3a,8-DimethyI-5-methoxy-l- benzylhexahydropyrrolo[2,3-b] indole MES 9276: The title compound can be prepared from eserine as previously described in WO 02/48150.

14. Preparation of 3a,8-Dimethyl-5-methoxy-l-(2- phenoxyethyl)hexahydropyrrolo[2,3-b]indole MES 10830: The title compound can be prepared from eserine employing 2-ρhenoxyethylamine in place of benzyl amine as described for Example 13. IH NMR (CDC1₃) δ = 7.31 (m, 3H), 6.97 (m, 2H), 6.69-66 (m, 2H), 6.38 (d, 8.0Hz, IH), 5.32 (s, IH), 4.18 (d, J= 6.5Hz, IH), 4.16 (d, J=6.5,1H), 3.77 (s, 3H), 3.31-3.14 (m, 2H), 2.91 (s, 3H), 2.90 (m, 2H), 1.98 (m, 2H), 1.46 (s, 3H) ppm.

15. Preparation of R-(+)-8-benzyl-l,3a-dimethyl-5- methoxyhexahydropyrrolo[2,3-b] indole MES 9203: The title compound can be prepared as described in WO 02/48150.

16. Preparation of R-(+)-8-benzyI-5-methoxy-3a~methyI~l-(2- phenoxyethyl)hexahydro-pyrrolo[2,3-b]indole MES 10838: The title compound can be prepared from Example 15 and 2-phenoxyethylamine in place of 5-methoxy-l,3a,8-trimethylhexahydropyrrolo[2,3-b]indole and benzyl amine as described for Example 13. IH NMR (CDC1₃) δ = 7.34-7.21 (m, 7H), 6.95 (m, IH), 6.86 (d, J= 7.6Hz, 2H), 6.68 (d, 2.5Hz, IH), 6.59 (dd, J= 3.75, 8.5Hz, IH), 6.25 (d, J=8.5Hz, IH), 4.57 (d, J=16.5Hz, IH), 4.48 (s, IH), 4.39 (d, J= 16.1Hz, IH), 4.04 (m, 2H), 3.76 (s, 3H), 3.06 (m, 2H), 2.91 (m, 2H), 2.01 (m, 2H), 1.43 (s, 3H) ppm.

17. Preparation of R-(+)-l,8-Dibenzyl~5-methoxy-3a- methylhexahydropyrrolo[2,3-b] indole MES 9237: The title compound can be prepared from 5-methoxytryptamine as described in WO 02/48150.

18. Preparation of S-(-)-8-Benzyl-l,3a-dimethyl-5- methoxyhexahydropyrrolo[2,3-b] indole MES 9242: The title compound can be prepared from 5-methoxytryptamine as previously described in WO 02/48150.

19. Preparation of l,8-Dibenzyl-3a-methylhexahydropyrrolo[2,3- b ndole MES 10895: N-Benzylaniline was converted to N-benzyl-3-methyl-

2-oxindole according to the procedures in WO 02/48150. N-Benzyl-3-methyl-2-oxindole (l.lg, 4.6mmol) was dissolved in THF

(50ml) and cooled to -78°C. t-Butyl lithium (l.leq, 5.1mmol, 3ml of a 1.7M solution in pentane) was added dropwise and stirring continued for 20min. Chloroacetonitrile (2.2eq, 10.2mmol, 770 mg) was added dropwise at -78°C and stirring was continued for lOmin. After warming to rt, and stirring for a further 16hr, the reaction was quenched with water (200ml) and extracted with ethyl acetate (200ml). The crude product was evaporated and purified by cliromatography on silica gel eluted with hexanes/ethyl acetate (7/3) to give the 3, 3 -disubstituted oxindole (270 mg).

The previous product (270 mg, 0.98mmol) was dissolved in THF (40ml) and lithium aluminum hydride (4mmol, 152 mg) added at rt. After stirring for 2hr, the reaction was quenched by the addition of excess sodium sulfate decahydrate. The reaction mixture was filtered to remove the inorganic salts and concentrated. The crude product was purified by chromatography on silica gel eluted with ethyl acetate to give 8-benzyl-3a- methylhexahydropyrrolo[2,3-b]indole (197 mg).

8-benzyl-3a-methylhexahydropyrrolo[2,3-b]indole (60 mg) was dissolved in acetonitrile (3ml) and to this added benzyl bromide (2eq) and potassium carbonate (2 mg). The reaction was stirred at rt for 16hr. Evaporation of volatiles and purification by chromatography on silica eluted with hexanes/ethyl acetate (9/1) gave l,8-Dibenzyl-3a- methylhexahydropyrrolo[2,3-b]indole MES 10895 (46 mg). IH NMR (CDC13) d = 7.26 (m, 10H), 7.05 (m, IH), 7.02 (m,lH), 6.69 (m,lH), 6.33 (d, J=7.8Hz, IH), 4.53 (s, IH), 4.44 (d, J= 16.5, IH), 4.31 (d, J= 16.4Hz, IH), 3.82 (s, 2H), 2.79 (m, 2H), 2.03 (m, 2H), 1.48 (s, 3H)ppm.

20. Preparation of 8-(4-Chlorobenzyl)-5-methoxy-3a- methylhexahydropyrrolo[2,3-b] indole MES 10901: The title compound can be prepared from N-(4-chlorobenzyl)aniline using the procedures detailed for Example 19.

21. Preparation of l~Benzyl-8~(4-chlorobenzyl)-5-methoxy-3a- methylhexahydro-pyrrolo[2,3-b] indole MES 10902: The title compound can be prepared from 8-(4-chlorobenzyl)-5-methoxy-3a- methylhexahydiOpyrrolo[2,3-b]indole MES 10901 using the procedures detailed for Example 19.

22. Preparation of l-Benzyl-3-(3-methoxybenzyl)pyrrolidin-2-one MES

10876: Mesitylene bromide (796 mg, 4mmol) was dissolved in dry tetrahydrofuran and cooled to 0°C under an argon atmosphere. t-Butyl lithium (δmrnol, 4.7ml of a 1.7M solution) was added slowly and stirred for lOmins. l-Benzyl-pyrrolidin-2-one (700 mg, 4mmol) was added at -78°C, and stirring continued for 20min. The enolate solution was divided into twoequal portions. One portion stirred at -78°C and 3-methoxybenzyl bromide (360 mg, l.δmmol) added in tetrahydrofuran (2ml). The resulting solution was stirred at -78°C for 3hr, then allowed to warm to rt overnight. To the reaction mixture was added HMPA (10ml) and stirred an additional 16hr. The reaction mixture was partitioned between ethyl acetate (200ml) and water (200ml), and the organic phase was washed with water (3 x 100ml) and dried over sodium sulfate. Purification by chromatography on silica gel eluted with hexanes/ethyl acetate (9:1-1:1) gave the desired product as a colorless oil (128 mg). IH NMR

(CDC1₃) δ = 7.35-7.17 (m, 6H), 6.79 (m, 3H), 4.48(d, J=14.8Hz, IH), 4.43 (d, J=16.1Hz,lH), 3.79 (s, 3H), 3.24 (dd, J=3.2, 12.9Hz, IH), 3.10 (m, 2H), 2.76 (m,2H), 2.02 (m, IH), 1.72 (m, lH)ppm.

23. Preparation of l-benzyl-3-(3-methoxybenzyl)-3-methylpyrrolidin-2- one MES 10889: l-benzyl-3-(3-methoxybenzyl)pyrrolidin-2-one (970 mg, 3.28mmol), was dissolved in dry tetrahydrofuran 940ml) and cooled to -78°C. t-Butyl lithium (l .leq, 3.61mmmol, 2.31 ml of a 1.7M solution) was added at - 78°C and stirred for lOmin. Without warming methyl iodide (4.4eq) was added and the resultant mixture allowed to stir at rt for 16hr. After quenching with water (40ml), the reaction mixture was extracted with ethyl acetate (2 x 70ml) and the combined organic phases were washed with water (100ml) and dried over sodium sulfate. Purification by chromatography on silica gel eluted with hexanes/ethyl acetate (7:3) gave the desired material (300 mg). IH NMR (CDC1₃) δ = δ = 7.34-7.10 (m, 6H), 6.80 (m, 3H), 4.48(d, J=14.7Hz, IH), 4.28 (d, J=14.7Hz,lH), 3.80 (s, 3H), 3.06 (d, J=13.4Hz, IH), 3.00 (m, IH), 2.63 (d, J=13.2Hz, IH), 2.63 (m,lH), 2.07 (m,lH), 1.67 (m, IH), 1.25 (s, 3H)ppm. Other Embodiments

Each patent, patent application, and publication referenced in this application is hereby incoiporated by reference. While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the appended claims.

Other embodiments are in the claims.

What is claimed is:

Claims

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein R is H, alkoxy, or halo, R is alkyl, R is H, alkyl, alkaryl, or C(O)R , R is H, alkyl, alkaryl, or aryl, R is aryl or alkaryl, R⁶ is H, halo, alkyl, or alkoxy, R⁷ is H, alkyl, aryl, OR⁸, or NR⁹R¹⁰, and R⁸, R⁹, and R¹⁰ are independently H, alkyl, aryl, or alkaryl, provided that when R¹ is methoxy, R² is methyl, R⁴ and R⁶ are H, and R⁵ is phenyl, R³ is not methyl or benzyl.

The compound of claim 1, wherein R⁶ is H.

3. The compound of claim 1, wherein R⁴ is H and R⁵ is phenyl or substituted phenyl.

4. The compound of claim 3, wherein said compound is: 10895 ¹⁰⁸⁴⁰ 10838

10901 10902

or a pharmaceutically acceptable salt thereof.

5. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein R is H, alkoxy, or halo, R is alkyl, R³ is (CH₂)₂-X-aryl, R⁴ is H, alkyl, or C(O)R^δ, R⁵ is H, halo, alkyl, or alkoxy, R⁶ is H, alkyl, aryl, OR⁷, or NR⁸R⁹, X is O, S, C(O)R¹⁰, OR¹¹, or NR¹²R¹³, and R⁷ ₉ R⁸, R⁹, R¹⁰, R¹¹, R¹², andR¹³ are independently H, alkyl, aryl, or alkaryl.

6. The compound of claim 5, wherein R is H.

7. The compound of claim 4, wherein said compound is 10830

or a pharmaceutically acceptable salt thereof.

8. A compound having the formula:

1 ^*) or a pharmaceutically acceptable salt thereof, wherein R is H, alkoxy, or halo, R^" is H or alkyl, R is alkyl or C(O)OR ι7 , τ R.4 is H, alkyl, aryl, or alkaryl, R is aryl or alkaryl, and R is H, halo, alkyl, or alkoxy, R⁷ is H, alkyl, or aryl, provided that when R , is methoxy, R² and R³ are methyl, R is H, R⁵ is not phenyl.

9. The compound of claim 8, wherein R is H.

10. The compound of claim 8, wherein said compound is

10835 10837 10833

10839

or a pharmaceutically acceptable salt thereof.

11. A compound having the formula:

1 9 or a pharmaceutically acceptable salt thereof, wherein R is H, alkoxy, or halo, R iiss aallkkyyll,, aarryyllooxxyy,, oorr aallkkaarryyllooxxyy, R³ is H, alkyl, or alkaryl, R⁴ is alkaryl or aryl, and R⁵ is H, halo, alkyl, or alkoxy.

12. The compound of claim 11, wherein R 5 i ^■s H

13. The compound of claim 11, wherein R⁴ is phenyl and R³ is H.

14. The compound of claim 13, wherein said compound is 10876 10889

or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein R¹ is H, alkoxy, or halo, R² is alkyl, R³ is H, alkyl, alkaryl, or C(O)R⁷, R⁴ is H, alkyl, alkaryl, or aryl, R⁵ is aryl or alkaryl, R⁶ is H, halo, alkyl, or alkoxy, R⁷ is H, alkyl, aryl, OR⁸, or NR⁹R¹⁰, and R⁸, R⁹, and R¹⁰ are independently H, alkyl, aryl, or alkaryl.

16. The compound of claim 15, wherein said compound is 10895 10840

10838 10901

9242 10902

or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the formula:

1 or a pharmaceutically acceptable salt thereof, wherein R is H, alkoxy, or halo, R is alkyl, R³ is (CH₂)₂-X-aryl or benzyl, R⁴ is H, alkyl, or C(0)R , R⁵ is H, halo, alkyl, or alkoxy, R⁶ is H, alkyl, aryl, OR⁷, or NR⁸R⁹, X is O, S, NC(O)R¹⁰, OR¹¹, or NR¹²R¹³, and R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², andR¹³ are independently H, alkyl, aryl, or alkaryl, wherein when R is benzyl, R and R are methyl, and R is methoxy.

18. The composition of claim 17, wherein said compound is

10830 9276

or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the formula:

1 7 or a pharmaceutically acceptable salt thereof, wherein R is H, alkoxy, or halo, R is H or alkyl, R³ is alkyl or C(O)OR⁷, R⁴ is H, alkyl, aryl, or alkaryl, R⁵ is aryl or alkaryl, and R^δ is H, halo, alkyl, or alkoxy, R⁷ is H, alkyl, or aryl.

20. The composition of claim 19, wherein said compound is

10835 10837 10833

10839

or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the formula:

• 1 9 or a pharmaceutically acceptable salt thereof, wherein R is H, alkoxy, or halo, R is alkyl, aryloxy, or alkaryloxy, R³ is H, alkyl, or alkaryl, R⁴ is alkaryl or aryl, and R⁵ is H, halo, alkyl, or alkoxy.

22. The composition of claim 21, wherein said compound is 10876 10889

or a pharmaceutically acceptabl salt thereof.

23. A method of treating an Aβ-associated disease, disorder, or condition , said method comprising administering to a mammal a compound having the formula:

1 9 or a pharmaceutically acceptable salt thereof, wherein R is H, alkoxy, or halo, R is alkyl, R³ is H, alkyl, alkaryl, or C(O)R⁷, R⁴ is H, alkyl, alkaryl, or aryl, R⁵ is aryl or alkaryl, R⁶ is H, halo, alkyl, or alkoxy, R⁷ is H, alkyl, aryl, OR⁸, or NR⁹R¹⁰, and R⁸, R , and R¹⁰ are independently H, alkyl, aryl, or alkaryl.

24. The method of claim 23, wherein said compound is 10895 10840

or a pharmaceutically acceptable salt thereof.

25. A method of treating an Aβ-associated disease, disorder, or condition said method comprising administering to a mammal a compound having the formula:

1 9 or a pharmaceutically acceptable salt thereof, wherein R is H, alkoxy, or halo, R is alkyl, R³ is (CH₂)₂-X-aryl or benzyl, R⁴ is H, alkyl, or C(O)R , R⁵ is H, halo, alkyl, or alkoxy, R⁶ is H, alkyl, aryl, OR⁷, or NR⁸R⁹, X is O, S, NC(O)R¹⁰, OR¹¹, or NR¹²R¹³, and R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², andR¹³ are independently H, alkyl, aryl, or alkaryl, wherein when R³ is benzyl, R and R² are methyl, and R¹ is methoxy.

26. The method of claim 25, wherein said compound is

or a pharmaceutically acceptable salt thereof.

27. A method of treating an Aβ-associated disease, disorder, or condition , said method comprising administering to a mammal a compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein R^l is H, alkoxy, or halo, R² is H or alkyl, R³ is alkyl or C(O)OR⁷, R⁴ is H, alkyl, aryl, or alkaryl, R⁵ is aryl or alkaryl, and R⁶ is H, halo, alkyl, or alkoxy, R⁷ is H, alkyl, or aryl.

28. The method of claim 27, wherein said compound is

10835 10837 10833

10839

or a pharmaceutically acceptable salt thereof.

29. A method of treating an Aβ-associated disease, disorder, or condition said method comprising administering to a mammal a compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein R¹ is H, alkoxy, or halo, R² iiss aallkkyyll,, aarryyllooxxyy,, oorr aallkkaarryyllooxxyy, R³ is H, alkyl, or alkaryl, R⁴ is alkaryl or aryl, and R⁵ is H, halo, alkyl, or alkoxy.

30. The method of claim 29, wherein said compound is 10876 10889

or a pharmaceutically acceptable salt thereof.

31. The method of any of claims 23-30, wherein said Aβ-associated disease, disorder, or condition is Alzheimer's disease, inclusion body myositis, congophilic amyloid angiopathy, Down's syndrome, or hereditary cerebral amyloidosis with haemorrhage of the Dutch type.

32. The method of any of claims 23-30, wherein said compound is administered in an amount sufficient to reverse, halt, or slow the progress of said Aβ-associated disease, disorder, or condition.

33. The method of any of claims 23-30, wherein said administering reduces the concentration of Aβ by at least 5%.

34. The method of claim 33, wherein said administering reduces the concentration of Aβ by at least 10%.

35. The method of claim 33, wherein said administering reduces the concentration of Aβ by at least 20%.

36. The method of claim 33, wherein said administering reduces the concentration of Aβ by at least 50%.

37. The method of claim 33, wherein said administering reduces the concentration of Aβ by at least 75%.

38. The method of claim 33, wherein said administering reduces the concentration of Aβ by at least 90%.

39. The method of claim 33, wherein said administering reduces the concentration of Aβ by at least 95%.