EP2194975A2 - Verfahren zur unterdrückung der bildung von amyloid-b-diffundierbaren liganden mit acylhydrazid-verbindungen - Google Patents

Verfahren zur unterdrückung der bildung von amyloid-b-diffundierbaren liganden mit acylhydrazid-verbindungen

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Publication number
EP2194975A2
EP2194975A2 EP08826259A EP08826259A EP2194975A2 EP 2194975 A2 EP2194975 A2 EP 2194975A2 EP 08826259 A EP08826259 A EP 08826259A EP 08826259 A EP08826259 A EP 08826259A EP 2194975 A2 EP2194975 A2 EP 2194975A2
Authority
EP
European Patent Office
Prior art keywords
hydroxy
group
alkyl
aryl
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08826259A
Other languages
English (en)
French (fr)
Inventor
Gary Charles Look
Lauri Schultz
Alexandre Mikhaylovich Polozov
Nikhil Bhagat
Jian Wang
David E. Zembower
William F. Goure
Todd Pray
Grant A. Krafft
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Acumen Pharmaceuticals Inc
Original Assignee
Acumen Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US11/777,264 external-priority patent/US9006283B2/en
Priority claimed from US11/777,266 external-priority patent/US8962677B2/en
Application filed by Acumen Pharmaceuticals Inc filed Critical Acumen Pharmaceuticals Inc
Publication of EP2194975A2 publication Critical patent/EP2194975A2/de
Withdrawn legal-status Critical Current

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    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
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    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • G—PHYSICS
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    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4709—Amyloid plaque core protein

Definitions

  • This invention relates to methods of inhibiting, regulating, and/or modulating the formation of soluble, globular, non- fibrillar, neurotoxic amyloid ⁇ i_ 42 oligomers from amyloid ⁇ i_4 2 monomers using acylhydrazide compounds.
  • This invention also relates to methods of treating a patient suffering from diseases associated with the formation of soluble, globular, non- fibrillar, neurotoxic amyloid ⁇ i_ 42 oligomers by administering acylhydrazide compounds to the patients.
  • AD Alzheimer's disease
  • a ⁇ amyloid beta
  • a ⁇ i_ 42 the 42-amino acid amyloid beta peptide
  • a ⁇ is an amphipathic peptide, the abundance of which is increased by gene mutations and risk factors linked to AD.
  • Fibrils formed from A ⁇ constitute the cores of amyloid senile plaques, which are hallmarks of AD brain.
  • Analogous fibrils generated in vitro are lethal to cultured brain neurons.
  • mice were treated with monoclonal antibodies against A ⁇ : (1) vaccinated mice showed reversal of memory loss, with recovery evident in 24 hours; and (2) cognitive benefits of vaccination accrued despite no change in senile plaque levels (Dodart et al. (2002) Nat. Neurosci 5:452-457; Kotilinek et al. (2002) J. Neurosci. 22:6331-6335).
  • Such findings are not consistent with a mechanism for memory loss dependent on neuron death caused by amyloid fibrils.
  • Salient flaws in the original amyloid cascade hypothesis have been eliminated by an updated amyloid cascade hypothesis that incorporates a role for additional neurologically active molecules formed by A ⁇ self-assembly.
  • These molecules are amyloid ⁇ -derived diffusible ligands (ADDLs), which assemble from A ⁇ i_ 42 at low concentrations (Lambert et al. (1998) Proc. Natl. Acad. Sci. USA 95:6448-6453).
  • ADDLs amyloid ⁇ -derived diffusible ligands
  • ADDLs rapidly inhibit long term potentiation (Lambert et al. (1998) Proc. Natl. Acad. Sci. USA 95:6448-6453; Walsh et al.
  • ADDLs occur in brain tissue and are strikingly elevated in AD brain tissue compared to age matched controls (Kayed et al. (2002) Science 300:486-489; Gong et al. (2003) Proc. Natl. Acad. Sci. USA 100:10417-10422) and in AD transgenic mice models (Kotilinek et al. (2002) J. Neurosci. 22:6331-6335; Chang et al. (2003) J. MoI. Neurosci. 20:305-313).
  • ADDLs Monome ⁇ c AB 1-42 ⁇ ⁇ ADDLs where formation of ADDLs is a separate pathway from formation of amyloid senile plaque both of which are in equilibrium with monomeric A ⁇ i_4 2 . Further experiments have shown important neurological properties of ADDLs. ADDLs were shown to have selective toxicity to hippocampal CAl neurons compared with CA3 neurons, and the complete absence of toxicity towards cerebellar neurons (Kim et al. (2003) FASEB J. 17:118-120).
  • ADDLs have been implicated as upstream activators of tau phosphorylation and have been shown to interfere with animal behavior at femtomolar levels (Matsubara et al. (2004) Neurobiol. Aging 25:833-841).
  • AD Alzheimer's disease
  • ADDLs antibodies specific to ADDLs are a powerful way to modulate the equilibrium between monomeric A ⁇ i_ 42 and ADDLs thereby providing treatment for disease conditions mediated by ADDLs.
  • antibody delivery is typically limited to injectable solutions which pose patient compliance issues as well as the presence of an attending clinician. Small molecules that modulate this equilibrium, deliverable by non- injectable means such as oral delivery, transdermal delivery, pulmonary delivery, nasal delivery, etc. would be particularly beneficial.
  • a number of small molecules developed originally as amyloid fibril blockers are purported to possess A ⁇ oligomer assembly blocking properties. Some of these compounds include AlzhmedTM (Gervais (2004) Neurobiol. Aging 25:S11-12), Clioquinol (Ritchie et al. (2003) Arch. Neural. 60:1685-1691), substituted ⁇ -cyclodextrins (Yu et al. (2002) J. MoI. Neurosci. 19:51-55), trehalose (Lui (2005) Neurobiol. Disease 20:74-81), simple amino, carbonyl, and nitro substituted phenols (De Felice et al. (2001) FASEB J. March 20; De Felice et al.
  • AlzhemedTM (3-amino-l-propanesulfonic acid), a so-called “GAG mimetic,” is proposed to reduce soluble and insoluble amyloid levels by binding to A ⁇ monomer, although no experimental details have appeared to confirm the proposed mode of action.
  • AlzhemedTM has recently completed a 20 month open-label extension of a Phase II trial, and there are reports of slowed cognitive decline in some patients with mild AD, however, no efficacy was observed during the blinded phase of the study (Gervais (2004) Neurobiol. Aging 25:S11-12).
  • binding assays indicate that these compounds are, at best, moderate antagonists to ADDL formation. Accordingly, it would be particularly beneficial to provide for small molecules which provide enhanced inhibition, regulation, and/or modulation of ADDL formation.
  • This invention is directed to the discovery that soluble, globular, non- fibrillar, neurotoxic A ⁇ 1-42 (ADDL) formation can be antagonized by certain compounds. It is contemplated that by antagonizing (or inhibiting, modulating, or regulating) ADDL formation, these compounds may be used to treat patients suffering from diseases mediated, at least in part by, ADDL formation. It is further contemplated that these compounds may also be used to inhibit, modulate or regulate neuronal dysfunction or neurotoxicity that is caused by ADDLs.
  • ADDL neurotoxic A ⁇ 1-42
  • the methods employ compounds of the formula:
  • A is a 5-10 membered heteroaryl ring having 1 to 3 heteroatoms or an aryl ring;
  • X 1 and X 2 are independently selected from the group consisting of oxygen, sulfur or N-OR 4 ;
  • R 1 is selected from the group consisting of hydroxy, halo, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C ⁇ alkoxy, -N(R 5 )(R 6 ), C 3-10 cycloalkyl, aryl, heteroaryl, heterocyclic, wherein the aryl, heteroaryl, and heterocyclic group is optionally substituted with 1-3 R 9 groups;
  • R 2 is selected from the group consisting of hydrogen, Cue alkyl, and Cue haloalkyl
  • R 3 is selected from the group consisting of Cue alkyl, Cue alkoxy, -N(R 5 )(R 6 ), and
  • R 7 is selected from the group consisting of hydrogen, C 1-6 alkyl, and aryl optionally substituted with 1 to 3 Of C 1-4 alkyl or halo;
  • R 8 is selected from the group consisting of aryl, biaryl, biaryl, heteroaryl, and heterocyclic, wherein each R 8 is optionally substituted with 1-4 R 9 groups; each R 9 is independently selected from the group consisting of hydroxy, halo, nitro, Ci_6 alkyl, C 2 _6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, aralkyl, aryl, -N(R 5 )(R 6 ), carboxyl, carboxyl ester, and heterocyclic; n is 0, 1, 2, or 3; and m is 0 or 1 ; or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof.
  • the invention also contemplates using compounds of formula II or III:
  • a 2 is a 5-10 membered heteroaryl ring having 1 to 3 heteroatoms or an aryl ring;
  • R 21 is selected from the group consisting of hydroxy, halo, nitro, C 1-6 alkyl, C 1-6 haloalkyl, -N-S(O) 2 -R 24 , and aryl;
  • R 22 is selected from the group consisting of hydrogen, Cue alkyl, and Cue haloalkyl;
  • R 23 is selected from the group consisting of C 1-6 alkyl, amino, and R 25 ;
  • R 24 is selected from the group consisting of C 1-6 alkyl, and aryl optionally substituted with halo or C 1-6 alkyl,
  • R 25 is selected from the group consisting of aryl, heteroaryl, and heterocyclic, all of which may be optionally substituted with 1-3 R 26 groups; each R 26 is independently selected from the group consisting of hydroxy, halo, Cue alkyl, aralkyl, and aryl; n is 0, 1, 2, or 3; or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof.
  • a 1 is a 5-10 membered heteroaryl ring having 1 to 3 heteroatoms or an aryl ring;
  • R 32 is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; R is selected from the group consisting of aryl, biaryl, heteroaryl, and heterocyclic, wherein each R 33 is optionally substituted with 1-4 R 35 groups;
  • R 34 is selected from the group consisting of Cue alkyl and aryl optionally substituted with halo;
  • R 35 is selected from the group consisting of hydroxy, nitro, halo, C 1-6 alkyl, C 2 _ 6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, halo, amino, alkylamino, dialkylamino, aminoacyl, aryl-alkylene, carboxyl, carboxyl ester, and heterocyclic; and n is 0, 1, 2, or 3; or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof.
  • this invention is directed to a method for antagonizing neurotoxic ADDL formation from monomeric A ⁇ i_ 42 by contacting monomeric A ⁇ i_ 42 with an effective amount of a compound of formula I, II, or III.
  • the invention is directed to a method of inhibiting, regulating and/or modulating the ADDL-induced neuronal dysfunction and/or neurotoxicity in a neuronal cell by inhibiting the formation of ADDLs.
  • the method comprises contacting A ⁇ i_ 42 monomers which may be in the presence of neuronal cells with an effective amount of a compound of formula I, II, or III.
  • the invention is directed to a method of inhibiting, regulating and/or modulating amyloid- ⁇ oligomer formation or the activity of such oligomers in a patient suffering from or at risk from suffering from a disease associated with the formation of A ⁇ i_ 42 oligomers.
  • the method comprises administering to the patient a therapeutically effective amount of a compound of formula I, II, or III.
  • the invention is directed to a method for treating a patient suffering from or at risk of suffering from an ADDL-related disease selected from the group consisting of Alzheimer's disease, Down's Syndrome, stroke, mild cognitive impairment, focal ischemia associated dementia, and neuronal degeneration.
  • the method comprises administering to said patient a therapeutically effective amount of a compound of formula I, II, or III.
  • the present invention relates to a composition for use in the treatment of a patient suffering from or at risk of suffering from a disease selected from the group consisting of Alzheimer's disease, Down's Syndrome, stroke, mild cognitive impairment, focal ischemia associated dementia, and neuronal degeneration wherein the composition comprises a therapeutically effective amount of a compound of formula I, II, or III.
  • One embodiment of the invention is directed to a method of enhancing cognitive function in a patient who has diminished cognitive function due to ADDL neurotoxicity.
  • the method comprises administering to the patient a therapeutically effective amount of a compound of formula I, II, or III.
  • the diminished cognitive function in a patient is due to the patient suffering from or at risk of suffering from a disease associated with the formation of and/or activity of ADDLs.
  • the disease is selected from the group consisting of Alzheimer's disease, Down's Syndrome, stroke and mild cognitive impairment.
  • the diminished cognitive function in a patient is due to the patient suffering from or at risk of suffering from a disease associated with insoluble amyloid fibrils, senile plaques, and/or tangles.
  • the diminished cognitive function in a patient is due to the patient suffering from or at risk from suffering from a disease associated with over-expression of A ⁇ i_4 2 protein.
  • the disease is selected from the group consisting of focal ischemia associated dementia and neuronal degeneration.
  • the invention is directed to a method of inhibiting, regulating and or modulating the binding of neurotoxic ADDLs to spines and/or synapses of a neuronal cell.
  • the method comprises contacting said neuronal cell with an effective amount of a compound of formula I, II, or III.
  • the invention is directed to a method of inhibiting, regulating and/or modulating the long term potentiation of neuronal cells.
  • the method comprises contacting said cells with an effective amount of a compound of formula I, II, or III.
  • the invention is directed to a method of treating a patient suffering from diminished cognitive function due to the patient suffering from or at risk of suffering from a disease selected from the group consisting of Alzheimer's disease, Down's Syndrome, stroke, mild cognitive impairment, focal ischemia associated dementia and neuronal degeneration.
  • the method comprises administering to said patient a therapeutically effective amount of a compound of formula I, II, or III.
  • the compound is administered in an amount of from about 0.05 milligrams to 1000 milligrams, one or more times per day. In another embodiment of the invention, the compound is administered in a pharmaceutical composition, further comprising a pharmaceutically acceptable excipient.
  • the compounds of the invention have an IC 50 of about 50 ⁇ M or less when tested in the FRET assay. It is contemplated that compounds of this invention have an IC50 of about 50 ⁇ M or less in an assay that tests for formation of ADDLs. In one embodiment, this assay is Example 16 described below. In another embodiment of the invention, the compounds have an IC 50 of 25 ⁇ M or less when tested in the FRET assay. In another embodiment of the invention, the compounds have an IC50 of 10 ⁇ M or less. In yet another embodiment of the invention, the compounds have an IC 50 of 5 ⁇ M or less.
  • This invention is directed to the discovery that the formation of soluble, oligomeric, globular, non-f ⁇ brillar, neurotoxic Ap 1-42 peptides (ADDLs) can be antagonized by compounds of formula I, II, or III. Without being limited by any theory, it is believed that the administration of a therapeutically effective amount of one or more of the compounds described herein will interact with key assembly motifs within the A ⁇ i_ 42 monomers or within critical motifs on the A ⁇ i_ 42 oligomers. This interaction, in turn, will prevent the formation of neurotoxic ADDLs or the activity of such ligands.
  • ADDLs neurotoxic Ap 1-42 peptides
  • ADDLs disruption of the ADDLs or the activity of such ligands will protect long term potentiation of neuronal cells thereby obviating and/or reversing the neurotoxicity associated with ADDL. In addition, this interaction does not interfere with the formation of A ⁇ senile plaques.
  • ADDL amyloid beta-derived diffusable ligands which have the following characteristics: soluble, oligomeric, globular, non- fibrillar, neurotoxic A ⁇ 1-42 peptides (GenBank Ref. No. IZOQ A, accessed on November 21, 2007).
  • the compounds described herein are useful in a method for inhibiting, regulating and/or modulating assembly of ADDLs either in vitro or in vivo.
  • soluble means the ability for a given substance, the solute (an example in the instant invention is the A ⁇ 1-42 oligomer), to dissolve in a solvent.
  • solute an example in the instant invention is the A ⁇ 1-42 oligomer
  • soluble A ⁇ oligomers are capable of being fractionated by centrifugation.
  • oligomeric means a protein complex of a finite number of monomer subunits. In the context of the invention, oligomers are referred to as trimers, low-n-mers, dodecamers (12-mers), and large-n-multimers composed of A ⁇ 1-42 peptides. The term “oligomeric” does not include senile amyloid plaques.
  • globular means a large soluble protein complex, which is to be distinguished from fibrils and amyloid plaques.
  • the globular structure ranges in size from 4 nanometers (nm) to about 12 nm, preferably, from about 4.7 to about 11 nm, which can be observed upon atomic force microscope analysis (AFM) of supernatant fractions of Ap 1-42 soluble oligomer preparations as described in US Patent No. 6,218,506.
  • non-fibrillar means the A ⁇ i_ 42 peptides and oligomeric complexes that are not aligned in a morphologically distinct pattern known as amyloid protofibrils or amyloid fibrils.
  • the compounds described herein are useful for antagonizing ADDL formation in vivo and the diseases associated with ADDL formation.
  • the terms “disease,” “disorder,” and “condition” are used inclusively and refer to any condition mediated, at least in part, by ADDLs.
  • the disease may be associated with insoluble amyloid fibrils, senile plaques, neurofibrillary tangles, and/or the over-expression of amyloid ⁇ 1-42 protein. Examples include, but are not limited to, Alzheimer's disease, Down's Syndrome, mild cognitive impairment, stroke, focal ischemia associated dementia, and neuronal degeneration.
  • Patients amenable to treatment include individuals at risk of disease but not exhibiting symptoms, as well as patients presently exhibiting symptoms. Therefore, the compounds described herein can be administered prophylactically to the general population without the need for any assessment of the risk of the patient.
  • amyloid fibrils means protein aggregates sharing specific structural traits. Histopathological techniques generally identify the structures by apple- green birefringence when stained with Congo red and seen under polarized light.
  • senile plaque or "senile plaque formation” refers to the extracellular deposit of amyloid in the gray matter of the brain. The deposits are associated with degenerative neural structures. It is understood that senile plaque is different from and distinguished over ADDLs.
  • tangles means the neurofibrillary tangles formed inside of degenerating neurons by bundling of paired helical filaments, which assemble from hyperphosphorylated forms of the microtubule-associated protein know as tau.
  • patient refers to animals, including mammals, humans, and non- human mammals.
  • a patient is an animal, particularly an animal selected from a mammalian species including rat, rabbit, bovine, ovine, porcine, canine, feline, murine, equine, and primate, particularly human.
  • the methods are especially useful for patients who have a known genetic risk of Alzheimer's disease.
  • Such individuals include those having relatives who have been diagnosed with the disease and those whose risk is determined by analysis of genetic or biochemical markers.
  • Genetic markers of risk for Alzheimer's disease include mutations in the APP gene, particularly mutations at position 717 and positions 670 and 671 referred to as the Hardy and Swedish mutations respectively.
  • Other markers of risk are mutations in the presenilin genes, PSl and PS2, and ApoE4, family history of Alzheimer's Disease, hypercholesterolemia or atherosclerosis.
  • Individuals presently suffering from Alzheimer's disease can be recognized from characteristic dementia, as well as the presence of risk factors described above.
  • a number of diagnostic test are available for identifying individuals who have Alzheimer's disease.
  • NINCDS-ADRDA National Institute of Neurological and Communicative Diseases and Stroke/ Alzheimer's Disease and Related Disorders Association
  • treatment can begin at any age (e.g., 10, 20, 30 years of age). Usually, however, it is not necessary to begin treatment until a patient reaches about 40, 50, 60, or 70 years of age. Treatment typically entails multiple dosages over a period of time. Treatment can be monitored by assaying for the presence of ADDLs over time.
  • Treating or “treatment” of a disease includes: (1) preventing the disease, i.e., causing the clinical symptoms of the disease not to develop in a patient that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • sensing refers to a patient or individual who has been diagnosed with or is predisposed to a disease.
  • a patient may also be referred to being "at risk of suffering” from a disease.
  • This patient has not yet developed characteristic disease pathology, however are known to be predisposed to the disease due to family history, being genetically predisposed to developing the disease, or diagnosed with a disease or disorder that predisposes them to developing the disease to be treated.
  • Alzheimer's disease In addition to Alzheimer's disease, several other disease are known to be associated with Ap 1-42 formation including, but are not limited to, Down's Syndrome, stroke and mild cognitive impairment. It is conceivable that similar to Alzheimer's disease, treatment of patients suffering from or at risk of suffering from these diseases is possible due to the parallel mechanisms of the diseases.
  • over-expression of A ⁇ 1-42 is associated with focal ischemia associated dementia and neuronal degeneration.
  • Over-expression of A ⁇ i_ 42 is believed to result in accumulation of ADDLs, thereby inducing neurotoxicity. Treating a patient suffering from or at risk of suffering from one of these diseases by administration of one or more of the compounds described herein will ameliorate the neurotoxicity of over-expressed
  • neurotoxicity refers to the toxic effect of ADDLs on neuronal cells either in vitro and/or in vivo.
  • ADDLs bind to specific neuronal receptors triggering aberrant neuronal signaling, which compromises long term potentiation and causes memory deficits.
  • ADDLs alter the function of the neuronal cell in such a manner that, while still viable, the neuron does not properly function.
  • neuronal dysfunction Such altered functionality is referred to herein as “neuronal dysfunction,” which is a subclass of neurotoxicity.
  • Persistent ADDL signaling causes aberrant transcription and the progressive loss of synapses, and very long term persistent ADDL signaling and accumulated structural pathology leads to eventual neuron death and gross brain dystrophy.
  • a pharmaceutical composition containing one or more compounds described herein is administered to a patient suspected of, or already suffering from such a disease associated with the accumulation of ADDLs, wherein said compounds are administered in an amount sufficient to treat, or at least partially treat, the symptoms of the disease (biochemical, histological and/or behavioral), including its complication and intermediate pathological phenotypes in development of the disease.
  • a pharmaceutical composition containing one or more compounds described herein is administered to a patient susceptible to, or otherwise at risk of, a disease associated with the accumulation of ADDLs, wherein said compounds are administered in an amount sufficient to eliminate or reduce the risk, lessen the severity, or delay the outset of the disease. This includes biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
  • a therapeutically effective amount intends to indicate the amount of one or more compounds described herein administered or delivered to the patient which is most likely to result in the desired response to treatment.
  • the invention is directed to enhancing cognitive function in a patient who has diminished function.
  • cognitive function refers to the intellectual process by which one becomes aware of, perceives, or comprehends ideas. Cognitive function embraces the quality of knowing, which includes all aspects of perception; recognition; conception; sensing; thinking; reasoning; remembering and imagining.
  • the term "diminished cognitive function” refers to memory loss, mental slowing, intellectual decline and/or amnesia. Memory loss may be characterized as the difficulty or failure for immediate or delayed recall. Mental slowing is the difficulty in processing or completing previously learned tasks in a timely manner or in processing new information quickly. Intellectual decline is defined as a loss of information, or an inability to utilize information previously possessed or utilized by a person. Amnesia is an extreme loss of cognitive ability which results in partial or total inability to recall past experiences and impaired or total loss of the ability to speak or write. Diminished cognitive function may be caused by a number of disease conditions which are more thoroughly discussed below.
  • Methods of assessing cognitive function include, but are not limited to, standardized instruments for example Folstein Mini-Mental State Examination; Modified Mini-Mental State Exam; Middlesex Elderly Assessment of Mental State; Short Portable Mental Status Questionnaire; Alzheimer's Disease Assessment Scale; Clock Drawing Test; Clinical Dementia Rating; Neuropsychiatric Inventory or any similarly designed test.
  • a skilled clinician would be able to assess the level of diminished cognitive function of a patient or enhanced cognitive function following treatment.
  • informal observations and interactions of individuals to a patient can also be used to assess cognitive function and include, but are not limited to, family members, friends, formal care givers such as nurses, and individuals who have previous intimate knowledge of the patient.
  • CT Computed Tomography
  • CAT Computed Axial Tomography
  • MRI Magnetic Resonance Imaging
  • fMRI Functional Magnetic Resonance Imaging
  • PET Positron Emission Tomography
  • SPECT Single Photon Emission Computed Tomography
  • DOI Diffuse Optical Imaging
  • DOT Diffuse Optical Tomography
  • an “effective amount” is an amount of one or more of the compounds described herein which treats the ADDL-mediated disease.
  • the compounds of this invention will decrease ADDL formation either in vitro or in vivo by at least 10%, 25%, 40%, 60%, 80%, 90% or 95% as compared to control.
  • the "therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated all of which is within the skill of the attending clinician to assess. It is contemplated that a therapeutically effective amount of one or more of the compounds described herein will alter ADDL formation (including inhibiting or reversing formation of ADDLs) in the patient as compared to binding of ADDLs in the absence of treatment. As such, impairment of long term potentiation and subsequent memory formation is decreased. A therapeutically effective amount is distinguishable from an amount having a biological effect (a)
  • a compound of the present invention may have one or more biological effects in vitro or even in vivo, such as reduction in ADDL formation to some extent.
  • a biological effect may not result in any clinically measurable therapeutically effect as described above as determined by methods within the skill of the attending clinician.
  • the present invention is also directed ADDL inhibition in a neuronal cell and/or neuronal tissue.
  • a “neuronal cell” or “neuron” is a cell that transmits and processes signals in the brain or other parts of the nervous system. Additionally, a neuronal cell, as used in the invention, can be isolated from animal brain tissue and grown in tissue culture.
  • the isolated cells can be comprised of an established neuronal cell line selected from for example, but are not limited to, MC65; HCN-2; SH-SY5Y; SK-N-AS; SK-N-FI; SK-N-DZ; H19-7/IGF-IR; QNR/D; QNR/K2; C8-D30; C8-S; C8-D1A; OLGA-PH-J/92; Daoy; RSC96; SWlO; RT4-D6P2T; RN33B; PC-12; DBRTG-05MG; C8-B4; SK-N-SH; B35; R3[33-10ras3]; Neuro-2A; and HCN-IA or any genetic, chemical, and/or biochemical modified variants thereof. (Commercially available from American Type Culture
  • the isolated cells can also be comprised of primary cells and/or astrocytes isolated from neuronal tissues selected from, for example, but are not limited to, the hippocampus; cerebellum; cortex; hypothalamus; mid-brain; spinal cord; striatum; frontal lobe; temporal lobe; parietal lobe; occipital lobe and any genetic, chemical, and/or biochemical modified variants thereof.
  • the isolated, cultured animal cell can be comprised of a neural stem cell or any differentiated, genetic, chemical, and/or biochemical modified variants thereof.
  • a neuronal cell or neuron can be isolated and distinguished from other cell types by detecting expression of neuronal markers selected from, but not limited to, CD133, GFAP, MAP-2, MPB, Nestin, Neural tubulin, Neurofilament, Neurosphere, Noggin, 04, 01, Synaptophysin, and Tau (http://stemcells.nih.gov/info/scireport/appendixE.asp, accessed on November 26, 2007).
  • neuronal markers selected from, but not limited to, CD133, GFAP, MAP-2, MPB, Nestin, Neural tubulin, Neurofilament, Neurosphere, Noggin, 04, 01, Synaptophysin, and Tau (http://stemcells.nih.gov/info/scireport/appendixE.asp, accessed on November 26, 2007).
  • Neuronal tissue refers to any portion of the central nervous system including, but not limited to, the brain or spinal cord. Neuronal tissue can be composed of, at least in part, neuronal cells.
  • the compounds useful in the methods of the invention contain one or more and any combination of the following characteristics: (1) low or sub-micromolar potency when tested in the FRET assay described herein; (2) non-aggregating; (3) little or no neuronal toxicity when administered to a patient; (4) favorable solubility in an aqueous environment; (5) chemically tractable; (6) dose dependent characteristics; (7) reversibly bind to the A ⁇ protein; (8) capable of amyloid ⁇ monomer binding; (9) capable of binding soluble amyloid ⁇ oligomers.
  • the compounds useful for treating patients are suitable for oral delivery.
  • the compounds are compliant with Lipinski's rule-of-f ⁇ ve which provides a criteria to evaluate drug likeness.
  • the rule states that, in general, an orally active drug has: no more than 5 hydrogen bond donors (OH and NH groups); no more than 10 hydrogen bond acceptors (notably N and O); a molecular weight under 500 g/mol; and a partition coefficient log P less than 5.
  • methods of the invention employ compounds of the formula:
  • A is a 5-10 membered heteroaryl ring having 1 to 3 heteroatoms or an aryl ring;
  • X 1 and X 2 are independently selected from the group consisting of oxygen, sulfur or
  • R 1 is selected from the group consisting of hydroxy, halo, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -N(R 5 )(R 6 ), C 340 cycloalkyl, aryl, heteroaryl, heterocyclic, wherein the aryl, heteroaryl, and heterocyclic group is optionally substituted with 1-3 R 9 groups;
  • R 2 is selected from the group consisting of hydrogen, Cue alkyl, and Cue haloalkyl;
  • R 3 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, -N(R 5 )(R 6 ), and
  • R 4 is selected from the group consisting of hydrogen and alkyl; each R 5 is independently selected from the group consisting of hydrogen, alkyl, and -SO 2 (R 7 ); each R 6 is independently selected from the group consisting of hydrogen and C 1-6 alkyl;
  • R 8 is selected from the group consisting of aryl, biaryl, heteroaryl, and heterocyclic, wherein each R is optionally substituted with 1-4 R groups;
  • each R 9 is independently selected from the group consisting of hydroxy, halo, nitro, Ci_6 alkyl, C 2 _6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C340 cycloalkyl, halo, aminoacyl, acylamino, aralkyl, -N(R 5 )(R 6 ), carboxyl, carboxyl ester, and heterocyclic; n is 0, 1, 2, or 3; and m is 0 or 1 ; or a pharmaceutically acceptable salt, stereoisomer, tautomer, or pro
  • the methods employ compounds of the formula:
  • a 2 is a 5-10 membered heteroaryl ring having 1 to 3 heteroatoms or an aryl ring;
  • R » 21 is selected from the group consisting of hydroxy, halo, nitro, Cue alkyl, C 1 ⁇ haloalkyl, -N-S(O) 2 -R 24 , and aryl;
  • R 22 is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
  • R 23 is selected from the group consisting of C 1-6 alkyl, amino, and R 25 ;
  • R 24 is selected from the group consisting of Cue alkyl, and aryl optionally substituted with halo or C 1-6 alkyl,
  • R 25 is selected from the group consisting of aryl, heteroaryl, and heterocyclic, all of which may be optionally substituted with 1-3 R 26 groups; each R 26 is independently selected from the group consisting of hydroxy, halo, C 1-6 alkyl, aralkyl, and aryl; n is 0, 1, 2, or 3; or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof.
  • methods of the invention employ a compound of the formula:
  • a 1 is a 5-10 membered heteroaryl ring having 1 to 3 heteroatoms or an aryl ring;
  • R 32 is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; R is selected from the group consisting of aryl, biaryl, heteroaryl, and heterocyclic, wherein each R 33 is optionally substituted with 1-4 R 35 groups;
  • R 34 is selected from the group consisting of Cue alkyl and aryl optionally substituted with halo;
  • R 35 is selected from the group consisting of hydroxy, nitro, halo, C 1-6 alkyl, C 2 _ 6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, halo, amino, alkylamino, dialkylamino, aminoacyl, aryl-alkylene, carboxyl, carboxyl ester, and heterocyclic; and n is 0, 1, 2, or 3; or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof.
  • the group A is selected from the group consisting of phenyl, biphenyl, naphthyl, benzothiophenyl, thiadiazolyl, indanyl, thiophenyl, indolyl, pyrazolyl, furanyl, oxoindolinyl, pyridyl, and benzodioxoyl.
  • R 1 is selected from the group hydroxy, chloro, fluoro, bromo, iodo, methyl, methoxy, trifluoromethyl, cyclopropyl, phenyl, pyrrolyl, methylsulfonamido, 4-chlorophenylsulfonylamido, nitro, benzo[d][l,3]dioxolyl, amino, thienyl, 5-chlorothienyl, and methylcarbonylamino.
  • the group A is optionally substituted and is selected from the group consisting of 2-(methylsulfonamido)phenyl, lH-indan-7-yl, lH-indol-7-yl, l-hydroxy-naphthalen-2-yl, l-phenyl-5 -(trifluoromethyl)- lH-pyrazol-4-yl, 2-(4- chlorophenyl sulfonamido) phenyl, 2,4-dihydroxyphenyl, 2,6-difluorophenyl, 2- acetamidophenyl, 2-aminophenyl, benzothiophen-2-yl, 2-fluoro-6-hydroxyphenyl, 2- hydroxy-3 -methylphenyl, 2-hydroxy-4-( 1 H-pyrrol- 1 -yl)phenyl, 2-hydroxy-4- methoxyphenyl, 2-hydroxy-5-methoxyphenyl, 2-hydroxy-5 -methylphenyl, 2-hydroxy-5
  • X 1 and X 2 are oxygen.
  • R 2 is selected from hydrogen, methyl, or trifluoromethyl.
  • n is 0. In other embodiments m is 1.
  • R .3 i •s selected from the group consisting of butyl, t- butyl, and amino.
  • R is optionally substituted and is selected from the group consisting of phenyl, thienyl, naphthyl, furanyl, piperazinyl, benzothiophenyl, pyrazolyl, morpholino, and piperidinyl.
  • R when a ring is substituted with one or more groups consisting of hydroxy, chloro, fluoro, bromo, iodo, methyl, t-butyl, methoxy, ethoxy, benzyl, phenyl, cyclohexyl, trifluoromethoxy, allyl, aminocarbonyl, amino, ethoxycarbonyl, diethylamino, morpholino, nitro, 2,4-difluorophenylsulfonylamino, and methylcarbonylamino .
  • R 3 is selected from the group consisting of 5-chloro- 2-(2,4-difluorophenylsulfonamido)phenyl, 1 -hydro xy-napthalen-2-yl, 1 -methyl- 1 H-pyrazol- 5-yl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,6-dihydroxyphenyl, 2-acetamido-5- chlorophenyl, 2-amino-5-chlorophenyl, benzothiophen-2-yl, 2-bromo-6-hydroxyphenyl, 2- furanyl, 2-hydroxy naphthalen-1-yl, 4-hydroxy-3'-methoxybiphen-3-yl, 2-hydroxy-3- methoxyphenyl, 2-hydroxy-3-methylphenyl, 2-hydroxy-4-methoxyphenyl, 2-hydroxy-4- methylphenyl, 2-hydroxy-4-morpholinophenyl, 2-hydroxy-5-methoxyphenyl, 2-hydroxy
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.
  • C x _ y alkyl refers to alkyl groups having from x to y carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), /j-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), f-butyl ((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 -), and neopentyl ((CH 3 ) 3 CCH 2 -).
  • Substituted alkyl refers to an alkyl group having from 1 to 5 and, in some embodiments, 1 to 3 or 1 to 2 substituents selected from the group consisting of alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycl
  • Alkylidene or alkylene refers to divalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.
  • (C u _ v )alkylene refers to alkylene groups having from u to v carbon atoms.
  • the alkylidene or alkylene groups include branched and straight chain hydrocarbyl groups.
  • (Ci_6)alkylene is meant to include methylene, ethylene, propylene, 2- methypropylene, pentylene, and the like.
  • aralkyl refers to the term aryl-alkylene wherein alkylene is as defined above and aryl is as defined below. Examples of this group include, but are not limited to benzyl, phenethyl, and the like.
  • Substituted alkylidene or “substituted alkylene” refers to an alkylidene group having from 1 to 5 and, in some embodiments, 1 to 3 or 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyl
  • (C x -C y )alkenyl refers to alkenyl groups having from x to y carbon atoms and is meant to include for example, ethenyl, propenyl, 1,3-butadienyl, and the like.
  • Substituted alkenyl refers to alkenyl groups having from 1 to 3 substituents and, in some embodiments, 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl,
  • Alkynyl refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond.
  • alkynyl is also meant to include those hydrocarbyl groups having one triple bond and one double bond.
  • (C 2 -Ce)alkynyl is meant to include ethynyl, propynyl, and the like.
  • Substituted alkynyl refers to alkynyl groups having from 1 to 3 substituents and, in some embodiments, from 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl,
  • Alkoxy refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.
  • Substituted alkoxy refers to the group -O-(substituted alkyl) wherein substituted alkyl is as defined herein.
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, substituted aryl-C(O)-, substituted hydrazino-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl
  • Acylamino refers to the groups -NR 20 C(O)alkyl, -NR 20 C(O)substituted alkyl, -NR 20 C(O)cycloalkyl, -NR 20 C(O)substituted cycloalkyl, -NR 20 C(O)alkenyl, -NR 20 C(O)substituted alkenyl, -NR 20 C(O)alkynyl, -NR 20 C(O)substituted alkynyl, -NR 20 C(O)aryl, -NR 20 C(O)substituted aryl, -NR 20 C(O)heteroaryl, -NR 20 C(O)substituted heteroaryl, -NR 20 C(O)heterocyclic, and -NR 20 C(O)substituted heterocyclic wherein R 20 is hydrogen or alkyl and wherein alkyl, substituted alkyl, alken
  • Acyloxy refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl
  • Amino refers to the group -NH 2 .
  • Substituted amino refers to the group -NR 21 R 22 where R 21 and R 22 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, -SO 2 -cycloalkyl, -SO 2 -substituted cylcoalkyl, -SO 2 -aryl, -SO 2 -substituted aryl, -SO 2 -heteroaryl, -SO 2 -substituted heteroaryl, -
  • R 21 is hydrogen and R 22 is alkyl
  • the substituted amino group is sometimes referred to herein as alkylamino.
  • R 21 and R 22 are alkyl
  • the substituted amino group is sometimes referred to herein as dialkylamino.
  • a monosubstituted amino it is meant that either R 21 or R 22 is hydrogen but not both.
  • Hydroamino refers to the group -NHOH.
  • Alkoxyamino refers to the group -NHO-alkyl wherein alkyl is defined herein.
  • Aminocarbonyl refers to the group -C(O)NR 23 R 24 where R 23 and R 24 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, and acylamino, and where R and R are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroary
  • Aminothiocarbonyl refers to the group -C(S)NR 23 R 24 where R 23 and R 24 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 23 and R 24 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Aminocarbonylamino refers to the group -NR 20 C(O)NR 23 R 24 where R 20 is hydrogen or alkyl and R 23 and R 24 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R and R are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined here
  • Aminothiocarbonylamino refers to the group -NR 20 C(S)NR 23 R 24 where R 20 is hydrogen or alkyl and R 23 and R 24 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 23 and R 24 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic
  • Aminocarbonyloxy refers to the group -0-C(O)NR 23 R 24 where R 23 and R 24 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 23 and R 24 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Aminosulfonyl refers to the group -SO 2 NR 23 R 24 where R 23 and R 24 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 23 and R 24 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Aminosulfonyloxy refers to the group -0-SO 2 NR 23 R 24 where R 23 and R 24 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 23 and R 24 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Aminosulfonylamino refers to the group -NR 20 -SO 2 NR 23 R 24 where R 20 is hydrogen or alkyl and R 23 and R 24 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R and R are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic
  • Aryl or “Ar” refers to an aromatic group of from 6 to 14 carbon atoms and no ring heteroatoms and having a single ring (e.g. , phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl).
  • aryl or “Ar” applies when the point of attachment is at an aromatic carbon atom (e.g., 5,6,7,8 tetrahydronaphthalene-2-yl is an aryl group as its point of attachment is at the 2-position of the aromatic phenyl ring).
  • biasing refers to the group aryl-arylene where the term aryl is as noted above and the term arylene refers to a divalent aryl group. Examples of this include, but are not limited to, biphenyl.
  • Substituted aryl refers to aryl groups which are substituted with 1 to 8 and, in some embodiments, 1 to 5, 1 to 3, or 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy
  • Aryloxy refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthyloxy.
  • Substituted aryloxy refers to the group -O-(substituted aryl) where substituted aryl is as defined herein.
  • Arylthio refers to the group -S-aryl, where aryl is as defined herein.
  • Substituted arylthio refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.
  • Hydrazino refers to the group -NHNH 2 .
  • Substituted hydrazino refers to the group -NR 26 NR 27 R 28 where R 26 , R 27 , and R 28 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, -SO 2 -cycloalkyl, -SO 2 -substituted cylcoalkyl, -SO 2 -aryl, -SO 2 -substituted aryl, -SO 2 -heteroary
  • Carbonyl refers to the divalent group -C(O)- which is equivalent to
  • Carboxyl or “carboxy” refers to -COOH or salts thereof.
  • Carboxyl ester or “carboxy ester” refers to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl,
  • alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • (Carboxyl ester)amino refers to the group -NR 20 -C(O)O-alkyl
  • (Carboxyl ester)oxy refers to the group -O-C(O)O-alkyl, -O-C(O)O-substituted alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl,
  • Cycloalkyl refers to a saturated or partially saturated cyclic group of from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • cycloalkyl applies when the point of attachment is at a non-aromatic carbon atom (e.g. 5,6,7,8,- tetrahydronaphthalene-5-yl).
  • Cycloalkyl includes cycloalkenyl groups.
  • cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and cyclohexenyl.
  • C u - V cycloalkyl refers to cycloalkyl groups having u to v carbon atoms.
  • Substituted cycloalkyl refers to a cycloalkyl group, as defined herein, having from 1 to 8, or 1 to 5, or in some embodiments 1 to 3 substituents selected from the group consisting of oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido, carboxyl, carboxyl ester, (carboxyl ester
  • Cycloalkyloxy refers to -O-cycloalkyl wherein cycloalkyl is as defined herein.
  • Substituted cycloalkyloxy refers to -O-(substituted cycloalkyl) wherein substituted cycloalkyl is as defined herein.
  • Cycloalkylthio refers to -S-cycloalkyl wherein cycloalkyl is as defined herein.
  • Substituted cycloalkylthio refers to -S -(substituted cycloalkyl).
  • Halo or halogen refers to fluoro, chloro, bromo, and iodo.
  • Haloalkyl refers to substitution of alkyl groups with 1 to 5 or in some embodiments 1 to 3 halo groups.
  • Haloalkoxy refers to substitution of alkoxy groups with 1 to 5 or in some embodiments 1 to 3 halo groups.
  • Heteroaryl refers to an aromatic group of from 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur and includes single ring (e.g. imidazolyl) and multiple ring systems (e.g. benzimidazol-2-yl and benzimidazol-6-yl).
  • single ring e.g. imidazolyl
  • multiple ring systems e.g. benzimidazol-2-yl and benzimidazol-6-yl.
  • the term “heteroaryl” applies if there is at least one ring heteroatom and the point of attachment is at an atom of an aromatic ring (e.g.
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ O), sulfmyl, or sulfonyl moieties.
  • heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, quinazolinonyl, benzimidazolyl, benzisoxazolyl, benzothienyl, or oxindolyl.
  • Substituted heteroaryl refers to heteroaryl groups that are substituted with from 1 to 8 or in some embodiments 1 to 5, or 1 to 3, or 1 to 2 substituents selected from the group consisting of the substituents defined for substituted aryl.
  • Heteroaryloxy refers to -O-heteroaryl wherein heteroaryl is as defined herein.
  • Substituted heteroaryloxy refers to the group -O-(substituted heteroaryl) wherein substituted heteroaryl is as defined herein.
  • Heteroarylthio refers to the group -S-heteroaryl wherein heteroaryl is as defined herein.
  • Substituted heteroarylthio refers to the group -S-(substituted heteroaryl) wherein substituted heteroaryl is as defined herein.
  • Heterocyclic or “heterocycle” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially saturated cyclic group having from 1 to 14 carbon atoms and from 1 to 6 heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen and includes single ring and multiple ring systems including fused, bridged, and spiro ring systems.
  • heterocyclic For multiple ring systems having aromatic and/or non-aromatic rings, the terms “heterocyclic”, “heterocycle”, “heterocycloalkyl”, or “heterocyclyl” apply when there is at least one ring heteroatom and the point of attachment is at an atom of a non- aromatic ring (e.g.
  • the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfmyl, sulfonyl moieties.
  • heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidinyl, N-methylpiperidin-3-yl, piperazinyl, N-methylpyrrolidin-3- yl, 3-pyrrolidinyl, 2-pyrrolidon-l-yl, morpholinyl, and pyrrolidinyl.
  • a prefix indicating the number of carbon atoms e.g., C 3 -C 10 ) refers to the total number of carbon atoms in the portion of the heterocyclyl group exclusive of the number of heteroatoms.
  • Substituted heterocyclic or “Substituted heterocycle” or “substituted heterocycloalkyl” or “substituted heterocyclyl” refers to heterocyclic groups, as defined herein, that are substituted with from 1 to 5 or in some embodiments 1 to 3 of the substituents as defined for substituted cycloalkyl.
  • Heterocyclyloxy refers to the group -O-heterocyclyl wherein heterocyclyl is as defined herein.
  • Substituted heterocyclyloxy refers to the group -O-(substituted heterocyclyl) wherein substituted heterocyclyl is as defined herein.
  • Heterocyclylthio refers to the group -S-heterocyclyl wherein heterocyclyl is as defined herein.
  • Substituted heterocyclylthio refers to the group -S-(substituted heterocyclyl) wherein substituted heterocyclyl is as defined herein.
  • heterocycle and heteroaryl groups include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1, 2,3, 4-tetrahydroisoquino line, 4,5,6,7-
  • Niro refers to the group -NO 2 .
  • Oxide refers to products resulting from the oxidation of one or more heteroatoms. Examples include N-oxides, sulfoxides, and sulfones.
  • “Spirocycloalkyl” refers to a 3 to 10 member cyclic substituent formed by replacement of two hydrogen atoms at a common carbon atom with an alkylene group having 2 to 9 carbon atoms, as exemplified by the following structure wherein the methylene group shown here attached to bonds marked with wavy lines is substituted with a spirocycloalkyl group:
  • Sulfonyl refers to the divalent group -S(O) 2 -.
  • Substituted sulfonyl refers to the group -SO 2 -alkyl, -SO 2 -substituted alkyl,
  • “Sulfonyloxy” refers to the group -OSO 2 -alkyl, -OSO 2 -substituted alkyl, -OSO 2 -alkenyl, -OSO 2 -substituted alkenyl, -OSO 2 -cycloalkyl, -OSO 2 -substituted cylcoalkyl, -OSO 2 -aryl, -OSO 2 -substituted aryl, -OSO 2 -heteroaryl, -OSO 2 -substituted heteroaryl, -OSO 2 -heterocyclic, -OSO 2 -substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroary
  • Thioacyl refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted heterocyclic-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted
  • Thiol refers to the group -SH.
  • Alkylthio refers to the group -S-alkyl wherein alkyl is as defined herein.
  • Substituted alkylthio refers to the group -S -(substituted alkyl) wherein substituted alkyl is as defined herein.
  • Thiocyanate refers to the group -SCN.
  • Compound and “compounds” as used herein refers to a compound encompassed by the generic formulae disclosed herein, any subgenus of those generic formulae, and any forms of the compounds within the generic and subgeneric formulae. Unless specified otherwise, the term further includes the racemates, stereoisomers, and tautomers of the compound or compounds.
  • Racemates refers to a mixture of enantiomers.
  • Solidvate or “solvates” of a compound refer to those compounds, where compounds is as defined above, that are bound to a stoichiometric or non-stoichiometric amount of a solvent.
  • Solvates of a compound includes solvates of all forms of the compound. Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts. Suitable solvates include water.
  • Stepoisomer or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • Prodrug refers to any derivative of a compound of the embodiments that is capable of directly or indirectly providing a compound of the embodiments or an active metabolite or residue thereof when administered to a subject.
  • Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of the embodiments when such compounds are administered to a subject (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
  • Prodrugs include ester forms of the compounds of the invention.
  • ester prodrugs include formate, acetate, propionate, butyrate, acrylate, and ethylsuccinate derivatives.
  • An general overview of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • prodrug refers to compounds of formula I, II, or III that include chemical groups which, in vivo, can be converted to the carboxylate group, hydroxyl group, or amine group on the R group, the hydroxyl group or amine group on the R ! group of the A ring or the amine of a heteroaryl A ring.
  • chemical groups which can act as prodrugs for carboxylates and hydroxyl groups are esters which can be chemically cleaved or enzymatically cleaved by esterases.
  • Examples of such chemical groups which can act as prodrugs for amines are amides which can be enzymatically cleaved by proteases and phosphoryloxymethyl carbamates which can be enzymatically cleaved by alkaline phosphatases (see Safadi et al. Pharmaceutical Research 1993, 10 (9), 1350-1355).
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium, and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.
  • arylalkyloxycabonyl refers to the group (aryl)-(alkyl)-O-C(O)-.
  • impermissible substitution patterns e.g., methyl substituted with 5 fluoro groups.
  • impermissible substitution patterns are well known to the skilled artisan.
  • FRET Fluorescence Resonance Energy Transfer
  • fluorescence polarization has also been used to measure, detect, identify, assay, analyze, and characterize various interactions and processes in biological systems (see e.g., Lundblad et al. (1996) MoI. Endocrinol. 10(6):607-612; Nasir and Jolley (1999) Comb. Chem. High Throughput Screen. 2(4): 177-190; Park and Raines (2004) Methods MoI. Biol. 261:161-166; references in any of the foregoing; and the like).
  • Fluorescence polarization (FP) methods, protocols, techniques, assays, and the like are described generally and specifically in a number of patents and patent applications, including: U.S. Patent No. 6,794,158; U.S. Patent No. 6,632,613; U.S. Patent
  • FP Fluorescence polarization
  • FRET and FP have been used in the field of amyloid research (see e.g., U.S.
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
  • the compounds of this invention may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • Effective doses of the compositions of the present invention for the treatment of the above described diseases, vary depending upon may different factors, including means of administration, physiological state of the patient, whether the patient is human or an animal, other medications administered, and whether treatment is prophylactic or therapeutic.
  • the patient is a human, but in certain embodiments, a patient is an animal, particularly an animal selected from a mammalian species including rat, rabbit, bovine, ovine, porcine, canine, feline, murine, equine, and primate.
  • the compounds can be administered on multiple occasions, wherein intervals between single dosages can be daily, weekly, monthly, or yearly. Intervals can also be irregular as indicated by measuring blood levels of A ⁇ i_ 42 protein or ADDLs, or ADDL complexes in the patient.
  • one or more of the compounds of the invention can be administered as a sustained-release formulation, in which case less frequent administration is required. Dosage and frequency may vary depending on the half- life of the compounds of the invention. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, and sometimes until the patient shows partial or complete amelioration of symptoms of the disease. Thereafter, the patient can be administered a prophylactic regime.
  • Administration of a pharmaceutical composition of on the compounds described herein can be carried out via a variety of routes including, but are not limited to, oral, topical, pulmonary, rectal, subcutaneous, intradermal, intranasal, intracranial, intramuscular, intraocular, or intra-articular injection and the like.
  • routes including, but are not limited to, oral, topical, pulmonary, rectal, subcutaneous, intradermal, intranasal, intracranial, intramuscular, intraocular, or intra-articular injection and the like.
  • the most typical route of administration is oral, although other routes can be equally effective.
  • One or more compounds described herein can optionally be administered in combination with other biological or chemical agents that are at least partly effective in treatment of a Ap 1-42 associated disease.
  • An example of such an agent is, but are not limited to, A ⁇ i_ 42 targeted antibodies as described in International Application Nos.: WO 2003/253673; WO 2006/014478, US Patent No. 2,489,195, US Publication No. 2007- 0048312, and US Application No. 11/571,532, which are incorporated herein by reference.
  • the compounds described herein may be administered to a patient in an amount sufficient to inhibit, regulate and/or modulate the formation of neurotoxic ADDLs or the activity of such ligands in said patient.
  • a skilled clinician would be able to readily ascertain appropriate amounts of the compounds described here to effectively inhibit, regulate and/or modulate the formation of neurotoxic ADDLs or the activity of such ligands in said patient.
  • Contemplated amounts of the compounds described herein include for example, but are not limited to, from about 0.05 to 2000 mg/m /day of one compound or more than one compound.
  • the compounds described herein may be administered for example, but are not limited to, orally, topically, pulmonaryly, rectally, subcutaneously, intradermally, intranasally, intracranially, intramuscularly, intraocularly, or intra-arterially and the like.
  • the carrier or excipient or excipient mixture can be a solvent or a dispersive medium containing for example, but are not limited to, various polar or non-polar solvents, suitable mixtures thereof, or oils.
  • carrier or “excipient” means a pharmaceutically acceptable carrier or excipient and includes any and all solvents, dispersive agents or media, coating(s), antimicrobial agents, iso/hypo/hypertonic agents, absorption-modifying agents, and the like.
  • carrier or “excipient” means a pharmaceutically acceptable carrier or excipient and includes any and all solvents, dispersive agents or media, coating(s), antimicrobial agents, iso/hypo/hypertonic agents, absorption-modifying agents, and the like.
  • the use of such substances and the agents for pharmaceutically active substances is well known in the art.
  • other or supplementary active ingredients can also be incorporated into the final composition.
  • Alzheimer's disease Down's syndrome, stroke, mild cognitive impairment, focal ischemia associated dementia and neuronal degeneration.
  • the compounds of this invention are usually administered in the form of pharmaceutical compositions.
  • These compounds can be administered by a variety of routes including oral, topical, pulmonary, rectal, subcutaneous, intradermal, intranasal, intracranial, intramuscular, intraocular, or intra-articular injection. These compounds are effective as both injectable and oral compositions.
  • Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • compositions which contain, as the active ingredient, one or more of the compounds described herein associated with pharmaceutically acceptable carriers.
  • the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient employed is typically an excipient suitable for administration to patient.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • intravenous formulation should possess certain qualities aside from being just a composition in which the therapeutic agent is soluble.
  • the formulation should promote the overall stability of the active ingredient(s), also, the manufacture of the formulation should be cost effective. All of these factors ultimately determine the overall success and usefulness of an intravenous formulation.
  • solvents ethanol, glycerol, propylene glycol
  • stabilizers ethylene diamine tetraacetic acid (EDTA), citric acid
  • antimicrobial preservatives benzyl alcohol, methyl paraben, propyl paraben
  • buffering agents citric acid/sodium citrate, potassium hydrogen tartrate, sodium hydrogen tartrate, acetic acid/sodium acetate, maleic acid/sodium maleate, sodium hydrogen phthalate, phosphoric acid/potassium dihydrogen phosphate, phosphoric acid/disodium hydrogen phosphate
  • tonicity modifiers sodium chloride, mannitol, dextrose.
  • the presence of a buffer may be necessary to maintain the aqueous pH in the range of from about 4 to about 8 and more preferably in a range of from about 4 to about 6.
  • the buffer system is generally a mixture of a weak acid and a soluble salt thereof, e.g., sodium citrate/citric acid; or the monocation or dication salt of a dibasic acid, e.g. , potassium hydrogen tartrate; sodium hydrogen tartrate, phosphoric acid/potassium dihydrogen phosphate, and phosphoric acid/disodium hydrogen phosphate.
  • the amount of buffer system used is dependent on (1) the desired pH;
  • the amount of buffer used is in a 0.5:1 to 50:1 mole ratio of buffer: drug (where the moles of buffer are taken as the combined moles of the buffer ingredients, e.g., sodium citrate and citric acid) of formulation to maintain a pH in the range of 4 to 8 and generally, a 1 :1 to 10:1 mole ratio of buffer (combined) to drug present is used.
  • One useful buffer in the invention is sodium citrate/citric acid in the range of
  • the buffer agent may also be present to prevent the precipitation of the drug through soluble metal complex formation with dissolved metal ions, e.g., Ca, Mg, Fe, Al, Ba, which may leach out of glass containers or rubber stoppers or be present in ordinary tap water.
  • the agent may act as a competitive complexing agent with the drug and produce a soluble metal complex leading to the presence of undesirable particulates.
  • the presence of an agent, e.g., sodium chloride in an amount of about of 1-8 mg/mL, to adjust the tonicity to the same value of human blood may be required to avoid the swelling or shrinkage of erythrocytes upon administration of the intravenous formulation leading to undesirable side effects such as nausea or diarrhea and possibly to associated blood disorders.
  • the tonicity of the formulation matches that of human blood which is in the range of 282 to 288 m ⁇ sm/kg, and in general is 285 mOsm/kg , which is equivalent to the osmotic pressure corresponding to a 0.9% solution of sodium chloride.
  • the intravenous formulation can be administered by direct intravenous injection, i.v. bolus, or can be administered by infusion by addition to an appropriate infusion solution such as 0.9% sodium chloride injection or other compatible infusion solution.
  • compositions can be formulated in an oral unit dosage form.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for a patient, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.05 to about 2000 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • Hard gelatin capsules containing the following ingredients are prepared:
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below:
  • the components are blended and compressed to form tablets, each weighing 240 mg.
  • a dry powder inhaler formulation is prepared containing the following components:
  • Lactose 95 The active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
  • Tablets each containing 30 mg of active ingredient, are prepared as follows: Ingredient Quantity (mg/tablet)
  • the active ingredient, starch, and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 5O 0 C to 6O 0 C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • the active ingredient, starch and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Suspensions each containing 50 mg of medicament per 5.0 ml dose are made as follows:
  • the active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • a subcutaneous formulation may be prepared as follows:
  • An intravenous formulation may be prepared as follows:
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Indirect techniques usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs.
  • Latentiation is generally achieved through blocking of the hydroxyl, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
  • the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions, which can transiently open the blood-brain barrier.
  • the compounds described herein are suitable for use in a variety of drug delivery systems described above. Additionally, in order to enhance the in vivo serum half- life of the administered compound, the compounds may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques may be employed which provide an extended serum half- life of the compounds.
  • a variety of methods are available for preparing liposomes, as described in, e.g., Szoka, et al, U.S. Patent Nos. 4,235,871, 4,501,728 and 4,837,028 each of which is incorporated herein by reference.
  • compositions are administered to a patient at risk of developing AD (determined for example by genetic screening or familial trait) in an amount sufficient to inhibit the onset of symptoms of the disease.
  • An amount adequate to accomplish this is defined as “prophylactically effective dose.” Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the age, weight and general condition of the patient, and the like.
  • the compounds administered to a patient are in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11 , more preferably from 5 to 9 and most preferably from 7 and 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the following examples are offered to illustrate this invention and are not to be construed in any way as limiting the scope of this invention. Unless otherwise stated, all temperatures are in degrees Celsius.
  • Compounds of the invention are characterized by assessing melting points, mass spectroscopy, and/or nuclear magnetic resonance. Melting points are measured on a Fisher- Johns Melting point apparatus (Fisher cat 12-144) and are uncorrected. Mass spectrometric analysis is performed on an Agilent LC/MSD Multimode Instrument using the following parameters:
  • Source ESI or APCI positive or negative mode, as noted for individual samples.
  • Nuclear Magnetic resonance (NMR) analysis is performed with a Varian 400 MHz machine.
  • the spectral reference is either TMS or the known chemical shift of the solvent.
  • Some compounds are run at elevated temperature (i.e., 75°C) to promote increased sample solubility.
  • the title compound was prepared from 2-hydroxybenzhydrazide (Alfa, 173 mg, 0.84 mmol), 4,4,4-trifluoro-l-(2-furyl)-l,3-butanedione (Aldrich, 122 mg, 0.8 mmol) and ethanol (1.6 mL) at 90 0 C for 8 hours.
  • Fluorescence (or F ⁇ rster) Resonance Energy Transfer is a distance- dependent, non-radiative transfer of energy in which the de-excitation of one fluorophore (donor) is coupled to excitation of another fluorophore (acceptor). FRET occurs if (1) the quantum of energy emitted by a donor fluorophore corresponds to an acceptor fluorophore 's excitation energy, (2) the orientations of donor and acceptor transition dipoles are nearly parallel and (3) the donor fluorescent emission spectrum overlaps the acceptor absorption spectrum.
  • FRET and FP assays are performed in 384-well Corning Non-Binding
  • the assay buffer consists of 25 mM MOPS-Tris (pH 8.0) with 100 mM MgCl 2 .
  • ADDL assembly is monitored on a Tecan GENios Pro plate reader, exciting at a wavelength of 485 nm and detecting emission at a wavelength of 515 nm.
  • Kinetic traces are collected by recording fluorescence intensity and polarization readings every five minutes over about a three hour time course.
  • Negative control reactions which do not appreciably assemble into ADDLs during this time, lack MgCl 2 but contain all other buffer and peptide components. Positive control reactions contain all buffer components in the absence of added small molecule or antibody reagents.
  • the compound was incubated with the peptide mixture at six concentrations from about 10 ⁇ M decreasing to about 0.03 ⁇ M.
  • a ⁇ i_42 ADDLs and a potential therapeutic compound under the Alternating Lever Cyclic Ratio (ALCR) rat model of AD were tested to show in vivo efficacy.
  • ACR Alternating Lever Cyclic Ratio
  • This highly sensitive model has been able to detect cognitive deficits due to direct injection of cell-derived A ⁇ oligomers into rat brain.
  • a direct injection of ADDLs made from synthetic Ap 1-42 and a putative therapeutic compound under the ALCR procedure were tested.
  • rats learned a complex sequence of lever-pressing requirements in order to earn food reinforcement in a two-lever experimental chamber. Subjects alternated between two levers by switching to the other lever after pressing the first lever enough to get food reward. The exact number of presses required for each food reward changed, first increasing from 2 responses per food pellet up to 56 presses per food pellet, then decreasing back to 2 responses per pellet. Intermediate values were based on the quadratic function, x - x. One cycle was an entire ascending and descending sequence of these lever press requirements (e.g., 2, 6, 12, 20, 30, 42, 56, 56, 42, 30, 20, 12, 6, and 2 presses per food reward). Six such full cycles were presented during each daily session.
  • Synthetic A ⁇ i_4 2 powder was dissolved in 1,1,1,3,3,3-hexafluorisopropanol (HFIP) to afford a solution of Ap 1-42 in HFIP of about 1 mM and allowed to incubate at ambient temperature for about 1 h.
  • the resulting solution was chilled on ice for about 5-10 min, then aliquoted into eppendorf tubes to provide about 50 ⁇ L of solution per tube.
  • the tubes were then placed in a chemical fume hood and allowed to stand overnight to allow the HFIP to evaporate under a slow stream of nitrogen. To remove final traces of HFIP, the tubes were subjected to two SpeedVac cycles of 15 min at room temperature and about 15 to 25 mm Hg of vacuum.
  • the resulting films of monomerized Ap 1-42 peptide were stored over desiccant at -80 0 C until used.
  • a tube of monomerized Ap 1-42 peptide was warmed to room temperature and the Ap 1-42 peptide was dissolved in anhydrous DMSO to afford a peptide stock DMSO solution containing about 10 ⁇ M to about 100 ⁇ M Ap 1-42 peptide in DMSO.
  • test compound Compound 2 and Compound 89 from Table 1
  • neural basal media phenol red free, Gibco 12348-017
  • peptide stock DMSO solution was added to 37 0 C neural basal to obtain the requisite A ⁇ i_ 42 peptide monomer concentration, provided that the maximum concentration of DMSO is 1% or less, and the tube was vortexed for 30 to 60 seconds, spun down briefly in a micro fuge and incubated at 37 0 C for 15 min prior to the start of injections.
  • peptide stock DMSO solution was added to 37 0 C compound neural basal media solution to obtain the requisite A ⁇ i_ 42 peptide monomer concentration, provided that the maximum concentration of DMSO is 1% or less, and the tube was vortexed for 30 to 36 seconds, spun down briefly in a microfuge and incubated at 37 0 C for 15 min prior to the start of injections.
  • compound neural basal media solution was incubated at 37 0 C for 15 min prior to the start of injections.
  • Rats Rats are trained under ALCR until their error rates are stable. Once the rats are placed upon the final ALCR procedure, training sessions are conducted 7 days each week until the end of the study.
  • Test were conducted about every fourth day. Animals received a 10-20 ⁇ L injection of control, peptide, or peptide plus compound solutions via the implanted cannula over about 3 to 4 minutes. Animals were tested about 3 hours following injection. Error Rate Analysis: All error rates were compared to baseline error rates consisting of at least 3 non-treatment days temporally contiguous to the injection. Student's T test of statistical inference was used for analysis of effects.
  • ADDLs ADDLs 1 nM

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