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WO2012159262A1 - Inhibiteurs sélectifs de glycosidases et leurs utilisations - Google Patents

Inhibiteurs sélectifs de glycosidases et leurs utilisations Download PDF

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Publication number
WO2012159262A1
WO2012159262A1 PCT/CN2011/074569 CN2011074569W WO2012159262A1 WO 2012159262 A1 WO2012159262 A1 WO 2012159262A1 CN 2011074569 W CN2011074569 W CN 2011074569W WO 2012159262 A1 WO2012159262 A1 WO 2012159262A1
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WO
WIPO (PCT)
Prior art keywords
pyrano
tetrahydro
compound
proviso
mmol
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.)
Ceased
Application number
PCT/CN2011/074569
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English (en)
Inventor
Ramesh Kaul
Ernest J. Mceachern
Changwei Mu
Harold G. Selnick
David J. Vocadlo
Yaode Wang
Zhongyong Wei
Yuanxi Zhou
Yongbao Zhu
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.)
Alectos Therapeutics Inc
Organon Pharma UK Ltd
Merck Sharp and Dohme LLC
Original Assignee
Alectos Therapeutics Inc
Merck Sharp and Dohme Ltd
Merck Sharp and Dohme LLC
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Filing date
Publication date
Application filed by Alectos Therapeutics Inc, Merck Sharp and Dohme Ltd, Merck Sharp and Dohme LLC filed Critical Alectos Therapeutics Inc
Priority to PCT/CN2011/074569 priority Critical patent/WO2012159262A1/fr
Priority to HRP20161079TT priority patent/HRP20161079T1/hr
Priority to AU2011349021A priority patent/AU2011349021B2/en
Priority to TW100147743A priority patent/TWI572609B/zh
Priority to PT118507730T priority patent/PT2655388T/pt
Priority to PL11850773.0T priority patent/PL2655388T3/pl
Priority to MEP-2016-170A priority patent/ME02497B/fr
Priority to RS20160685A priority patent/RS55095B1/sr
Priority to EP11850773.0A priority patent/EP2655388B1/fr
Priority to MYPI2013002307A priority patent/MY165728A/en
Priority to ES11850773.0T priority patent/ES2589164T3/es
Priority to LTEP11850773.0T priority patent/LT2655388T/lt
Priority to BR112013016179A priority patent/BR112013016179A2/pt
Priority to DK11850773.0T priority patent/DK2655388T3/en
Priority to NZ612703A priority patent/NZ612703A/en
Priority to HUE11850773A priority patent/HUE030624T2/en
Priority to HK14104031.7A priority patent/HK1191016B/en
Priority to CA2822493A priority patent/CA2822493C/fr
Priority to CN201180066766.4A priority patent/CN103339138B/zh
Priority to KR1020137019485A priority patent/KR101979036B1/ko
Priority to RU2013134345A priority patent/RU2609210C2/ru
Priority to JP2013544980A priority patent/JP5861194B2/ja
Priority to US13/997,484 priority patent/US9243020B2/en
Priority to PCT/CA2011/001397 priority patent/WO2012083435A1/fr
Priority to SI201130936A priority patent/SI2655388T1/sl
Priority to MX2013007434A priority patent/MX343822B/es
Priority to ARP110104876 priority patent/AR085004A1/es
Publication of WO2012159262A1 publication Critical patent/WO2012159262A1/fr
Priority to IL227055A priority patent/IL227055A/en
Priority to ZA2013/05531A priority patent/ZA201305531B/en
Priority to CO13173187A priority patent/CO6821931A2/es
Anticipated expiration legal-status Critical
Priority to JP2015230912A priority patent/JP6322177B2/ja
Priority to US14/966,221 priority patent/US9815861B2/en
Priority to CY20161100886T priority patent/CY1118157T1/el
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • This application relates to compounds which selectively inhibit glycosidases and uses thereof.
  • a wide range of cellular proteins, both nuclear and cytoplasmic, are post- translationally modified by the addition of the monosaccharide 2-acetamido-2-deoxy-B-D- glucopyranoside ( ⁇ - ⁇ -acetylglucosamine) which is attached via an O-glycosidic linkage. 1
  • This modification is generally referred to as O-linked N-acetylglucosamine or O-GlcNAc.
  • the enzyme responsible for post-translationally linking ⁇ - ⁇ -acetylglucosamine (GlcNAc) to specific serine and threonine residues of numerous nucleocytoplasmic proteins is O-GlcNAc transferase (OGT).
  • a second enzyme known as glycoprotein 2-acetamido-2-deoxy-P-D- glucopyranosidase (O-GlcNAcase) 6 ' 7 removes this post-translational modification to liberate proteins making the O-GlcNAc-modification a dynamic cycle occurring several times during the lifetime of a protein.
  • 14 O-GlcNAc is also found on many structural proteins. 15"17 For example, it has been found on a number of cytoskeletal proteins, including neurofilament proteins, 18 ' 19 synapsins, 6 ' 20 synapsin-specific clathrin assembly protein AP-3, 7 and ankyrinG. 14 O-GlcNAc modification has been found to be abundant in the brain. 21 ' 22 It has also been found on proteins clearly implicated in the etiology of several diseases including Alzheimer's disease (AD) and cancer.
  • AD Alzheimer's disease
  • AD and a number of related tauopathies including Downs' syndrome, Pick's disease, Niemann-Pick Type C disease, and amyotrophic lateral sclerosis (ALS) are characterized, in part, by the development of neurofibrillary tangles (FTs).
  • FTs neurofibrillary tangles
  • PHFs paired helical filaments
  • tau Normally tau stabilizes a key cellular network of microtubules that is essential for distributing proteins and nutrients within neurons.
  • tau becomes hyperphosphorylated, disrupting its normal functions, forming PHFs and ultimately aggregating to form FTs.
  • UDP-GlcNAc uridine diphosphate-N- acetylglucosamine
  • OGT recognizes many of its substrates 54 ' 55 and binding partners 41 ' 56 through its tetratricopeptide repeat (TPR) domains. 57 ' 58 As described above, O-GlcNAcase 6 ' 7 removes this post- translational modification to liberate proteins making the O-GlcNAc-modification a dynamic cycle occurring several times during the lifetime of a protein. 8 O-GlcNAc has been found in several proteins on known phosphorylation sites, 10 ' 37 ' 38 ' 59 including tau and neurofilaments. 60 Additionally, OGT shows unusual kinetic behaviour making it extremelyly sensitive to intracellular UDP-GlcNAc substrate concentrations and therefore glucose supply. 41
  • TPR tetratricopeptide repeat
  • hyperphosphorylation is widely recognized as a valid therapeutic strategy for treating AD and other neurodegenerative disorders.
  • O-GlcNAcase inhibitors to limit tau hyperphosphorylation, have been considered for treatment of AD and related tauopathies.
  • the O- GlcNAcase inhibitor thiamet-G has been implicated in the reduction of tau phosphorylation in cultured PC-12 cells at pathologically relevant sites.
  • oral administration of thiamet-G to healthy Sprague-Dawley rats has been implicated in reduced phosphorylation of tau at Thr231, Ser396 and Ser422 in both rat cortex and hippocampus. 63 .
  • O- GlcNAcase is a member of family 84 of glycoside hydrolases that includes enzymes from organisms as diverse as prokaryotic pathogens to humans (for the family classification of glycoside hydrolases see Coutinho, P.M. & Henrissat, B. (1999) Carbohydrate-Active
  • O-GlcNAcase acts to hydrolyse O-GlcNAc off of serine and threonine residues of post-translationally modified
  • O-GlcNAcase appears to have a role in the etiology of several diseases including type II diabetes, 14 ' 82 AD, 16 ' 21 ' 83 and cancer. 22 ' 84
  • O-GlcNAcase was likely isolated earlier on, 18 ' 19 about 20 years elapsed before its biochemical role in acting to cleave O- GlcNAc from serine and threonine residues of proteins was understood. 6 More recently O- GlcNAcase has been cloned, 7 partially characterized, 20 and suggested to have additional activity as a histone acetyltransferase. 20 However, little was known about the catalytic mechanism of this enzyme.
  • HEXA and HEXB encode enzymes catalyzing the hydrolytic cleavage of terminal ⁇ - ⁇ -acetylglucosamine residues from glycoconjugates.
  • the gene products of HEXA and HEXB predominantly yield two dimeric isozymes, hexosaminidase A and hexosaminidase B, respectively.
  • Hexosaminidase A ( ⁇ ), a heterodimeric isozyme is composed of an a- and a B-subunit.
  • Hexosaminidase B ( ⁇ ) a homodimeric isozyme, is composed of two B-subunits.
  • the two subunits, a- and B- bear a high level of sequence identity. Both of these enzymes are classified as members of family 20 of glycoside hydrolases and are normally localized within lysosomes. The proper functioning of these lysosomal ⁇ -hexosaminidases is critical for human development, a fact that is underscored by the tragic genetic illnesses, Tay-Sach's and Sandhoff diseases which stem from a dysfunction in, respectively, hexosaminidase A and hexosaminidase B. 85 These enzymatic deficiencies cause an accumulation of glycolipids and glycoconjugates in the lysosomes resulting in neurological impairment and deformation. The deleterious effects of accumulation of gangliosides at the organismal level are still being uncovered. 86
  • STZ has long been used as a diabetogenic compound because it has a particularly detrimental effect on B-islet cells.
  • 96 STZ exerts its cytotoxic effects through both the alkylation of cellular DNA 96 ' 97 as well as the generation of radical species including nitric oxide.
  • PARP poly(ADP-ribose) polymerase
  • STZ toxicity is a consequence of the irreversible inhibition of O-GlcNAcase, which is highly expressed within ⁇ -islet cells.
  • 92 ' 102 This hypothesis has, however, been brought into question by two independent research groups.
  • 103 ' 104 Because cellular O-GlcNAc levels on proteins increase in response to many forms of cellular stress 105 it seems possible that STZ results in increased
  • PUGNAc is another compound that suffers from the same problem of lack of selectivity, yet has enjoyed use as an inhibitor of both human O-GlcNAcase 6 ' 110 and the family 20 human ⁇ -hexosaminidases.
  • 111 This molecule, developed by Vasella and coworkers, was found to be a potent competitive inhibitor of the ⁇ -N-acetyl-glucosaminidases from Canavalia ensiformis, Mucor rouxii, and the ⁇ -hexosaminidase from bovine kidney.
  • PUGNAc can be used in an animal model to reduce myocardial infarct size after left coronary artery occlusions.
  • 114 Of particular significance is the fact that elevation of O-GlcNAc levels by administration of PUGNAc, an inhibitor of O-GlcNAcase, in a rat model of trauma hemorrhage improves cardiac function.
  • 112 ' 115 elevation of O-GlcNAc levels by treatment with PUGNAc in a cellular model of ischemia/reperfusion injury using neonatal rat ventricular myocytes improved cell viability and reduced necrosis and apoptosis compared to untreated cells.
  • the invention provides, in part, compounds for selectively inhibiting glycosidases, prodrugs of the compounds, uses of the compounds and the prodrugs, pharmaceutical compositions including the compounds or prodrugs of the compounds, and methods of treating diseases and disorders related to deficiency or overexpression of O-GlcNAcase, and/or accumulation or deficiency of O-GlcNAc.
  • the invention provides a compound of Formula (I) or a
  • R may be H, F or OR 3 ;
  • R 4 may be H, F, or OR 3 ;
  • each R 5 may be independently H or F;
  • each R 6 may be independently selected from the group consisting of: H, C 1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and Ci-6 alkoxy; and two R 6 groups may be connected together with the nitrogen atom to which they are attached to form a ring, with the proviso that when R 1 is OR 3 , R 2 is H; and with the proviso that when R 4 is OR 3 , each R 5 is H; and with the proviso that either R 1 or R 4 is other than OR 3 ; and with the proviso that either R 1 or R 2 is other than F.
  • each optionally substituted moiety in Formula (I) may include one or more heteroatoms selected from P, O, S, N, F, CI, Br, I, or B.
  • the compound may be a prodrug; the compound may selectively inhibit an O-glycoprotein 2-acetamido-2-deoxy-P-D-glucopyranosidase (O- GlcNAcase); the compound may selectively bind an O-GlcNAcase (e.g., a mammalian O- GlcNAcase); the compound may selectively inhibit the cleavage of a 2-acetamido-2-deoxy-P- D-glucopyranoside (O-GlcNAc); the compound may not substantially inhibit a mammalian ⁇ - hexosaminidase.
  • O- GlcNAcase O-glycoprotein 2-acetamido-2-deoxy-P-D-glucopyranosidase
  • O-GlcNAcase O-glycoprotein 2-acetamido-2-deoxy-P-D-glucopyranosidase
  • O-GlcNAcase O-glycoprotein 2-acetamid
  • the invention provides a pharmaceutical composition including a compound according to the invention, in combination with a pharmaceutically acceptable carrier.
  • the invention provides methods of selectively inhibiting an O- GlcNAcase, or of inhibiting an O-GlcNAcase in a subject in need thereof, or of increasing the level of O-GlcNAc, or of treating a neurodegenerative disease, a tauopathy, cancer or stress, in a subject in need thereof, by administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
  • R may be H, F or OR 3 ;
  • R 4 may be H, F, or OR 3 ;
  • each R 5 may be independently H or F;
  • each R 6 may be independently selected from the group consisting of: H, C 1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and Ci-6 alkoxy; and two R 6 groups may be connected together with the nitrogen atom to which they are attached to form a ring, with the proviso that when R 1 is OR 3 , R 2 is H; and with the proviso that when R 4 is OR 3 , each R 5 is H; and with the proviso that either R 1 or R 4 is other than OR 3 ; and with the proviso that either R 1 or R 2 is other than F.
  • the condition may be Alzheimer's disease, Amyotrophic lateral sclerosis (ALS), Amyotrophic lateral sclerosis with cognitive impairment (ALSci), Argyrophilic grain dementia, Bluit disease, Corticobasal degeneration (CBD), Dementia pugilistica, Diffuse neurofibrillary tangles with calcification, Down's syndrome, Familial British dementia, Familial Danish dementia, Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17),
  • Gerstmann-Straussler-Scheinker disease Guadeloupean parkinsonism
  • Hallevorden-Spatz disease neurodegeneration with brain iron accumulation type 1
  • Multiple system atrophy Myotonic dystrophy
  • Niemann-Pick disease type C
  • Pallido-ponto-nigral degeneration Parkinsonism-dementia complex of Guam
  • Pick's disease Post's disease
  • Prion diseases including Creutzfeldt- Jakob Disease (CJD), Variant Creutzfeldt- Jakob Disease (vCJD), Fatal Familial Insomnia, and Kuru
  • Prion diseases including Creutzfeldt- Jakob Disease (CJD), Variant Creutzfeldt- Jakob Disease (vCJD), Fatal Familial Insomnia, and Kuru
  • Prion diseases including Creutzfeldt- Jakob Disease (CJD), Variant Creutzfeldt- Jakob Disease (vCJD), Fatal Familial Insomnia, and Kuru
  • Prion diseases including Creutzfeldt- Jakob Disease (CJD), Variant Creutzfeldt- Jakob Disease (vCJD), Fatal Familial Insomnia, and Kuru
  • Prion diseases including Creutzfeldt- Jakob Disease (CJD), Variant Creutzfeldt- Jakob Disease (vCJD), Fatal Familial Insomnia
  • Parkinson's disease Schizophrenia, Mild Cognitive Impairment (MCI), Neuropathy
  • the stress may be a cardiac disorder, e.g., ischemia; hemorrhage; hypovolemic shock; myocardial infarction; an interventional cardiology procedure; cardiac bypass surgery; fibrinolytic therapy; angioplasty; or stent placement.
  • ischemia e.g., ischemia; hemorrhage; hypovolemic shock; myocardial infarction; an interventional cardiology procedure; cardiac bypass surgery; fibrinolytic therapy; angioplasty; or stent placement.
  • the invention provides a method of treating an O-GlcNAcase- mediated condition that excludes a neurodegenerative disease, a tauopathy, cancer or stress, in a subject in need thereof, by administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
  • R may be H, F or OR 3 ;
  • R 4 may be H, F, or OR 3 ;
  • each R 5 may be independently H or F;
  • each R 6 may be independently selected from the group consisting of: H, C 1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and Ci-6 alkoxy; and two R 6 groups may be connected together with the nitrogen atom to which they are attached to form a ring, with the proviso that when R 1 is OR 3 , R 2 is H; and with the proviso that when R 4 is OR 3 , each R 5 is H; and with the proviso that either R 1 or R 4 is other than OR 3 ; and with the proviso that either R 1 or R 2 is other than F.
  • the condition may be inflammatory or allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic
  • ILD interstitial lung disease
  • idiopathic pulmonary fibrosis or ILD associated with rheumatoid arthritis
  • systemic lupus erythematosus ankylosing spondylitis
  • systemic sclerosis Sjogren's syndrome, polymyositis or dermatomyositis
  • systemic anaphylaxis or hypersensitivity responses drug allergies, insect sting allergies
  • autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Guillain-Barre syndrome, systemic lupus erythematosus, myastenia gravis, glomerulonephritis, autoimmune thyroiditis, graft rejection, including allograft rejection or graft-versus-host disease
  • inflammatory bowel diseases such as Crohn's disease and ulcerative colitis
  • R 1 may be H, F or OR 3 ;
  • R 2 may be H or F;
  • each R 3 may be independently H or acyl;
  • R 4 may be H, F, or OR 3 ;
  • each R 5 may be independently H or F;
  • each R 6 may be independently selected from the group consisting of: H, C 1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and C 1-6 alkoxy; and two R 6 groups may be connected together with the nitrogen atom to which they are attached to form a ring, with the proviso that when R 1 is OR 3 R 2 is H; and with the proviso that when R 4 is OR 3 , each R 5 is H; and with the proviso that either R 1 or R 4 is other than OR 3 ; and with the proviso that either R 1 or R 2 is other than F.
  • the administering may increase the level of O-GlcNAc in the subject.
  • the subject may be a human.
  • the invention provides use of a compound of an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
  • R may be H, F or OR 3 ;
  • R 4 may be H, F, or OR 3 ;
  • each R 5 may be independently H or F;
  • each R 6 may be independently selected from the group consisting of: H, C 1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and Ci-6 alkoxy; and two R 6 groups may be connected together with the nitrogen atom to which they are attached to form a ring, with the proviso that when R 1 is OR 3 , R 2 is H; and with the proviso that when R 4 is OR 3 , each R 5 is H; and with the proviso that either R 1 or R 4 is other than OR 3 ; and with the proviso that either R 1 or R 2 is other than F, in the preparation of a medicament.
  • the medicament may be for selectively inhibiting an O-GlcNAcase, for increasing the level of O-GlcNAc, for treating a condition modulated by an O-GlcNAcase, for treating a neurodegenerative disease, a tauopathy, a cancer, or stress.
  • the invention provides a method for screening for a selective inhibitor of an O-GlcNAcase, by a) contacting a first sample with a test compound; b) contacting a second sample with a compound of Formula (I)
  • R may be H, F or OR 3 ;
  • R 2 may be H or F;
  • each R 3 may be independently H or acyl;
  • R 4 may be H, F, or OR 3 ;
  • each R 5 may be independently H or F;
  • each R 6 may be independently selected from the group consisting of: H, C 1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and Ci-6 alkoxy; and two R 6 groups may be connected together with the nitrogen atom to which they are attached to form a ring, with the proviso that when R 1 is OR 3 , R 2 is H; and with the proviso that when R 4 is OR 3 , each R 5 is H; and with the proviso that either R 1 or R 4 is other than OR 3 ; and with the proviso that either R 1 or R 2 is other than F; c) determining the level of inhibition of the O-GlcNAcase in the first and second samples, where the test compound is a selective inhibitor of a O-Gl
  • the invention provides, in part, novel compounds that are capable of inhibiting an O- glycoprotein 2-acetamido-2-deoxy-P-D-glucopyranosidase (O-GlcNAcase).
  • O-GlcNAcase is a mammalian O-GlcNAcase, such as a rat, mouse or human O-GlcNAcase.
  • one or more of the compounds according to the invention exhibit enhanced permeability. Permeability can be assessed using a variety of standard experimental techniques, including without limitation in situ perfusion, ex vivo tissue diffusion, in vitro cell monolayers (e.g. Caco-2 cells, MDCK cells, LLC-PK1 cells), and artificial cell membranes (e.g. PAMPA assay); suitable techniques for measuring effective permeability (Peg) or apparent peameability (P app ) are reviewed for example by Volpe in The AAPS Journal, 2010, 12(4), 670-678. In some embodiments, one or more of the compounds according to the invention show enhanced permeability when tested in one or more of these assays for determining P eff or P app .
  • a compound that exhibits enhanced permeability exhibits greater oral absorption. In some embodiments, a compound that exhibits enhanced permeability exhibits greater brain penetrance when administered in vivo. In some embodiments, a compound that exhibits enhanced permeability achieves higher brain concentrations when administered in vivo. In some embodiments, a compound that exhibits enhanced permeability exhibits a higher brain/plasma concentration ratio when administered in vivo.
  • "enhanced permeability” means an increase in measured P e fr or P app by any value between 10% and 100%, or of any integer value between 10% and 100%, for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or over 100%), or an increase by 1-fold, 2-fold, or 3 -fold, or more, as compared to a suitable reference compound disclosed in for example WO 2006/092049 or WO 2008/025170.
  • "enhanced permeability” means a measurable P app value (i.e. a value greater than zero) in the assay described below for determination of P app in LLC-PK1 cells.
  • "enhanced permeability” means a P app value greater than 2 x 10 6 cm/s in the assay described below for determination of P app in LLC-PK1 cells.
  • a compound according to the invention exhibits superior selectivity in inhibiting an O-GlcNAcase.
  • one or more of the compounds according to the invention are more selective for an O-GlcNAcase over a ⁇ - hexosaminidase.
  • one or more of the compounds selectively inhibit the activity of a mammalian O-GlcNAcase over a mammalian ⁇ -hexosaminidase.
  • a selective inhibitor of an O-GlcNAcase does not substantially inhibit a ⁇ - hexosaminidase.
  • the ⁇ -hexosaminidase is a mammalian ⁇ - hexosaminidase, such as a rat, mouse or human ⁇ -hexosaminidase.
  • a compound that "selectively" inhibits an O-GlcNAcase is a compound that inhibits the activity or biological function of an O-GlcNAcase, but does not substantially inhibit the activity or biological function of a ⁇ -hexosaminidase.
  • a selective inhibitor of an O-GlcNAcase selectively inhibits the cleavage of 2-acetamido-2-deoxy ⁇ -D- glucopyranoside (O-GlcNAc) from polypeptides.
  • a selective inhibitor of an O-GlcNAcase selectively binds to an O-GlcNAcase.
  • a selective inhibitor of an O-GlcNAcase inhibits hyperphosphorylation of a tau protein and/or inhibits formations of FTs.
  • inhibits means a decrease by any value between 10% and 90%, or of any integer value between 30% and 60%, or over 100%, or a decrease by 1-fold, 2-fold, 5-fold, 10-fold or more. It is to be understood that the inhibiting does not require full inhibition.
  • a selective inhibitor of an O-GlcNAcase elevates or enhances O-GlcNAc levels e.g., O-GlcNAc-modified polypeptide or protein levels, in cells, tissues, or organs (e.g., in brain, muscle, or heart (cardiac) tissue) and in animals.
  • O-GlcNAc levels e.g., O-GlcNAc-modified polypeptide or protein levels
  • O-GlcNAc-modified polypeptide or protein levels in cells, tissues, or organs (e.g., in brain, muscle, or heart (cardiac) tissue) and in animals.
  • elevating or “enhancing” is meant an increase by any value between 10% and 90%), or of any integer value between 30% and 60%, or over 100%), or an increase by 1- fold, 2-fold, 5-fold, 10-fold, 15-fold, 25-fold, 50-fold, 100-fold or more.
  • a selective inhibitor of an O-GlcNAcase exhibits a selectivity ratio, as described herein, in the range 10 to 100000, or in the range 100 to 100000, or in the range 1000 to 100000, or at least 10, 20, 50, 100, 200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 6000, 7000, 10,000, 25,000, 50,000, 75,000, or any value within or about the described range.
  • One or more of the compounds of the present invention elevate O-GlcNAc levels on O-GlcNAc-modified polypeptides or proteins in vivo specifically via interaction with an O- GlcNAcase enzyme, and are effective in treating conditions which require or respond to inhibition of O-GlcNAcase activity.
  • one or more of the compounds of the present invention are useful as agents that produce a decrease in tau phosphorylation and NFT formation. In some embodiments, one or more of the compounds are therefore useful to treat Alzheimer's disease and related tauopathies. In some embodiments, one or more of the compounds are thus capable of treating Alzheimer' s disease and related tauopathies by lowering tau
  • one or more of the compounds produce an increase in levels of O- GlcNAc modification on O-GlcNAc-modified polypeptides or proteins, and are therefore useful for treatment of disorders responsive to such increases in O-GlcNAc modification; these disorders include without limitation neurodegenerative, inflammatory, cardiovascular, and immunoregulatory diseases.
  • a compound is also useful as a result of other biological activites related to their ability to inhibit the activity of glycosidase enzymes.
  • one or more of the compounds of the invention are valuable tools in studying the physiological role of O-GlcNAc at the cellular and organismal level.
  • the invention provides methods of enhancing or elevating levels of protein O-GlcNAc modification in animal subjects, such as, veterinary and human subjects. In alternative embodiments, the invention provides methods of selectively inhibiting an O-GlcNAcase enzyme in animal subjects, such as, veterinary and human subjects. In alternative embodiments, the invention provides methods of inhibiting
  • the invention provides compounds described generally by Formula (I) and the salts, prodrugs, and enantiomeric forms thereof:
  • R 1 may be H, F or OR 3 ;
  • R 2 may be H or F;
  • each R 3 may be independently H or acyl;
  • R 4 may be H, F, or OR 3 ;
  • each R 5 may be independently H or F;
  • each R 6 may be independently selected from the group consisting of: H, C 1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and C 1-6 alkoxy; and two R 6 groups may be connected together with the nitrogen atom to which they are attached to form a ring, with the proviso that when R 1 is OR 3 , R 2 is H; and with the proviso that when R 4 is OR 3 , each R 5 is H; and with the proviso that either R 1 or R 4 is other than OR 3 ; and with the proviso that either R 1 or R 2 is other than F.
  • each optionally substituted moiety may be substituted with one or more substituents.
  • R 7 may be H, C 1-6 alkyl, or C3-6 cycloalkyl.
  • R 1 as set forth in Formula (I) may be H, F, OH, or OC(0)R 7 , where R 7 may be H, C 1-6 alkyl, or C3-6 cycloalkyl. In some embodiments, R 1 may be H, F or OH.
  • R 2 as set forth in Formula (I) may be H or F.
  • R 3 as set forth in Formula (I) may be H or C(0)R 7 , where R 7 may be H, C 1-6 alkyl, or C3-6 cycloalkyl. In some embodiments, R 3 may be H.
  • R 4 as set forth in Formula (I) may be H, F, OH, or OC(0)R 7 , where R 7 may be H, C 1-6 alkyl, or C3-6 cycloalkyl. In some embodiments, R 4 may be H, F, or OH.
  • each R 5 as set forth in Formula (I) may be independently H or F.
  • R 6 2 as set forth in Formula (I), may be optionally substituted
  • R 6 2 may be optionally substituted 1-aziridinyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, morpholin-4-yl, 1-piperizinyl, azetidin-2- pyrrolidin-2-one-l-yl, or piperid-2-one-l-yl.
  • R 6 2 may be
  • compounds according to Formula (I) include the compounds described in Table 1.
  • “compounds” refers to the compounds discussed herein and includes precursors and derivatives of the compounds, including acyl-protected derivatives, and pharmaceutically acceptable salts of the compounds, precursors, and derivatives.
  • the invention also includes prodrugs of the compounds, pharmaceutical compositions including the compounds and a pharmaceutically acceptable carrier, and pharmaceutical compositions including prodrugs of the compounds and a pharmaceutically acceptable carrier.
  • all of the compounds of the invention contain at least one chiral center.
  • the formulations, preparation, and compositions including compounds according to the invention include mixtures of enantiomers and individual enantiomers. In general, the compound may be supplied in any desired degree of enantiomeric purity.
  • the substituents may include, in addition to the substituents listed above, halo, OOCR, ROCR, where R is H or a substituent set forth above.
  • Alkyl refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing no unsaturation and including, for example, from one to ten carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and which is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, the alkyl group may be optionally substituted by one or more substituents as described herein. Unless stated otherwise specifically herein, it is understood that the substitution can occur on any carbon of the alkyl group.
  • alkenyl refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one double bond and including, for example, from two to ten carbon atoms, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and which is attached to the rest of the molecule by a single bond or a double bond.
  • the alkenyl group may be optionally substituted by one or more substituents as described herein. Unless stated otherwise specifically herein, it is understood that the substitution can occur on any carbon of the alkenyl group.
  • alkenyl refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one triple bond and including, for example, from two to ten carbon atoms. Unless stated otherwise specifically in the specification, the alkenyl group may be optionally substituted by one or more substituents as described herein.
  • Aryl refers to a phenyl group, an aromatic ring including 6 carbon atoms. Unless stated otherwise specifically herein, the term “aryl” is meant to include aryl groups optionally substituted by one or more substituents as described herein.
  • Heteroaryl refers to a single aromatic ring group containing one or more
  • heteroaryl groups include furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, 1,2,3-oxadiazole, 1,2,3-triazole, 1,2,4- triazole, 1,3,4-thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, imidazole.
  • heteroaryl is meant to include heteroaryl groups optionally substituted by one or more substituents as described herein.
  • Acyl refers to a group of the formula -C(0)R a , where R a is a C 1-10 alkyl or C 3-15 cycloalkyl group as described herein.
  • the alkyl or cycloalkyl group(s) may be optionally substituted as described herein.
  • Arylacyl refers to a group of the formula -C(0)Rb, where Rb is an aryl or heteroaryl group as described herein.
  • Rb is an aryl or heteroaryl group as described herein.
  • the aryl or heteroaryl group(s) may be optionally substituted as described herein.
  • Alkoxy refers to a group of the formula -OR c , where R c is a C 1-10 alkyl group as described herein.
  • the alkyl group(s) may be optionally substituted as described herein.
  • Cycloalkyl refers to a stable monovalent monocyclic, bicyclic or tricyclic
  • hydrocarbon group consisting solely of carbon and hydrogen atoms, having for example from 3 to 15 carbon atoms, and which is saturated and attached to the rest of the molecule by a single bond.
  • cycloalkyl is meant to include cycloalkyl groups which are optionally substituted as described herein.
  • Halo refers to bromo, chloro, fluoro, iodo, etc.
  • suitable halogens include fluorine or chlorine.
  • two R 6 groups as set forth in Formula (I) may be connected together with the nitrogen atom to which they are attached to form a ring. In these
  • ring refers to a stable nitrogen-containing monocyclic group having 3 to 6 members that may be saturated or monounsaturated and may consist solely of C, H and N atoms or may also include heteroatoms in the ring, for example O and S.
  • a ring in these embodiments include 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, 2,5-dihydro-lH- pyrrol-l-yl, 1-piperidinyl, 1,2,3,6-tetrahydropyridin-l-yl, morpholin-4-yl, thiomorpholin-4-yl,
  • optionally substituted alkyl means that the alkyl group may or may not be substituted and that the description includes both substituted alkyl groups and alkyl groups having no substitution.
  • optionally substituted alkyl groups include, without limitation, methyl, ethyl, propyl, etc.
  • optionally substituted alkyl and alkenyl groups include Ci_6 alkyl s or alkenyls.
  • optionally substituted carbonyl groups, or sulfonyl groups include optionally substituted forms of such groups formed from various hydrocarbyls such as alkyl, alkenyl and 5- to 6-membered monocyclic aromatic group (e.g., phenyl, pyridyl, etc.), as described herein.
  • the invention provides methods of treating conditions that are modulated, directly or indirectly, by an O-GlcNAcase enzyme or by O-GlcNAc-modified protein levels, for example, a condition that is benefited by inhibition of an O-GlcNAcase enzyme or by an elevation of O-GlcNAc-modified protein levels.
  • Such conditions include, without limitation, Glaucoma, Schizophrenia, tauopathies, such as Alzheimer's disease, neurodegenerative diseases, cardiovascular diseases, diseases associated with inflammation, diseases associated with immunosuppression and cancers.
  • One or more of the compounds of the invention are also useful in the treatment of diseases or disorders related to deficiency or over-expression of O-GlcNAcase or accumulation or depletion of O-GlcNAc, or any disease or disorder responsive to glycosidase inhibition therapy.
  • diseases and disorders include, but are not limited to, Glaucoma, Schizophrenia, neurodegenerative disorders, such as Alzheimer's disease (AD), or cancer.
  • diseases and disorders may also include diseases or disorders related to the accumulation or deficiency in the enzyme OGT.
  • a method of protecting or treating target cells expressing proteins that are modified by O-GlcNAc residues, the dysregulation of which modification results in disease or pathology is also included.
  • treating includes treatment, prevention, and amelioration.
  • the invention provides methods of enhancing or elevating levels of protein O-GlcNAc modification in animal subjects, such as, veterinary and human subjects.
  • This elevation of O-GlcNAc levels can be useful for the prevention or treatment of Alzheimer's disease; prevention or treatment of other neurodegenerative diseases (e.g.
  • Parkinson's disease Huntington's disease
  • providing neuroprotective effects preventing damage to cardiac tissue; and treating diseases associated with inflammation or
  • the invention provides methods of selectively inhibiting an O-GlcNAcase enzyme in animal subjects, such as veterinary and human subjects.
  • the invention provides methods of inhibiting
  • a compound of the invention may be used to study and treat AD and other tauopathies.
  • the methods of the invention are effected by administering a compound according to the invention to a subject in need thereof, or by contacting a cell or a sample with a compound according to the invention, for example, a pharmaceutical composition comprising a therapeutically effective amount of the compound according to Formula (I). More particularly, they are useful in the treatment of a disorder in which the regulation of O- GlcNAc protein modification is implicated, or any condition as described herein.
  • Disease states of interest include Alzheimer's disease (AD) and related neurodegenerative tauopathies, in which abnormal hyperphosphorylation of the microtubule-associated protein tau is involved in disease pathogenesis.
  • a compound may be used to block hyperphosphorylation of tau by maintaining elevated levels of O-GlcNAc on tau, thereby providing therapeutic benefit.
  • Tauopathies that may be treated with a compound of the invention include:
  • Alzheimer's disease Amyotrophic lateral sclerosis (ALS), Amyotrophic lateral sclerosis with cognitive impairment (ALSci), Argyrophilic grain dementia, Bluit disease, Corticobasal degeneration (CBD), Dementia pugilistica, Diffuse neurofibrillary tangles with calcification, Down's syndrome, Familial British dementia, Familial Danish dementia, Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Gerstmann-Straussler- Scheinker disease, Guadeloupean parkinsonism, Hallevorden-Spatz disease
  • neurodegeneration with brain iron accumulation type 1 Neurodegeneration with brain iron accumulation type 1
  • Multiple system atrophy Myotonic dystrophy
  • Niemann-Pick disease type C
  • Pallido-ponto-nigral degeneration Parkinsonism- dementia complex of Guam
  • Pick's disease PiD
  • Post-encephalitic parkinsonism Prion diseases
  • CJD Creutzfeldt- Jakob Disease
  • vCJD Variant Creutzfeldt- Jakob Disease
  • Fatal Familial Insomnia and Kuru
  • Progressive supercortical gliosis Progressive supranuclear palsy (PSP), Richardson's syndrome, Subacute sclerosing panencephalitis, Tangle-only dementia, and Glaucoma.
  • One or more of the compounds of this invention are also useful in the treatment of conditions associate with tissue damage or stress, stimulating cells, or promoting
  • a compound of this invention may be used to provide therapeutic benefit in a variety of conditions or medical procedures involving stress in cardiac tissue, including but not limited to: ischemia; hemorrhage;
  • hypovolemic shock myocardial infarction; an interventional cardiology procedure; cardiac bypass surgery; fibrinolytic therapy; angioplasty; and stent placement.
  • a compound in treating pathology associated with cellular stress may be confirmed by testing the ability of a compound to prevent cellular damage in established cellular stress assays, 105 ' 116 ' 117 and to prevent tissue damage and promote functional recovery in animal models of ischemia-reperfusion, 70 ' 114 and trauma- hemorrhage. 72 ' 112 ' 115
  • Compounds that selectively inhibit O-GlcNAcase activity may be used for the treatment of diseases that are associated with inflammation, including but not limited to, inflammatory or allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias, delayed-type
  • ILD interstitial lung disease
  • autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Guillain-Barre syndrome, systemic lupus erythematosus, myastenia gravis, glomerulonephritis, autoimmune thyroiditis, graft rejection, including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn' s disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); eos
  • compounds that affects levels of protein O-GlcNAc modification may be used for the treatment of diseases associated with immunosuppression, such as in individuals undergoing chemotherapy, radiation therapy, enhanced wound healing and burn treatment, therapy for autoimmune disease or other drug therapy (e.g., corticosteroid therapy) or combination of conventional drugs used in the treatment of autoimmune diseases and graft/transplantation rejection, which causes immunosuppression; or immunosuppression due to congenital deficiency in receptor function or other causes.
  • diseases associated with immunosuppression such as in individuals undergoing chemotherapy, radiation therapy, enhanced wound healing and burn treatment, therapy for autoimmune disease or other drug therapy (e.g., corticosteroid therapy) or combination of conventional drugs used in the treatment of autoimmune diseases and graft/transplantation rejection, which causes immunosuppression; or immunosuppression due to congenital deficiency in receptor function or other causes.
  • One or more of the compounds of the invention may be useful for treatment of neurodegenerative diseases, including Parkinson' s disease and Huntington's disease.
  • Other conditions that may be treated are those triggered, affected, or in any other way correlated with levels of O-GlcNAc post-translational protein modification. It is expected that one or more of the compounds of this invention may be useful for the treatment of such conditions and in particular, but not limited to, the following for which a association with O-GlcNAc levels on proteins has been established: graft rejection, in particular but not limited to solid organ transplants, such as heart, lung, liver, kidney, and pancreas transplants (e.g.
  • kidney and lung allografts cancer, in particular but not limited to cancer of the breast, lung, prostate, pancreas, colon, rectum, bladder, kidney, ovary; as well as non-Hodgkin's lymphoma and melanoma; epilepsy, pain, fibromyalgia, or stroke, e.g., for neuroprotection following a stroke.
  • compositions including compounds according to the invention, or for use according to the invention are contemplated as being within the scope of the invention.
  • pharmaceutical compositions including an effective amount of a compound of Formula (I) are provided.
  • the compounds of Formula (I) and their pharmaceutically acceptable salts, enantiomers, solvates, and derivatives are useful because they have pharmacological activity in animals, including humans.
  • one or more of the compounds according to the invention are stable in plasma, when administered to a subject.
  • a compound according to the invention may be provided in combination with any other active agents or
  • compositions where such combined therapy is useful to modulate O- GlcNAcase activity, for example, to treat neurodegenerative, inflammatory, cardiovascular, or immunoregulatory diseases, or any condition described herein.
  • a compound according to the invention, or for use according to the invention may be provided in combination with one or more agents useful in the prevention or treatment of Alzheimer' s disease. Examples of such agents include, without limitation,
  • acetylcholine esterase inhibitors such as Aricept® (Donepezil), Exelon® (Rivastigmine), Razadyne® (Razadyne ER®, Reminyl®, Nivalin®, Galantamine), Cognex® (Tacrine), Dimebon, Huperzine A, Phenserine, Debio-9902 SR (ZT-1 SR), Zanapezil (TAK0147), ganstigmine, NP7557, etc.;
  • NMDA receptor antagonists such as Namenda® (Axura®, Akatinol®, Ebixa®,
  • gamma-secretase inhibitors and/or modulators such as FlurizanTM (Tarenflurbil, MPC-7869, R-flurbiprofen), LY450139, MK 0752, E2101, BMS-289948, BMS- 299897, BMS-433796, LY-411575, GSI-136, etc.;
  • beta-secretase inhibitors such as ATG-Z1, CTS-21166, etc.
  • alpha-secretase activators such as NGX267, etc;
  • amyloid- ⁇ aggregation and/or fibrillization inhibitors such as AlzhemedTM (3 APS, Tramiprosate, 3-amino-l-propanesulfonic acid), AL-108, AL-208, AZD-103, PBT2, Cereact, ONO-2506PO, PPI-558, etc.;
  • tau aggregation inhibitors such as methylene blue, etc.
  • microtubule stabilizers such as AL-108, AL-208, paclitaxel, etc.
  • RAGE inhibitors such as TTP488, etc.
  • 5-HTla receptor antagonists such as Xaliproden, Lecozotan, etc.
  • 5-HT4 receptor antagonists such as PRX-03410, etc.
  • kinase inhibitors such as SRN-003-556, amfurindamide, LiCl, AZD1080, NP031112, SAR-502250, etc.
  • humanized monoclonal anti- ⁇ antibodies such as Bapineuzumab (AAB-001),
  • amyloid vaccines such as AN- 1792, ACC-001
  • neuroprotective agents such as Cerebrolysin, AL-108, AL-208, Huperzine A, etc.;
  • L-type calcium channel antagonists such as MEM- 1003, etc.
  • nicotinic receptor antagonists such as AZD3480, GTS-21, etc.
  • nicotinic receptor agonists such as MEM 3454, Nefiracetam, etc.
  • peroxisome proliferator-activated receptor (PPAR) gamma agonists such as
  • Avandia® (Rosglitazone), etc.
  • PDE4 inhibitors such as MK-0952, etc.
  • hormone replacement therapy such as estrogen (Premarin), etc.
  • MAO monoamine oxidase
  • NS2330 Rasagiline (Azilect®), TVP- 1012, etc.
  • Azilect® Rasagiline
  • TVP- 1012 TVP- 1012, etc.
  • AMP A receptor modulators such as Ampalex (CX 516), etc.
  • nerve growth factors or NGF potentiators such as CERE-110 (AAV-NGF), T-588, T- 817MA, etc.;
  • agents that prevent the release of luteinizing hormone (LH) by the pituitary gland such as leuoprolide (VP-4896), etc.;
  • GABA receptor modulators such as AC-3933, NGD 97-1, CP-457920, etc.;
  • benzodiazepine receptor inverse agonists such as SB-737552 (S-8510), AC-3933, etc.;
  • noradrenaline-releasing agents such as T-588, T-817MA, etc.
  • combination of compounds according to the invention, or for use according to the invention, with Alzheimer's agents is not limited to the examples described herein, but includes combination with any agent useful for the treatment of Alzheimer's disease.
  • Combination of compounds according to the invention, or for use according to the invention, and other Alzheimer's agents may be administered separately or in conjunction.
  • the administration of one agent may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • a compound may be supplied as a "prodrug" or protected forms, which release the compound after administration to a subject.
  • a compound may carry a protective group which is split off by hydrolysis in body fluids, e.g., in the bloodstream, thus releasing the active compound or is oxidized or reduced in body fluids to release the compound.
  • a “prodrug” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention.
  • the term “prodrug” refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention.
  • Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a subject.
  • prodrug is also meant to include any covalently bonded carriers which release the active compound of the invention in vivo when such prodrug is administered to a subject.
  • Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention.
  • Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and acetamide, formamide, and benzamide derivatives of amine functional groups in one or more of the compounds of the invention and the like.
  • prodrugs may be found in "Smith and Williams' Introduction to the Principles of Drug Design,” H.J. Smith, Wright, Second Edition, London (1988); Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam); The Practice of Medicinal Chemistry, Camille G. Wermuth et al, Ch 31, (Academic Press, 1996); A
  • Suitable prodrug forms of one or more of the compounds of the invention include embodiments in which R 1 or R 4 is OC(0)R or R 3 is (CO)R, where R is optionally substituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl, with the proviso that either R 1 or R 4 is other than OC(0)R.
  • the ester groups may be hydrolyzed in vivo (e.g. in bodily fluids), releasing the active compounds in which R 1 or R 4 is OH and R 3 is H.
  • Preferred prodrug embodiments of the invention include compounds of Formula (I) where either R 1 or R 4 is OC(0)CH 3 .
  • Preferred prodrug embodiments of the invention also include compounds of Formula (I) where R 3 is (CO)CH 3 .
  • Compounds according to the invention, or for use according to the invention can be provided alone or in combination with other compounds in the presence of a liposome, an adjuvant, or any pharmaceutically acceptable carrier, diluent or excipient, in a form suitable for administration to a subject such as a mammal, for example, humans, cattle, sheep, etc. If desired, treatment with a compound according to the invention may be combined with more traditional and existing therapies for the therapeutic indications described herein.
  • Compounds according to the invention may be provided chronically or intermittently.
  • “Chronic” administration refers to administration of the compound(s) in a continuous mode as opposed to an acute mode, so as to maintain the initial therapeutic effect (activity) for an extended period of time. "Intermittent” administration is treatment that is not consecutively done without interruption, but rather is cyclic in nature. The terms "administration,”
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved, for example, by the United States Food and Drug Administration or other governmental agency as being acceptable for use in humans or domestic animals.
  • a compound of the present invention may be administered in the form of a pharmaceutically acceptable salt.
  • pharmaceutical compositions in accordance with this invention may comprise a salt of such a compound, preferably a physiologically acceptable salt, which are known in the art.
  • the term “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer,
  • “pharmaceutically acceptable salt” as used herein means an active ingredient comprising compounds of Formula I used in the form of a salt thereof, particularly where the salt form confers on the active ingredient improved pharmacokinetic properties as compared to the free form of the active ingredient or other previously disclosed salt form.
  • a “pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a “pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,
  • a "pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,
  • Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
  • pharmaceutically acceptable salt encompasses all acceptable salts including but not limited to acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartarate, mesylate, borate, methylbromide, bromide, methylnitrite, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate
  • Pharmaceutically acceptable salts of a compound of the present invention can be used as a dosage for modifying solubility or hydrolysis characteristics, or can be used in sustained release or prodrug formulations.
  • pharmaceutically acceptable salts of a compound of this invention may include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N- methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
  • compositions will typically include one or more carriers acceptable for the mode of administration of the preparation, be it by injection, inhalation, topical administration, lavage, or other modes suitable for the selected treatment.
  • Suitable carriers are those known in the art for use in such modes of administration.
  • Suitable pharmaceutical compositions may be formulated by means known in the art and their mode of administration and dose determined by the skilled practitioner.
  • a compound may be dissolved in sterile water or saline or a pharmaceutically acceptable vehicle used for administration of non-water soluble compounds such as those used for vitamin K.
  • the compound may be administered in a tablet, capsule or dissolved in liquid form.
  • the table or capsule may be enteric coated, or in a formulation for sustained release.
  • Many suitable formulations are known, including, polymeric or protein microparticles encapsulating a compound to be released, ointments, gels, hydrogels, or solutions which can be used topically or locally to administer a compound.
  • a sustained release patch or implant may be employed to provide release over a prolonged period of time.
  • Many techniques known to skilled practitioners are described in Remington: the Science & Practice of Pharmacy by Alfonso Gennaro, 20 th ed., Williams & Wilkins, (2000).
  • Formulations for parenteral administration may, for example, contain excipients, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes.
  • Biocompatible, biodegradable lactide polymer
  • lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of a compound.
  • Other potentially useful parenteral delivery systems for modulatory compounds include ethylene- vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.
  • a compound or a pharmaceutical composition according to the present invention may be administered by oral or non-oral, e.g., intramuscular, intraperitoneal, intravenous, intraci sternal injection or infusion, subcutaneous injection, transdermal or transmucosal routes.
  • a compound or pharmaceutical composition in accordance with this invention or for use in this invention may be administered by means of a medical device or appliance such as an implant, graft, prosthesis, stent, etc.
  • Implants may be devised which are intended to contain and release such compounds or compositions.
  • An example would be an implant made of a polymeric material adapted to release the compound over a period of time.
  • a compound may be administered alone or as a mixture with a
  • compounds or pharmaceutical compositions in accordance with this invention or for use in this invention may be administered by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • a compound of the invention may be used to treat animals, including mice, rats, horses, cattle, sheep, dogs, cats, and monkeys. However, a compound of the invention can also be used in other organisms, such as avian species ⁇ e.g., chickens). One or more of the compounds of the invention may also be effective for use in humans.
  • the term "subject” or alternatively referred to herein as "patient” is intended to be referred to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. However, one or more of the compounds, methods and pharmaceutical compositions of the present invention may be used in the treatment of animals.
  • a "subject” may be a human, non- human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc.
  • the subject may be suspected of having or at risk for having a condition requiring modulation of O-GlcNAcase activity.
  • an “effective amount” of a compound according to the invention includes a therapeutically effective amount or a prophylactically effective amount.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as inhibition of an O-GlcNAcase, elevation of O-GlcNAc levels, inhibition of tau phosphorylation, or any condition described herein.
  • a therapeutically effective amount of a compound may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects.
  • a “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as inhibition of an O-GlcNAcase, elevation of O-GlcNAc levels, inhibition of tau phosphorylation, or any condition described herein.
  • a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount may be less than a therapeutically effective amount.
  • a suitable range for therapeutically or prophylactically effective amounts of a compound may be any integer from 0.1 nM-0.1 M, 0.1 nM-0.05 M, 0.05 nM-15 ⁇ or 0.01 nM-10 ⁇ .
  • an appropriate dosage level in the treatment or prevention of conditions which require modulation of O-GlcNAcase activity, will generally be about 0.01 to 500 mg per kg subject body weight per day, and can be administered in singe or multiple doses. In some embodiments, the dosage level will be about 0.1 to about 250 mg/kg per day. It will be understood that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound used, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the patient undergoing therapy.
  • dosage values may vary with the severity of the condition to be alleviated.
  • specific dosage regimens may be adjusted over time according to the individual need and the professional judgement of the person administering or supervising the administration of the compositions.
  • Dosage ranges set forth herein are exemplary only and do not limit the dosage ranges that may be selected by medical practitioners.
  • the amount of active compound(s) in the composition may vary according to factors such as the disease state, age, sex, and weight of the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • compounds of the invention should be used without causing substantial toxicity, and as described herein, one or more of the compounds exhibit a suitable safety profile for therapeutic use.
  • Toxicity of a compound of the invention can be determined using standard techniques, for example, by testing in cell cultures or experimental animals and determining the therapeutic index, i.e., the ratio between the LD50 (the dose lethal to 50% of the population) and the LD100 (the dose lethal to 100% of the population). In some circumstances however, such as in severe disease conditions, it may be necessary to administer substantial excesses of the compositions.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula (I).
  • different isotopic forms of hydrogen (H) include protium (3 ⁇ 4), deuterium ( 2 H) and tritium ( 3 H).
  • Protium is the predominant hydrogen isotope found in nature.
  • Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within generic Formula (I) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • a compound of Formula (I) may be used in screening assays for compounds which modulate the activity of glycosidase enzymes, preferably the O-GlcNAcase enzyme.
  • the ability of a test compound to inhibit O-GlcNAcase-dependent cleavage of O-GlcNAc from a model substrate may be measured using any assays, as described herein or known to one of ordinary skill in the art. For example, a fluoresence or UV-based assay known in the art may be used.
  • a "test compound” is any naturally-occurring or artificially-derived chemical compound. Test compounds may include, without limitation, peptides, polypeptides, synthesised organic molecules, naturally occurring organic molecules, and nucleic acid molecules.
  • a test compound can "compete" with a known compound such as a compound of Formula (I) by, for example, interfering with inhibition of O-GlcNAcase-dependent cleavage of O-GlcNAc or by interfering with any biological response induced by a compound of Formula (I).
  • a test compound can exhibit any value between 10% and 200%, or over 500%), modulation when compared to a compound of Formula (I) or other reference compound.
  • a test compound may exhibit at least any positive or negative integer from 10%> to 200% modulation, or at least any positive or negative integer from 30% to 150%) modulation, or at least any positive or negative integer from 60%> to 100%
  • modulation or any positive or negative integer over 100% modulation.
  • a compound that is a negative modulator will in general decrease modulation relative to a known compound, while a compound that is a positive modulator will in general increase modulation relative to a known compound.
  • test compounds are identified from large libraries of both natural products or synthetic (or semi-synthetic) extracts or chemical libraries according to methods known in the art.
  • test extracts or compounds are not critical to the method(s) of the invention. Accordingly, virtually any number of chemical extracts or compounds can be screened using the exemplary methods described herein. Examples of such extracts or compounds include, but are not limited to, plant-, fungal-, prokaryotic- or animal-based extracts, fermentation broths, and synthetic compounds, as well as modification of existing compounds.
  • Synthetic compound libraries are commercially available.
  • libraries of natural compounds in the form of bacterial, fungal, plant, and animal extracts are commercially available from a number of sources, including Biotics (Sussex, UK), Xenova (Slough, UK), Harbor Branch Oceanographic Institute (Ft. Pierce, FL, USA), and PharmaMar, MA, USA.
  • Biotics Sussex, UK
  • Xenova Slough, UK
  • Harbor Branch Oceanographic Institute Ft. Pierce, FL, USA
  • PharmaMar, MA PharmaMar, USA.
  • natural and synthetically produced libraries are produced, if desired, according to methods known in the art, e.g., by standard extraction and fractionation methods.
  • any library or compound is readily modified using standard chemical, physical, or biochemical methods.
  • compounds shown to be useful agents for treatment are chemically modified according to methods known in the art.
  • Compounds identified as being of therapeutic, prophylactic, diagnostic, or other value may be subsequently analyzed using a suitable animal model, as described herein on known in the art.
  • one or more of the compounds are useful in the development of animal models for studying diseases or disorders related to deficiencies in O-GlcNAcase, over-expression of O-GlcNAcase, accumulation of O-GlcNAc, depletion of O-GlcNAc, and for studying treatment of diseases and disorders related to deficiency or over-expression of O-GlcNAcase, or accumulation or depletion of O-GlcNAc.
  • diseases and disorders include neurodegenerative diseases, including Alzheimer's disease, and cancer.
  • Various alternative embodiments and examples of the invention are described herein. These embodiments and examples are illustrative and should not be construed as limiting the scope of the invention.
  • ABCN 1 , -azobis(cyclohexane-carbonitrile)
  • DIPEA diisopropylethylamine
  • TBDMSC1 tert-butyldimethylsilyl chloride
  • TBAF tetra- «-butylammonium fluoride
  • EtOAc layer was separated, dried over sodium sulphate and concentrated to crude product which was purified on silica gel by flash column chromatography (EtOAc/hexanes, 3 :7), affording tert- butyl ethyl((3aR,5S,6S,7R,7aR)-5-(iodomethyl)-6,7-bis((4-methoxybenzyl)oxy)-5, 6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)carbamate as a white solid (0.23 g, 92.4%).
  • the title compound was prepared via a synthetic sequence as described for Example 7, starting from the above material (0.41 g, 0.73 mmol).
  • the title compound and its intermediate ((3aR,5R,6R,7R,7aR)-6-(benzoyloxy)-2-((tert-butoxycarbonyl)(ethyl)amino)-7- fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl benzoate were purified under conditions as described for Example 7 and ((3aR,5R,6R,7S,7aR)-6-(benzoyloxy)-2- ((tert-butoxycarbonyl)(ethyl)amino)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol- 5-yl)methyl benzoate, respectively.
  • the overall yield for the title compound from the above material was
  • Methanesulfonyl chloride (0.038 mL, 0.495 mmol) was added in portions to a stirred solution of tert-butyl ethyl((3aR,5R,6S,7R,7aR)-5-(hydroxymethyl)-6,7-bis((4- methoxybenzyl)oxy)-5 , 6, 7, 7a-tetrahydro-3 aH-pyrano [3 ,2-d]thiazol-2-yl)carbamate (0.190g, 0.323 mmol) in dry pyridine (5 mL) at -20°C.
  • the production of fluorescent product is measured every 60 sec for 45 min with a Tecan Infinite M200 plate-reader with excitation at 355 nM and emission detected at 460 nM, with 4-Methylumbelliferone (Sigma M1381) used to produce a standard curve.
  • the slope of product production is determined for each concentration of compound tested and plotted, using standard curve fitting algorithms for sigmoidal dose response curves.
  • the values for a four parameter logistic curve fit of the data are determined.
  • Ki values are determined using the Cheng-Prusoff equation; the K m of O-GlcNAcase for substrate is 0.2 mM.
  • Examples 1 to 30 were tested in the above described assay and exhibited 3 ⁇ 4 values for inhibition of O-GlcNAcase in the range 0.1 nM-10 ⁇ .
  • the production of fluorescent product is measured every 60 sec for 45 min with a Tecan Infinite M200 plate-reader with excitation at 355 nM and emission detected at 460 nM, with 4-Methylumbelliferone (Sigma M1381) used to produce a standard curve.
  • the slope of product production is determined for each concentration of compound tested and plotted, using standard curve fitting algorithms for sigmoidal dose response curves. The values for a four parameter logistic curve fit of the data are determined.
  • Ki values are determined using the Cheng-Prusoff equation.
  • the selectivity ratio for inhibition of O-GlcNAcase over ⁇ -hexosaminidase is defined here as: Ki ( ⁇ -hexosaminidaseyKi (O-GlcNAcase)
  • the compounds described herein exhibit a selectivity ratio in the range of about 10 to 100000.
  • many compounds of the invention exhibit high selectivity for inhibition of O-GlcNAcase over ⁇ -hexosaminidase.
  • Assay for determination of cellular activity for compounds that inhibit O-GlcNAcase activity results in an increase in the level of O-GlcNAcylated protein in cells.
  • An increase in O- GlcNAcylated protein can be measured by an antibody, such as RL-2, that binds to O- GlcNAcylated protein.
  • the amount of O-GlcNAcylated protein:RL2 antibody interaction can be measured by enzyme linked immunosorbant assay (ELISA) procedures.
  • tissue culture cell lines expressing endogenous levels of O-GlcNAcase, can be utilized; examples include rat PC-12, and human U-87, or SK-N-SH cells.
  • Cells are plated in 96-well plates with approximately 10,000 cells / well.
  • Compounds to be tested are dissolved in DMSO, either 2 or 10 mM stock solution, and then diluted with DMSO and water in a two-step process using a Tecan workstation. Cells are treated with diluted compounds for 24 h (5.4 ⁇ . into 200 ⁇ .
  • the ELISA portion of the assay is performed in a black Maxisorp 96-well plate that is coated overnight at 4°C with 100 ⁇ , /well of the cell lysate (1 : 10 dilution of the lysate with PBS containing protease inhibitors, phosphatase inhibitors, and PMSF. The following day the wells are washed 3 times with 300 ⁇ , /well of Wash buffer (Tris-buffered saline with 0.1% Tween 20). The wells are blocked with 100 ⁇ , /well Blocking buffer (Tris buffered saline w/0.05% Tween 20 and 2.5% Bovine serum albumin).
  • the detection reagent is added, 100 ⁇ , /well of Amplex Ultra RED reagent (prepared by adding 30 of 10 mM Amplex Ultra Red stock solution to 10 mL PBS with 18 ⁇ , 3% hydrogen peroxide, H 2 0 2 ). The detection reaction is incubated for 15 minutes at room temperature and then read with excitation at 530 nm and emission at 590 nm. [00236] The amount of O-GlcNAcylated protein, as detected by the ELISA assay, is plotted for each concentration of test compound using standard using standard curve fitting algorithms for sigmoidal dose response curves. The values for a four parameter logistic curve fit of the data are determined, with the inflection point of the curve being the potency value for the test compound.
  • LLC-PK1 cells Bi-directional transport was evaluated in LLC-PK1 cells in order to determine apparent permeability (P app ). LLC-PK1 cells can form a tight monolayer and therefore can be used to assess vectorial transport of compounds from basolateral to apical (B— >A) and from apical to basolateral (A— » B).
  • MicroBeta Wallac Trilux scintillation counter Perkin Elmer Life Sciences, Boston, MA
  • LCMS/MS Applied Biosystems SCIEX API 5000 triple quadruple mass spectrometer
  • P app was expressed as 10 "6 cm/s.

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Abstract

La présente invention a pour objet des composés pour l'inhibition sélective de glycosidases, des promédicaments des composés, et des compositions pharmaceutiques comprenant les composés ou les promédicaments des composés. L'invention concerne également des méthodes de traitement de maladies et de troubles associés à une déficience en ou à une surexpression de l'O-Glc NAcase, à une accumulation de ou à une déficience en O-Glc NAc.
PCT/CN2011/074569 2010-12-23 2011-05-24 Inhibiteurs sélectifs de glycosidases et leurs utilisations Ceased WO2012159262A1 (fr)

Priority Applications (33)

Application Number Priority Date Filing Date Title
PCT/CN2011/074569 WO2012159262A1 (fr) 2011-05-24 2011-05-24 Inhibiteurs sélectifs de glycosidases et leurs utilisations
CN201180066766.4A CN103339138B (zh) 2010-12-23 2011-12-21 选择性糖苷酶抑制剂及其用途
CA2822493A CA2822493C (fr) 2010-12-23 2011-12-21 Inhibiteurs selectifs de glycosidases et leurs utilisations
TW100147743A TWI572609B (zh) 2010-12-23 2011-12-21 選擇性醣苷酶抑制劑及其用途
PT118507730T PT2655388T (pt) 2010-12-23 2011-12-21 Inibidores de glicosidase seletivos e as suas utilizações
PL11850773.0T PL2655388T3 (pl) 2010-12-23 2011-12-21 Selektywne inhibitory glikozydazy i ich zastosowania
MEP-2016-170A ME02497B (fr) 2010-12-23 2011-12-21 Inhibiteurs sélectifs de glycosidases et leurs utilisations
RS20160685A RS55095B1 (sr) 2010-12-23 2011-12-21 Selektivni inhibitori glikozidaze i njihove upotrebe
EP11850773.0A EP2655388B1 (fr) 2010-12-23 2011-12-21 Inhibiteurs sélectifs de glycosidases et leurs utilisations
MYPI2013002307A MY165728A (en) 2010-12-23 2011-12-21 Selective glycosidase inhibitors and uses thereof
ES11850773.0T ES2589164T3 (es) 2010-12-23 2011-12-21 Inhibidores selectivos de glucosidasas y usos de los mismos
LTEP11850773.0T LT2655388T (lt) 2010-12-23 2011-12-21 Selektyvieji glikozidazės inhibitoriai ir jų panaudojimas
BR112013016179A BR112013016179A2 (pt) 2010-12-23 2011-12-21 inibidores seletivos da glicosidase e usos dos mesmos.
DK11850773.0T DK2655388T3 (en) 2010-12-23 2011-12-21 Selective glykosidaseinhibitorer and uses thereof
NZ612703A NZ612703A (en) 2010-12-23 2011-12-21 Selective glycosidase inhibitors and uses thereof
HUE11850773A HUE030624T2 (en) 2010-12-23 2011-12-21 Selective glycosidase inhibitors and their use
HK14104031.7A HK1191016B (en) 2010-12-23 2011-12-21 Selective glycosidase inhibitors and uses thereof
HRP20161079TT HRP20161079T1 (hr) 2010-12-23 2011-12-21 Selektivni inhibitori glikozidaze i njihove uporabe
AU2011349021A AU2011349021B2 (en) 2010-12-23 2011-12-21 Selective glycosidase inhibitors and uses thereof
KR1020137019485A KR101979036B1 (ko) 2010-12-23 2011-12-21 선택적인 글리코시다아제 저해제 및 이의 용도
RU2013134345A RU2609210C2 (ru) 2010-12-23 2011-12-21 Селективные ингибиторы гликозидазы и их применение
JP2013544980A JP5861194B2 (ja) 2010-12-23 2011-12-21 選択的グルコシダーゼインヒビターおよびその使用
US13/997,484 US9243020B2 (en) 2010-12-23 2011-12-21 Selective glycosidase inhibitors and uses thereof
PCT/CA2011/001397 WO2012083435A1 (fr) 2010-12-23 2011-12-21 Inhibiteurs sélectifs de glycosidases et leurs utilisations
SI201130936A SI2655388T1 (sl) 2010-12-23 2011-12-21 Selektivni inhibitorji glikozidaze
MX2013007434A MX343822B (es) 2010-12-23 2011-12-21 Inhibidores selectivos de glucosidasas, y usos de los mismos.
ARP110104876 AR085004A1 (es) 2010-12-23 2011-12-22 Inhibidores selectivos de glicosidasas y usos de los mismos
IL227055A IL227055A (en) 2010-12-23 2013-06-19 Compounds that specifically inhibit glycosidases and their uses
ZA2013/05531A ZA201305531B (en) 2010-12-23 2013-07-22 Selective glycosidase inhibitors and uses thereof
CO13173187A CO6821931A2 (es) 2010-12-23 2013-07-22 Inhibidores selectivos de la glicosidasa y usos de los mismos
JP2015230912A JP6322177B2 (ja) 2010-12-23 2015-11-26 選択的グルコシダーゼインヒビターおよびその使用
US14/966,221 US9815861B2 (en) 2010-12-23 2015-12-11 Selective glycosidase inhibitors and uses thereof
CY20161100886T CY1118157T1 (el) 2010-12-23 2016-09-07 Εκλεκτικοι αναστολεις γλυκοσιδασης και χρησεις αυτων

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EP2847199A4 (fr) * 2012-05-08 2015-11-11 Merck Sharp & Dohme Inhibiteurs de glycosidase perméables et leurs utilisations
US9938299B2 (en) 2012-12-24 2018-04-10 Alectos Therapeutics, Inc. Glycosidase inhibitors and uses thereof
CN108368131A (zh) * 2015-12-14 2018-08-03 阿米库斯治疗学公司 用于治疗阿尔茨海默氏病和/或大脑淀粉样血管病的新颖化合物和方法

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EP2847199A4 (fr) * 2012-05-08 2015-11-11 Merck Sharp & Dohme Inhibiteurs de glycosidase perméables et leurs utilisations
US9611275B2 (en) 2012-05-08 2017-04-04 Alectos Therapeutics, Inc. Permeable glycosidase inhibitors and uses thereof
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US9938299B2 (en) 2012-12-24 2018-04-10 Alectos Therapeutics, Inc. Glycosidase inhibitors and uses thereof
CN108368131A (zh) * 2015-12-14 2018-08-03 阿米库斯治疗学公司 用于治疗阿尔茨海默氏病和/或大脑淀粉样血管病的新颖化合物和方法

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