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WO2008137102A2 - Procédés de modulation de la bêta-amyloïde et composés utiles pour cette modulation - Google Patents

Procédés de modulation de la bêta-amyloïde et composés utiles pour cette modulation Download PDF

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Publication number
WO2008137102A2
WO2008137102A2 PCT/US2008/005719 US2008005719W WO2008137102A2 WO 2008137102 A2 WO2008137102 A2 WO 2008137102A2 US 2008005719 W US2008005719 W US 2008005719W WO 2008137102 A2 WO2008137102 A2 WO 2008137102A2
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WO2008137102A3 (fr
Inventor
Soan Cheng
Daniel D. Comer
Long Mao
David Pleynet
Chengzhi Yu
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TorreyPines Therapeutics Inc
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TorreyPines Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • invention compounds are useful in modulating amyloid- beta levels.
  • invention compounds are useful for treatment of diseases associated with aberrant amyloid-beta levels, e.g., neurodegenerative diseases.
  • AD Alzheimer's disease
  • a progressive neurodegenerative disorder that is the predominant cause of dementia in people over 65 years of age.
  • Clinical symptoms of the disease begin with subtle short-term memory problems. As the disease progresses, difficulty with memory, language and orientation worsen to the point of interfering with the ability of the person to function independently. Other symptoms, which are variable, include myoclonus and seizures. Duration of AD from the first symptoms of memory loss until death is 10 years on average.
  • AD Alzheimer's disease
  • Down syndrome diffuse Lewy body disease
  • progressive supranuclear palsy Hereditary Cerebral Hemorrhage with Amyloidosis-Dutch Type (HCHWA-D)
  • CAA cerebral amyloid angiopathy
  • MCI mild cognitive impairment
  • AD Alzheimer's disease
  • a ⁇ peptides are derived from processing of an amyloid precursor protein (APP). mRNA generated from the APP gene on chromosome 21 undergoes alternative splicing to yield several isoforms, two of which (APP695 and 751 amino acid isoforms) predominate in the brain.
  • the major APP isoforms are single- transmembrane proteins, composed of an extracellular amino-terminal domain (approximately 590-680 amino acids) and a cytoplasmic tail containing intracellular trafficking signals (approximately 55 amino acids).
  • the A ⁇ peptide sequence is located partially on the extracellular side of the membrane and extends partially into the transmembrane region.
  • APP is trafficked through the constitutive secretory pathway, where it undergoes post-translational processing, including cleavage via either of two pathways, an amyloidogenic pathway and a non-amyloidogenic pathway.
  • amyloidogenic pathway APP is cleaved by /3-secretase (BACE) at the beginning of the A ⁇ domain that defines the amino terminus of the A ⁇ peptide.
  • BACE /3-secretase
  • Cleavage by BACE generates a soluble N-terminus, sAPP/3, as well as an amyloidogenic C- terminal fragment (C99).
  • BACE can also cleave APP 10 amino acids after the beginning of the A ⁇ domain (between amino acid 10 and 11) to generate a longer N-terminal soluble fragment and a shorter C-terminal fragment (C89). Additional cleavage of either C89 or C99 by ⁇ -secretase, a presenilin-dependent enzyme, produces A ⁇ peptides of various lengths. In the non-amyloidogenic pathway, APP is cleaved by osecretase within the A ⁇ domain, precluding A ⁇ formation.
  • A/342 is the species initially deposited in brain plaques, and is highly prone to aggregation in vitro. Therefore, the A/342 species of amyloid peptide, in particular, may be a viable target in the development of therapeutics for the treatment of disease or disorders characterized by A ⁇ accumulation.
  • AD Alzheimer's disease
  • invention compounds have been discovered that are useful for a variety of therapeutic applications, e.g., for modulating amyloid-beta levels. Accordingly, invention compounds find use in the treatment of a variety of diseases. Compositions and kits comprising invention compounds are also provided.
  • ⁇ amyloid-beta
  • ⁇ amyloid-beta
  • compounds herein are useful in the treatment of neurodegenerative disorders, such as AD.
  • Figure 1 presents the structures of several benzaldehydes subjected to the conversion reactions described in Example 71.
  • Figure 2 presents the structures of the compounds prepared according to Example 72. Reagents and conditions (a) embrace contacting compound 5c with the corresponding amine, in the presence of TEA at room temperature for 17h.
  • Figure 3 presents the structures of the compounds prepared according to Example 73. Reagents and conditions (a) embrace contacting compound 5b with the corresponding amine, in the presence of TEA at room temperature for 17h.
  • Figure 4 presents the structures of the compounds prepared according to Example 74.
  • Reagents and conditions (a) embrace contacting compound 5 a with the corresponding amine, in the presence of TEA at room temperature for 17h.
  • Figure 5 presents the structures of the compounds prepared according to Example 84.
  • Reagents and conditions (a) embrace contacting compound 162 with the corresponding amine, in the presence of TEA at room temperature for 17h.
  • the present invention provides novel compounds selected from the group consisting of compounds having a structure corresponding to Formula (I):
  • Ring A is optionally substituted arylene, optionally substituted heteroarylene or optionally substituted heterocycloalkyl, wherein a substituent, when present on Ring A, can cooperate with a substituent, when present on Ring B, to form a fused ring system;
  • Ring B is optionally substituted arylene or optionally substituted heteroarylene, wherein a substituent, when present on Ring B, can cooperate with a substituent, when present on Ring A, to form a fused ring system;
  • Ring C is aryl, heteroaryl, or fused benzocyclohexyl, wherein aryl, heteroaryl or fused benzocyclohexyl are substituted with at least one of halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl; provided however, that halogen(s) is(are) not
  • Z A is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino;
  • Z B is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino;
  • L A is a covalent bond or a linker selected from the group consisting -C(R') 2 -, -O-, -S-, -NR'-, -C(O)-, -S(O)-, and -S(O) 2 -, wherein each R' is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl; and
  • reference to a certain element such as hydrogen or H is meant to include all isotopes of that element. For instance, if a group is defined to include hydrogen or H, it also can include deuterium and/or tritium. In the structures provided herein, where a nitrogen atom appears to be divalent, it is assumed that the nitrogen atom is t ⁇ valent and the third substituient is hydrogen.
  • Compounds of the present invention may have asymmetric centers and may occur, except when specifically noted, as mixtures of stereoisomers or as individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention.
  • Compounds of the present invention embrace all conformational isomers.
  • Compounds of the present invention may also exist in one or more tautomeric forms, including both single tautomers and mixtures of tautomers.
  • hydrocarbyl refers to any organic radical comp ⁇ sing carbon and hydrogen, and having a directly attachable carbon atom to any molecule presented herein.
  • substituted hydrocarbyl refers to a hydrocarbyl group that is substituted according to the definition provided below. Hydrocarbyl groups include saturated and unsaturated hydrocarbons, straight and branched chain aliphatic hydrocarbons, cyclic hydrocarbons, and aromatic hydrocarbons.
  • substituted refers to an atom or group of atoms that has been replaced with another substituent.
  • substituted includes any level of substitution, e g mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is chemically permissible. Substitutions can occur at any chemically accessible position and on any atom, such as substitution(s) on carbons or any heteroatom.
  • substituted compounds are those where one or more bonds to a hydrogen or carbon atom(s) contained therein are replaced by a bond to non-hydrogen and/or non- carbon atom(s).
  • alkyl refers to saturated hydrocarbyl chains comprising from 1 to 20 carbon atoms.
  • alkyl includes straight chain alkyl groups, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like.
  • the phrase also includes branched chain isomers of straight chain alkyl groups, including but not limited to, the following which are provided by way of example: -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH(CH 2 CH 3 ) 2 , -C(CHj) 3 , -C(CH 2 CH 3 ) 3 , -CH 2 CH(CHa) 2 , -CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 2 CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 C(CH 2 CH 3 ) 3 , -CH(CH 3 )CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CH 3 ) 2) -CH 2 CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 ) 2 -CH 2
  • alkyl groups include primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups.
  • Preferred alkyl groups include alkyl groups having from 1 to 16 carbon atoms, or from 1 to 3 carbon atoms, such as methyl, ethyl, propyl, and -CH(CH 3 ) 2 .
  • substituted alkyl refers to an alkyl group that is substituted according to the definition provided above.
  • substituted alkyl groups include, but are not limited to, replacements of carbon or hydrogen atom(s) with a halogen atom(s), such as trifluoromethyl; an oxygen atom(s) in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, and ester groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, N-alkyloxides, imides, and enamines; a silicon atom in groups such as in trialkylsilyl groups, di alkyl aryl si 1 yl groups, alkyldiaryl
  • alkylene refers to divalent alkyl groups comprising from 1 to 20 carbon atoms and "substituted alkylene” refers to alkylene groups further bearing one or more substituents as set forth above.
  • alkenyl includes straight chain alkenyl groups, as well as branched chain isomers of straight chain alkenyl groups. Preferably, alkenyl groups comprise from 1 to 8 double bond(s).
  • substituted alkenyl refers to an alkenyl group that is substituted according to the definition provided above.
  • alkenylene refers to divalent alkenyl groups comprising from 2 to 20 carbon atoms and "substituted alkenylene” refers to alkenylene groups further bearing one or more substituents as set forth above.
  • alkynyl refers to unsaturated hydrocarbyl chains comprising from 2 to 20 carbon atoms and comprising at least one carbon-carbon triple bond (-C ⁇ 2-).
  • alkynyl includes straight chain alkynyl groups, as well as branched chain isomers of straight chain alkynyl groups. Preferably, alkynyl groups comprise from 1 to 8 triple bond(s).
  • substituted alkynyl refers to an alkynyl group that is substituted according to the definition provided above.
  • alkynylene refers to divalent alkynyl groups comprising from 2 to 20 carbon atoms and "substituted alkynylene” refers to alkynylene groups further bearing one or more substituents as set forth above.
  • cycloalkyl refers to an alicyclic moiety having 3 to 20 carbon atoms and comprising any chemically permissible amount of saturated or unsaturated bonds.
  • cycloalkyl groups comprise from 4 to 7 carbons atoms.
  • Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • substituted cycloalkyl refers to a cycloalkyl group that is substituted according to the definition provided above.
  • Substituted cycloalkyl groups can have one or more atom substituted with straight or branched chain alkyl groups and can further comprise cycloalkyl groups that are substituted with other rings including fused rings.
  • Examples of cycloalkyl groups that are substituted with fused rings include, but are not limited to, adamantyl, norbornyl, bicyclo[2.2.2]octyl, decalinyl, tetrahydronaphthyl, and indanyl, bornyl, camphenlyl, isocamphenyl, and carenyl groups.
  • Representative substituted cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6- disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which may be substituted with, for example, alkyl, alkoxy, amino, thio, or halo groups.
  • cycloalkylene refers to divalent cycloalkyl groups comprising from 3 to 20 carbon atoms
  • substituted cycloalkylene refers to cycloalkylene groups further bearing one or more substituents as set forth above.
  • heterocyclyl refers to nonaromatic cyclic hydrocarbyl compounds of which at least one ring member is a heteroatom.
  • Heterocyclic groups include monocyclic, bicyclic, and polycyclic ring compounds containing from 3 to 20 ring members of which one or more is a heteroatom such as, but not limited to, N, O, and S.
  • Heterocyclic groups include, any level of saturation.
  • heterocyclic groups include unsaturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms; saturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms; condensed unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms; unsaturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; unsaturated 3 to 8 membered rings containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms.
  • Preferred heterocyclyl groups contain 5 or 6 ring members.
  • heterocyclic groups include, but are not limited to, pyrrolidine, pyrazolidine, imidazolidine, morpholine, thiomorpholine, piperidine, and piperazine.
  • substituted heterocyclyl or “substituted heterocyclic” refers to a heterocyclyl group that is substituted according to the definition provided above.
  • heterocycloalkyl refers to an alkyl moiety, as defined herein, substituted with a heterocyclyl moiety, as defined herein.
  • heterocyclene or “heterocyclylene” refers to divalent heterocyclic (i.e., ring-containing) groups comprising from 3 to 20 carbon atoms and "substituted heterocycloalkylene” refers to heterocycloalkylene groups further bearing one or more substituents as set forth above.
  • aryl refers to single-ring aromatic radicals which may include from 5 to 20 carbon atoms.
  • Aryl groups include, but are not limited to, phenyl, biphenyl, anthracenyl, and naphthenyl.
  • substituted aryl group refers to an aryl group that is substituted according to the definition provided above.
  • substituted aryl groups may be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) and also includes aryl groups in which one or more aromatic carbons of the aryl group is bonded to a substituted and/or unsubstituted alkyl, alkenyl, or alkynyl group.
  • substituted aryl includes, but is not limited to tolyl, hydroxyphenyl, and the like.
  • arylene refers to divalent aryl groups comprising from 3 to 20 carbon atoms and "substituted arylene” refers to arylene groups further bearing one or more substituents as set forth above.
  • heteroaryl refers to single-ring aromatic radicals comprising 3 to 20-carbon atoms, wherein the aromatic ring consists of carbon atoms and heteroatoms, such as N, S, and O or (ii) an 8- to 10-membered bicyclic or polycyclic ring system containing carbon atoms and heteroatoms, such as N, S, and O, wherein at least one of the rings in the bicyclic system is an aromatic ring.
  • the heteroaryl ring may be attached at any heteroatom or carbon atom.
  • heteroaryl compounds include, for example, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, thiophenyl, thiazolyl, furanyl, pyridofuranyl, pyrimidofuranyl, pyridothienyl, pyridazothienyl, pyridooxazolyl, pyridazooxazolyl, pyrimidooxazolyl, pyridothiazolyl, pyridazothiazolyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g.
  • 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, and 1 ,2,5-oxadiazolyl benzoxazolyl, benzoxadiazolyl, benzoxazinyl (e.g. 2H-l,4-benzoxazinyl), thiazolyl, isothiazolyl, thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, and 1 ,2,5-thiadiazolyl).
  • substituted heteroaryl refers to a heteroaryl group that is substituted according to the definition provided above.
  • heteroarylene refers to divalent aryl groups containing one or more heteroatoms (e.g., N, O, S, or the like) as part of the aromatic ring, and typically having in the range of 3 up to 20 carbon atoms and "substituted heteroarylene” refers to heteroarylene groups further bearing one or more substituents as set forth above.
  • cycloalkylaryl refers to an cycloalkyl moiety as defined herein, substituted by, one or more aryl substiruents. Such substitution may be by a single covalent bond, or the aryl ring may be fused to the cycloalkyl moiety.
  • substituted cycloalkylaryl refers to a cycloalkylaryl group that is substituted according to the definition provided above.
  • Substituted cycloalkylaryl groups can have one or more atom substituted with straight or branched chain alkyl groups and can further comprise cycloalkyl groups that are substituted with other rings including fused rings.
  • cycloalkylaryl groups that are substituted with fused rings include, but are not limited to, adamantyl, norbornyl, bicyclo[2.2.2]octyl, decalinyl, tetrahydronaphthyl, and indanyl, bornyl, camphenlyl, isocamphenyl, and carenyl groups.
  • Representative substituted cycloalkylaryl groups may be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6- disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which may be substituted with, for example, alkyl, alkoxy, amino, thio, or halo groups.
  • alkoxy refers to an oxygen-containing alkyl or cycloalkyl group, as defined above, and the term “alkoxylene” refers to an oxygen-containing alkylene or cycloalkylene group.
  • alkylamido refers to an alkyl group, as defined above, which comprises -C(O)NR 2 wherein each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or the like. Furthermore, alkylamido embraces embodiments wherein R, together with N, forms a cyclic structure.
  • alkyleneamido refers to an alkylene group, as defined above, which comprises -C(O)NR 2 wherein each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or the like. Furthermore, alkyleneamido embraces embodiments wherein R, together with N, forms a cyclic structure.
  • amino refers to -NR 2 wherein each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and the like. Furthermore, amino embraces embodiments wherein R, together with N, forms a cyclic structure.
  • alkylamino refers to an alkyl group, as defined above, which comprises an amino group, as defined above
  • alkyleneamino refers to an alkylene group, as defined above, which comprises an amino group, as defined above.
  • halogen refers to F, Cl, Br, or I.
  • linker refers to any chemical moiety which can be used to join, attach, or connect two or more radicals of hydrocarbyl, substituted hydrocarbyl, heteroatom-containing substituted hydrocarbyl, or substituted heteroatom-containing hydrocarbyl groups.
  • each E is independently N, NR 1 , C, CR 2 , S, or O, provided that no more than four E's are heteroatoms;
  • each R 1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or a divalent form of any of the above, which cooperates with R 3 or R 4 (on Ring B) to form a fused ring system;
  • each R 2 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or a divalent form of any of the above, which cooperates with R 3 or R 4 (on Ring B) to form a fused ring system;
  • each M is independently selected from CR 2 or N, provided that no more than three M' s are N;
  • each Q is independently selected from N, NR 1 , CR 2 , C(R 2 ) 2 , S, or O, provided that at least one Q is a heteroatom, but no more than four Q' s are heteroatoms; and n is O, 1, 2 or 3.
  • substituted or unsubstituted alkyl substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkyl amino, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl contemplated herein include substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted alkoxylene, substituted or unsubstituted alkyleneamido, substituted or unsubstituted alkyl eneamino, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted arylene, respectively.
  • presently preferred divalent moieties when present, include alkoxylene (e.g., -CH 2 -O-, -CH 2 CH 2 -O-, and the like), alkyleneamido, alkyleneamino, and the like.
  • alkoxylene e.g., -CH 2 -O-, -CH 2 CH 2 -O-, and the like
  • alkyleneamido alkyleneamino
  • Ring A is
  • each E is independently N, NR 1 , C, CR 2 , S, or O, provided that no more than four E's are heteroatoms; with compounds wherein no more than three E's are heteroatoms being preferred in some embodiments; with compounds wherein no more than two E's are heteroatoms being preferred in some embodiments; and with compounds wherein only one E is heteroatom being preferred in some embodiments.
  • Presently preferred embodiments herein include compounds of Formula (I) wherein Ring A is an imidazole or a pyrazole.
  • R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstiruted cycloalkyl, or substituted or unsubstituted aryl.
  • Presently preferred embodiments herein include compounds wherein R 1 is C 1 -C 6 alkyl (especially methyl).
  • each R 2 is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl.
  • Presently preferred embodiments herein include compounds wherein R 2 is Ci-C ⁇ alkyl (especially methyl) or halogen.
  • Ring A is:
  • R 1 is Ci-C 6 alkyl (especially methyl)
  • R 2 is C I -C O alkyl (especially methyl) or halogen
  • G is CR or N (especially CR, with CH being presently preferred)
  • R is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, or substituted or unsubstituted amino.
  • Ring A is
  • each M is independently selected from CR 2 or N, provided that no more than three M's are N. In certain embodiments of the present invention, it is preferred that no more than two M's are N. In other embodiments of the present invention, it is preferred that only one M is N. In still other embodiments of the present invention, it is preferred that all M's are CR 2 . [0055] In still another aspect of the present invention, Ring A is
  • each Q is independently selected from N, NR 1 ,
  • A is a 4, 5, 6 or 7-membered heterocyclyl ring.
  • Exemplary rings include pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, and the like.
  • each E' is independently N 1 NR 3 , C, CR 4 , S, or O, provided that no more than four E's are heteroatoms;
  • R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or a divalent form of any of the above, which cooperates with R 1 or R 2 (on Ring A) to form a fused ring system;
  • each R 4 is independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or a divalent form of any of the above, which cooperates with R 1 or R 2 (on Ring A) to form a fused ring system; and
  • each M' is independently selected from CR 4 or N, provided that no more than three M "s are N.
  • Ring B is
  • each E' is independently N, NR 3 , C, CR 4 , S, or O, provided that no more than four E's are heteroatoms; preferably no more than three E's are heteroatoms; with no more than two E's being heteroatoms being presently preferred.
  • Ring B is
  • each M' is independently selected from CR 4 or N, provided that no more than three M "s are N; with no more than two M"s being N being presently preferred.
  • Ring B is
  • A is Ring A as defined above;
  • each R is independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino; and
  • Y is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl.
  • Ring B is
  • Y is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl; with Y selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted lower alkyl, and substituted or unsubstituted alkoxy, amino, and alkylamino being especially preferred, particularly hydrogen, fluoro, methoxy.
  • Ring C is:
  • each E" is independently N, NR 5 , C, CR 6 , S, or O, provided that no more than four E"s are heteroatoms;
  • R 5 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;
  • each R 6 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl; and
  • each M" is independently selected from CR 6 or N, provided that no more than three M"s are N.
  • Ring C is
  • a presently preferred Ring C is a pyrazole.
  • Ring C is
  • each M" is CR 2 . In other embodiments of the present invention, one M" is N. In still other embodiments of the present invention, two M"s are N.
  • each R 7 is independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted alkoxy, or substituted or unsubstituted amino.
  • the ortho R 7 is lower alkyl, especially methyl.
  • L A is a covalent bond or a linker selected from the group consisting -C(R')2-, -O-, -S-, -NR'-, -C(O)-, -S(O)-, and -S(O) 2 -, wherein each R' is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl.
  • L A include a covalent bond, -CH 2 -, -O-, -C(O) -, and -NH-.
  • An especially preferred linker L A is a covalent bond.
  • L B includes a covalent bond, -CH 2 - -CH(CH 3 K -C(CH 3 ) 2 -, cyclopropylene, -0-, -NH-, -C(O) -, -O-C(O) - and -S(O) 2 -.
  • Especially preferred linkers, L B include -CH 2 - -CH(CH 3 )- -C(CH 3 ) 2 - and cyclopropylene.
  • Z A is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino.
  • Z A is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl and substituted cycloalkyl.
  • Z A is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl. In certain embodiments, it is presently preferred that Z A is hydrogen.
  • ZB is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino.
  • ZB is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl and substituted cycloalkyl.
  • ZB is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, t-butyl, n-pentyl, cyclopropyl, cyclobutyl, and cyclopentyl.
  • Z B is hydrogen.
  • Z B is methyl.
  • Z B is ethyl.
  • Z B is cyclopropyl.
  • presently preferred combinations of Z A and Z B are those wherein each of Z A and Z B is hydrogen, or those wherein at least one of Z A and Z B is not hydrogen, or those wherein Z A is hydrogen and Z B is methyl, or those wherein Z A is hydrogen and Z B is cyclopropyl.
  • Presently preferred compounds according to the invention include compounds having one of the following structures:
  • each of G, Y, Z B , R 2 and R 7 are as defined above; with especially preferred compounds comprising those wherein Z 8 is alkyl (especially cyclopropyl), and Y is methoxy or halogen.
  • compositions comprising compounds of Formula (I) and a pharmaceutically acceptable carrier; and kits comprising compounds of Formula (I) (or compositions containing same) and instructions for use.
  • compounds contemplated by the present invention can be prepared in two steps by first contacting an appropriately substituted imidazole and para-fluoro-substituted nitrobenzene in the presence of K2CO3 in suitable solvent (e.g., DMSO or DMF) at about 50 °C for about 20 hr (step a), followed by treatment of the resulting phenyl-substituted imidazole with NaBH 4 and NiCl 2 , in methanol/dichloromethane (1 :1) at a temperature in the range of about 0 °C up to about room temperature for about 30 minutes (step b).
  • suitable solvent e.g., DMSO or DMF
  • compounds contemplated by the present invention can be prepared in two steps by first contacting a suitable substituted and protected pyrazole with a para-halogenated nitrobenzene in the presence of Pd(PPh 3 )4, Na 2 CO 3 , and LiCl, ethanol-toluene at about 9O°C, for about 17hr (step a), followed by treatment of the resulting phenyl-substituted pyrazole with NiCl 2 , NaBH 4 in methanol-dichloromethane at a temperature in the range of about O°C up to about 30minutes (step b).
  • compounds contemplated by the present invention can be prepared in two steps by first converting an appropriately substituted nitrobenzenediazonium to a triazole compound under suitable conditions with sodium azide and methylpropyne (step 1), followed by treatment of the resulting triazole compound with NaBH 4 and NiCl 2 , in methanol-dichloromethane (1 :1) at a temperature in the range of about 0 °C up to about room temperature for about 50 minutes (step T).
  • Ring C can be modified in a variety of ways for incorporation thereof into compounds of the invention, e.g., an appropriately substituted benzaldehyde can be treated with Z B -NH 2, in the presence of:
  • Ring C can be elaborated by treating an appropriately substituted cyano-benzene with H 2 , Raney Nickel and IN NH 3 in methanol at about 60 °C.
  • Ring C can be elaborated by treating an appropriately substituted bromomethyl-substituted benzene with Z B -NH 2 , in ethanol at room temperature.
  • Ring C can be elaborated by treating an appropriately substituted aminomethyl-substituted benzene with a suitable protecting group (e.g., Boc 2 O) in a suitable solvent (e.g., THF), under suitable reaction conditions (e.g., room temperature for about 2hr) (step a).
  • a suitable protecting group e.g., Boc 2 O
  • THF a suitable solvent
  • reaction conditions e.g., room temperature for about 2hr
  • the resulting protected amine can be treated with NaH, and methyl or ethyl iodide in DMF at a temperature in the range of about -20 °C up to about room temperature (step b).
  • the resulting substituted amine can be de-protected by treatment with trifluoroacetic acid at room temperature (step c).
  • amyloid-beta or "A ⁇ ” refers to a peptide that corresponds in sequence to a peptide derived from both beta-secretase (BACE) and gamma-secretase cleavage of an amyloid precursor protein (APP).
  • BACE beta-secretase
  • APP amyloid precursor protein
  • a ⁇ peptides include those that terminate at positions 33, 34, 37, 38, 39, 40 and 42, respectively, relative to human A ⁇ l-42 (SEQ ID NO:1; Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Glu-Val-His- His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser-Asn-Lys-Gly-Ala-Ile-Ile- Gly-Leu-Met-Val-Gly-Gly-Val-Val-Ile-Ala) or A ⁇ l-42 homologs from other species.
  • a ⁇ 42 includes peptides corresponding to amino acids 1-42, 2-42, and 11-42 of SEQ ID NO: 1 or its homologs.
  • the phrase "modulate” or “modulating” with respect to A ⁇ level refers to a detectable increase or decrease in the amount of at least one species of A ⁇ peptide (such as A ⁇ 43, A ⁇ 42, A ⁇ 40, A ⁇ 39, A ⁇ 38, A ⁇ 37, A ⁇ 34, 11-43, 11-42, 11-40, 1 1-39, 11-38, 11-37, 11-34, etc.); a detectable increase or decrease in the relative amount of different species of A ⁇ peptides (such as the ratio of A ⁇ 42 to A ⁇ 40); a detectable increase or decrease in the amount, or relative amount, of A ⁇ in a particular form (such as monomelic, oligomeric, or fibrillar form; in solution or aggregated in a plaque; in a particular conformation; etc.); and/or a detectable increase or decrease in the amount, or relative amount, of A ⁇ in a particular location (such as an intracellular, membrane-associated or extracellular location, or in a particular tissue or body fluid).
  • modulation is detectable as a decrease in the level of A ⁇ 42 or A ⁇ 40, or an increase in the level of A ⁇ 37 or A ⁇ 38.
  • Modulation of A ⁇ level can be evidenced, for example, by an increase or decrease of at least 5%, such as at least 10%, 20%, 30%, 40%, 50%, 75%, 90% or more, of the amount, or relative amount, of an A ⁇ species, of total A ⁇ , or of a particular form of A ⁇ , relative to a reference level. Modulation can be an increase or decrease that is a statistically significant difference relative to the reference level.
  • APP amyloid precursor protein
  • the APP can be from any species, but is preferably human or mammalian, and can be any isoform, including the major isoforms APP695, APP751 and APP770, or other isoforms such as APP714, L- APP752, L-APP733, L-APP696, L-APP677, APP563, and APP365.
  • the APP can contain one or more additions, deletions or mutations, including mutations found in families with AD or other amyloidoses (e.g.
  • an assay can use just a portion of an APP, so long as the fragment can be processed to A ⁇ by one or more cleavage reactions.
  • the APP C-terminal fragments designated C99 and C89, or portions thereof lacking some or all C-terminal residues that normally reside in the cytosol can be used.
  • the source of APP or fragment can be an in vivo, ex vivo or in vitro substance.
  • a source of APP or cleavable fragment can be a live organism (including a human subject, or a veterinary or laboratory animal, such as a transgenic animal), a sample therefrom (such as a tissue (e.g. brain), body fluid (e.g. blood, plasma, cerebrospinal fluid, urine, etc.), or extract thereof), a cell (such as a primary cell or cell line, a recombinant cell, or extract thereof), extracellular medium or purified protein.
  • tissue e.g. brain
  • body fluid e.g. blood, plasma, cerebrospinal fluid, urine, etc.
  • a cell such as a primary cell or cell line, a recombinant cell, or extract thereof
  • extracellular medium or purified protein extracellular medium or purified protein.
  • cells including human or other mammalian cells that endogenously or recombinantly express APP can be used, such as SH- SY5Y-APP, CHO-APP Swe , HEK-APP 751 , primary cells (e.g. mixed brain cultures) obtained from APP-expressing animals, and the like.
  • animals that endogenously express APP can be used, such as mice, rats, guinea pigs, rabbits, and the like.
  • APP- expressing transgenic animals can be used, including but not limited to the Tg2576 mouse, which contains a gene encoding human APP695 with the Swedish (Lys670Asn, Met671Leu) double mutation under the control of the hamster prion protein gene promoter (Hsiao et al. (1996) Science 274:99-102; U.S. Patent No.
  • V717F PDAPP mouse which contains a gene encoding human APP695 (Val717Phe) under the control of the platelet derived growth factor (PDGF) chain gene promoter (Games et al. (1995) Nature 373:523-527; U.S. Patent No. 5,811,633); and the ClOO mouse, which contains a gene encoding the neurotoxic C- terminal 100 amino acids of APP under the control of the dystrophin neural promoter (Neve et al. (1996) Neurobiol. Aging 17:191-203; U.S. Patent Nos. 5,672,805).
  • PDGF platelet derived growth factor
  • the substance containing the APP or cleavable fragment is contacted with a compound.
  • the contacting can be by therapeutic or prophylactic administration of the compound (e.g. by oral, intravenous, intraperitoneal, etc. routes).
  • the contacting can be by introduction of the compound into the culture medium.
  • the contacting can be by mixing the compound with the lysate or solution.
  • Electrophoresis 18:527-532 describes an assay using electrophoresis and immunoblotting that is suitable to detect changes in the level of A ⁇ 37, A ⁇ 38, A ⁇ 40 and/or A ⁇ 42.
  • Alternative A ⁇ assay formats including mass spectroscopy, imaging methods in live organisms (e.g. multiphoton microscopy and positron emission tomography), are also known in the art.
  • treating refers to any manner in which one or more of the symptoms of a disease or disorder are ameliorated or otherwise beneficially altered, whether in a permanent or temporary manner, which can be attributed to or associated with administration of the compound or composition herein.
  • the term encompasses any pharmaceutical use, including prophylactic uses in which the development of one or more of the symptoms of a disease or disorder is prevented, delayed or reduced, whether in a permanent or temporary manner, which can be attributed to or associated with administration of the composition.
  • disease associated with aberrant A ⁇ levels refers to any condition characterized by an abnormal amount of at least one species of A ⁇ peptide; by an abnormal relative amount of different species of A ⁇ peptides (such as the ratio of A ⁇ 42 to A ⁇ 40); by an abnormal amount, or relative amount, of A ⁇ in a particular form (such as monomelic, oligomeric, or fibrillar form; in solution or aggregated in a plaque; in a particular conformation, etc.); and/or by an abnormal amount, or relative amount, of A ⁇ in a particular location (such as intracellular, membrane-associated or extracellular location, or in a particular tissue or body fluid).
  • a ⁇ levels are known in the art and/or described herein, and include, for example, Alzheimer's Disease, Down syndrome, Parkinson's disease, diffuse Lewy body disease, Hereditary Cerebral Hemorrhage with Amyloidosis-Dutch Type (HCHWA-D), cerebral amyloid angiopathy (CAA), mild cognitive impairment (MCI), macular degeneration and cataracts.
  • HHWA-D Hereditary Cerebral Hemorrhage with Amyloidosis-Dutch Type
  • CAA cerebral amyloid angiopathy
  • MCI mild cognitive impairment
  • macular degeneration cataracts.
  • Compounds of the present invention can also be used in the treatment of neurological disorders, including but not limited to neurodegenerative disorders and other dementias or traumatic conditions.
  • neurological disorders include prion diseases (including Creutzf el dt- Jakob, Gerstmann-Straussler-Scheinker disease, Kuru and fatal familial insomnia), age-related dementia and other conditions with memory loss, such as vascular dementia, diffuse white matter disease (Binswanger's disease), dementia of endocrine or metabolic origin, dementia of head trauma and diffuse brain damage, cerebral ischemia or infaction including embolic occlusion and thrombotic occlusion as well as intracranial hemorrhage of any type (including, but not limited to, epidural, subdural, subarachnoid and intracerebral), and intracranial and intravertebral lesions (including, but not limited to, contusion, penetration, shear, compression and laceration).
  • prion diseases including Creutzf el dt- Ja
  • Compounds and compositions of the instant invention may be used to treat or ameliorate a variety of other disorders.
  • Compounds and compositions that may be used in therapeutic applications in one embodiment have reasonably high bioavailability in a target tissue (i.e. brain, for neurological disorders; particular peripheral organs for other conditions), reasonably good potency, and reasonably low toxicity.
  • contacting refers to bringing into association, either directly or indirectly, two or more substances. Contacting may occur in vivo, ex vivo or in vitro.
  • a source of APP, amyloid precursor fragment thereof and/or A ⁇ or source of BACE activity that is a human or other animal can be contacted with a compound, for example, by therapeutic or prophylactic administration of the compound.
  • a source of APP, amyloid precursor fragment thereof and/or A ⁇ that is a tissue, tissue extract or cell can be contacted with a compound, for example, by introduction of the compound into the culture medium.
  • a source of APP, amyloid precursor fragment thereof and/or A ⁇ that is a fluid, such as extracellular medium, can be contacted with a compound, for example, by admixing the compound with the fluid.
  • disease associated with aberrant A ⁇ levels refers to any condition characterized by an abnormal amount of at least one species of A ⁇ peptide (such as A ⁇ 43, A ⁇ 42, A ⁇ 40, A ⁇ 39, A ⁇ 38, A ⁇ 37, A ⁇ 34, 11-43, 1 1-42, 11-40, 1 1-39, 11-38, 1 1-37, 1 1-34, etc.); by an abnormal relative amount of different species of A ⁇ peptides (such as the ratio of A ⁇ 42 to A ⁇ 40); by an abnormal amount, or relative amount, of A ⁇ in a particular form (such as monomelic, oligomeric, or fibrillar form; in solution or aggregated in a plaque; in a particular conformation, etc.); and/or by an abnormal amount, or relative amount, of A ⁇ in a particular location (such as intracellular, membrane-associated or extracellular location, or in a particular tissue or body fluid).
  • a ⁇ peptide such as A ⁇ 43, A ⁇ 42, A ⁇ 40, A ⁇ 39, A ⁇ 38, A ⁇ 37, A ⁇
  • the abnormal amount of one or more A ⁇ peptides, A ⁇ forms and/or A ⁇ can be relative to a condition that is a normal, non-disease state.
  • Diseases and disorders characterized by altered A ⁇ levels are known in the art and/or described herein, and include, for example, Down syndrome, Parkinson's disease, diffuse Lewy body disease, progressive supranuclear palsy, Hereditary Cerebral Hemorrhage with Amyloidosis-Dutch Type (HCHWA-D), cerebral amyloid angiopathy (CAA), and mild cognitive impairment (MCI).
  • Embodiments of the invention include methods of treating any disease associated with aberrant A ⁇ levels, such as AD.
  • Compounds of the present invention can be administered to a subject to treat (including to prevent or to ameliorate) conditions associated with altered A ⁇ production, fibril formation/deposition, degradation and/or clearance, or any altered isoform of A ⁇ .
  • Compounds and compositions of the instant invention may be used to treat or ameliorate a variety of disorders.
  • Compounds and compositions that may be used in therapeutic applications in one embodiment have reasonably high bioavailability in a target tissue (i.e. brain, for neurodegenerative disorders; particular peripheral organs for other amyloidogenic conditions), and reasonably low toxicity.
  • a target tissue i.e. brain, for neurodegenerative disorders; particular peripheral organs for other amyloidogenic conditions
  • Those skilled in the art can assess compounds described herein for their pharmaceutical acceptability using standard methods.
  • compounds of the instant invention can be used in the treatment of cancer or other diseases characterized by abnormal cellular proliferation, inflammatory disease, bacterial or viral infection, autoimmunue disease, acute pain, muscle pain, neuropathic pain, allergies, neurological disease, dermatological conditions, cardiovascular disease, diabetes, gastrointestinal disorders, depression, endocrine or other disease characterized by abnormal hormonal metabolism, obesity, osteoporosis or other bone disorders, pancreatic disease, epilepsy or seizure disorders, erectile or sexual dysfunction, opthamological disorders or diseases of the eye, cholesterol imbalance, hypertension or hypotension, migraine or headaches, obsessive compulsive disorder, panic disorder, anxiety disorder, post traumatic stress disorder, chemical dependency or addiction, and the like.
  • Amyloidoses include all conditions in which deposition of amyloid in the brain or periphery is a characteristic, including amyloidosis associated with rheumatic diseases, idiopathic diseases, inherited conditions, inflammatory conditions, infectious diseases and malignancies.
  • Amyloidosis disorders include, for example, conditions associated with altered A ⁇ levels described above (e.g.
  • Alzheimer's disease Down syndrome, HCHWA-D, cerebral amyloid angiopathy (CAA), and mild cognitive impairment (MCI) etc.
  • familial amyloid polyneuropathy familial amyloid cardiomyopathy (Danish type)
  • isolated cardiac amyloid, amyloid angiopathy systemic senile amyloidosis, familial systemic amyloidosis, light-chain amyloidosis (AL), dialysis-associated amyloidosis, renal amyloidosis, pri on-related encephalopathies
  • diabetes in which amylin may be deposited in the kidney or pancreas
  • atrial amyloidosis and pituitary amyloidosis.
  • compositions of the invention comprise one or more compounds provided herein.
  • the compounds are, in one embodiment, formulated in combination with a pharmaceutically acceptable carrier into pharmaceutical preparations.
  • pharmaceutically acceptable carrier refers to any carrier known to those skilled in the art to be suitable for the particular mode of administration.
  • the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients.
  • pharmaceutically acceptable salt refers to any salt prepration that is appropriate for use in a pharmaceutical application.
  • Pharmaceutically- acceptable salts include amine salts, such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para- chloro- benzyl-2-pyrrolidin-r-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine, tris(hydroxymethyl)aminomethane, and the like; alkali metal salts, such as lithium, potassium, sodium, and the like; alkali earth metal salts, such as barium, calcium, magnesium, and the like; transition metal salts, such as zinc, aluminum, and the like; other metal salts, such as sodium hydrogen phosphate, disodium phosphate, and the
  • prodrug refers to a compound that, upon in vivo administration, is metabolized by one or more steps or processes or otherwise converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • Prodrugs can be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to a compound described herein.
  • prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when administered to a mammalian subject, can be cleaved to form a free hydroxyl, free amino, or free sulfhydryl group, respectively.
  • prodrugs include, for example, esters, enol ethers, enol esters, acetates, formates, benzoate derivatives, and the like of alcohol and amine functional groups in the compounds of the present invention.
  • compositions herein comprise one or more compounds provided herein.
  • the compounds are, in one embodiment, formulated into suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation and dry powder inhalers.
  • suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation and dry powder inhalers.
  • the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Fourth Edition 1985, 126).
  • compositions include, for example, solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation and dry powder inhalers.
  • compositions effective concentrations of one or more compounds or pharmaceutically acceptable derivatives thereof is (are) mixed with a suitable pharmaceutical carrier.
  • the compounds may be derivatized as the corresponding salts, esters, enol ethers or esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs prior to formulation, as described above.
  • concentrations of the compounds in the compositions are effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates one or more of the symptoms of diseases or disorders to be treated.
  • compositions are formulated for single dosage administration.
  • the weight fraction of compound is dissolved, suspended, dispersed or otherwise mixed in a selected carrier at an effective concentration such that the treated condition is relieved, prevented, or one or more symptoms are ameliorated.
  • the active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated.
  • the therapeutically effective concentration may be determined empirically by testing the compounds in in vitro and in vivo systems described herein and in PCT publications WO 04/018997 and WO 04/110350, and then extrapolated therefrom for dosages for humans.
  • the concentration of active compound in the pharmaceutical composition will depend on absorption, inactivation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art.
  • a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.1 ng/ml to about 50- 100 ⁇ g/ml.
  • the pharmaceutical compositions in another embodiment, should provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day.
  • Pharmaceutical dosage unit forms are prepared to provide from about 0.01 mg, 0.1 mg or 1 mg to about 500 mg, 1000 mg or 2000 mg, and in one embodiment from about 10 mg to about 500 mg of the active ingredient or a combination of essential ingredients per dosage unit form.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.
  • solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO) or polyethylene glycol (PEG), using surfactants, such as TWEEN ® , or dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as prodrugs of the compounds, may also be used in formulating effective pharmaceutical compositions.
  • cosolvents such as dimethylsulfoxide (DMSO) or polyethylene glycol (PEG)
  • surfactants such as TWEEN ®
  • dissolution in aqueous sodium bicarbonate such as sodium bicarbonate
  • the resulting mixture may be a solution, suspension, emulsion, or the like.
  • the form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle.
  • the effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.
  • the pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof.
  • the pharmaceutically therapeutically active compounds and derivatives thereof are, in one embodiment, formulated and administered in unit-dosage forms or multiple-dosage forms.
  • Unit- dose forms as used herein refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent.
  • unit-dose forms include ampoules and syringes and individually packaged tablets or capsules. Unit-dose forms may be administered in fractions or multiples thereof.
  • a multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit-doses which are not segregated in packaging.
  • compositions containing active ingredient in the range of 0.005% to 100% (wt%) with the balance made up from non-toxic carrier may be prepared. Methods for preparation of these compositions are known to those skilled in the art.
  • the contemplated compositions may contain 0.001%-100% (wt%) active ingredient, in one embodiment 0.1-95% (wt%), in another embodiment 75-85% (wt%).
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension.
  • a carrier such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension.
  • the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.
  • nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.
  • Oral pharmaceutical dosage forms are either solid, gel or liquid.
  • the solid dosage forms are tablets, capsules, granules, and bulk powders.
  • Types of oral tablets include compressed, chewable lozenges and tablets which may be enteric-coated, sugar-coated or film-coated.
  • Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art.
  • the formulations are solid dosage forms, in one embodiment, capsules or tablets.
  • the tablets, pills, capsules, troches, and the like can contain one or more of the following ingredients, or compounds of a similar nature: a binder; a lubricant; a diluent; a glidant; a disintegrating agent; a coloring agent; a sweetening agent; a flavoring agent; a wetting agent; an emetic coating; and a film coating.
  • binders include microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, molasses, polvinylpyrrolidine, povidone, crospovidones, sucrose and starch paste.
  • Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid.
  • Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.
  • Glidants include, but are not limited to, colloidal silicon dioxide.
  • Disintegrating agents include crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose.
  • Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate.
  • Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as saccharin, and any number of spray dried flavors.
  • Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate.
  • Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether.
  • Emetic-coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates.
  • Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.
  • the compound, or pharmaceutically acceptable derivative thereof could be provided in a composition that protects it from the acidic environment of the stomach.
  • the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine.
  • the composition may also be formulated in combination with an antacid or other such ingredient.
  • the dosage unit form when it is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil.
  • dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents.
  • the compounds can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum, or the like.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics.
  • the active ingredient is a compound or pharmaceutically acceptable derivative thereof as described herein. Higher concentrations, up to about 98% by weight of the active ingredient may be included.
  • tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
  • they may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Aqueous solutions include, for example, elixirs and syrups.
  • Emulsions are either oil- in-water or water-in-oil.
  • Elixirs are clear, sweetened, hydroalcoholic preparations.
  • Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative.
  • An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid.
  • Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives.
  • Pharmaceutically acceptable substances used in non-effervescent granules, to be reconstituted into a liquid oral dosage form include diluents, sweeteners and wetting agents.
  • Pharmaceutically acceptable substances used in effervescent granules, to be reconstituted into a liquid oral dosage form include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.
  • Solvents include glycerin, sorbitol, ethyl alcohol and syrup.
  • preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol.
  • non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil.
  • emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate.
  • Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia.
  • Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as saccharin.
  • Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
  • Organic acids include citric and tartaric acid.
  • Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.
  • Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof.
  • Flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds which produce a pleasant taste sensation.
  • the solution or suspension in for example propylene carbonate, vegetable oils or triglycerides, is in one embodiment encapsulated in a gelatin capsule.
  • a gelatin capsule Such solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545.
  • the solution e.g., for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be easily measured for administration.
  • a pharmaceutically acceptable liquid carrier e.g., water
  • liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
  • Other useful formulations include those set forth in U.S. Patent Nos. RE28,819 and 4,358,603.
  • such formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or poly-alkylene glycol, including, but not limited to, 1 ,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550- dimethyl ether, polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol, and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.
  • BHT butyl
  • compositions include, but are not limited to, aqueous alcoholic solutions including a pharmaceutically acceptable acetal.
  • Alcohols used in these formulations are any pharmaceutically acceptable water-miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol.
  • Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal.
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • the injectables, solutions and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol.
  • compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
  • a compound provided herein is dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g.,
  • Parenteral administration of the compositions includes intravenous, subcutaneous and intramuscular administrations.
  • Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions.
  • the solutions may be either aqueous or nonaqueous.
  • suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
  • PBS physiological saline or phosphate buffered saline
  • Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
  • aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection.
  • Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil.
  • Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple-dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride.
  • Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN ® 80). A sequestering or chelating agent of metal ions include EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.
  • the concentration of the pharmaceutically active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect.
  • the exact dose depends on the age, weight and condition of the patient or animal as is known in the art.
  • the unit-dose parenteral preparations are packaged in an ampoule, a vial or a syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art. [0149] Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect.
  • Injectables are designed for local and systemic administration.
  • a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1% w/w up to about 90% w/w or more, in certain embodiments more than 1% w/w of the active compound to the treated tissue(s).
  • the compound may be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug.
  • the form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle.
  • the effective concentration is sufficient for ameliorating the symptoms of the condition and may be empirically determined.
  • lyophilized powders which can be reconstituted for administration as solutions, emulsions and other mixtures. They may also be reconstituted and formulated as solids or gels.
  • the sterile, lyophilized powder is prepared by dissolving a compound provided herein, or a pharmaceutically acceptable derivative thereof, in a suitable solvent.
  • the solvent may contain an excipient which improves the stability or other pharmacological component of the powder or reconstituted solution, prepared from the powder. Excipients that may be used include, but are not limited to, dextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent.
  • the solvent may also contain a buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, in one embodiment, about neutral pH.
  • the resulting solution will be apportioned into vials for lyophilization.
  • Each vial will contain a single dosage or multiple dosages of the compound.
  • the lyophilized powder can be stored under appropriate conditions, such as at about 4 °C to room temperature.
  • Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration.
  • the lyophilized powder is added to sterile water or other suitable carrier. The precise amount depends upon the selected compound. Such amount can be empirically determined.
  • Topical mixtures are prepared as described for the local and systemic administration.
  • the resulting mixture may be a solution, suspension, emulsions, or the like, and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration.
  • the compounds or pharmaceutically acceptable derivatives thereof may be formulated as aerosols for topical application, such as by inhalation (see, e.g., U.S. Patent Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment of inflammatory diseases, particularly asthma).
  • These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the formulation will, in one embodiment, have diameters of less than 50 microns, in one embodiment less than 10 microns.
  • the compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application.
  • Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies.
  • Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.
  • These solutions particularly those intended for ophthalmic use, may be formulated as 0.01% - 10% (vol%) isotonic solutions, pH about 5-7, with appropriate salts.
  • Transdermal patches including iotophoretic and electrophoretic devices, are well known to those of skill in the art.
  • such patches are disclosed in U.S. Patent Nos. 6,267,983, 6,261,595, 6,256,533, 6,167,301, 6,024,975, 6,010715, 5,985,317, 5,983,134, 5,948,433, and 5,860,957.
  • rectal suppositories are used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients.
  • Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used.
  • spermaceti and wax agents to raise the melting point of suppositories include spermaceti and wax.
  • Rectal suppositories may be prepared either by the compressed method or by molding.
  • the weight of a rectal suppository in one embodiment, is about 2 to 3 gm.
  • Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration.
  • the compounds provided herein, or pharmaceutically acceptable derivatives thereof, may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated. Many such targeting methods are well known to those of skill in the art. All such targeting methods are contemplated herein for use in the instant compositions. For non-limiting examples of targeting methods, see, e.g., U.S. Patent Nos.
  • liposomal suspensions including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers.
  • tissue-targeted liposomes such as tumor-targeted liposomes
  • liposome formulations may be prepared according to methods known to those skilled in the art.
  • liposome formulations may be prepared as described in U.S. Patent No. 4,522,811. Briefly, liposomes such as multilamellar vesicles (MLVs) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask.
  • MLVs multilamellar vesicles
  • a solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed.
  • PBS phosphate buffered saline lacking divalent cations
  • Compounds and compositions provided herein may be administered in combination, or sequentially, with another therapeutic agent.
  • Such other therapeutic agents include those known for treatment, prevention, or amelioration of one or more symptoms of neurodegenerative diseases and disorders, such as AD.
  • Such therapeutic agents include, but are not limited to, donepezil hydrochloride (Aracept), rivastigmine tartrate (Exelon), tacrine hydrochloride (Cognex) and galantamine hydrobromide (Reminyl).
  • kits are provided.
  • Kits according to the invention include package(s) comprising compounds or compositions of the invention.
  • the phrase "package" means any vessel containing compounds or compositions presented herein.
  • the package can be a box or wrapping.
  • Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art. See, e.g., U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • the kit can also contain items that are not contained within the package but are attached to the outside of the package, for example, pipettes.
  • Kits may optionally contain instructions for administering compounds or compositions of the present invention to a subject having a condition in need of treatment. Kits may also comprise instructions for approved uses of compounds or compositions herein by regulatory agencies, such as the United States Food and Drug Administration. Kits may optionally contain labeling or product inserts for the present compounds. The package(s) and/or any product insert(s) may themselves be approved by regulatory agencies.
  • the kits can include compounds or compositions in the solid phase or in a liquid phase (such as buffers) provided in a package.
  • the kits also can include buffers for preparing solutions for conducting the methods, and pipettes for transferring liquids from one container to another.
  • the kit may optionally also contain one or more other compounds for use in combination therapies as described herein.
  • the compounds described herein include compounds which modulate A ⁇ levels.
  • Compounds can be evaluated for activity in modulating A ⁇ level using a variety of assays known in the art and/or described herein. Generally, a source of APP or fragment thereof and/or A ⁇ is contacted with a compound for a suitable period of time, and a level of A ⁇ is directly or indirectly assessed, as described below. The level of A ⁇ in the presence of the compound is compared to the level in a suitable control (such as a vehicle control or a positive control) to determine whether the compound modulates A ⁇ level.
  • a suitable control such as a vehicle control or a positive control
  • the source of APP, amyloid precursor fragment and/or A ⁇ used to assess the activity of a compound in modulating A ⁇ will depend on the product being detected and the nature of the assay.
  • an APP C-terminal fragment corresponding to a beta-secretase cleavage product can be used, such as C99.
  • full-length APP may be preferred.
  • Suitable sources of APP, amyloid precursor fragment and/or A ⁇ used to assess the activity of a compound include live laboratory animals (e.g. natural and transgenic animals), as well as tissues (e.g. brain), tissue extracts, body fluids (e.g. blood, plasma, cerebrospinal fluid, urine, etc.) and primary cells from humans or laboratory animals.
  • Other sources include recombinant cell lines, cell lysates therefrom (whole cell extracts, membrane fractions, etc.) and extracellular medium therefrom.
  • substantially purified APP or A ⁇ may alternatively be used. Methods of isolating tissues, production and maintenance of primary and recombinant cells, preparation of lysates, and protein purification compatible with A ⁇ assays are known in the art.
  • in vivo or in vitro sources can be used that contain APP, or an amyloid precursor fragment thereof, and have the ability to proteolytically process it to produce A ⁇ .
  • a ⁇ form e.g. monomelic, oligomeric or fibrillar form, or conformation
  • fibril deposition or fibril degradation in vitro or in vivo sources containing A ⁇ monomers, oligomers or fibrils can be used, which optionally may not also contain APP- or amyloid precursor fragment-producing cells.
  • a ⁇ form e.g. monomelic, oligomeric or fibrillar form, or conformation
  • fibril deposition or fibril degradation in vitro or in vivo sources containing A ⁇ monomers, oligomers or fibrils can be used, which optionally may not also contain APP- or amyloid precursor fragment-producing cells.
  • Transgenic animals useful in evaluating compound activity can express any desired wild-type or mutant APP, amyloid precursor fragment or A/3 isoform, as described herein.
  • the resulting animals can advantageously serve as models of human disease, and in particular, models of Alzheimer's disease and other neurodegenerative and amyloidosis-associated diseases.
  • Transgenic animals include, but are not limited to rodents, including mice, rats and hamsters, sheep, goats, chickens, pigs, cattle, monkeys, primates and other non-human mammals.
  • the animal can further exogenously express one or more other genes involved in the APP processing or degradation pathway, such as wild-type or mutant presenilin (PS-I or PS-2), BACE, IDE and/or neprilysin, and/or one or more other genes involved in pathogenesis, such as tau.
  • one or more other genes involved in the APP processing or degradation pathway such as wild-type or mutant presenilin (PS-I or PS-2), BACE, IDE and/or neprilysin, and/or one or more other genes involved in pathogenesis, such as tau.
  • the exogenous gene(s) can be expressed in all tissues or only in selected tissues (e.g. neural tissues), at any or all developmental stages, and at physiological, supra- or sub-physiological levels, by appropriate choice of regulatory elements.
  • Transgenic animals can further be homozygous, hemizygous, heterozygous or chimeric for the exogenous gene(s).
  • Transgenic animals can contain the exogenous gene(s) as well as, or instead of (e.g. through "knock-in” methodology), the endogenous counterpart. Methods of producing transgenic animals are described in standard laboratory manuals including, for example, Hogan et al., (1994), Manipulating the Mouse Embryo: A Laboratory Manual, 2 nd ed., Cold Spring Harbor Laboratory, New York.
  • APP-expressing transgenic animals are known in the art, and include the Tg2576 mouse, which contains human APP695 with the Swedish (Lys670Asn, Met671Leu) double mutation under the control of the hamster prion protein gene promoter (Hsiao et al. (1996) Science 274:99-102; U.S. Patent No. 5,877,399); the V717F PDAPP mouse, which contains human APP695 (Val717Phe) under the control of the platelet derived growth factor (PDGF) chain gene promoter (Games et al. ( ⁇ 995) Nature 373:523-527; U.S. Patent No.
  • Cells useful in evaluating compound activity can express, either endogenously or recombinantly, any desired wild-type or mutant APP and/or A/3 isoform, as described herein.
  • Cells can be primary cells or cell lines derived from any animal, including humans and other mammals, such as transgenic animals described above.
  • the cells can be of any differentiated lineage, such as neural lineage (e.g. cortical neural cells, microglia, glia, astrocytes), fibroblasts, lymphocytes and epithelial cells, or can be totipotent or pluripotent (see Freshney, R. I. (2000) "Culture of Animal Cells: A Manual of Basic Technique," 4 th ed., Wiley-Liss).
  • An exemplary cell line suitable for assessing the activity of a compound in modulating A ⁇ is SH-SY5Y-APP751, which is described in the Example section herein.
  • a further exemplary cell line is HGB, which expresses endogenous APP.
  • Exemplary primary cells suitable for assessing the activity of a compound in modulating A ⁇ are mixed brain cultures from Tg2576 transgenic mice, or other APP-expressing transgenic animals.
  • Mixed brain cultures can be prepared, for example, by dissecting brain tissues from approximately 17-day old mouse embryos, dissociating the brain tissue with papain, and culturing the cells by standard procedures for primary neuronal cultures.
  • APP-, amyloid precursor fragment- or A/S-encoding nucleic acid under the control of suitable constitutive or inducible regulatory elements, can be transiently or stably introduced into primary cells or cell lines by various well-known transfection methods (Sambrook and Russell (2000) "Molecular Cloning: A Laboratory Manual” Cold Spring Harbor Laboratory Press; Ausubel et al. (eds.) (current edition) "Current Protocols in Molecular Biology” John Wiley & Sons.). D. ASSAYS THAT DIRECTLY ASSESS A ⁇ LEVELS
  • Compounds can be evaluated for their ability to modulate A ⁇ using assays that directly assess the level of A ⁇ .
  • the ability of a compound to modulate A ⁇ can be evaluated by determining the amount of a particular A ⁇ peptide (such as A ⁇ 43, A ⁇ 42, A ⁇ 40, A ⁇ 39, A ⁇ 38, A ⁇ 37, A ⁇ 34, 1 1-43, 11-42, 11-40, 11-39, 11-38, 1 1-37, 11-34, etc.); by determining the amount of A ⁇ peptides collectively; by determining the amount of a particular A ⁇ peptide relative to the amount of a second A ⁇ peptide (such as the ratio of A ⁇ 42 to A ⁇ 40); by determining the amount, or relative amount, of A ⁇ in a particular form (such as monomeric, oligomeric, or fibrillar form; in solution or aggregated in a plaque; in a particular conformation, etc.); and/or by determining the amount, or relative amount, of A ⁇ in a particular location (
  • a ⁇ A ⁇ species or forms, or A ⁇ peptides collectively, in a sample.
  • the level of A ⁇ can optionally be quantified using internal standards and/or calibration curves generated by performing the assay with known amounts of standards.
  • immunodetection methods can be used that employ A ⁇ -specific antibodies (e.g. monoclonal and polyclonal antibodies, single-chain antibodies, chimeric antibodies, bifunctional antibodies, humanized antibodies, CDR- grafted antibodies and CDR-grafted alternative scaffolds, as well as antigen-binding fragments thereof)-
  • a ⁇ -specific antibodies e.g. monoclonal and polyclonal antibodies, single-chain antibodies, chimeric antibodies, bifunctional antibodies, humanized antibodies, CDR- grafted antibodies and CDR-grafted alternative scaffolds, as well as antigen-binding fragments thereof
  • Such antibodies can optionally be specific for particular A ⁇ species or forms.
  • antibodies that bind an epitope at or near the N- terminus, C-terminus, or central portion of A ⁇ can be used to simultaneously detect multiple isoforms of A ⁇ .
  • Exemplary antibodies include, but are not limited to, 6E10, B436, antibody raised against A ⁇ 12-28, 21F12, A387, Clone GB-10, and the A/340- selective antibodies. Moreover, antibodies selective for any desired epitope of any A ⁇ species can be readily prepared by well known methods described in the art.
  • Antibody or binding agent can optionally be detectably labeled or, if a secondary antibody or binding agent is employed, the secondary antibody or agent can be detectably labeled.
  • Exemplary detectable labels include radioactive, fluorescent, bioluminescent, chemiluminescent and enzymatic labels. Methods of detecting such labels, and of quantitatively or qualitatively assessing the amount of bound peptide based on such detection, are well known in the art.
  • Immunodetection methods that can be adapted for assessing A/3 levels are well known to one of skill in the art. Representative methods include, but are not limited to, immunoprecipitation (optionally in combination with electrophoretic separation or a denaturing or non-denaturing gel, or mass spectroscopic analysis), western hybridization, immunocytochemistry, fluorescence resonance energy transfer (FRET)-based methods, and various formats of enzyme-linked immunosorbent assays (ELISA).
  • FRET fluorescence resonance energy transfer
  • ELISA enzyme-linked immunosorbent assays
  • non-denaturing separation conditions e.g. non-denaturing electrophoresis or chromatography
  • urea-bis-bicine-SDS based electrophoresis can be performed, which can resolve A/337, A/338, A/339, A/340, A/32- 42, and A/33-42 species (Wiltfang et al., (2001) J. Biol. Chem., 276: 42645-42657).
  • Immunodetection methods can readily be adapted for use with non-antibody-based agents that bind A/3, such as A/3-binding proteins, fragments thereof, and small molecule compounds. Proteins and compounds that bind A ⁇ are known in the art or can be identified by routine screening assays.
  • Any method of determining the amount of A ⁇ deposited in tissues of live organisms including imaging methods, such as multiphoton microscopy and positron emission tomography, can be employed.
  • imaging agents cross the blood-brain barrier and bind amyloid deposits with high affinity, such as the thioflavin-T analogue 2-[4' -(methylamino)phenyl]benzothiazole (Mathis et al. (2002) Bioorg. Med. Chem. Lett. 12:295-298) and the Congo red derivative methoxy-X04 (Klunk ⁇ ⁇ /. (2002) J. Neuropathol. Exp. Neurol. 61 :797-805).
  • imaging agents cross the blood-brain barrier and bind amyloid deposits with high affinity, such as the thioflavin-T analogue 2-[4' -(methylamino)phenyl]benzothiazole (Mathis et al. (2002) Bioorg. Med. Chem. Lett. 12:295-298)
  • Compounds can alternatively be evaluated for their ability to modulate A ⁇ using assays that indirectly assess the level of A ⁇ . Those skilled in the art can determine suitable assays for evaluating modulation of A ⁇ levels. For example, the amount of uncleaved APP, or of a product of APP processing other than A ⁇ , can be assessed.
  • Methods of determining the amount of APP or of APP processing products are known in the art, and include immunodetection assays similar to those described above for A ⁇ , employing suitable antibodies.
  • the reaction mixture was degassed by bubbling nitrogen though it for 30 minutes before Pd(PPh 3 ) 4 (2.31 g, 2.0 mmol) was added.
  • the reaction mixture was stirred at 100°C for 16 hours. After the reaction mixture had cooled, it was extracted with EtOAc (3x100 mL) and water (100 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO 4 and filtered. Removal of the solvent in vacuo gave an oily residue which was purified by column chromatography.
  • the compound 4-(2-fluoro-4-nitro-phenyl)-l -methyl- IH- pyrazole 62 was obtained as a yellow powder (3.46 g, 65%).
  • the reaction mixture was degassed by bubbling nitrogen though it for 30 minutes before Pd(PPl ⁇ ) 4 (1.39 g, 1.20 mmol) was added.
  • the reaction mixture was heated at 100°C for 17 hours and allowed to cool to room temperature.
  • the reaction mixture was then extracted with EtOAc (3x100 mL), washed with water (100 mL), brine (100 mL), dried over MgSO 4 and filtered. Removal of the solvent in vacuo gave an oily residue which was purified by column chromatography.
  • the compound 4-(l -methyl- lH-pyrazol-4-yl)-phenylamine 72 was obtained as a pale yellow powder (820 mg, 40%).
  • Reagents and conditions (a) NaBH(OAc) 3 , HOAc, DCE, 2 N MeNH 2 in MeOH, rt, 2 h.
  • Reagents and conditions (a) NaBH 4 , NiCl 2 -OH 2 O, DCM/MeOH, 0°C - rt, 1.5 h; (b) Br 2 , HOAc, DCM, 2 h, (c) (CHj) 2 CHCH 2 B(OH) 2 , Pd(OAc) 2 , PCy 3 , K 3 PO 4 , Toluene, Water, 100°C, 16 h; (d) NaNO 2 , HBr; (e) Cu(I)Br, HBr; (f) K 4 [Fe(CN) 6 ], Pd(OAc) 2 , Na 2 CO 3 , DMAC, 120°C, N 2 , 16 h; (g) H 2 , Raney Ni, IN NHj/MeOH, 60 0 C, 16 h; (h) BoC 2 O, THF, rt, 2 h; (i) NaH, CH 3 I / DMF, -20 0 C
  • reaction mixture was heated at 100°C for 16 h before it was allowed to cool to room temperature and filtered through a pad of celite and washed with EtOAc (300 ml). The organic layer was washed with water (50 ml) and then brine (50 ml), dried over MgSO 4 and filtered. Removal of the solvent in vacuo gave a brown oil which was purified by flash column chromatography on silica gel (eluting with 2% to 20% ethyl acetate in hexane gradient over 50 min.
  • Reagents and conditions (a) Cu(I)CN, DMF, 155°C, 16 h; (b) (CHj) 2 CHCH 2 B(OH) 2 , Pd(OAc) 2 , PCy 3 , K 3 PO 4 , Toluene, Water, 100 0 C, 16 h; (c) H 2 , Raney Ni, IN NH 3 ZMeOH, 60°C, 16 h; (d) BoC 2 O, THF, rt, 2 h; (e) NaH, CH 3 LOMF, -20°C - rt; (f) TFA, 15 min.
  • Reagents and conditions (a) NaNO 2 , HBr; (b) Cu(I)Br, HBr; (c) Cu(I)CN, DMF, 155 0 C, 16 h; (d) H 2 , Raney Ni, IN NH 3 MeOH, 60°C, 16 h, (e) BoC 2 O, THF, rt, 2 h; (f) NaH, CH 3 I / DMF, -20°C - rt; (g) TFA, 15 mm.
  • Reagents and conditions (a) n-BuLi, DMF, THF, N 2 , -78 - 0°C, 80 min; (b) Cyclopropyl amine, NaBH(OAc) 3 , i-Pr 2 NEt, DCE, rt, 16 h.
  • Reagents and conditions (a) n-BuLi, DMF, THF, N 2 , -78 - 0°C, 80 min; (b) Cyclopropyl amine, NaBH(OAc) 3 , J-Pr 2 NEt, DCE, rt, 16 h.
  • reaction mixture was quenched with one drop of water and the product isolated by reverse-phase HPLC. Pure fraction was concentrated to yield l-(2,4-dichloro-benzyl)-3-[3-fluoro-4-(4-methyl-imidazol-l-yl)-phenyl]-l ,3-dimethyl- urea (2) as a tan oil (0.027 g, 51%).
  • R1 methyl (3a), cyclopropyl (3b) Reagents and conditions: (a) DCE, AcOH, NaBH(OAc) 3, 1 h;
  • Reagents and conditions (a) K 2 CO 3 , DMSO, rt; b) NaBH 4 , NiCl 2 , DCM-MeOH (1 : 1); c) pyridine, p- nitrophenyl chloroformate, DCM, 0 °C to rt; d) NaBH(OAc) 3 , HOAc, DCE, rt, e) DIEA 1 DMSO, rt.
  • Reagents and conditions a) NaBH(OAc) 3 , HOAc, DCE, rt; b) DIEA, DMSO, rt.
  • Amine intermediates 12 and 13 were prepared via reductive amination of aldehyde 11. Further coupling of 12 with carbamate intermediates 5b and 5c using DIEA in DMSO at room temperature provided the title compounds 14a and 14b, respectively. 15a and 15b were prepared by the same procedure.
  • Reagents and conditions a) NaCNBH 3 , HCl, cyclopropylamine, MeOH, rt; b) DIEA, DMF, rt.
  • Amine intermediate 17 was prepared via reductive amination of aldehyde 16 using sodium cyanoborohydride in the presence of anhydrous HCl in methanol at room temperatue. Further coupling of 17 with carbamate intermediates 5b and 5c using DIEA in DMF at room temperature, followed by HPLC purification, provided the title compounds 18a and 18b, respectively.
  • Reagents and conditions a) DIEA, DMSO, rt.
  • Reagents and conditions a) DIEA, DMSO, rt.
  • Reagents and conditions (a) NaNO 2 , HBr; (b) Cu(I)Br, HBr; (c) n-BuLi, DMF, THF, -78°C, Ih; (d) Cyclopropyl amine, NaBH(OAc) 3 , 1-Pr 2 NEt, 16h; (e) i-pr 2 NEt, DMF, rt, 16 h
  • Reagents and conditions (a) Br 2 J 2 , Dark, O°C, KOH; (b) n-BuLi, N-formylpipe ⁇ dine, THF, -78°C, 2 h; (c) CH 3 CH 2 B(OH) 2 , Pd(OAc) 2 , PCy 3 , K 3 PO 4 , Toluene, Water, 100°C, 16 h; (d) Methyl amine, NaBH(OAc) 3 , HOAc, MeOH, 16h; (e) i-pr 2 NEt, DMF, rt, 16 h
  • Reagents and conditions (a) NaBH 4 , NiCl 2 .6H 2 O, DCM/MeOH, 0°C, 2h; (b) NaNO 2 , HBr; (c) Cu(I)Br, HBr; (d) n-BuLi, DMF, THF, -78 0 C, Ih; (e) Cyclopropyl amine, NaBH(OAc) 3 , i-Pr 2 NEt, 16h; (I) I-Pr 2 NEt 1 DMF 1 H, 16 h.
  • Reagents and conditions (a) Cu(I)CN, DMF, 155 0 C, 16 h; (b) H 2 , Raney Ni, IN NH 3 /MeOH, 60°C, 16 h; (c) BoC 2 O, THF, rt, 2 h; (d) NaH, CH 3 I / DMF, -20°C - rt; (e) TFA, 15 min; (f) i-pr 2 NEt, DMF, it, 16 h. [0293] The synthesis of compounds 49a-c is outlined above. Bromide 40 was converted to nitrile 44 by reacting with Cu(I)CN in DMF at 155°C.
  • Reagents and conditions (a) CH 3 CH 2 B(OH) 2 , Pd(OAc) 2 , PCy 3 , K 3 PO 4 , Toluene, Water, 100 0 C, 1 h; (b) Cyclopropyl amine, NaBH(OAc) 3 , J-Pr 2 NEt 1 16h; (c) i-pr 2 NEt, DMF, rt, 16 h.
  • Reagents and conditions (a) CH 3 CH 2 B(OH) 2 , Pd(OAc) 2 , PCy 3 , K 3 PO 4 , Toluene, Water, 100 0 C, 1 h, (b) methyl amine, NaBH(OAc) 3 , HOAc, MeOH, 16h, (c) i-pr 2 NEt, DMF, rt, 16 h.
  • Reagents and conditions (a) cyclopropylamine or methylamine in MeOH, DCE, AcOH, NaBH(OAc 3 ), 3h at room temp.; (b) Carbamate 5a, 5b or 5c, DMF, DIEA Ih, room temp.
  • Benzylamines 66a-b were synthesized using aldehyde 65, cyclopropylamine or methylamine in methanol and the previously described procedure for reductive aminations. Compounds 66a or 66b were then reacted with the appropriate carbamate in DMF at room temperature for Ih. Products 67a-d were isolated by reverse-phase HPLC.
  • Compound 70 was synthesized by the selective bromination of 68 followed by the alkylation of bromophenol 69 with l-bromo-2-chloroethane. Procuct 70 was then dissolved in dry THF and cooled to -78°C and treated with n-BuLi and stirred for 30 min. DMF was then added dropwise, reaction stirred for 5 min., then allowed to react while warming to room temperature. Compound 71 was isolated by normal- phase chromatography. Compound 72 was prepared by dissolving compound 71 in methanol and treating with cyclopropylamine with stirring for 1 h. After cooling to 0°C in an ice bath, NaBH 4 was added and the mixture stirred for Ih while warming to room temperature. Compound 72 was then treated with tert-butyloxycarbonyl anhydride and DIEA in THF. The mixture was stirred for 18 h. The Boc protected product 73 was isolated by column chromatography. EXAMPLE 67
  • Reagents and conditions (a) 37% aq.sol. HCHO, NaBH 3 CN, AcOH, MeCN, 0°C to rt, 2h; (b) rcBuli, DMF, THF, -78 0 C to 0°C, Ih.
  • the aldehyde 79 was synthesized as outlined above.
  • Compound 78 was prepared by reductive alkylation of reagent 77 with formaldehyde. Subsequent lithium-halogen exchange on intermediate 78, followed by reaction with DMF afforded the aldehyde title compound 79.
  • Reagents and conditions (a) Pyrrolidine, K 2 CO 3 , DMF, 120°C, 66h; (b) Piperidine, K 2 CO 3 , DMF, 120°C, 66h; (c) DIBALH, toluene, -78 0 C, 2h.
  • the aldehydes 83 and 84 were synthesized as outlined above. Nucleophilic displacement reaction on compound 80 with the corresponding amines, namely pyrrolidine and piperidine, gave the benzonitrile intermediates 81 and 82, respectively. Subsequent reduction of the nitrile group in compounds 81 and 82 with DIBALH at -78°C afforded the aldehyde title compounds 83 and 84, respectively. [0307] 4-amino substituted benzaldehydes, such as those shown below, were prepared in a similar manner.
  • R 2 Me, Cyclopropyl
  • N-alkylated benzylamines 87 were prepared as outlined above.
  • the corresponding aldehydes 85 were subjected to a stepwise reductive amination protocol, without isolation of the imine intermediate 86, to afford the N-alkylated benzylamine title compounds 87.
  • N-Substituted ureas 88-101 were synthesized as outlined in Figure 2. Reaction of intermediate 5c with the corresponding amines in the presence of triethylamine afforded the N-substituted urea title compounds 88-101. More compounds, e.g. compound 1332, 1428, 1542, and the like, can be synthesized in similar manner — see Table 1. Similarly, exemplary 2-Ethoxy compounds can also be prepared in this manner — see Table 1. EXAMPLE 73
  • N-S ⁇ bstituted ureas 102-115 were synthesized as described in Figure 3. Reaction of intermediate 5b with the corresponding amines in the presence of triethylamine afforded the N-substituted urea title compounds 102-115. More compounds, e.g. compound 1331, 1478, 1524, and the like, can similarly be synthesized — see Table 1.
  • N-Substituted ureas 116-128 were synthesized as outlined in Figure 4. Reaction of intermediate 5a with the corresponding amines in the presence of triethylamine afforded the N-substituted urea title compounds 116-128. More compounds, e.g. compound 1330, 1481, 1537, and the like, can similarly be synthesized — see Table 1.
  • Reagents and conditions a) NaBH(OAc) 3 , HOAc 5 DCE, rt; b) DIEA, DMSO, rt.
  • Amine intermediate 130 was prepared via reductive amination of aldehyde 129 using one equivalent of cyclopentyl amine under similar conditions. Further coupling of 130 with carbamate intermediates 5b, 5c using DIEA in DMSO at room temperature, followed by HPLC purification, provided the title compounds 131a and 131b, respectively.
  • EXAMPLE 76 SYNTHESIS OF CYCLOBUTYL-UREA ANALOGS
  • Reagents and conditions a) NaBH(OAc) 3 , HOAc, DCE, rt; b) DIEA, DMSO, rt.
  • Cyclopropylmethyl-(2,5-dimethylbenzyl) amine 137 was prepared as outlined above. 2,5-Dimethylbenzylamine 135 was subjected to a stepwise reductive alkylation protocol, without isolation of the imine intermediate 136, to afford cyclopropylmethyl-(2,5-dimethylbenzyl) amine 137.
  • Cyclopropylmethyl-(5-isopropyl-4-methoxy-2-methylbenzyl) amine 140 was prepared as outlined above. 5-isopropyl-4-methoxy-2-methylbenzylamine 138 was subjected to a stepwise reductive alkylation protocol, without isolation of the imine intermediate 139, to afford cyclopropylmethyl-(5-isopropyl-4-methoxy-2- methylbenzyl) amine 140.
  • Reagents and conditions (a) K 2 CO 3 , DMSO, rt; b) H 2 , 10% Pd-C, MeOH, rt; c) p-nitrophenyl chloroformate, DCM, 0 °C; d) DIEA 1 DMSO, rt.
  • Reagents and conditions (a) NaH, DMSO, rt; b) H 2 , 10% Pd-C, MeOH, rt; c) pyridine, p-nitrophenyl chloroformate, DCM, 0 °C; d) DIEA, DMSO, rt.
  • Reagents and conditions a) NaH, ethanol, DMSO, rt; b) H 2 , 10% Pd-C, MeOH, rt; c) pyridine, p- nitrophenyl chloroformate, DCM, 0 0 C; d) DIEA, DMSO, rt.
  • Reagents and conditions (a) K 2 CO 3 , DMSO, rt; b) NaBH 4 , NiCl 2 , MeOH-DCM (1 :1), rt; c) p- nitrophenyl chloroformate, DCM, 0 0 C; d) DIEA, DMSO, rt.
  • Reagents and conditions (a) K 2 CO 3 , DMF, 55 0 C, 18h; (b) NiCl 2 , NaBH 4 , MeOH/DCM, 0°C to rt, 60min; (c) p-nitrophenylchloroformate, DCM, pyridine, -10 D C to rt, 30min.
  • Reagents and conditions (a) Pd(PPh 3 ) 4 , Na 2 CO 3 , LiCl, EtOH-toluene, 90°C, 17h, (b) NiCl 2 , NaBH 4 , MeOH/DCM, 0°C to rt, 30min, (c) p-nitrophenylchloroformate, DCM, pyridine, -10°C to it, 30min
  • Reagents and conditions (a) Pd(PPh 3 ) 4 , Na 2 CO 3 , LiCl, EtOH-toluene, 90°C, 17h, (b) NiCl 2 , NaBH 4 , MeOH/DCM, 0 0 C to rt, 30min, (c) p-nitrophenylchloroformate, DCM, pyridine, -10°C to rt, 30min [0323]
  • the carbamate 187 was synthesized as outlined above. Reagents 179 and 184 were coupled according to a Suzuki-Miyaura protocol. The resulting nitro intermediate 185 was reduced to yield aniline 186. Subsequent reaction of compound 186 with p-nitrophenylchloroformate, in the presence of pyridine afforded the carbamate title compound 187.
  • Reagents and conditions (a) Pd(PPh 3 ) 4 , Na 2 CO 3 , LiCl, EtOH-toluene, 90°C, 17h; (b) p- Nitrophenylchloroformate, DCM, pyridine, - 10°C to rt, 30mi ⁇ .
  • the carbamate 190 was synthesized as outlined above. Reagents 179 and 188 were coupled according to a Suzuki-Miyaura protocol. The resulting aniline intermediate 189 was reacted with p-nitrochloroformate, in the presence of pyridine afforded the carbamate title compound 190.
  • Reagents and conditions (a) Corresponding amine, TEA, rt, 17h.
  • Reagents and conditions (a) Corresponding amine, TEA, rt, 17h.
  • Reagents and conditions (a) Corresponding amine, TEA, rt, 17h.
  • Step 1 To a solution of 141 (5.4Og, 30 mmol) in distilled water (30 mL) was added dropwise NaN 3 (2.34 g, 36 mmol) in distilled water (18 mL). The reaction mixture was stirred at 0 °C / 5°C for 30 min before it was allowed to warm to RT. After 90 min, diethylether (150 mL) was added and the reaction mixture was extracted. The ether layer was dried over MgSO 4 and substantially all of the ether removed in vacuo (the ether was not removed completely (5-10 mL left) because azides can be explosive as dry powders).
  • Step 2 Compound 142 (553 mg, 2.36 mmol) was dissolved in MeOHiCH 2 Cl 2 1 :1 (20 mL) and cooled to -5°C to 0°C by means of a dry-ice / acetone bath. NiCl 2 .6H 2 O (180 mg, 0.76 mmol) and NaBH 4 (269 mg, 7.27 mmol) were added in portions under N 2 according to the following chart:
  • Reagents and conditions for systhesis of 3a (a) Pd 2 (dba) 3 , Zn(CN) 2 , Dppf, Zn, DMA, 125 °C; b) cyclopropylamine, NaBH(OAc) 3 , HOAc, DCE, rt.
  • Step a To a solution of triflate 1 (1.19 g, 3.83 mmol) in 39 mL of DMA was added zinc cyanide (450 mg, 3.83 mmol), Dppf (170 mg, 0.31 mmol) and zinc (60 mg, 0.92 mmol). Pd 2 (dba) 3 (140 mg, 0.15 mmol) was added rapidly to the reaction mixture at room temperature under an argon atmosphere. The resulting reaction mixture was stirred at 125 °C for 12 hrs, cooled down to the room temperature and filtered through a bed of celite.
  • Step b To a solution of compound 2a (374 mg, 2 mmol) in 15 mL of 1 ,2- dichloroethane was added cyclopropyl amine (342 mg, 6 mmol), acetic acid (0.23 mL, 4 mmol) and sodium triacetoxyborohydride (551 mg, 2. 6mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 hrs and concentrated in vacuo. The crude product was purified on silica gel column chromatography (hexanes: ethyl acetate, 1 :2) to afford the desired product 3a (388 mg, 85%) as a yellow oil.
  • Reagents and conditions (a) NaN ⁇ , C11SO 4 , sodium ascorbate, methylpropyne, EtOH / toluene, rt, 20 h, (b) NiCl 2 , NaBH 4 , MeOH/DCM, 0 0 C , 10 mm; (c) p-Nitrophenylchloroformate, DCM, pyridine, -10°C to rt, 30 min, (d) Corresponding amine, TEA, it, 17 h
  • Reagents and conditions (a) K 2 CO 3 , DMSO, it; (b) H 2 SO4, 80 °C; (c) H 2 , 10% Pd-C, MeOH, rt; (d) p- nitrophenyl chloroformate, DCM, 0 0 C; (e) DIEA, DMSO, rt.
  • Reagents and conditions (a) MeCN, 90°C, 5h; (b) Corresponding amine, 2-propanol, reflux, 16h.
  • Compound 207 was synthesized as outlined above.
  • the intermediate 206 prepared from aniline 4b and diphenyl cyanocarbonimidate 205, was reacted with corresponding amine to afford the cyano guanidine derivative 207.
  • Compounds 174- 178 were prepared in a smilar fashion.
  • Reagents and conditions (a) ACN, TEA, 70°C, 18h; (b) DMSO, NaOH, 70°C, 4h; (c) NiCl 2 . H 2 O, NaBH 4 , DCM:MeOH 1 : 1, 0°C, 0.5h; (d) DCM, Pyridine, p-nitrophenylchloroformate, 0°C to room temp, 2h; (e) secondary amine, DMF, TEA, 70 0 C, 0.5h. [0337] Compound 60 was synthesized from commercially available compounds 58 and 59 and the product was isolated by precipitation from water. The product was collected on a filter and washed with water to obtain compound 60.
  • nitro group on 60 was then reduced to obtain aniline 61.
  • Aniline 61 was then reacted with p- nitrophenylchloroformate in DCM/pyridine to produce carbamate 62.
  • Carbamate 62 was then combined with five different secondary amines in DMF/TEA to yield ureas 63a-e which were purified by reverse-phase HPLC.
  • Reagents and conditions (a) ACN, TEA, 70°C, 3.5h; (b) DMSO:ACN 1 :1, NaOH, 80°C, 2h; (c) NiCl 2 -H 2 O, NaBH 4 , DCM:MeOH 1:1, 0°C, 0.5h; (d) DCM, Pyridine, p-nitrophe ⁇ ylchloroformate, O°C to room temp, 2h; (e) secondary amine, DMF, TEA, 7O°C, 0.5h.
  • Compound 65 was synthesized from commercially available compounds 58 and 64 and the product was isolated by precipitation from water. The product was collected on a filter and washed with water to obtain compound 65. The nitro group on 65 was then reduced to obtain aniline 66. Aniline 66 was reacted with p- nitrophenylchloroformate in DCM/pyridine to produce carbamate 67. Carbamate 67 was then combined with three different secondary amines in DMF/TEA with heating to yield ureas 68a-c which were purified by reverse-phase HPLC.
  • Reagents and conditions (a) NaN 3 , CuSO 4 , sodium ascorbate, methylpropyne, EtOH / toluene, rt, 2Oh, (b) NiCl 2 , NaBH 4 , MeOH/DCM, 0°C , l Omin; (c) p-Nitrophenylchloroformate, DCM, pyridine, -10°C to rt, 30min; (d) Corresponding amine, TEA, rt, 17h [0339]
  • the nitro intermediate 38 was obtained by the copper catalyzed reaction of reagent 37 with sodium azide followed by cycloaddition with methylpropyne. The intermediate 38 was reduced to the corresponding aniline 39. Subsequent reaction of 39 withp-nitro chloro formate afforded carbamate 40, which was reacted with the corresponding amines to afford the title compounds 41-44.
  • Reagents and conditions (a) Corresponding amine, TEA, rt, 17h.
  • Table 1 illustrates representative compounds which were synthesized using exemplary routes described in the preceding Examples.
  • the SH-SY5Y-APP cell line was derived by transfecting the human neuroblastoma line SH-SY5Y with a plasmid expressing wild type I1APP 751 and selecting for stable expression of APP and secretion of A ⁇ .
  • SH-SY5Y-APP cells were plated at 20,000 cells/well in 384-well tissue culture plates. After 24 h, the culture medium was replaced with fresh medium containing compound. Replicates of 4 wells per test concentration were used, with 11 concentrations at !4 log steps. Vehicle (0.2% DMSO) and a positive control gamma-secretase inhibitor (Tian et al. (2002) J. Biol. Chem. 277:31499-31505) were included as controls. After incubation for 20 h at 37°C, the culture medium was transferred to a new plate and appropriate concentrations of fluorescently-labeled antibodies were added for the FRET assay.
  • the FRET assay utilizes fluorescence resonance energy transfer between the donor europium on the A ⁇ 42 -specific antibody A387 (PCT publication WO 04/018997) to the acceptor XL665 on the A ⁇ i-i 2 -specific antibody B608 when the two antibodies are bound to the same A ⁇ 42 molecule.
  • Europium is excited at 337 nm and its emission at 620 nm is transferred to XL665, which then emits at 665 nm.
  • the fluorescence emission at 665 nm from XL665 was corrected against the europium emission at 620 nm as an internal control.
  • Cytotoxicity was determined with an alamarBlueTM assay, which measures the ability of respiring cells to metabolize a substrate to a fluorescent product. Supernatant of cells treated with compound, as described above, was removed, and a solution containing 10% by volume of the cell viability indicator dye alamarBlueTM (Biosource, San Diego) was added. Cells were incubated for 3 h at 37 °C, after which fluorescence was read on a CytoFluor (Applied Biosystems) spectrophotometer, using a 530-nm excitation filter and 580-nm emission filter. The compounds set forth in Table I above produced less than 30% decrease in AlamarBlue fluorescence at 10 ⁇ M relative to control cells.

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Abstract

La présente invention concerne des nouveaux composés utiles pour une variété d'applications thérapeutiques, par exemple, pour la modulation des niveaux de la bêta-amyloïde. Ainsi, ces composés ont une utilisation dans le traitement d'une variété de maladies. Des compositions et kits comprenant ces composés sont également décrits. Dans un aspect de la présente invention, des composés qui ont une activité de modulation des bêta-amyloïdes (AjS) sont décrits. En conséquence, ces composés sont applicables pour le traitement de maladies associées à des niveaux aberrants de Aβ et/ou de toute condition dans laquelle la modulation des niveaux Aβ procure un effet thérapeutique. Les composés décrits dans la présente sont de préférence utiles pour le traitement des troubles neurodégénératifs tels que la maladie d'Alzheimer.
PCT/US2008/005719 2007-05-04 2008-05-01 Procédés de modulation de la bêta-amyloïde et composés utiles pour cette modulation Ceased WO2008137102A2 (fr)

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