WO2009152027A1 - Dérivés de 5,7-dihydro-6h-pyrrolo[2,3-d]pyrimidin-6-one utilisables en vue de l'inhibition de la mark - Google Patents

Dérivés de 5,7-dihydro-6h-pyrrolo[2,3-d]pyrimidin-6-one utilisables en vue de l'inhibition de la mark Download PDF

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WO2009152027A1
WO2009152027A1 PCT/US2009/046251 US2009046251W WO2009152027A1 WO 2009152027 A1 WO2009152027 A1 WO 2009152027A1 US 2009046251 W US2009046251 W US 2009046251W WO 2009152027 A1 WO2009152027 A1 WO 2009152027A1
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alkyl
formula
dihydro
compound according
alkoxy
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PCT/US2009/046251
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Andrew Haidle
Matthew Stanton
Michael Altman
Kaleen Konrad
Anna Zabierek
Jason Katz
James Jewell
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Merck & Co., Inc.
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Publication of WO2009152027A1 publication Critical patent/WO2009152027A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates to methods and materials for the treatment or prevention of neurodegenerative diseases such as Alzheimer's disease.
  • neurodegenerative diseases such as Alzheimer's disease.
  • MARK microtubule affinity regulating kinase
  • AD Alzheimer's disease
  • AD Alzheimer's disease
  • AD Alzheimer's disease
  • NFTs neurofibrillary tangles
  • tau is a soluble cytoplasmic protein which has a role in microtubule stabilisation. Excessive phosphorylation of this protein renders it insoluble and leads to its aggregation into paired helical filaments, which in turn form NFTs.
  • amyloid cascade hypothesis proposes that abnormal accumulation of A ⁇ peptides, particularly A ⁇ 42, initiates a cascade of events leading to the classical symptoms of AD and ultimately, to the death of the patient.
  • a ⁇ pathology e.g. Rapoport, M., et al (2002) Proc. Natl. Acad. Sci USA 99:6364-6369
  • dysregulation of tau function is a key step in the cascade of Alzheimer's disease pathology leading ultimately to neuronal death.
  • tau mutations and NFTs are found in other dementias in which A ⁇ pathology is absent, such as frontotemporal dementia, Pick's disease and parkinsonism linked to chromosome 17 (FTDP- 17) [Mizutani, T.
  • Tau is a 352-441 amino acid protein encoded by the Mapt (Microtubule-associated protein tau) gene which is widely expressed in the central nervous system (CNS) with localisation primarily in axons [Binder et al J Cell Biol. 1985, 101(4), 1371-1378].
  • Mapt Microtubule-associated protein tau
  • the major function of tau is regulation of the stability of microtubules (MTs), intracellular structural components comprised of tubulin dimers which are integral in regulating many essential cellular processes such as axonal transport and elongation as well as generation of cell polarity and shape.
  • Tau binding to tubulin is a key factor in determining the rates of polymerisation/depolymerisation (termed dynamic instability) of MTs, and tau is therefore key to the regulation of many essential cellular processes [see, for example, Butner, K. A., Kirschner, M.W. (1991) J.Cell. Biol. 115: 717-730].
  • Tau is a basic protein with numerous serine and threonine residues, many of which are susceptible to phosphorylation, While normal tau has two to three phosphorylated amino acid residues, hyperphosphorylated tau found in AD and other tauopathies typically has eight or nine phosphorylated residues.
  • kinases promote phosphorylation of these sites, including proline-directed kinases such as glycogen synthase kinase 3 ⁇ (GSK3 ⁇ ) and cyclin dependent kinase 5 (cdk5), and non-proline-directed kinases such as protein kinase A (PKA) and calmodulin (CaM) kinase II, which phosphorylate tau at Lys-(Ile/Cys)-Gly-Ser sequences, also known as KXGS motifs.
  • proline-directed kinases such as glycogen synthase kinase 3 ⁇ (GSK3 ⁇ ) and cyclin dependent kinase 5 (cdk5)
  • non-proline-directed kinases such as protein kinase A (PKA) and calmodulin (CaM) kinase II, which phosphorylate tau at Lys-(Ile/Cys)-Gly-Ser sequences, also
  • Phosphorylation at these sites is important for the regulation of tau-MT binding and while the degree of phosphorylation is normally low, it has been shown to be increased in brain tissue from AD patients. Phosphorylation of one particular residue within the KXGS motifs, Ser-262 has been shown to be elevated in tau protein extracted from the NFTs in AD [Hasegawa, M. et al (1992) J. Biol. Chem 267:17047-17054] and phosphorylation at this site also appears to dramatically reduce MT binding [Biernat, J. et al. (1993) Neuron 11: 153-163].
  • MARK microtubule affinity-regulating kinase
  • AMPK AMP-dependent protein kinase
  • MARK is thought to phosphorylate tau, perhaps in response to an external insult, such as the disruption of Ca 2+ homeostasis caused by A ⁇ , priming it for further phosphorylation events. It is not clear whether the phosphorylation of tau by MARK leads directly to its detachment from MTs or the subsequent phosphorylation events cause detachment.
  • the resulting unbound, hyperphosphorylated tau is delocalised to the somatodendritic compartment and is then cleaved by caspases to form fragments prone to aggregation [Drewes, G. (2004). Trends Biochem. Sci 29:548-555; Gamblin, T.C., et al, (2003) Proc. Natl. Acad. Sci. U.S.A. 100:10032-10037].
  • These aggregates can grow into filaments, which are potentially toxic, eventually forming the NFTs found in AD.
  • MARK inhibitors will enable the prevention or amelioration of neurodegeneration in AD and other tauopathies.
  • WO 2008/012571, WO 2007/141571, WO 2007/085873 and WO 2007/088401 disclose various classes of compounds as MARK inhibitors, but do not disclose or suggest the compounds described herein.
  • WO 2007/140222 discloses pyrrolopyrimidine compounds as inhibitors of protein kinases, useful in treating proliferative diseases and other conditions, including Alzheimer's disease, The compounds are apparently indiscriminately active against a wide range of kinases, although there is no mention of activity towards MARK.
  • R 1 represents Ar or C 1-4 alkyl which is optionally substituted with Ar, where Ar represents phenyl or pyridyl either of which optionally bears up to 3 halogen substituents;
  • R 1a represents methyl; or R' and R 1a together with the carbon atom to which they are attached complete a bicyclic group of formula (a):
  • R represents H, halogen, OH, C 1-4 alkyl, C 1-4 alkoxy or benzyloxy;
  • Z represents CH 2 or O
  • R 2 represents a group selected from:
  • X represents CR 5 or N
  • R 3 , R 4 and R 5 independently represent H, halogen, C 1-4 alkoxy or C 1-4 alky! which is optionally substituted with OH, C 1-4 alkoxy, or with up to 3 halogen atoms; or one of R 3 , R 4 and R s represents and the other two of R 3 , R 4 and R 5 are as defined previously;
  • R 8 represents H or C 1-6 alkyl which is optionally substituted with up to 3 halogen atoms, or with OR b , COR b , CO 2 R b , NR b 2 or C0NR b 2 ;
  • R b represents H or C 1-4 alkyl which is optionally substituted with OH or C 1-4 alkoxy; or
  • R s represents or R 8 together with R 3 or R 4 and the intervening atoms may complete a 5- or 6-membered ring; or
  • R 7 and R 8 together with the nitrogen to which they are both attached may complete a monocyclic or bicyclic ring system of up to 10 ring atoms in total, of which up to two, in addition to the nitrogen to which R 7 and R 8 are bonded, are selected from N, O and S, the remainder being carbon, said ring system optionally bearing up to 3 substituents independently selected from halogen, CF 3 , C 1-4 alky], C 3 ⁇ cycloalkyl, pheny
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I as defined above or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier.
  • the invention further provides a compound of formula I as defined above or a pharmaceutically acceptable salt or hydrate thereof for use in therapeutic treatment of humans or animals.
  • the invention further provides the use of a compound of formula I as defined above or a pharmaceutically acceptable salt or hydrate thereof for the manufacture of a medicament for treatment or prevention of a neurodegenerative disease associated with hyperphosphorylation of tau in a human patient.
  • Neurodegenerative diseases associated with hyperphosphorylation of tau include AD, fronto temporal dementia, Pick's disease and parkinsonism linked to chromosome 17 (FTDP-17).
  • the invention further provides a compound of formula I as defined above, or a pharmaceutically acceptable salt or hydrate thereof, for use in reducing or preventing the hyperphosphorylation of tau in a human patient.
  • R 1 , R 1a and R 2 are as defined previously, such that when R 1 and R 1a together with the carbon atom to which they are attached complete a bicyclic group of formula (a), it has the stereochemical configuration shown in formula (b):
  • R 1a represents methyl
  • R 6 represents C 1-6 alkyl which is optionally substituted with 1-3 halogens or with CO 2 C 1- 4 alkyl, or R represents
  • R 7 represents H or C 1-4 alkyl, or together with R a and the intervening atoms completes a ring of 4-7 members;
  • C 1-x alkyl where x is an integer greater than 1 refers to straight-chained and branched alkyl groups wherein the number of constituent carbon atoms is in the range 1 to x.
  • Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl.
  • Derived expressions such as "C 2-6 alkenyl”, “hydroxyC 1-6 alkyl”, “heteroarylC 1-6 alkyl”, “C 2-6 alkynyl” and " C 1-6 alkoxy” are to be construed in an analogous manner. Most suitably, the number of carbon atoms in such groups is not more than 6.
  • halogen as used herein includes fluorine, chlorine, bromine and iodine of which fluorine and chlorine are preferred.
  • C 3-6 cycloalkyl refers to nonaromatic monocyclic hydrocarbon ring systems comprising from 3 to 6 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyciohexyl.
  • heterocyclyl refers to a ring system in which at least one of the ring atoms is N, O or S. Depending on the maximum number of ring atoms permitted, said ring system may be mono- or bicyclic. Any ring comprised by said system may saturated or unsaturated to any degree, including aromatic unless indicated otherwise. Attachment may be via any available ring atom unless indicated otherwise.
  • N-heterocyclyl indicates attachment via a ring nitrogen and "C-heterocyclyl” indicates attachment via a ring carbon.
  • heteroaryl refers to heterocyclic groups in which at least one ring comprising a heteroatom is aromatic.
  • the compounds of formula I may be in the form of pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds of formula I or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, benzenesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable salt may be formed by neutralisation of said acidic moiety with a suitable base.
  • Examples of pharmaceutically acceptable salts thus formed include alkali metal salts such as sodium or potassium salts; ammonium salts; alkaline earth metal salts such as calcium or magnesium salts; and salts formed with suitable organic bases, such as amine salts (including pyridinium salts) and quaternary ammonium salts.
  • suitable organic bases such as amine salts (including pyridinium salts) and quaternary ammonium salts.
  • a nitrogen atom forming part of a heteroaryi ring may be in the form of the N-oxide.
  • a sulphur atom forming part of a nonaromatic heterocycle may be in the form of the S-oxide or S,S-dioxide.
  • a heteroaryi group may be attached to the remainder of the molecule via a ring carbon or a ring nitrogen, provided that this is consistent with preservation of aromaticity.
  • R 1a represents methyl and R 1 represents Ar or a C 1-4 alkyl group which is optionally substituted with Ar, where Ar represents phenyl or pyridyl which optionally bears up to 3 halogen substituents.
  • R 1 represents C 1- 4 alkyl such as methyl, ethyl, n-propyl or isopropyl, in particular ethyl.
  • R 1 examples include 3-fiuoro-2-pyr ⁇ dyl, 4-fluorophenyI, 2-fluorophenyl, 2,4-difluorophenyl, phenyl, 5- fluoro-2- ⁇ yridyl, 2,6-difluorophenyl, 2-pyridyl and 2,5 ⁇ difluorophenyl, Alternatively, R 1 and R 1a together with the carbon atom to which they are attached complete a bicyclic group of formula (a):
  • R represents H, halogen (in particular F, Cl or Br), OH, C 1-4 alkyl (in particular methyl), C 1-4 alkoxy (in particular methoxy) or benzyloxy, and Z represents CH 2 or O. Most suitably, Z represents CH 2 .
  • R 2 represents a phenyl or pyridyl group of formula II:
  • R 3 , R 4 and R 5 are as defined previously.
  • Suitable identities for R 3 , R 4 and R 5 include H, halogen (especially F or Cl), C 1-4 alkoxy (such as methoxy) and C 1-4 alkyl which is optionally substituted with OH or with up to 3 fluorines (such as hydroxymethyl or CF 3 ).
  • at least one of R 3 , R 4 and R 5 is H.
  • one of R 3 and R 4 (preferably R 4 ) is a group represented by the formula IV:
  • R 3 and R 4 represent a group of formula IV
  • the other one of R 3 and R 4 together with the intervening atoms, optionally completes a 5- or 6-membered ring with R 8 .
  • Said ring typically comprises only carbon atoms apart from the nitrogen to which R 8 is bonded.
  • the ring is 6-membered.
  • R 2 is a group of formula:
  • n is 1, 2 or 3; preferably 1 or 2, and in a particular embodiment m is 1.
  • Each R a is independently H or C 1-4 alkyl which is optionally substituted with 1-3 halogens; or two R a groups attached to the same carbon may complete a carbonyl group; or one R a group together with the R 7 and the intervening atoms may complete a ring of 4-7 members; provided that when m>l, only one -CRV maybe other than CH 2 .
  • a ring completed by R a and R 7 together typically comprises only carbon atoms apart from the nitrogen to which R 7 is attached. Examples of groups in accordance with formula IV therefore include:
  • R 7 represents H, C 1-4 aUcyl, acetyl or t-butoxycarbonyl, in particular H or C 1-4 alkyl, or together with R a completes a ring of 4-7 members as described above, Alternatively, R 7 may complete a ring in combination with R 8 , as described hereinafter.
  • R 8 represents H or C 1-6 alkyl which is optionally substituted with up to 3 halogens or with OR b , COR b , CO 2 R b , NR b 2 or CONR b 2 , where R b represents H or C 1-4 alkyl which is optionally substituted with OH or C 1-4 alkoxy.
  • examples of groups represented by R 8 include H, 2-methoxy-l -methyl ethyl, 2- hydroxyethyl, 3,3,3-trifluoropropyl, isopropyl, N,N-dimethylcarbamoylmethyl, 2-(2- hydroxyethoxy)ethyl, 2-hydroxy-3,3-dimethylbutyl, 2-methoxyethyl, 2-hydroxy-2-methylpro ⁇ yl, 2-fluoroethyl, and 2,2-difluoroethyl.
  • R 8 together with R 3 or R 4 and the intervening atoms completes a 5- or 6-membered ring as described previously
  • R 8 together with R 7 and the nitrogen to which they are both attached complete a monocyclic or bicyclic ring system of up to 10 ring atoms in total.
  • Said ring atoms are selected from C, N, O and S, but not more than two are other than carbon, apart from the nitrogen to which R and R are both attached.
  • substituents preferably at least one of the substituents is halogen or C 1-4 alkyl.
  • the monocyclic or bicyclic ring system may comprise folly saturated, unsaturated or aromatic rings, but in a particular embodiment it is saturated.
  • Suitable monocyclic systems include azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, pyrrole, pyrazole, imidazole and triazole.
  • suitable bicyclic systems include azabicyclo[3.1,0]hexyl, azabicyclo[2.2.1]heptyl, 5,6,7,8-tetrahydroirnidazo[1,2- a]pyrazine, tetrahydropyridine and telrahydroquinoline.
  • R 8 is a group of formula: where n, R c and Y are as defined previously.
  • R 7 is very suitably H.
  • n is very suitably 0, 1 or 2.
  • Each R c is preferably H.
  • Specific examples of the moiety therefore include a bond, -CH 2 - and -CH 2 CH 2 -.
  • Y represents a monocyclic or bicyclic ring system of up to 10 ring atoms, 0-3 of which are selected from O, N and S, the remainder being carbon.
  • the monocyclic or bicyclic ring system may comprise fully saturated, unsaturated or aromatic rings.
  • Examples of monocyclic rings included in the definition of Y include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, pyrrolidinyl, piperidinyl, hompiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furyl, thienyl and isoxazolyl.
  • Examples of bicyclic systems included in the definition of Y include pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, and tetrahydronaphthalenyl.
  • R 8 specific identities of R 8 include: (pyrazolo[1,5-a]pyridin-3-yl)methyl; (5-oxopyrrolidin-2-yl)methyl; 2-(l-hydroxycyclopentyl)ethyl; 1 -phenylpiperidin-4-yl; 2-( 1 H-pyrazol- 1 -yl)ethyl ; cyclopentyl; (3 -methy loxetan-3 -y l)methy 1 ; (imidazo[ 1 ,2-a]pyridine-3-yl)methyl; 2-(l H-1 ,2,3-triazol- 1 -yl)ethyl;
  • R 2 represents a pyrazolyl group of formula III:
  • R 6 represents Cj.galkyl which is optionally substituted with up to 3 halogens or with C 1-4 alkoxy or C ⁇ 2 C 1-4 alkyl, or R 6 represents: where n, R° and Y are as described above.
  • suitable identities for R 6 include: benzyl, isopropyl; (piperidin-4-yl)methyl;
  • a subset of the compounds of the invention consists of the compounds of formula V:
  • R 1 is ethyl
  • a second subset of the compounds of the invention consists of the compounds of formula VI: VI and pharmaceutically acceptable salts and hydrates thereof: wherein R 1 and R 6 have the same definitions and specific identities as described above.
  • R 1 is ethyl
  • a third subset of the compounds of the invention consists of the compounds of formula VII:
  • R 3 and R 4 are both H.
  • R 3 and R 4 complete a fused-ring structure represented by:
  • R 7 represents H, methyl, acetyl or t-butoxycarbonyl and X is H.
  • X is H.
  • the compounds of formula VII is suitably (but not necessarily) OH which is attached to the 4-position of the indane ring.
  • R 1 , R 1a and R 2 have the same meanings as before.
  • the reaction may be carried out in an ethereal solvent such as THF in the presence of strong base such as sodium bis(trimethylsilyl)amide.
  • R 2 is an electron-rich heteroaryl group (such as 1-alkyl-1H- pyrazol-4-yl)
  • the reaction can be carried out at higher temperature in the absence of base, e.g. in dioxan.
  • R 2 -NH-CHO is treated with NaH in DMF, then reacted with the sulfones (1).
  • Sulfones (1) are obtainable by reaction of compounds (2) with (R 1 )(R 1a )CH-NH 2 , followed by oxidation of the thioether functionality
  • the thioether (2) may be oxidised to the sulfones, then reacted with R 2 NH 2 or R 2 -NH-CHO in the manner described above, then reacted with (R 1 )(R 1a )CH-NH 2 to provide the compounds of formula I.
  • Chiral compounds of formula IA are obtainable via use of (R 1 )(R 1a )CH-NH2 in the appropriate chiral form.
  • An alternative route, suitable for preparing compounds of formula V and analogs thereof, includes reductive alkylation of R 7 R 8 NH with aldehydes of formula (3a):
  • R 1 , R 1a , R 3 , R 7 , R 8 and X have the same meanings as before.
  • the reaction takes place in the presence of sodium triacetoxyborohydride.
  • the aldehydes (3a) are available via oxidation of vinyl derivatives (3b).
  • the vinyl derivatives are obtainable by reaction of sulfones (1) with the appropriate amine. Details of these procedures are provided in the Examples section.
  • the starting materials and reagents described above may be obtained from commercially available precursors by means of well known synthetic procedures and/or the methods disclosed in the Examples section herein.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as di-/?-toluoyl-D-tartaric acid and/or di-/?-toluoyl- L-tartaric acid, followed by fractional crystallization and regeneration of the free base,
  • an optically active acid such as di-/?-toluoyl-D-tartaric acid and/or di-/?-toluoyl- L-tartaric acid
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
  • any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T. W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley Sc Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • compositions comprising the active ingredient (i.e. the compound of formula I or pharmaceutically acceptable salt or hydrate thereof) and a pharmaceutically acceptable carrier.
  • active ingredient i.e. the compound of formula I or pharmaceutically acceptable salt or hydrate thereof
  • pharmaceutically acceptable carrier i.e. the compound of formula I or pharmaceutically acceptable salt or hydrate thereof
  • these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, transdermal patches, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the principal active ingredient typically is mixed with a pharmaceutical carrier, e.g.
  • a tableting ingredient such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate and dicalcium phosphate, or gums, dispersing agents, suspending agents or surfactants such as sorbitan monooleate and polyethylene glycol, and other pharmaceutical diluents, e.g. water, to form a homogeneous preformulation composition containing a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 rng, of the active ingredient.
  • Tablets or pills of the composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylceliulose, methylcellulose, poly(ethylene glycol), ⁇ oly(vinylpyrrolidone) or gelatin.
  • the compound of formula I is administered to a patient suffering from AD, FTDP- 17, Pick's disease or frontotemporal dementia, preferably AD.
  • the compound of formula I is administered to a patient suffering from mild cognitive impairment or age-related cognitive decline.
  • a favourable outcome of such treatment is prevention or delay of the onset of AD.
  • Age-related cognitive decline and mild cognitive impairment (MCI) are conditions in which a memory deficit is present, but other diagnostic criteria for dementia are absent (Santacruz and Swagerty, American Family Physician, 63 (2001), 703-13). (See also "The ICD-10 Classification of Mental and Behavioural Disorders", Geneva: World Health Organization, 1992, 64-5).
  • age-related cognitive decline implies a decline of at least six months' duration in at least one of: memory and learning; attention and concentration; thinking; language; and visuospatial functioning and a score of more than one standard deviation below the norm on standardized neuropsychologic testing such as the MMSE. In particular, there may be a progressive decline in memory. In the more severe condition MCI, the degree of memory impairment is outside the range considered normal for the age of the patient but AD is not present.
  • the differential diagnosis of MCI and mild AD is described by Petersen et at,, Arch. Neurol, 56 (1999), 303-8. Further information on the differential diagnosis of MCI is provided by Knopman et al, Mayo Clinic Proceedings, 78 (2003), 1290- 1308. In a study of elderly subjects, Tuokko et al ⁇ Arch, Neurol, 60 (2003) 577-82) found that those exhibiting MCI at the outset had a three-fold increased risk of developing dementia within 5 years.
  • the compound of formula I is advantageously administered to patients who suffer impaired memory function but do not exhibit symptoms of dementia.
  • impairment of memory function typically is not attributable to systemic or cerebral disease, such as stroke or metabolic disorders caused by pituitary dysfunction.
  • Such patients may be in particular people aged 55 or over, especially people aged 60 or over, and preferably people aged 65 or over.
  • Such patients may have normal patterns and levels of growth hormone secretion for their age.
  • Such patients may possess one or more additional risk factors for developing Alzheimer's disease.
  • Such factors include a family history of the disease; a genetic predisposition to the disease; elevated serum cholesterol; and adult-onset diabetes mellitus.
  • the compound of formula I is administered to a patient suffering from age-related cognitive decline or MCI who additionally possesses one or more risk factors for developing AD selected from: a family history of the disease; a genetic predisposition to the disease; elevated serum cholesterol; adult-onset diabetes mellitus; elevated baseline hippocampal volume; elevated CSF levels of total tau; elevated CSF levels of phospho- tau; and lowered CSF levels of A ⁇ (l-42).
  • a genetic predisposition (especially towards early onset AD) can arise from point mutations in one or more of a number of genes, including the APP, presenilin-1 and presenilin-2 genes. Also, subjects who are homozygous for the ⁇ 4 isoform of the apolipoprotein E gene are at greater risk of developing AD.
  • the patient's degree of cognitive decline or impairment is advantageously assessed at regular intervals before, during and/or after a course of treatment in accordance with the invention, so that changes therein may be detected, e.g. the slowing or halting of cognitive decline.
  • a variety of neuropsychological tests are known in the art for this purpose, such as the Mini-Mental State Examination (MMSE) with norms adjusted for age and education (Folstein et al.J. Psych. Res, 12 (1975), 196-198, Anthony el al, Psychological Med, 12 (1982), 397-408; Cockrell et al, , Psychopharmacology, 24 (1988), 689-692; Crum et al. , J. Am. Med.
  • MMSE Mini-Mental State Examination
  • the MMSE is a brief, quantitative measure of cognitive status in adults. It can be used to screen for cognitive decline or impairment, to estimate the severity of cognitive decline or impairment at a given point in time, to follow the course of cognitive changes in an individual over time, and to document an individual's response to treatment.
  • Another suitable test is the Alzheimer Disease Assessment Scale (ADAS), in particular the cognitive element thereof (AD AS-cog) (See Rosen et al , Am. J. Psychiatry, 141 (1984), 1356-64).
  • a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.01 to 100 mg/kg per day, and more preferably about 0.05 to 50 mg/kg of body weight per day, of the active compound.
  • the compounds may be administered on a regimen of 1 to 4 times per day. In some cases, however, a dosage outside these limits may be used.
  • the compound of formula I optionally may be administered in combination with one or more additional compounds known to be useful in the treatment or prevention of AD or the symptoms thereof.
  • additional compounds thus include cognition-enhancing drugs such as acetylcholinesterase inhibitors (e.g. donepezil and galanthamine), NMDA antagonists (e.g. memantine) or PDE4 inhibitors (e.g. ArifloTM and the classes of compounds disclosed in WO 03/018579, WO 01/46151, WO 02/074726 and WO 02/098878).
  • Such additional compounds also include cholesterol-lowering drugs such as the statins, e.g. simvastatin.
  • Such additional compounds similarly include compounds known to modify the production or processing of A ⁇ in the brain ("amyloid modifiers"), such as compounds which modulate the secretion of A ⁇
  • Such additional compounds further include growth hormone secretagogues, e.g. as described in WO 2004/080459.
  • the amyloid modifier may be a compound which inhibits the secretion of A ⁇ , for example an inhibitor of ⁇ -secretase (such as those disclosed in WO 01/53255, WO 01/66564, WO 01/70677, WO 01/90084, WO 01/77144, WO 02/30912, WO 02/36555, WO 02/081435, WO 02/081433, WO 03/018543, WO 03/013506, WO 03/013527, WO 03/014075, WO 03/093251, WO 03/093252, WO 03/093253, WO 03/093264, WO 2004/031137, WO 2004/031 138, WO 2004/031 139, WO 2004/039370, WO 2004/039800, WO 2004/101538, WO 2004/101539 and WO 2005/030731), or a ⁇ -secretase inhibitor (such as those disclosed in WO 01/53255,
  • the amyloid modifier may be a compound which modulates the action of ⁇ - secretase so as to selectively attenuate the production of A ⁇ (l-42).
  • NSAIDs non-steroidal antiinflammatory drugs
  • analogues see WO 01/78721 and US 2002/0128319 and Weggen et al Nature, 414 (2001) 212-16; Morihara et al, J. Neurochem., 83 (2002), 1009-12; and Takahashi et al, J.
  • the amyloid modifier may be a compound which inhibits the aggregation of
  • Suitable examples include chelating agents such as clioquinol (Gouras and Beal, Neuron, 30 (2001), 641-2) and the compounds disclosed in WO 99/16741, in particular that known as DP- 109 (Kalendarev et al, J. Pharm. Biomed. Anal, 24 (2001), 967-75).
  • inhibitors of A ⁇ aggregation suitable for use in the invention include the compounds disclosed in WO 96/28471, WO 98/08868 and WO 00/052048, including the compound known as ApanTM (Praecis); WO 00/064420, WO 03/017994, WO 99/59571 and the compound known as AlzhemedTM (Neurochem); WO 00/149281 and the compositions known as PTI-777 and PTI-00703 (ProteoTech); WO 96/39834, WO 01/83425, WO 01/55093, WO 00/76988, WO 00/76987, WO 00/76969, WO 00/76489, WO 97/26919, WO 97/16194, and WO 97/16191. Further examples include phytic acid derivatives as dsiclosed in US 4,847,082 and inositol derivatives as taught in US 2004/0204387.
  • the amyloid modifier may be an antibody which binds selectively to A ⁇ .
  • Said antibody may be polyclonal or monoclonal, but is preferably monoclonal, and is preferably human or humanized.
  • the antibody is capable of sequestering soluble A ⁇ from biological fluids, as described in WO 03/016466, WO 03/016467, WO 03/015691 and WO
  • Suitable antibodies include humanized antibody 266 (described in WO 01/62801) and the modified version thereof described in WO 03/016466. Suitable antibodies also include those specific to A ⁇ -derived diffusible ligands (ADDLS), as disclosed in WO 2004/031400.
  • ADDLS A ⁇ -derived diffusible ligands
  • the expression "in combination with” requires that therapeutically effective amounts of both the compound of formula I and the additional compound are administered to the subject, but places no restriction on the manner in which this is achieved.
  • the two species may be combined in a single dosage form for simultaneous administration to the subject, or may be provided in separate dosage forms for simultaneous or sequential administration to the subject. Sequential administration may be close in time or remote in time, e.g. one species administered in the morning and the other in the evening.
  • the separate species may be administered at the same frequency or at different frequencies, e.g. one species once a day and the other two or more times a day.
  • the separate species may be administered by the same route or by different routes, e.g. one species orally and the other parenterally, although oral administration of both species is preferred, where possible.
  • the additional compound is an antibody, it will typically be administered parenterally and separately from the compound of formula I.
  • MARK3 activity was assayed in vitro using a Cdc25C biotinylated peptide substrate (Cell Signalling Technologies).
  • the phosphopeptide product was quantitated using a Homogenous Time-Resolved Fluorescence (HTRF) assay system (Park et al., 1999, Anal. Biochem. 269:94- 104).
  • HTRF Homogenous Time-Resolved Fluorescence
  • the reaction mixture contained 50 mM HEPES/Tris-HCl, pH 7.4; 10 mM NaCl, 5 mM MgCl 2 , 0.2 mM NaVO 4 , 5 mM ⁇ -glycerol phosphate, 0.1 % Tween-20, 2 mM dithiothreitol, 0.1% BSA, 10 ⁇ M ATP, 1 ⁇ M peptide substrate, and 10 nM recombinant MARK3 enzyme (University of Dundee) in a final volume of 12 ⁇ l.
  • the buffer additionally contained protease inhibitor cocktail (Roche EDTA-free, 1 tab per 50 ml).
  • the kinase reaction was incubated for 2 hours at 25°C, and then terminated with 3 ⁇ l Stop/Detection Buffer (50 mM HEPES, pH 7.0, 16,6 mM EDTA, 0.5M KF, 0.1 % Tween-20, 0.1 % BSA, 2 ⁇ g/ml SLX ent 665 (CISBIO), and 2 ⁇ g/ml Eu 3+ cryptate label antibody (CISBIO)).
  • the reaction was allowed to equilibrate overnight at 0°C, and relative fluorescent units were read on an HTRF enabled plate reader (e.g. TECAN GENios Pro).
  • Inhibitor compounds were assayed in the reaction described above to determine compound ICSOs, Aliquots of compound dissolved in DMSO were added to the reaction wells in a third-log dilution series covering a range of 1 nM to 10 ⁇ M. Relative phospho substrate formation, read as HTRF fluorescence units, was measured over the range of compound concentrations and a titration curve generated.
  • Ethanol (27.0 g, 0.574 mol) was added dropwise to a suspension of sodium hydride (60 wt%, 23.0 g, 0.574 mol) in tetrahydrofuran (300 mL); the mixture was stirred at room temperature for 1 hour.
  • solutions of diethyl succinate (100 g, 0.574 mol) in tetrahydrofuran (100 mL) followed by ethyl formate (42.5 g, 0.574 mol) in tetrahydrofuran (100 mL) were added dropwise.
  • Step 3 Ethyl [4-chl oro-2-(methylthio)pyrimidin-5-yl 1 acetate
  • Step 6 5,5-Dimethyl-7-[(1 S )-1-methylpropyl]-2-(methylsulfonyl)-5,7-dihvdro-6H-pyrrolo[2,3-d]pyrimidin-6-one
  • Step 2 5,5-Dimethyl-7-r(1S)-1-methvlpropvll-2-[f4-vinylphenyl)amino1-5,7-dihydro-6H- pyrrolof2,3-(f
  • the organic layer was washed with one portion of water and one portion of brine, dried over sodium sulfate, filtered, and concentrated to afford an orange oil.
  • the oil was dissolved in methanol (41 ml), tetrahydrofuran (41 ml) and saturated aqueous sodium bicarbonate solution (41 ml). The reaction was stirred at room temperature for 40 minutes and then partitioned between ethyl acetate and water. The organic layer was washed with one portion of brine, dried over sodium sulfate, filtered, and concentrated.
  • Step 3 4-( ⁇ 5 ,5 -Dimelhy 1-7- IY 1 S)- 1 -meth ⁇ lprop ⁇ l1-6-oxo-6 J-dihydro-5 -pyrrolof 2,3 - Jlpyrimidin- 2-yl I ammo)benzaldehyde
  • Step 4 2-f ( 4-([(2-Metho ⁇ y -1-methyleth y l ) amino1meth y Uphen y l ') aminol-5,5-dimethyl-7-Kiy ) -1- methy lpropyl] - 5 ,7-dihydro -6H-pyrrolo [2,3 -d ⁇ pyr imidin-6 -one
  • reaction mixture was stirred for 1 hour and then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with one portion of brine, dried over sodium sulfate, filtered, and concentrated.
  • Step 1 tert-but ⁇ l (4-hydr ⁇ xy-2,3-dihvdro- 1 H-inden- 1 -ypcarbamate
  • Step 2 ( 1 SM-hydroxy-2,3 -dihydro- 1 H-inden- 1 -amim ' um trifluoroacetate
  • Enantiomer peak 2 (5 g, 20.06 mmol) from Step 1 was dissolved in dichloromethane (120 ml) and cooled to 0 °C. Trifluoroacetic acid (40 ml, 519 mmol). was quickly added and the reaction was allowed to warm to ambient temperature. After 30 minutes, the reaction mixture was concentrated to an oil, then dissolved in 100 mL of heptane and concentrated in vacuo to afford (1S)-4-hydroxy-2,3-dihydro-lH-inden-1-aminium trifluoroacetate.
  • Step 1 ethyl 244-chloro-2-(methylsulfonyl)pyrimidin-5-yll-2-methylpropanoate
  • r ⁇ -CPBA (30.1 g, 131 mmol) was added over a period of 5 minutes to a stirred solution of ethyl 2-[4-chloro-2-(methylthio)pyrimidin-5-yl] ⁇ 2-methylpropanoate (18 g, 65.5 mmol) in dichloromethane (250 ml) at 0 °C.
  • the reaction mixture was stirred at 0 °C for 10 minutes, then allowed to warm to ambient temperature.
  • additional r ⁇ -CPBA (3.77 g, 16.38 mmol) was added and the reaction mixture was stirred overnight at ambient temperature.
  • Step 2 ethyl 2-f4-chloro-2-fphenylamino)pyrimidin-5-vn-2-methylpropanoate
  • the reaction mixture was cooled to 0 °C and slowly quenched with 100 mL of saturated sodium bicarbonate solution, followed by 50 mL of methanol.
  • the resulting slurry was stirred overnight at ambient temperature, then diluted with an additional 750 mL water and 500 mL ethyl acetate.
  • the organic layer was separated, and the aqueous layer was washed with ethyl acetate (2 x 250 mL).
  • the combined organic layers were washed 1 x 300 mL water, then 2 x 100 mL brine, dried over magnesium sulfate, filtered, and concentrated.
  • Step 3 2-anilino-7- ⁇ iS)-4-hvdroxv-2,3-dihvdro-1H-inden-1-yll-5,5-dimethyl-5J-dihvdro-6H- pyrrolo[2,3-d1pyrimidin-6-one.
  • Example 69 7-[(l 1 S)-4-hydroxy-2,3-dihydro-1H-inden-1-yl]-5,5-dimethyl-2-(1,2,3,4-tetrahydroisoquinolin-6- ylamino)-5,7 ⁇ dihydro-6H- ⁇ yrrolo[2,3 ⁇ (f]pyrimidin-6-one
  • Step 1 5,5-dimethyl-2-fmethylthioV7-j ⁇ l ⁇ -4- ⁇ etrahvdro-2/j r -pyran-2-yloxyV2,3-dihvdro-1H- inden- 1 -yl] - 5 ,7 -dihydro-6H-pyrrolo ⁇ 23-d] pyr imidin-6-one
  • Step 2 7-r(iy)-4-hvdroxy-2,3-dihvdro-1H-inden-1-yll-5,5-dimethyl-2-fmethylsulfonyl)-5J- dihydro-6H-pyrro ⁇ oj-2,3- ⁇ i1pyrimidin-6-one
  • Oxone (1835 mg, 2.98 mmol) in water (2388 ⁇ l) was added to a mixture of SjS-dimethyl ⁇ - tmethylthioH-JOSH-ttetrahydro ⁇ H-pYran ⁇ 6H-pyrrolo[2,3-d]pyrimidin ⁇ 6-one (254 mg, 0.597 mmol), saturated sodium bicarbonate (1.2 mL), THF (1.2 ml), and methanol (1.2 ml) at 20 °C. After 16 hours, the reaction mixture was filtered and washed with dichloromethane.
  • Step 3 5 ,5 ⁇ dimethyl-2-fmethv!sulfon ⁇ D- 7- i ⁇ 1 ) S r )-4-Ctetrahvdro-2/f-pyran-2-yloxy ' )-2,3 -dihydro-
  • reaction mixture was concentrated and purified by column chromatography on silica gel, eluting (ethyl acetate/hexanes gradient) to afford 5,5- dimethyl-2-(methylsulfonyl)-7-[(1S)-4-(tetrahydro-2H-pyran-2-yloxy)-2,3-dihydro--1H-inden-1- yl]-5,7-dihydro-6H-pyrrolo[2,3- ⁇ ]pyrimidin-6-one.
  • Step 4 tert-butyl 6-( ⁇ 5,5-dimethyl-6-oxo-7-IY iSV4-ftetrahvdro-2ff-pyran-2-yloxyV2,3-dihydro ⁇ 1 /f-inden- 1 -yl] -6,7-dihydro-5H-pyrrolo [2,3 -d] pyrimidin-2-yl ⁇ amino)-3 ,4-dih ⁇ droisoquinoline- 2( I /JVcarboxylate
  • reaction mixture was added via syringe to a solution of 5,5-dimethyl-2- (methylsulfonyl)-7-[(1S)-4-(tetrahydro-2/f-pyran-2-yloxy)-2,3-dihydro- 1 /f-inden- 1 -yl]-5,7- dihydro-6/f-pyrrolo[2,3- ⁇
  • Step 5 7-[fl5 f )-4-hvdroxy-23-dihvdro-lH-inden-1-yll-5,5-dimethyl-2-(1.23,4- tetrahydroisoquinolin-6-ylamino)-5,7-dihydro-6H- ⁇ yrrolor2,3- ⁇ f1pyrimidin-6-one
  • reaction mixture was concentrated and purified by preparative ⁇ PLC Reverse phase (C- 18), eluting with acetonitrile/water + 0.05% TFA to give 7-t(1S)-4-hydroxy-2,3-dihydro-l/Mnden-1-yl]-5,5-dimethyl-2-(1,2,3,4- ietrahydroisoquinolin-6-ylamino)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one.
  • Step 1 fert-butyl 7-(formylamino)-3,4-dihvdroisoquinoline-2f1H)-carboxylate
  • Step 2 tert-butyl 7- ⁇ [4-chloro-5-C2-ethoxy- 1 , 1 -dimemyl-2-oxoethyl)pyrimidin-2 ⁇ yl] amino ⁇ -3 ,4- dihydroisoquinoline-2fl//)-carboxylate
  • reaction mixture was allowed to warm to ambient temperature and after 30 minutes was quenched with saturated sodium bicarbonate solution and diluted with ethyl acetate. Organics were separated, dried over magnesium sulfate, filtered, and concentrated to afford residue. The residue was dissolved in THF (60 ml), methanol (50 ml), acetonitrile (10 ml), and saturated sodium bicarbonate solution (15 ml) and stirred. After 3 days, the reaction mixture was partially concentrated, then diluted with ethyl acetate. Organics were washed with water and then brine, dried over magnesium sulfate, filtered, and concentrated to afford residue.
  • Step 3 tert-butyl 7-r ⁇ 7-[(iy)-4-hvdroxy-23-dihvdro-l/f-inden-1-yl1-5.5-dimethyl-6-oxo-6.7- dihvdro-5H-pyn:olo[2J-(f
  • Step 4 7-[fl 1 S f )-4-hvdroxy-2,3-dihvdro-lH-inden-1-vn-5.5-dimethyl-2-(L2.3.4- tetrahydroisoquinolin-7-ylamino)-5,7-dihvdro-6H-pyrrolor23-( ⁇ 1pyrimidin-6-one
  • pyrimidin-2-yl ⁇ amino)-3,4-dihydroisoquinoline- 2(1H)-carboxylate (162 mg, 0.299 mmol) in Dichloromethane (10 ml) was added TFA (2.304 ml, 29.9 mmol
  • Step 1 ethyl 2-[4-chloro-2-f1,2,3,4-tetrahvdroisoquinolin-7-ylamino)pyrimidin-5-yl]-2- methylpropanoate trifluoroacetate
  • Step 2 ethyl 2- ⁇ 4-chloro-2-[T2-methyl-1,2,3,4-tetrahydroisoqui ⁇ olin-7-vl)amino]pyrimidm-5- yl ⁇ -2-methylpropanoate
  • Step 3 7-f ⁇ SV4-hvdro ⁇ y-2,3-dihvdro-l#-inden-l -yll-5.5-dimethyl-2-r(2-methyl-l .2.3.4- tetrahydroisoquinolin-7-yl)aminol-5,7-dihydro-6H-pyrrolo
  • Step 1 ethyl 2- ⁇ 2-[(2-acetyl-1,2,3,4-tetrahvdroisoquinolin-7-yl)amino-
  • Step 2 2- [(2-acetyl- 1 ,2,3.4-tetrahydroi$oquinolin-7-yl)ammo1 -7- f f 1 ⁇ )-4-hvdro ⁇ y-2.3 -dihydro-
  • the compounds of the invention gave essentially complete inhibition of MARK (in all three isoforms tested), but inhibited other kinases to a much lesser extent, consistent with a high degree of selectivity for the desired target.

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Abstract

La présente invention concerne des composés de formule I qui sont de puissants inhibiteurs sélectifs de la kinase régulant l'affinité pour les microtubules (MARK). Ces composés peuvent donc être utilisés dans le traitement de la maladie d'Alzheimer et d'autres affections associées à une hyperphosphorylation de la protéine tau.
PCT/US2009/046251 2008-06-12 2009-06-04 Dérivés de 5,7-dihydro-6h-pyrrolo[2,3-d]pyrimidin-6-one utilisables en vue de l'inhibition de la mark WO2009152027A1 (fr)

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