WO2008135488A1 - Inhibiteurs de l'aspartyle protéase - Google Patents

Inhibiteurs de l'aspartyle protéase Download PDF

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WO2008135488A1
WO2008135488A1 PCT/EP2008/055326 EP2008055326W WO2008135488A1 WO 2008135488 A1 WO2008135488 A1 WO 2008135488A1 EP 2008055326 W EP2008055326 W EP 2008055326W WO 2008135488 A1 WO2008135488 A1 WO 2008135488A1
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compound according
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Catarina BJÖRKLUND
Ingemar KVARNSTRÖM
Susana Ayesa
Per-Ola Johansson
Ismet Dorange
Karolina Ersmark
Bertil Samuelsson
Åsa ROSENQUIST
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Medivir Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms

Definitions

  • This invention relates to novel compounds having inhibitory activity on aspartyl proteases. It further concerns pharmaceutical compositions comprising these compounds as active ingredients as well as processes for preparing these compounds and compositions and their in the preparation of a medicament or their use in therapy.
  • a number of aspartic proteases are known to date, including pepsin A and C, Renin, BACE, BACE2, Napsin and Cathepsin D, which have been implicated in pathological conditions.
  • aspartyl protease BACE causesthe production of the protein ⁇ amyloid (A ⁇ ) in the brain, which is characteristic of Alzheimer's disease (AD).
  • AD is a progressive neurogdegenerative disease of the brain characterized by gradualloss of cognitive function related to memory, reasoning, orientation and judgement and eventually death.
  • Pathologicalfeatures of AD is accumulation of abnormal aggregated protein breakdown products, ⁇ -amyloid plaque and neurofibrillary tangles, in the brain.
  • Plaque relatively specific for AD is primary a result from extracellular accumulation of aggregated A ⁇ .
  • Fibrillary tangles consists mainly of hyperphosphorylatedtau protein and are also found in other neurodegenerative disorders. It is believed that A ⁇ is the fundamental causative agent of neuronal cell loss and dysfunction which is associated with cognitive and behavioural decline.
  • a ⁇ is a peptide comprised of 40-42 amino acid residues, which is formed by proteolytic cleavage of the large transmembrane amyloid precursor protein (APP).
  • APP large transmembrane amyloid precursor protein
  • APP is processed along two pathways, the major ⁇ - and the minor ⁇ -secretase pathway.
  • the ⁇ -secretase pathway results in nonpathogenic products known as soluble APP, whereas the ⁇ - secretase pathway producespathogenic A ⁇ peptides by cleavage by ⁇ -secretase at the position corresponding to the N-terminus of A ⁇ , followed by cleavage by ⁇ -secretase at the C-terminus.
  • a ⁇ amyloid cascade hypothesis, supported by genetic and pathological evidence, claims that the formation of A ⁇ plays an early and vital role in all cases of AD.
  • a ⁇ forms aggregates that are thought to initiate a pathogenic cascade that leads to neuronal loss and dementia.
  • BACE was identified a few years ago as a type 1 glycosylated transmembrane homodimer with two aspartic acids at the active catalytic site.
  • BACE and BACE-2 (64 % amino acid sequencesimilarity to BACE) constitute a novel class of aspartic proteases closely related to the pepsin family.
  • the function of BACE-2 is relatively unknown and several studies indicate that this enzyme is not involved in the A ⁇ generation.
  • BACE knockout homozygote mice show complete absenceof producing A ⁇ and the animals appear to develop normally and have no discernable abnormalities. Tissue cultures and animal studies indicated that ⁇ -secretase is expressed in all tissues but at highest levels in the neurons in the brain. Therefore, in vivo inhibition of BACE is likely to reducethe production of A ⁇ and is considered to be an attractive therapeutic target for the treatment and prevention of AD.
  • aspartyl protease inhibitors which can be represented by the formula (I):
  • R 1 is H, Q-C 6 alkyl, C r C 6 alkoxy, Ci-C 4 alkoxyCi-C 4 alkyl, Ci-C 4 alkoxyCi-C 4 alkoxyCi-C 4 alkyl, C 0 -C 4 alkandiylcarbocyclyl or C 0 -C 4 alkandiylheterocyclyl;
  • R 3 is Ci-Qalkoxy, Ci-C 6 alkoxyC r C 6 alkoxy, -O-C 0 -C 3 alkanediylaryl, -0-C 0 - C 3 alkanediylheterocyclyl, azido, amino or S(O) r Ci-C 6 alkyl; wherein the Ci -C 6 alkoxy moieties are independently optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from fluoro and chloro;
  • R 4 is Ci-C 6 alkyl and R 4 is H; or R 4 and R 4 together with the carbonatom to which they are attached define C 3 -C 6 cycloalkyl;
  • R 5a and R 5b are independently selected from H, halo, C r C 4 alkyl, haloC r C 4 alkyl, C r C 4 alkoxy, cyano;
  • L 1 is a bond, methyleneor ethylene
  • V and V are independently a bond, -NRc-, -CRdRd- or -O-;
  • W is H, Ci-C ⁇ alkyl, Cs-C ⁇ cycloalkyl, aryl or heterocyclyl;
  • X' is H, F, OH, NRaRb;
  • X" is H or when X' is F, X" can also be F;
  • Ra is H or Ci-Cealkyl
  • Rb is H or Ci-C ⁇ alkyl; or Ra and Rb together with the nitrogen atom to which they are attached define a heterocyclyl group;
  • Rc is H, Ci -C ⁇ alkyl, Co-C3alkandiylcarbocyclyl or Co-C3alkandiylheterocyclyl;
  • Rd is independently H, Ci-C ⁇ alkyl, halo, Ci-C4alkoxy; k is 0, 1, 2 or 3; m is 0 whereby ring A defines a cyclopentane or cyclopentene ring; or m is 1 whereby ring A defines a benzene, cyclohexene or cyclohexane ring; n is 0, 1 or 2; p is 0 or 1 ; q is 0, 1 or 2; therebydefining a bond, methyleneor ethylene, or when q is 1, the methylenemay alternatively be a 1 , 1 -cyclopropyl group; r is 0,1 or 2; s is 0 or 1 ; and wherein: carbocyclyl is independently aryl, C3-C6cycloalkyl or C3-C6cycloalkenyl; aryl is independently phenyl, naphthyl or phenyl fused to Cs-C ⁇ cycloalky
  • Ci-C4alkoxyCi-C3alkoxyCo-C3alkyl Ci-C4alkoxyCi-C3alkoxyCo-C3alkyl, halo, haloCi-C4alkyl, hydroxy, hydroxyCi-C4alkyl, amino, aminoCi -Gialkyl, carbamoyl, amido, cyano, azido, Ci-C4alkylcarbonyl, or a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, (any of which cyclic amines being optionally substituted with Ci-C4alkyl or fluoro) or Co-Csalkandiylaryl 1 ; where aryl is independently phenyl, naphthyl, or phenyl fused to Cs-C ⁇ cycloalkyl or Cs- C ⁇ cycloalkenyl; and wherein each occurrence of aryl 1
  • the compounds of general formula (I) have several centres of chirality, conveniently the compounds display at least 75%, preferably at least 90%, such as in excessof 95%, enantiomeric purity at each of the chiral centres.
  • the chiral centre wheretothe group R is attached typically has the stereochemistry shown in the partial structure:
  • R 1 is as recited above. Typical values for R 1 include hydrogen, C r C 6 alkyl, C r C 6 alkoxy, C 0 - C 3 alkanediylcarbocyclyl and C 0 -C 3 alkanediylheterocyclyl, whereineach C r C 6 alkyl, C 1 - C 6 alkoxy, carbocyclyl and heterocyclyl moiety is optionally substituted.
  • R 1 is C 0 -C 3 alkanediylcarbocyclyl or C 0 - C 3 alkanediylheterocyclyl whereinthe carbocyclyl or heterocyclyl moiety is either directly linked to the backbone of the macrocycle, i.e. C 0 , or via an intermediate methylene, ethylene or 1,3- propanediyl group, i.e. C 1 , C 2 or C 3 respectively and wherein the carbocyclyl or heterocyclyl moiety is optionally substituted as defined above.
  • the carbocyclyl or heterocyclyl moiety is linked either directly, i.e.
  • R 1 a methylene group, i.e. C 1 , to the macrocyclic backbone.
  • the optional substituents to the carbocyclyl or heterocyclyl moiety of R 1 are as defined above. Representative values include one or two substituents independently selected from C r C 4 alkyl such as methyl, ethyl or isopropyl, and C r C 6 alkoxy, such as methoxy, ethoxy or isopropoxy.
  • R 1 is optionally substituted monocyclicaryl or heterocyclyl.
  • R 1 is optionally substituted phenyl or optionally substituted benzyl, wherein the optional substituent preferably is in one of the meta positions or in the para position.
  • Preferred substituents according to this embodiment include C r C 6 alkoxy.
  • Further typical values for R 1 include hydrogen, Ci-C ⁇ alkyl such as methyl, Ci-C ⁇ alkoxy such as methoxy, and Ci-CsalkoxyG-C ⁇ alkyl such as 3-methoxypropyl or 2-methoxyethyl
  • the chiral centre to which X' and X" are attached has typically the configuration as shown in the partial structure:
  • X' and X" are as defined above.
  • X' is fluoro or more preferably hydroxy and X" is preferably H.
  • X' and X" are both fluoro.
  • the chiral centre whereto the group R is attached has the stereochemistry shown in the partial structure:
  • R 3 is as defined above. Typical values for R 3 include optionally substituted Ci-C 6 alkoxy such as optionally substituted methoxy, ethoxy and propoxy. Preferably R 3 is Ci-C 6 alkoxy, especially methoxy. Preferred substituents to the alkoxy moiety include halo such as chloro and mono- di and trifluoro.
  • R 3 include optionally substituted Q-C 6 alkoxy-Ci-C 6 alkoxy such as optionally substituted methoxypropoxy and methoxyethoxy.
  • Preferred substituents to the alkoxy moieties include halo such as chloro and mono- di and trifluoro.
  • the invention includes compounds of general formula (I) wherein p is 0 or 1, i.e. compounds according to structures (Ia) and (Ib) respectively.
  • the invention further includes compounds whereinboth p and q are 0, i.e. compounds according to the structure (Ic):
  • R is Ci-C4alkyl, such as isopropyl and R is hydrogen.
  • the chiral centre wheretothe group CH 2 -G is attached has the stereochemistry shown in the partial structure:
  • G is O.
  • G is NRa, whereinRa is hydrogen or Ci-C 6 alkyl, preferably hydrogen or methyl.
  • Preferred compounds of formula (I) are those having the stereochemistry indicated in formula (Id):
  • the group W is bonded either directly to the amide nitrogen, i.e. q is O, or W is bonded via a methyleneor ethylene moiety, i.e. q is 1 or 2 respectively. In favoured embodiments of the invention W is bonded directly to the amide nitrogen or via a methylene moiety, i.e. q is 0 or 1 respectively.
  • the moiety linking W to the amide nitrogen may be a 1,1 -cyclopropyl group, in which case compounds of the invention have the partial structure:
  • Preferred compounds according to this embodiment include those whereinp is 0 and W is phenyl or substituted phenyl, as shown in the structure below:
  • W is hydrogen, C r C 6 alkyl, C 3 -C 6 cycloalkyl, aryl or heterocyclyl which is optionally substituted with one, two or three substituents.
  • W is optionally substituted C r C 6 alkyl such as methyl, ethyl or isopropyl.
  • Preferred substituents to W according to this embodiment include halo such as mono-, di- or trifluoro.
  • a favouredembodiment of the invention include compounds wherein p and q are 0 and W is optionally substituted C r C 6 alkyl, preferably butyl or isobutyl.
  • W is an optionally substituted bicyclic aryl or heterocyclyl moiety.
  • Representative bicyclic rings include naphthyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl or isoindolinyl.
  • W is an optionally substituted monocyclic ring, such as optionally substituted phenyl, C 3 -C 6 cycloalkyl or monocyclic heterocyclyl.
  • the heterocyclic ring according to this embodiment typically contains 1 , 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms, independently selected from nitrogen, oxygen and sulphur.
  • monocyclic heterocyclyl include pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like, each of which is optionally substituted.
  • W is an optionally substituted monocyclic aryl, heterocyclyl or cycloalkyl, more preferably W is cyclopropyl or phenyl.
  • a favouredembodiment of the invention include compounds whereinq is 1 and W is optionally substituted phenyl, pyridyl or pyrimidinyl.
  • the ring is preferably mono substituted with the substituent in the meta or para position.
  • Preferred configurations according to this embodiment include meta or para substituted phenyl, for example p-fh ⁇ oro phenyl.
  • the substituents are preferably in the two meta positions or in the meta and para positions.
  • Preferred optional substituents to W include one or two substituents independently selected form halo such as fluoro or chloro; C 3 -C4cycloalkyl such as cyclopropyl; haloCi-C4alkyl such as fluoromethyl and trifluoromethyl; Ci-C4alkyl such as methyl, ethyl and isopropyl.
  • halo such as fluoro or chloro
  • C 3 -C4cycloalkyl such as cyclopropyl
  • haloCi-C4alkyl such as fluoromethyl and trifluoromethyl
  • Ci-C4alkyl such as methyl, ethyl and isopropyl.
  • ring A in general formula (I) is a six membered ring, i.e. m is 1.
  • ring A is a five membered ring, i.e. m is 0.
  • Preferred values for ring A according to this embodiment include cyclopentene and preferably cyclopentane.
  • ring A is cyclopentane
  • the stereochemistry is typically as indicated in the partial structures below:
  • the chain (CH 2 )Ii-(O)S-L 1 -L 2 -V 1 -L 3 of the macrocyclic ring linking ring A with the benzene ring is typically a saturated or partially unsaturated 3, 4 or 5 membered chain, which chain is optionally substituted by R 1 .
  • V 1 is NRc and Rc is H or CH 3 .
  • V A i ⁇ s O or CRdRd are included wherein
  • L is typically a bond or CH 2 and k is typically 0 or 1.
  • k is typically 0 or 1.
  • the other variables are as defined above.
  • the chain (CH 2 )k-(O) s -L 1 -L 2 -V 1 -L 3 comprise, apart from carbon atoms, one or two heteroatoms independently selected from N and O.
  • L is CHR .
  • L is typically a bond and s is 0.
  • Typical compounds according to these configurations are those whereinR is aryl, CH 2 -aryl, heteroaryl or CH 2 -heteroaryl, any of which is optionally substituted.
  • R is optionally substituted benzyl.
  • Rc in this configuration is typically H or Ci-C ⁇ alkyl, preferably H or CH3.
  • L 1 in this configuration is typically a bond and is
  • R 1 and k are as defined above.
  • R 1 is Ci-C 6 alkyl, such as methyl, or R 1 is optionally substituted benzyl, k is preferably 0 or 1.
  • the other variables are as defined above.
  • R and k are as defined above.
  • R is C r C 6 alkyl, such as methyl, or R is optionally substituted benzyl, k is preferably O or 1.
  • the other variables are as defined above.
  • V is typically NRa and Ra is H or C 1 -C 6 alkyl, preferably H or CH 3 .
  • Typical values for both R in this configuration are hydrogen.
  • compounds of the invention typically comprise any of the partial structures shown below:
  • Typical values for the two R 2 in this configuration are hydrogen.
  • R a and R are typically hydrogen, halo or Ci-C4alkyl, preferably fluoro or methyl.
  • n 1 or preferably 0.
  • [O] S-(CH 2 X and -(CH2) n -G are bonded to the benzene ring meta to each other as shown in the partial structure below.
  • Preferred compounds according to this embodiment include those whereinG is O, s is 0 and L 1 is a bond, thus having the partial structure shown below:
  • k and n are independently O or 1 and the other variables are as defined above. It is to be understood that the above defined subgroups of compounds of formulae (I) are meant to also comprise any prodrugs, iV-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms of such compounds.
  • a macrocyclic ring of 14-17 ring atoms as used herein is meant to denote a macrocyclic ring constituted of 14, 15, 16 or 17 ring atoms, whereinthe number of ring atoms is counted in the way giving the lowest number of atoms.
  • the structure shown below illustrates a macrocyclic ring of 16 ring atoms.
  • 'Ci_C 4 alkyl' as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as for example methyl, ethyl, 1 -propyl, 2 -propyl, 1-butyl, 2-butyl, 2-methyl-l -propyl, 2-methyl-2-propyl;
  • Ci-C 4 alkyl radicals encompasses Ci-C 4 alkyl radicals and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 2-methyl-l- butyl, 2 -methyl- 1-pentyl, 2-ethyl- 1-butyl, 3-methyl-2-pentyl, and the like.
  • Ci -Qalkyl is Q-C 4 alkyl, especially methyl.
  • Ci-C 6 alkyl moiety is optionally substituted with one, two or where valence allows three substituents independently selected from halo, hydroxy, nitro, cyano, carboxy, Q -Qalkyl, Ci-C 4 alkoxy, C 3 -C 7 cycloalkyl, halod -Qalkyl, C 1 -C 4 alkoxyC 1 -C 3 alkyl, C 1 -C 4 alkoxyC 1 -C 4 alkoxyC 0 -C 3 alkyl, C r C 6 alkanoyl, amino, amido, carbamoyl, azido, oxo, mercapto, C 0 -C 3 alkanediylaryl C 0 -C 3 alkanediylheteroaryl, it being understood that heterocyclic and arylic moieties in the C 0 -C 3 alkanediylaryl and C 0 - C 3 alkaned
  • C2-C6alkenyl' as a group or part of a group defines straight and branched chain hydrocarbon radicals having saturated carbon-carbonbonds and at least one double bond, and having from 2 to 6 carbon atoms, such as, for example, ethenyl (or vinyl), 1 -propenyl, 2- propenyl (or allyl), 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl -2 -propenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-methyl-2-butenyl, 2-methyl-2-pentenyl and the like.
  • C2-C6alkenyl is C2-C4alkenyl.
  • C2-C6alkynyl' as a group or part of a group defines straight and branched chain hydrocarbon radicals having saturated carbon-carbonbonds and at least one triple bond, and having from 2 to 6 carbon atoms, such as, for example, ethynyl, 1 -propynyl, 2-propynyl, 1- butynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like.
  • C2-C6alkynyl is C2-C4alkynyl.
  • 'C 0 _c 3 alkanediyr defines a bond (Co) or a bivalent straight or branched saturated hydrocarbon chain having from 1 to 3 carbon atoms such as, for example, methylene, ethylene, 1,3-propanediyl, 1,2-propanediyl, and the like, especially methylene.
  • 'C j -C 3 alkanediyr is a bivalent straight or branched saturated hydrocarbon chain having from 1 to 3 carbon atoms such as, for example, methylene, ethylene, 1,3-propanediyl, 1,2-propanediyl, and the like, especially methylene.
  • n 4, 5, 6, 7, 8, 9 or 10
  • Co-C3alkanediyl encompasses Co-C3alkanediyl and the higher homologues thereof having 4, 5, 6, 7, 8, ,9 or 10 carbonatoms.
  • Ci-C ⁇ alkoxy means a radical O-Ci-C ⁇ alkyl wherein Ci-C ⁇ alkyl is as defined above.
  • Ci -C ⁇ alkoxy of interest include but are not limited to methoxy, ethoxy n-propoxy and isopropoxy.
  • 'halo' is generic to chloro, bromo, iodo and preferably fluoro.
  • 'haloCi-C4alkyl' as a group or part of a group, is meant to include mono- and polyhalo substituted Ci -C4alkyl, in particular Ci-C4alkyl substituted with one, two, three, four, five, six, or more halo atoms, such as methyl or ethyl with one or more fluoro atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl. Preferred is trifluoromethyl.
  • the halogen atoms may be the same or different.
  • the carbonatom to which the oxo is linked is a saturated carbon.
  • Ci-C ⁇ alkyl as a group or part of a group, unless the context suggests otherwise, includes NH 2 , NHCi-C ⁇ alkyl or N(Ci-C6-alkyl)2, wherein in the amino definitions each Ci-C ⁇ alkyl is especially Ci -Oalkyl variants. Included are also radicals whereinthe two Ci-C ⁇ alkyl groups of the N(C 1 - C ⁇ -alkyl)2 together with the nitrogen atom to which they are attached form a saturated cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.
  • Ci-C ⁇ alkyl groups of the dialkylcarbamoyl together with the nitrogen atom to which they are attached form a saturated cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl, N -C r C 4 alkyl -piperazinyl and morpholinyl.
  • 'Co-C 3 alkanediycarbocyclyr as applied herein is meant to include aryl, C 3 -C 6 cycloalkyl and C 3 - C 6 cycloalkenyl.
  • 'C 0 -C 3 alkanediylaryl' as applied herein is meant to include an aryl moiety such as a phenyl or naphthyl or a phenyl fused to a C 5 -C 6 cycloalkyl (for example indanyl), or a C 5 -C 6 cycloalkenyl which aryl is directly bonded (i.e. C 0 ) or through an intermediate methylene, ethylene, 1,2- propanediyl or 1 ,3 -propanediyl group as defined for Ci-C 3 alkanediyl above.
  • aryl moiety such as a phenyl or naphthyl or a phenyl fused to a C 5 -C 6 cycloalkyl (for example indanyl), or a C 5 -C 6 cycloalkenyl which aryl is directly bonded (i.e. C 0 ) or through an intermediate m
  • Suitable aryl groups include but are not limited to phenyl, naphtyl, tetrahydronaphthyl, indenyl and indanyl. Unless otherwise indicated the aryl and/or its fused cycloalkyl moiety is optionally substituted with one, two or where valence allows three substituents independently selected from halo, hydroxy, nitro, cyano, carboxy,Ci-C 4 alkyl, C r C 4 alkoxy, C 3 -C 7 cycloalkyl, haloQ-Qalkyl, Ci -C 4 alkoxyC r C 3 alkyl, Ci-C 4 alkoxyC r C 4 alkoxyC 0 -C 3 alkyl, C r C 6 alkanoyl, amino, amido, carbamoyl, azido, oxo, mercapto, C 0 -C 3 alkanediylaryl C 0 -C 3 alkanedi
  • 'Co-C3alkanediylheterocyclyT as applied herein is meant to include a 5-6 membered saturated, partly unsaturated or unsaturated heterocyclic ring containing 1 to 3 heteroatoms each independently selected from nitrogen, oxygen and sulphur, the ring being optionally fused with a benzene ring.
  • heterocyclyl groups include but are not limited to pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl, tetrahydrofuranyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazinolyl, isothiazinolyl, thiazolyl, isothiazolyl, thiazolidinyl, thiadiazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, azetidinyl, piperidinyl,
  • the ring system is optionally substituted with one, two or where valence allows three substituents independently selected from halo, hydroxy, nitro, cyano, carboxy,Ci-C4alkyl, Ci-C4alkoxy, C3- Cvcycloalkyl, haloCi-C 4 alkyl, Ci-C 4 alkoxyCi-C 3 alkyl, Ci-C 4 alkoxyCi-C 4 alkoxyCo-C3alkyl, Ci- C ⁇ alkanoyl, amino, amido, carbamoyl, azido, oxo, mercapto, Co-C3alkanediylaryl, Co- C3 alkanediylheteroaryl, , it being understood that heterocyclic and carbocyclic moieties in the Co-C3alkanediy
  • aryl and heterocyclyl moieties within the scope of the above definitions are thus a monocyclicring with 5 or especially 6 ring atoms, or a bicyclic ring structure comprising a 6 membered ring fused to a 5 or 6 membered ring.
  • 'Co-C3alkanediylC3C7cycloalkyl' as applied herein is meant to include a C3-Cycycloalkyl group such as cyclopropyl, cyclobutyl,cyclopentyl,cyclohexyl or cycloheptyl, which is directly bonded (i.e. Co) or through an intermediate methylene, ethylene, 1,2 -propanediyl or 1,3- propanediyl group as defined for Ci-C3alkanediyl above.
  • the cycloalkyl group may contain an unsaturated bond.
  • the cycloalkyl moiety is optionally substituted with 1-3 substituents selected from halo, hydroxy, nitro, cyano, carboxy,Ci-C4alkyl, Ci-C4alkoxy, haloCi-C4alkyl, Ci-C4alkoxyCi-C4alkyl, Ci-C ⁇ alkanoyl, amino, amido, carbamoyl, azido, oxo, mercapto, nitro Co-C3alkanediylaryl, C0-C3 alkanediylheterocyclyl, it being understood that heterocyclic and carbocyclic moieties in the Co-C3alkanediylaryl or Co-C3alkanediylheterocyclyl substituent may itself be substituted as provided herein but typically not with a further Co- C3 alkanediylaryl or Co-C3alkanediylheterocyclyl. 'C
  • radical positions on any molecular moiety used in the definitions may be anywhere on such a moiety as long as it is chemically stable.
  • Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated.
  • pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl
  • pentyl includes 1- pentyl, 2-pentyl and 3 -pentyl.
  • each definition is independent.
  • prodrug' as used throughout this text means the pharmacologicallyacceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of formula (I).
  • the reference by Goodman and Gilman (The PharmacologicalBasis of Therapeutics, 8 th ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing prodrugs generally is hereby incorporated.
  • Prodrugs preferably have excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo.
  • Prodrugs of a compound of the present invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parentcompound.
  • ester prodrugs that are hydrolysable in vivo and are derived from those compounds of formula (I) having a hydroxy and/or a carboxyl group.
  • An in vivo hydrolysableester is an ester, which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically acceptable esters for carboxy include Ci -C ⁇ alkoxymethyl esters for example methoxymethyl, Ci-Cealkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, Cs-CscycloalkoxycarbonyloxyCi-C ⁇ alkyl esters for example 1 -cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci-C6alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxy ethyl which may be formed at any carboxy group in the compounds of this invention.
  • An in vivo hydro lysableester of a compound of the formula (I) containinga hydroxy group includes inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown will give the parent hydroxy group.
  • inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown will give the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxy-methoxy.
  • a selection of in vivo hydro lysableester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N- alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxy acetyl.
  • substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring.
  • salts of the compounds of formula (I) or any subgroup of compounds of formula (I) are those whereinthe counter-ion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable acid and base addition salts as mentionedhereinabove are meant to comprise the therapeutically active non -toxic acid and base addition salt forms which the compounds of formula (I) are able to form.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulphuric, nitric, phosphoric acids and the like; or organic acids such as, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic),malonic, succinic (i.e.
  • butanedioicacid maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulphonic, ethanesulphonic, benzenesulphonic,/?-toluenesulphonic, cyclamic, salicylic, / ⁇ -aminosalicylic, pamoic acids and the like.
  • Acid addition salt forms can be converted to the free base form by treatment with an appropriate base.
  • the compounds of formula (I) containingan acidic proton may also be converted into their nontoxic metal or amine addition salt forms by treatment with an appropriate organic or inorganic base.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, JV-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • Base addition salt forms can be converted to the free acid form by treatment with an appropriate acid.
  • addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) or any of the subgroups of compounds of formula (I), as well as the salts thereof, are able to form.
  • Such solvates are for example hydrates, alcoholates and the like.
  • 'quaternary amine' as used above and hereinafter defines the quaternary ammonium salts which the compounds of formula (I) or any of the subgroups of compounds of formula (I), are able to form by reaction between a basic nitrogen of a compound of formula (I) or any of the subgroups of compounds of formula (I), and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
  • an appropriate quaternizing agent such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
  • reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulphonates, alkyl methanesulphonates, and alkyl p-toluenesulphonates.
  • a quaternary amine has a positively charged nitrogen.
  • Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counter ion of choice can be introduced using ion exchange resins.
  • iV-oxide forms of the present compounds are meant to comprise the compounds of formula (I) whereinone or several nitrogen atoms are oxidized to the so-called iV-oxide.
  • the compounds according to the invention may contain one or more asymmetrically substituted carbon atoms, asymmetricor chiral centre.
  • the presence of one or more of these asymmetric centres in compounds according to the invention can give rise to stereochemically isomeric forms, stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, both in pure form and mixed with each others, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof.
  • stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates.
  • the term 'stereoisomerically pure' concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excessof 100% (i.e.
  • Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by application of art-known procedures (cf. Advanced Organic Chemistry: 3rd Edition: author J March, pp 104-107).
  • enantiomers may be separated from each other using known procedures including, for example, formation of diastereomericmixtures by reaction with a convenient optically active auxiliary species followed by separation of the diastereomers, using for instance selective crystallisation, and finally cleavage of the auxiliary species.
  • optically active auxiliary species are optically active acids and bases such as tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulphonic acid.
  • enantiomers may be separated by chromatographic techniques using chiral stationary phases. Pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecif ⁇ cally .
  • the compound When a specific stereoisomer of a compound is desired, the compound will preferably be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the compounds of formula (I) may have metal binding, chelating or complex forming properties and therefore may exist as metal complexes or metal chelates. Such metalated derivatives of the compounds of formula (I) are intended to be included within the scope of the present invention.
  • the invention relates to the compounds of formula (I) or any subgroup of compounds of formula (I) per se, the prodrugs, iV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof.
  • One embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as the JV-oxides, salts, as the possible stereoisomeric forms thereof.
  • the invention further relates to methods for the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I), the prodrugs, JV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, its intermediates, and the use of the intermediates in the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I).
  • the invention also relates to the use of a compound of formula (I) or any subgroup of compounds of formula (I), or a prodrug, iV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof, for the manufacture of a medicament.
  • the invention relates to the use of a of a compound of formula (I) or any subgroup of compounds of formula (I), or a prodrug, iV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof in therapy.
  • the term 'therapy' also includes 'prophylaxis' unless there are specific indications to the contrary.
  • the terms 'therapeutic' and 'therapeutically' should be construed accordingly.
  • the compounds of formula (I) or any of the subgroups of formula (I) have enzyme inhibiting properties, in particular they are inhibitors of aspartyl proteases such as BACE.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a compound of any of the subgroups of formula (I) or a pharmaceutically acceptable salt thereof as specified herein, and a pharmaceutically acceptable adjuvant, diluent or carrier for administration to a subject in need thereof.
  • a therapeutically effective amount in this context is an amount sufficient to act in a prophylactic way against or to stabilize conditions associated with BACE activity such as Alzheimer's disease in affected subjects or subjects being at risk of being affected.
  • the invention further relates to a process of preparing a medicament or a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable adjuvant, diluent or carrier with a therapeutically effective amount of a compound of formula (I) or any of the subgroups of formula (I) as specified herein, or a pharmaceutically acceptable salt or a solvate, prodrug, N-oxide, quaternary amine, metal complex or stereochemically isomeric form thereof as specified herein.
  • the compounds of the present invention are also useful for the inhibition of BACE activity.
  • a further embodimentof the invention relates to use of the compounds of formula (I) or any of the subgroups of formula (I) or a pharmaceutically acceptable salt, or solvate thereof as hereinbefore defined in the treatment and/or prophylaxis of Alzheimer's disease by inhibiting the activity of B ACE.
  • the compounds of the present invention have also utility in treating, ameliorating, controlling or reducing the risk of Alzheimer's disease.
  • the compounds may be useful for the prevention of dementia of the Alzheimer's type, as well as for the treatment of early stage, intermediate stage or late stage dementia of the Alzheimer's type.
  • the compounds may also be useful in treating, ameliorating, controlling or reducing the risk of diseases mediated by abnormal cleavage of amyloid precursor protein (also referred to as APP), and other conditions that may be treated or prevented by inhibition of ⁇ -secretase.
  • APP amyloid precursor protein
  • Such conditions include mild cognitive impairment, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld- Jakob disease, prion disorders, amyotrophic! lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, Down syndrome, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes and atherosclerosis.
  • the invention relates to a method for the treatment and/or prophylaxis of diseases or conditions which are associated with activity of BACE, in particular to a method for the treatment or prophylaxis of the above mentioneddiseases, said method comprising administering to a patient a pharmaceutically active amount of a compound of formula (I) or any of the subgroups of formula (I).
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of formula I/salt/so lvate (active ingredient) may be in the range from 0.001 mg/kg to 75 mg/kg, in particular from 0.5 mg/kg to 30 mg/kg. This daily dose may be given in divided doses as necessary. Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
  • the compounds of formula (I) and pharmaceutically acceptable salts, solvates, prodrugs, TV-oxides, quaternary amines, metal complexes, or stereochemically isomeric forms thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compound of formula (I) /salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.10 to 70 %w/w, of active ingredient, and, from 1 to 99.95 %w/w, more preferably from 30 to 99.90 %w/w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.
  • a representative tablet within the scope of the pharmaceutical composition of the invention could have a mass of 500 - 1500 mg with a loading of active ingredient in the range 35 - 75%, with the balance being excipients, such as binders, disintegrants, antioxidants and the like.
  • compositions of this invention may be administered in standard manner for the disease or condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • the oral delivery route, particularly capsules or tablets is favoured.
  • the pharmaceutical composition of this invention may also contain, or be co- administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more of the diseases or conditions referred to hereinabove.
  • the compounds of the present invention may be used in combination with one or more other pharmacological agents that treat, prevent, control ameliorate or reducethe risk for side effects or toxicity of the compounds of the present invention.
  • Such other pharmacological agents may be administered, by route and in amount commonly used therefore, contemporaneously or sequentially with the compounds of the present invention.
  • the pharmaceutical compositions of the present invention include those that contain one or more active ingredients, in addition to the compounds of the present invention.
  • the combination may be administered as part of a unit dosage form combination product, or as a kit or a treatment protocol whereinone or more additionalpharmacological agents are administered in separate dosage forms as a part of a treatment regimen.
  • the present invention is also directed to combinations of the compounds of the invention with one or more pharmacologically active agents useful in the treatment and/or the prophylaxis of Alzheimer's disease.
  • combinations include combinations with anti -Alzheimer's agents, for example other BACE inhibitors or ⁇ -secretase inhibitors; HMG-CoA reductase inhibitors; NSAIDs including ibuprofen; vitamin E; anti -amyloid antibodies, including anti- amyloid humanized monoclonal antibodies; CB-I receptor antagonists or CB- 1 receptor inverse agonists; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, and tacrine; growth hormone secretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin; histamine
  • the compounds of the present invention and intermediates useful for the synthesis of these compounds are prepared by methods and techniques known to those skilled in the art.
  • the general schemes below illustrate typical synthetic routes to the compounds of the invention and to intermediates thereof.
  • Alternative routes which will be readily apparent to the ordinary skilled organic chemist, may alternatively be used to synthesize various portions of the molecules as illustrated by the general schemes and the preparative examples below.
  • Scheme 1 illustratesa synthetic route to a lactone which is a useful intermediate in the preparation of compounds of formula (I).
  • the isopropylidene derivative (Ia) achieved for example as described in Tetrahedron lett., 1987, 28, 1143, can be transferred into the methyl glycoside (Ib) by acidic hydrolysis of the acetal group effected by treatment with a suitable acid, such as sulphuric acid, in the presence of methanol.
  • a suitable acid such as sulphuric acid
  • the achieved free secondary hydroxy group can then be transformed into a desired group R 3 .
  • R 3 is an 0-linked substituent can be prepared by alkylation of the hydroxy group, effected for example by treatment with a suitable alkylating agent such as an alkyl halide like, methyl iodide, in the presence of a base like silver oxide thus giving the ether derivative (Ic).
  • Inversion of the stereochemistry of the alcohol (Ib) can be effected for example by subjecting the alcohol to Mitsunobu conditions i.e. reaction with an azodicarboxylate such as DIAD or the like in the presence OfPh 3 P and for instance p-nitrobenzoic acid, followed by hydrolysis of the afforded p-nitrobenzoic ester by for example treatment with sodium methoxide or the like.
  • Mitsunobu conditions i.e. reaction with an azodicarboxylate such as DIAD or the like in the presence OfPh 3 P and for instance p-nitrobenzoic acid, followed by hydrolysis of the afforded p-nitrobenzoic ester by for example treatment with sodium methoxide or the like.
  • lactones (IAb) whereinR is azide or the alcohol can be reacted with a thiol or alcohol to give alkylthio and alkoxy derivatives respectively.
  • Lactones (IAb) whereinR is amine are conveniently achieved by reduction of the previously described azide derivative for example by treatment with Ph 3 P or by catalytic hydrogenation using a catalyst like Lindlar's catalyst, or alternatively, the Gabriel synthesis may be used, i.e.
  • Lg is a leaving group
  • the primary hydroxy group of the lactone (2a) can be selectively alkylated for example by activation with dibutyltin oxide followed by reaction with a desired alkylating agent Q-(CH 2 ) n - Lg whereinLg is a suitable leaving group such as a halide like bromide or iodide in the presence of tetrabutylammonium bromide or the like thus forming the ether derivative (2b).
  • the substituent Q-(CH 2 ) n can be introduced by using the Mitsunobu conditions (Mitsunobu, 1981, Synthesis, January, 1 -28; Rano et al, Tetrahedron Lett., 1995, 36, 22, 3779-3792; Krchnak et al., Tetrahedron Lett., 1995, 36, 5, 6193-6196; Richter et al., Tetrahedron Lett., 1994, 35, 27, 4705-4706) i.e. reaction of the primary hydroxy group of the diol (If) with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine followed by displacement with a desired alcohol.
  • Replacement of the secondary hydroxy group of the alcohol (2b) by azide may be effected by transforming the hydroxy group to a leaving group, for example a derivative of sulphonic acid like a triflate or tosylate or the like by subjecting the alcohol to sulphonylating conditions such as treatment with the appropriate anhydride or halide optionally in the presence of a base, for instance pyridine, followed by displacement of the leaving group with azide for example sodium azide, thus giving the azide derivative (2c).
  • the linear amino compound (2e) can then be achieved by opening of the lactone with a desired amino derivative (2d) in the presence of for example 2-hydroxypyridineand a base like isopropyl diethylamine.
  • Lactones useful for the synthesis of compounds of formula (I) whereinG is S or NH and n is 1 or 2 can be prepared from the diol 2a for example by a Mitsunobu reaction with a thiol or amino derivative respectively, as illustrated in scheme 2B.
  • the primary hydroxy group of the lactone (2a) can be converted to a thioether or an amine for example by transforming it into a leaving group followed by displacement of the formed leaving group with the desired group Q-(CH2) n -S or Q-(CH2) n -NRa.
  • a convenient method to effect this transformation is by way of a Mitsunobu reaction, i.e. reaction of the hydroxy group with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine or the like followed by displacement with a desired thiol or amine to provide the thioether(2Bb) or the amine derivative (2Bc) respectively.
  • an azide derivative such as sodium azide or DPPA in the Mitsunobu reaction with the alcohol (2a
  • An alternative method to obtain the amino derivative (2Bc) is to selectively oxidize the primary hydroxy group of the alcohol (2a) to the corresponding aldehyde, effected for example by treatment with Dess -Martin periodinane or by any other suitable oxidation reagent, followed by a reductive amination with the desired amino derivative Q- (CH2)n-NHRa in the presence of a reducing agent like NaCNBH 3 .
  • a reducing agent like NaCNBH 3
  • Compounds wherein the group Q is linked directly to a sulphur or nitrogen atom i.e. an intermediate for the preparation of compounds of formula (I) whereinG is S or NRa and n is 0, may be prepared by transformation of the primary hydroxy group of the diol (2a) into a leaving group such as a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like by treatment with the appropriate sulphonylating agent in a solvent like for instance pyridine or dichloromethane optionally in the presence of triethylamine or the like, followed by displacement of the leaving group with a desired thiol Q-SH or a amine Q-NHRa optionally in the presence of a base.
  • a leaving group such as a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like
  • a solvent like for instance pyridine or dichloromethane optionally in the presence of triethyl
  • the oxidation can be performed either at the last step of the synthesis or on any suitable intermediate. Many suitable methods for this oxidation are described in the literature for example, a peroxyacid such as AcOOH, mCPBA can be used.
  • the group Q-(CH2) n can alternatively be introduced prior to introduction of the group R 3 , as shown in scheme 3.
  • the amino acid (3Aa), carrying the desired side chain R 4 and R 4 can be coupled to the amine W-(CH 2 ) q -NH 2 using any convenient method for peptide coupling known in the art.
  • a coupling agent like HATU or isobutylchloroformatein the presence of a tertiary amine such as ethyldiisopropylamine (DIEA) or N-methylmorpholine in a solvent like dimethyl formamide can be used.
  • DIEA ethyldiisopropylamine
  • N-methylmorpholine in a solvent like dimethyl formamide
  • the azide derivative (4a), prepared for example as outlined in scheme 1, whereinPg is a hydroxy protecting group for example a benzyl group can be transformed to the corresponding amine by reduction of the azide using any convenient reduction method such as hydrogenation in the presence of a suitable catalyst, such as Lindlar's catalyst or the like in the presence of BoC 2 O to provide the boc protected amino derivative (4b). Protection of the secondary hydroxy group, using a protecting group (Pg 2 ) which is orthogonal to the one used for the primary hydroxy group (Pg 1 ), followed by removal of the primary hydroxy protecting group using the appropriate conditions according to the group used, such as for example catalytic hydrogenation in the case of a benzyl group, provides the primary alcohol (4c).
  • Suitable protecting groups for the above route will be recognized by skilled person and a numerous of useful protecting groups are described in Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981).
  • benzyl can be used as Pg and acetyl as Pg 2 .
  • the group (CH 2 ) n -Q can then be introduced as described above.
  • Trichloroacetimidates are conveniently prepared by reaction of the corresponding alcohol with trichloroacetonitrile in the presence of a base like NaH.
  • n 1 or 2 and G is O, S or NRa may be prepared by a Mitsunobu reaction of the primary alcohol (4c) with a desired alcohol, Q-(CH2) n -0H, thiol, Q-(CH 2 )I-SH or amine Q-(CH 2 ) n -NHRa respectively.
  • n O and G is O
  • S or N may be prepared by transforming the primary hydroxy group of the alcohol (4c) to a leaving group such as a halide like chloride or bromide or to a derivative of sulphonic acid such as a triflate, tosylate or the like which subsequently is displaced by a desired alcohol Q-OH, thiol Q-SH or amine Q- NHRa optionally in the presence of a base, for example as described hereinabove.
  • An alternative method for the preparation of compounds whereinG is S and n is O is to react the alcohol (4a) with a desired derivative of diphenyl disulphide in the presence of nBusP.
  • G is NRa and n is O may alternatively be achieved by oxidation of the hydroxy group of the alcohol (4a) followed by a reductive amination with a desired aniline derivative Q-NRa in the presence of a suitable catalyst like NaCNBH 4 or the like. Removal of the Boc group according to standard procedures such as treatment with an acid, for example TFA, followed by removal of the hydroxy protecting group using the appropriate conditions, then provides the amine (4e).
  • Scheme 5 illustratesa method to prepare a benzyl amine derivative which is a useful building block for the preparation of macrolactams.
  • the hydroxy protected cyanobenzyl derivative (5a) is conveniently be prepared by protection of commercially available cyanobenzyl alcohol, illustrated herein as 3 -cyanobenzyl alcohol, with a suitable protecting group, for example a trityl or monomethoxy trityl group using standard conditions well known in the art.
  • Benzyl amine derivatives wherein R 1 is H are conveniently prepared by directly reducing the cyano group to the methyl amino group using for instance LAH or diborane or the like, followed by protection of the afforded primary amine as described above. Removal of the hydroxy protecting group using standard conditions such as treatment with acid in the case of a trityl or monomethoxy trityl group as protecting group, provides the alcohol (5c). The afforded alcohol (5 c) can then be used in the coupling to the primary alcohol of the lactone If or the linear compound 4c employing for example the Mitsunobu conditions as described in scheme 2 and 4 respectively.
  • the hydroxy group of the alcohol (5 c) can be transformed into a leaving group such as a bromide for example by treatment with bromine or carbontetrabromide in the presence of triphenylphosphine or the like thus affordingthe bromoderivative (5d), or the hydroxy group can be transformed into a derivative of sulphonic acid by reaction with a suitable sulphonylating agent such as a sulphonic halide or anhydride optionally in the presence of a base for example pyridine.
  • a suitable sulphonylating agent such as a sulphonic halide or anhydride optionally in the presence of a base for example pyridine.
  • the afforded compound can then be coupled to the primary alcohol of the lactone If or the linear compound 4c by way of a displacement reaction.
  • Scheme 6 illustratesa route to another substituted phenyl derivative, Q, useful for the preparation of compounds of formula (I).
  • the afforded alcohol (6c) can then either be used directly in the coupling to the primary hydroxyl group of the lactone If or the linear compound 4c employing the Mitsunobu conditions, or the hydroxy group can be transferred to a leaving group such as a halide like bromide or a derivative of sulphonic acid like a triflate or a tosylate or the like as described above, and subsequently coupled to the primary hydroxyl group of the lactone If or the linear compound 4c as described above.
  • a leaving group such as a halide like bromide or a derivative of sulphonic acid like a triflate or a tosylate or the like as described above
  • Scheme 7 illustratesa further useful building block for the preparation of compounds of the invention.
  • Aryl iodides (7a), prepared according to procedures known in the art, can be allylated by using allyltributyltin in the presence of a transition metal catalyst, such as palladium triphenylphosphine, to give the allyl derivative (7b).
  • a transition metal catalyst such as palladium triphenylphosphine
  • Reduction of the methyl ester by subjecting the compound to a reducing agent such as DIBAL or LAH or the like in a solvent like provides the benzyl alcohol derivative (7c).
  • the afforded alcohol can then either be used directly in the coupling to the primary hydroxyl group of the lactone If or the linear compound 4c employing the Mitsunobu conditions, or the hydroxy group can be transferred to a leaving group such as a halide like bromide or a derivative of sulphonic acid like a triflate or a tosylate or the like as described above, and subsequently coupled to the primary hydroxyl group of the lactone If or the linear compound 4c as described above.
  • schemes 5, 6 and 7 illustrate a strategy starting from a 1,3 substituted phenyl derivative, the skilled person will realise that the same strategy is also applicable to other phenyl derivatives, for example the corresponding 1,2- or 1 ,4disubstituted derivatives.
  • the free hydroxy group of compound (4a) can be replaced by two fluoro atoms by oxidizing the hydroxy group to a keto group using any convenient method such as using a reagent like Dess Martin periodinane or oxone® (potassium monopersulphate triple salt) or any other suitable oxidizing agent, followed by treatment of the afforded keto compound with a fluorinating agent like DAST or Deoxofluor or the like in a solvent like dichloromethane, to give the difluoro compound (8a).
  • a fluorinating agent like DAST or Deoxofluor or the like in a solvent like dichloromethane
  • the monofluoro compound (8c) with the desired stereochemistry can be obtained by first inverting the stereochemistry at the steric centre wheretothe hydroxy group is attached and thereafter replace the hydroxy group with fluorine, effected for example by subjecting the afforded inverted alcohol to fluorinating conditions such as treatment with DAST or Deoxofluor in a solvent like dichloromethane as described e.g. by Singh, R. P. and Shreve, J. M. in Synthesis, 17, 1999, p. 2561-2578, or any other suitable fluorinatingconditions.
  • Inversion of the stereochemistry of the alcohol (4a) can be performed for example by subjecting the alcohol to a Mitsunobu reaction with for instance p-nitrobenzoic acid and reagents like DIAD and Ph 3 P followed by hydrolysis of the afforded p-nitrobenzoic ester by for example treatment with sodium methoxide or the like.
  • Scheme 8 illustrates the replacement of the hydroxy group with fluoro or difluoro as the last step of the synthesis, the skilled person will realise that this transformation alternatively may be performed at any other suitable stage of the synthesis for example on any of the intermediates described above.
  • Pg is an N-protecting group
  • Q is substituted phenyl
  • the configuration of compound (9a), prepared as described above has to be inverted, for example as described in scheme 8.
  • the inverted alcohol (9b) can then be subjected to Mitsunobu conditions, i.e.
  • azido derivative (9c) can alternatively be achieved by transformation of the hydroxy group to a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like by treatment with the appropriate sulphonylating agent in a solvent like for instance pyridine or dichloromethane optionally in the presence of triethylamine or the like, followed by displacement of the leaving group with sodium azide or the like.
  • Reduction of the azide using any conventional reduction method such as hydrogenation in the presence of a suitable catalyst, or treatment with triphenylphosphine provides the corresponding amine (9d).
  • Macrocyclic compounds of the invention can then be achieved by coupling of any of the amines described above, to a suitable acid followed by ring closure.
  • Scheme 10 illustrates schematically the formation of a macrolactame.
  • a coupling agent like HATU or the like
  • a tertiary amine like diisopropylethylamine or the like in a solvent like DMF provides the amide (10c).
  • the free amine and acid are then achieved by simultaneous removal of the boc group and hydrolysis of the tert. butyl ester effected by treatment with a strong acid such as TFA or HCl or the like.
  • Macrolactamization is then effected by treatment of the resulting amino acid with peptide coupling agents like 1 -hydroxy-7- azabenzotriazole (HOAt) and HATU or the like in a dilute solution in a solvent like dichloromethane or DMF, in the presence of a tertiary amine such as diisopropyl amine (DIEA) or the like, to provide the macrolactame (1Od) .
  • peptide coupling agents like 1 -hydroxy-7- azabenzotriazole (HOAt) and HATU or the like in a dilute solution in a solvent like dichloromethane or DMF, in the presence of a tertiary amine such as diisopropyl amine (DIEA) or the like, to provide the macrolactame (1Od) .
  • DIEA diisopropyl amine
  • X is a leaving group, e.g. Br or I
  • the bicyclic lactone (15a), prepared from the commercially available diester 3,4- bis(methoxycarbonyl)cyclopentanone as described in WO2005/073195 can be opened by treatment with a base, such as potassium carbonate or lithium hydroxide or the like to provide the diester (15b). Conversion of the hydroxy group into an amino group can then be performed using any convenient procedure whereof many are described in the literature. For example the Mitsunobu conditions may be employed i.e.
  • Aryl iodides (16a), prepared according to procedures known in the art, can be allylated by using allyltributyltin in the presence of a transition metal catalyst, such as palladium triphenylphosphine, to give the allyl derivative (16b).
  • a transition metal catalyst such as palladium triphenylphosphine
  • Bis(tricyclohexylphosphine)[(phenylthio)methylene]ruthenium (IV) dichloride can be used for large-scale production. Also other catalysts containingother transition metals such as Mo can be used for this reaction.
  • Further compounds of the invention can be prepared according to a similar strategy, as shown in scheme 17.
  • Scheme 18 exemplifies a route to compounds of the invention whereinthe macrocycle comprises an amine function.
  • Aldehydes (18a) can be prepared from the corresponding tert. butyl ester for example according to the procedure described by S. J. Stachel et al. in Med. Chem. Lett., 16 (2006) 641-644. Hydrolysis of the methyl ester followed by coupling of the amine (18d) as described above, provides the amide (18e).
  • any functional groups present on any of the constituent compounds used in the preparation of the compounds of the invention are appropriately protected where necessary.
  • functionalities on the natural or non -natural amino acids are typically protected as is appropriate in peptide synthesis.
  • Suitable protecting groups are described in Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981) and “The Peptides: Analysis, Synthesis, Biology", Vol. 3, Academic Press, New York (1981), the disclosure of which are hereby incorporated by reference.
  • the methoxy compound (Ha) (24 g, 0.1619 mol) was dissolved in dry DCM (480 mL, BBr 3 (IM in DCM, 48.68g, 0.1943mol) was added at 0 0 C and the reaction mixture was stirred for 3h. The reaction was quenched by addition of water and the solution was transferred to a separatory funnel. The mixture was extracted with DCM, the organic phase was washed with brine and dried over anhydrous Na 2 SO 4 . The solvent was evaporated and the crude product was subjected to flash chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in petroleum ether which gave the title compound as a yellow viscous liquid (2 Ig, 97%).
  • Tributyltin hydride (132. Ig, 0.454mol) was dissolved in toluene (1.4 lit) and heated to reflux. A catalytic amount of AIBN (10.5 g, 0.0643 mol) was added and the solution was refluxed for another 30 min. Then the compound Hc (140 g, 0.3783 mol) dissolved in toluene (700 ml) was added drop -wise to the solution. The reaction was stirred at reflux for 6h and then cooled down to room temperature.
  • Diisopropyl azodicarboxylate (25.27g, 0.125mol) was added and the reaction mixture was stirred at -15 0 C for 15min whereafter diphenylphosphorylazide (25.8 g, 0.09375 mol) was added drop-wise while maintaining the temperature at -15 0 C.
  • diphenylphosphorylazide 25.8 g, 0.09375 mol
  • the reaction mixture was warmedto 0 0 C and stirred for 30 min and then allowed to attain room temperature and was stirred for another 12h.
  • reaction mixture was cooled to 0 0 C and lithium aluminium hydride (450 mg) was added as a slurry in THF (18 ml), and the suspension was stirred at r.t. for Ih and then refluxed for 1 h.
  • the reaction mixture was cooled to 0 0 C and water (0.55 ml), 10%NaOH (0.55 ml) and water (1,84 ml) were added successively.
  • the resulting suspension was filtered through Celite, and the solid was washed with THF and DCM. The filtrate was evaporated and the residue partitioned between DCM and water.
  • the organic extract was dried by sodium sulfate and then evaporated.
  • the diesterlm (0.396 g, 1.32 mmol) was dissolved in THF/MeOH, 1 :1 (19 ml) and cooled to 0
  • the diester Io (0.228 g, 0.66 mmol) was dissolved in THF/MeOH, 1 :1 (8 ml) and cooled to 0 0 C.
  • IM NaOH (aq) (660 ⁇ l, 0.66 mmol) was added and the reaction mixture was stirred at room temperature for 3.5 h.
  • the reaction mixture was diluted with H 2 O and washed with Et 2 O.
  • the aqueous phase was cooled to 0 0 C and acidified with 6 M HCl (aq) to pH ⁇ 2 and extracted with EtOAc.
  • the organic extracts were dried (Na 2 SO 4 ) and concentrated which gave the title compound (0.218 g, 100%) as a white solid.
  • the reaction was quenched by careful addition of H 2 O at 0 0 C and then filtered. The filtrate was partitioned between DCM and H 2 O and the organic phase was dried (Na 2 SO 4 ) and concentrated.
  • the crude product was dissolved in EtOAc (10 ml) and BoC 2 O (1.1 g, 5.0 mmol) was added. The reaction mixture was stirred overnight. The reaction was quenched by addition of MeOH, the reaction mixture was concentrated and the residue partitioned between DCM and NaHCO 3 (aq. sat.) and the organic phase was dried (Na 2 SO 4 ) and concentrated.
  • the dibenzyl compound 4ci (75 g, 0.1953 mol) was cooled to 0 0 C and a IM solution of HCl in methanol (965 mL) slowly was added. The reaction mixture was stirred over night at room temperature and then neutralized with aqueous solution of NaHCO 3 and concentrated. The residue was extracted with ethyl acetate (500 mLx2) and washed with H 2 O (500 mL) and brine (500 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated.
  • the crude product (mixture of ⁇ - and ⁇ -anomer) was purified by flash column chromatography (silica gel 240-400 mesh, eluent 15% ethyl acetate in petroleum ether) which gave the monomethoxy derivative as light -yellow liquid (60 g, 86% yield).
  • the reaction mixture was cooled to room temperature and then neutralized with an aqueous NaHCO 3 solution and then concentrated.
  • the residue was diluted with DCM, the organic phase washed with water (250 mLx2) and brine (300 mL) and then dried over anhydrous Na 2 SO 4 .
  • the monohydroxy compound 4civ (20 g, 0.0558 mol) was dissolved in dry DCM (400 mL) and the solution was cooled to 0 0 C and PDC (41 g, 0.1117 mol) and 4A molecular sieves powder ( ⁇ 7 g) was added. The reaction mixture was stirred at room temperature for 12h. The solid was filtered off through Celite and the clear filtrate was concentrated and the crude material was subjected to flash column chromatography over silica gel (230-400 mesh, eluent 10% ethyl acetate in petroleum ether) which gave the lactone 4cv as light-yellow liquid (13 g, 65%).
  • the lactone 4cv (13 g, 0.0365 mol) was dissolved in 70% methanol in water (500 mL) then Pd on carbon (10%) (2.1 g) and Pd(OH) 2 on carbon (20%) (2.1 g) was added.
  • the reaction mixture was stirred at room temperature under hydrogen atmosphere in an autoclave at a pressure of 10kg/cm for 12h.
  • the solid was filtered off through Celite, the clear filtrate was concentrated and the crude material was subjected to flash column chromatography over silica gel (230-400 mesh, eluent 30% ethyl acetate in DCM) which gave the dihydroxy lactone as a white solid (5.1 g, 79%).
  • the afforded dihydroxy compound was selectively /?-methoxy-benzylated at the primary alcohol according to the method described in Example 1 step i, but using p-methoxybenzyl (1.15 eq.) bromide instead of (li?/5)-l-(3-(bromomethyl)phenyl)-l-(t-butoxycarbonylamino)ethane which gave the title compound.
  • the alkene 5c was dissolved in ethanol (7 ml) and THF (0.8 ml) and palladiumon carbon(10%) ( ⁇ 50 mg) was added. The mixture was then subjected to hydrogenation (atmospheric pressure) for 2 h after which the slurry was filtered through Celite. Purificationby RP-LC-MS (acetonitrile-10 mM aq. ammonium formate, 40-65% over 9 min) gave the title compound (0.008 g, 13% calculated from the diene 5c). MS m/z 628.15 (M+H) + .
  • the diene 6c (0.223 g, 0.298 mmol) was dissolved in dry 1,2-dichloroethane (210 ml) and the solution was degassed with nitrogen for 15 min.
  • Hoveyda-Grubbs 2:nd generation catalyst (0.037 g, 0.060 mmol) was added and the mixture was heated to 90 0 C under nitrogen atmosphere.
  • An additional ⁇ .020 g of Hoveyda-Grubbs 2:nd generation catalyst was added after 2.5 hours and the mixture was then stirred at 90 0 C overnight.
  • the alkene 6d was dissolved in ethanol (4.5 mL) and THF (0.5 ml) and palladiumon carbon (10%) (-0.02 g) was added. The mixture was then subjected to hydrogenation (atmospheric pressure) for 1 h after which the slurry was filtered through Celite to give the title compound (22 mg, 10% calculated from the diene 6b). MS m/z 723.3 (M+H) + .
  • the alkene 7c (0.090 g, 0.13 mmol) was treated according to the method described in Example 5 step e, which, after purification by RP-LC-MS, acetonitrile-10 mM aq. ammonium formate, 40-
  • the alkene 8 c was treated according to the method described in Example 5 step e, which, after purification by RP-LC-MS, acetonitrile-10 mM aq. ammonium formate, 50-90% over 9 min, gave the title compound (0.004 g, 15% calculated from the diene 8b). MS m/z 678.3 (M+H) + .
  • the alkene 9c was treated according to the method described in Example 5 step e, which, after purification by RP-LC-MS, acetonitrile-10 mM aq. ammonium formate, 40-65% over 9 min, gave the title compound (0.012 g, 8% calculated from the diene 9b). MS m/z 548.2 (M+H) + .
  • the unsaturated compound 1Of was dissolved in ethanol (5 rnL) and subjected to hydrogenation.
  • the lactone 10c (0.116 g, 0.3 mmol), was dissolved in DCM (0.5 ml), 2-hydroxypyridine(0.212 g, 0.6 mmol), 4-fluoroaniline (0.428 ml, 1.2 mmol), and DIEA (10 ml) were added.
  • the reaction mixture was stirred at 70 0 C overnight and at RT for 72h.
  • the mixture was diluted with DCM and washed with 5% aq. citric acid and H 2 O.
  • the organic phase was dried (Na 2 SO 4 ) and concentrated. Purificationby flash column chromatography (hexane/ ethyl acetate 100.0- 60:40) provided the linear azide derivative (0.193 g, 38.7%).
  • the unsaturated macrocyclic compound l ie was dissolved in ethanol (5 rnL) and subjected to hydrogenation. The solution was applied to a H-Cube equipment passing through a Pd/C cartridge (atmospheric pressure, and 25 0 C). The solution was concentrated and the residue purified by preparative HPLC-MS which gave the title compound (0.042 g, 20% calculated from the diene 1 Ib). MS m/z 674.8 (M+H) + .
  • the diene 12a (0.163 g, 0.24 mmol) was dissolved in dry 1 ,2-dichloroethane (160 ml) and the solution was degassed with nitrogen for 15 min. Hoveyda-Grubbs 2:nd generation catalyst (0.035 g, 0.22 mmol) was added and the mixture was then stirred at 90 0 C overnight. The solvent was evaporated and the crude material was purified first by flash column chromatography (CHCl 3 100%), and then with (EtOAc/MeOH, 1 :0-9: 1). MS m/z 653.86 (M+H) + which gave the title compound.
  • the unsaturated macrocyclic compound 12b was dissolved in ethanol (8 mL), and a few drops of
  • Hoveyda-Grubbs 2:nd generation catalyst (0.05 g, 0.31 mmol) was added and the mixture was stirred at 90 0 C overnight. The solvent was evaporated and the crude material was purified first by flash column chromatography (CHCh 100%), and then with (EtO Ac/MeOH, 1 :0-9:1). MS m/z 749 (M+H) + .
  • the unsaturated macrocyclic compound 13b was the dissolved in ethanol (8 mL), and subjected to hydrogenation. The solution was applied to a H -Cube equipment passing through a Pd/C cartridge (atmospheric pressure, and 25 0 C). The solution was concentrated and purified by preparative HPLC-MS which gave the title compound (0.109 g, 43% calculated from the diene 13a). MS m/z 751.15 (M+H) + .
  • Methanesulfonic acid 3-(3-allyl-phenoxyV2-azido-l-[2-(l-benzylcarbamoyl-2-methyl- propylcarbamovO-2-methoxy-ethyl1 -propyl ester 14a
  • the azide 6a (857 mg, 1.637 mmol) was dissolved in pyridine (17 rnL) and the mixture was cooled to 0 0 C.
  • Methanesulfonyl chloride (254 ⁇ L, 3.273 mmol) was added dropwise during 10 minutes and the mixture was stirred at 0 0 C for 30 minutes and then for an additional hours at room temperature.
  • TruPointTM Beta-Secretase Assay Kit may be used.
  • the assay is based on the close proximity of two labels, a fluorescent europium chelate and a quencher of europium fluorescence. Fluorescence is strongly quenched when the labels are in close proximity of each other, and when the labels are separated, lanthanidefluorescence can be measured by time -resolved fluorometry (TRF).
  • TRF time -resolved fluorometry
  • the enzyme to be used in the assay is recombinant BACEl and the substrate is a 10 amino acids long peptide with a fluorescent europium chelate coupled to one end and a quencher of europium fluorescence (QSY 7) coupled via lysine to the other end; EU-CEVNLDAEFK-QSY 7.
  • the cleavage site by BACEl is the peptide bond between L and D.
  • a spectroscopic response is generated by peptidase cleavage, and the activity is measured by a continuous detection of increased fluorescence intensity exhibited by the cleavage product.
  • the compounds are tested at a range of concentrations whereas the enzyme and substrate concentrationsare fixed.
  • the substrate is prepared at a 120 ⁇ M stock solution in distilled water. The stock solution should be freshly diluted to 400 nM to the amount needed for the day.
  • reaction buffer 15 ⁇ l
  • inhibitor of different concentrationsin DMSO 1 ⁇ l
  • reaction buffer 15 ⁇ l
  • DMSO 1 ⁇ l
  • the enzyme with inhibitor in DMSO is preincubated at room temperature (20-25 0 C) for 30 min whereafter the reactions are started by addition of substrate, 15 ⁇ l/well, thus giving a total volume of 31 ⁇ l/well and a substrate concentration of 200 nM.
  • Product TR-fluorescence is monitored during 90 min with a 1420 VICTOR.
  • the IC 50 value was calculated with GraFit software.
  • Activity of the inhibitors is determined by measuring the TR-fluorescence at ⁇ ex 330 nm and ⁇ em 615 nm. The inhibition is calculated as follows:
  • Table 1 shows the enzymatic inhibition exhibited by a representative selection of compounds according to the invention when tested in a BACE enzyme assay such as the one described above.
  • Category A indicates an IC 50 value of ⁇ 1 ⁇ M
  • category B indicates 1 - 5 ⁇ M
  • category C indicates > 5 ⁇ M.
  • the compounds are selective for one aspartyl protease over another.
  • an assay using Fluorescence Resonance Energy Transfer (FRET) to generate a spectroscopic response to peptidase cleavage can be used. The activity is measured by a continuous detection of increased fluorescence intensity exhibitedby the cleavage product (peptide -EVANS).
  • the enzyme to be used in the assay is recombinant human renin (supplied by Proteos), the substrate consists of a peptide which in one end is linked to a fluorophore, 5-(aminoethyl)aminonaphthalene sulphonate (EDANS), and in the other end to a non- fluorescent chromophore, 4'-dimethylaminoazobenzene (Dabcyl), typically Arg-Glu(EDANS)-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr- Lys(DABCYL)-Arg (Sigma- Aldrich).
  • EDANS 5-(aminoethyl)aminonaphthalene sulphonate
  • Dabcyl 4'-dimethylaminoazobenzene
  • the cleavage site by human renin is the peptide bond between Leu and VaI.
  • the compounds are tested at a range of concentrations whereas the enzyme and substrate concentrationsare fixed.
  • the substrate is prepared at a 20 ⁇ M stock solution in DMSO. To each well of a 96-well polypropylene plate is added the enzyme containingassay buffer (90.0 ⁇ l) and inhibitor of different concentrations ⁇ ⁇ l). To control wells is added DMSO (1 ⁇ l) instead of inhibitor.
  • the renin enzyme is preactivated by incubation at 37 0 C for 20 min whereafter the reactions are started by addition of substrate, 10 ⁇ l/well, thus giving a total volume of 100 ⁇ l/well and a substrate concentrationof 2 ⁇ M.
  • the assay is performed during 20 min at 37 0 C.
  • the total concentration of DMSO is not above 1 %.
  • Product fluorescence (emission filter 340 nM, excitation filter 500 nM) is monitored with a Thermo Labsystems Fluoroskan Ascent plate reader.
  • the Ki is determined by Prism Software.
  • Activity of the inhibitors is determined by measuring the fluorescence at ⁇ ex 340nm and ⁇ em 500 nm. Percent inhibition is calculated as follows: % Inhibition is equal to the (Fluorescence ⁇ inhibitor - Fhxorescencebackground); divided by the (Fluorescence mmus inhibitor - Fluorescence ⁇ c£gro « ⁇ rf);

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Abstract

La présente invention concerne des composés de formule (I), N-oxydes, des sels d'addition, des amines quaternaires, des complexes métalliques, des formes stéréochimiquement isomères et leurs métabolites : où G représente -O-, -S(=O)r-, -CRdRd ou -NRa-; W représente H, C1-C6alkyle, C3-C6cycloalkyle, aryle ou hétérocyclyle; L1 est une liaison, méthylène ou éthylène; L2 correspond à CHR1 ; ou L1 et L2 forment ensemble CH=CH; L3 est une liaison, C(=O) ou CH2 ; V1 et V2 sont indépendamment une liaison, NRa, CRdRd ou O; R1 est H, C1-C 6alkyle, C1-C6alkoxye, C1-C4alkoxyC1-C4alkyle, C1-C4alkoxyC1-C4alkoxyC1-C4alkyle, C0-C3alkandiylcarbocyclyle ou C0-C3alkandiylhétérocyclyle; R2b sont tous deux H, ou les deux R2b forment ensemble =O; l'anneau A est un noyau à cinq ou six éléments saturés, partiellement insaturés ou un noyau aromatique; et les autres variables sont telles que définies dans l'invention. Les composés de l'invention sont des inhibiteurs du BACE et sont utiles, entre autres, pour le traitement et/ou la prévention d'affections associées à l'activité BACE, telle la maladie d'Alzheimer.
PCT/EP2008/055326 2007-05-04 2008-04-30 Inhibiteurs de l'aspartyle protéase WO2008135488A1 (fr)

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CN105646154A (zh) * 2016-01-14 2016-06-08 上海马氏化学科技有限公司 一种新型含保护基的3-烯丙基苯酚衍生物的合成和脱保护的方法

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WO2005049585A1 (fr) * 2003-11-05 2005-06-02 Novartis Ag Lactames macrocycliques et leur utilisation pharmaceutique

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Publication number Priority date Publication date Assignee Title
WO2005049585A1 (fr) * 2003-11-05 2005-06-02 Novartis Ag Lactames macrocycliques et leur utilisation pharmaceutique

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Title
HANESSIAN S ET AL: "Structure.based desigh and synthesis of macroheterocyclic peptidomimetic inhibitors of the aspartic protease beta-site amyloid precursor protein cleaving enzyme (BACE)", JOURNAL OF MEDICINAL CHEMISTRY, US AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 49, no. 15, 1 January 2006 (2006-01-01), pages 4544 - 4567, XP002449025, ISSN: 0022-2623 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105646154A (zh) * 2016-01-14 2016-06-08 上海马氏化学科技有限公司 一种新型含保护基的3-烯丙基苯酚衍生物的合成和脱保护的方法
CN105646154B (zh) * 2016-01-14 2022-07-12 上海马氏化学科技有限公司 一种新型含保护基的3-烯丙基苯酚衍生物的合成和脱保护的方法

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