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WO2006040149A9 - Composes heterocycliques de cetones pour traiter la maladie d'alzheimer - Google Patents

Composes heterocycliques de cetones pour traiter la maladie d'alzheimer Download PDF

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Publication number
WO2006040149A9
WO2006040149A9 PCT/EP2005/011002 EP2005011002W WO2006040149A9 WO 2006040149 A9 WO2006040149 A9 WO 2006040149A9 EP 2005011002 W EP2005011002 W EP 2005011002W WO 2006040149 A9 WO2006040149 A9 WO 2006040149A9
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Prior art keywords
alkyl
cycloalkyl
heterocyclyl
aryl
heteroaryl
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PCT/EP2005/011002
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WO2006040149A1 (fr
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Emmanuel Hubert Demont
Sally Redshaw
Daryl Simon Walter
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Glaxo Group Ltd
Emmanuel Hubert Demont
Sally Redshaw
Daryl Simon Walter
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Application filed by Glaxo Group Ltd, Emmanuel Hubert Demont, Sally Redshaw, Daryl Simon Walter filed Critical Glaxo Group Ltd
Publication of WO2006040149A1 publication Critical patent/WO2006040149A1/fr
Publication of WO2006040149A9 publication Critical patent/WO2006040149A9/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/06—Peri-condensed systems
    • 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

Definitions

  • the present invention relates to novel ketone compounds having Asp2 ( ⁇ -secretase, BACE1 or Memapsin-2) inhibitory activity, processes for their preparation, to compositions containing them and to their use in the treatment of diseases characterised by elevated ⁇ - amyloid levels or ⁇ -amyloid deposits, particularly Alzheimer's disease.
  • Asp2 ⁇ -secretase, BACE1 or Memapsin-2
  • Alzheimer's disease is a degenerative brain disorder in which extracellular deposition of ⁇ -amyloid (A ⁇ ) in the form of senile plaques represents a key pathological hallmark of the disease (Selkoe, D. J. (2001 ) Physiological Reviews 81: 741-766). The presence of senile plaques is accompanied by a prominent inflammatory response and neuronal loss.
  • a ⁇ exists in soluble and insoluble, fibrillar forms and a specific fibrillar form has been identified as the predominant neurotoxic species (Vassar, R. and Citron, M. (2000) Neuron 27: 419-422).
  • dementia correlates more closely with the levels of soluble amyloid rather than plaque burden (Naslund, J.
  • a ⁇ is known to be produced through the cleavage of the beta amyloid precursor protein (also known as APP) by a ⁇ aspartyl protease enzyme known as Asp2 (also known as ⁇ - secretase, BACE1 or Memapsin-2) (De Strooper, B. and Konig, G. (1999) Nature 402: 471-472).
  • Asp2 also known as ⁇ - secretase, BACE1 or Memapsin-2
  • APP is cleaved by a variety of proteolytic enzymes (De Strooper, B. and Konig, G. (1999) Nature 402: 471-472).
  • the key enzymes in the amyloidogenic pathway are Asp2 ( ⁇ -secretase) and ⁇ -secretase both of which are aspartic proteinases and cleavage of APP by these enzymes generates A ⁇ .
  • the non-amyloidogenic, ⁇ -secretase pathway which precludes A ⁇ formation, has been shown to be catalysed by a number of proteinases, the best candidate being ADAM10, a disintegrin and metalloproteinase.
  • Asp1 has been claimed to show both ⁇ - and ⁇ -secretase activity in vitro.
  • Asp2 is most highly expressed in the pancreas and brain while Asp1 expression occurs in many other peripheral tissues.
  • the Asp2 knockout mouse indicates that lack of Asp2 abolished A ⁇ production and also shows that in this animal model endogenous Asp1 cannot substitute for the Asp2 deficiency (Luo, Y. et al. (2001 ) Nat Neurosci. 4: 231-232; Cai, H. et al. (2001) Nat Neurosci. 4: 233-234; Roberds, S. L. et al. (2001) Hum. MoI. Genet. 10: 1317-1324).
  • said agent is a potent inhibitor of the Asp2 enzyme, but should ideally also be selective for Asp2 over other enzymes of the aspartyl proteinase family, e.g. Cathepsin D (Connor, G. E. (1998) Cathepsin D in Handbook of Proteolytic Enzymes, Barrett, A. J., Rawlings, N. D., & Woesner, J. F. (Eds) Academic Press London. pp828- 836).
  • Cathepsin D Connor, G. E. (1998) Cathepsin D in Handbook of Proteolytic Enzymes, Barrett, A. J., Rawlings, N. D., & Woesner, J. F. (Eds) Academic Press London. pp828- 836).
  • WO 2004/014843 Takeda
  • WO 2004/043916 Merck
  • WO2005/058915 describes a series of hydroxyethylamine compounds having ⁇ -secretase activity, and their use in the treatment of Alzheimer's disease.
  • R 1 represents halogen or C 1-3 alkyl
  • R 2 represents C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen, C 1-3 alkoxy, amino, cyano or hydroxy; m represents an integer from 0 to 4; n represents an integer from 0 to 2;
  • A-B represents -NR 5 -SO 2 -;
  • R 5 represents hydrogen, C 1-6 alkyl, C 3-6 alkenyl, C 3 . 6 alkynyl, C 3- i 0 cycloalkyl, -C 0-6 alkyl- aryl, -C 0-6 alkyl-heteroaryl, -C 0-8 alkyl-heterocyclyl, -C 3-10 cycloalkyl-aryl, -C 3-10 cycloalkyl- heteroaryl or -C 3-10 cycloalkyl-heterocyclyl;
  • R 8 represents hydrogen, C 1-6 alkyl or C 3-10 cycloalkyl
  • R 9 represents hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, -C 0-6 alkyl-aryl, -C 0-6 alkyl- heteroaryl, -C 0-6 alkyl-heterocyclyl, -C 3-10 cycloalkyl-aryl, -C 3-10 cycloalkyl-heteroaryl or - C 3-10 cycloalkyl-heterocyclyl;
  • R 3 represents C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-6 alkyl-C 3 . 10 cycloalkyl, -C 0-6 alkyl- aryl, -C 0-6 alkyl-heteroaryl or -C 0-6 alkyl-heterocyclyl;
  • R 4 represents hydrogen, C 1-10 alkyl, C 3-10 alkenyl, C 3-10 alkynyl, -C 3-10 cycloalkyl, -C 3-10 cycloalkenyl, -C 0-6 alkyl-aryl, -C 0-6 alkyl-heteroaryl, -C 0-6 alkyl-heterocyclyl, -C 1-6 alkyl-C 3- 1o cycloalkyl, -C 3- - I0 cycloalkyl-aryl, -C 3-10 cycloalkyl-heteroaryl, -C 3-10 cycloalkyl- heterocyclyl, -C(R a R b )-CONH-C 1-6 alkyl, -C(R a R b )-CONH-C 3- i 0 cycloalkyl, -C 2-6 alkyl-S-d.
  • alkyl -C 2-6 alkyl-NR c R d , -C 2-6 alkyl-0-C o-6 alkyl-aryl, -C 2-6 alkyl-O-C 0-6 alkyl-heteroaryl or -C 2-6 alkyl-O-C 0-6 alkyl-heterocyclyl;
  • R a and R b independently represent hydrogen, Ci -6 alkyl or R a and R b together with the carbon atom to which they are attached may form a C 3-10 cycloalkyl or heterocyclyl group;
  • R c and R d independently represent hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl or R c and R d together with the nitrogen atom to which they are attached may form a nitrogen containing heterocyclyl group; wherein said alkyl and cycloalkyl groups may be optionally substituted by one or more (e.g.
  • aryl, heteroaryl or heterocyclyl groups may be optionally substituted by one or more (e.g.
  • the invention provides compounds of formula (I) wherein: R 1 represents halogen or C 1-3 alkyl;
  • R 2 represents C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen, C 1-3 alkoxy, amino, cyano or hydroxy;
  • m represents an integer from O to 4;
  • n represents an integer from O to 2;
  • A-B represents -NR 5 -SO 2 - or -NR 5 -CO-;
  • R 8 represents hydrogen, C 1-6 alkyl or C 3-10 cycloalkyl
  • R 9 represents hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C3-10 cycloalkyl, -C 0-6 alkyl-aryl, -C 0-6 alkyl- heteroaryl, -C 0-6 alkyl-heterocyclyl, -C 3-10 cycloalkyl-aryl, -C 3-10 cycloalkyl-heteroaryl or - C 3-10 cycloalkyl-heterocyclyl;
  • R 3 represents C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-6 alkyl-C 3-10 cycloalkyl, -C 0-6 alkyl- aryl, -C 0-6 alkyl-heteroaryl or -C 0-6 alkyl-heterocyclyl;
  • R 4 represents hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, -C 3- i 0 cycloalkenyl, -C 0-6 alkyl-aryl, -C 0-6 alkyl-heteroaryl, -C 0-6 alkyl-heterocyclyl, -C 0-6 alkyl-C 3-10 cycloalkyl, -C 3-10 cycloalkyl-aryl, -C 3- io cycloalkyl-heteroaryl, -C 3-10 cycloalkyl-heterocyclyl, -C(R a R b )- CONH-C 1-6 alkyl, -C(R a R b )-CONH-C 3-10 cycloalkyl, -C 2-6 alkyl-S-C 1-6 alkyl, -C 2-6 alkyl- NR c R d , -C(
  • R a and R b independently represent hydrogen, Ci -6 alkyl or R a and R b together with the carbon atom to which they are attached may form a C 3-10 cycloalkyl or heterocyclyl group;
  • R c and R d independently represent hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl or R c and R d together with the nitrogen atom to which they are attached may form a nitrogen containing heterocyclyl group; wherein said alkyl and cycloalkyl groups may be optionally substituted by one or more (e.g. 1 to 6) halogen, C 1-6 alkyl, haloC-i -6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 alkylamino, amino, cyano, hydroxy or -COOR 22 groups; and wherein said aryl, heteroaryl or heterocyclyl groups may be optionally substituted by one or more (e.g.
  • R 4 represents hydrogen, C 1-I0 alkyl, C 3-10 alkenyl, C 3-10 alkynyl, -C 3-10 cycloalkenyl, -C 0-6 alkyl-aryl, -C 0-6 alkyl-heteroaryl, -C 0-6 alkyl-heterocyclyl, -C 0-6 alkyl-C 3-10 cycloalkyl, -C 3-10 cycloalkyl-aryl, -C 3-10 cycloalkyl-heteroaryl, -C 3-10 cycloalkyl-heterocyclyl, -C(R a R b )-C0NH-C 1-6 alkyl, -C(R a R b )-CONH-C 3-10 cycloalkyl, -C 2-6 alkyl-S-C 1-6 alkyl, -C 2-6 alkyl-NR d , -
  • A-B represents -NR 5 -SO 2 -.
  • the term 'C x-y alkyl' as used herein as a group or a part of the group refers to a linear or branched saturated hydrocarbon group containing from x to y carbon atoms. Examples of C 1-6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like.
  • C x-y alkenyl' refers to a linear or branched hydrocarbon group containing one or more carbon-carbon double bonds and having from x to y carbon atoms.
  • Examples of C 2-6 alkenyl groups include ethenyl, propenyl, butenyl, pentenyl or hexenyl and the like.
  • C x-y alkynyl' refers to a linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds and having from x to y carbon atoms.
  • Examples of C 2-6 alkynyl groups include ethynyl, propynyl, butynyl, pentynyl or hexynyl and the like.
  • C x-y alkoxy' refers to an -O-C x-y alkyl group wherein C x-y alkyl is as defined herein.
  • Examples of C 1-6 alkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like.
  • 'C x-y cycloalkyl' refers to a saturated monocyclic or bridged hydrocarbon ring of x to y carbon atoms.
  • saturated monocyclic C 3- - I0 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the like.
  • bridged hydrocarbon rings include tricyclodecyl, bicycloheptyl and the like.
  • the term 'C x-y cycloalkyl' refers to a saturated monocyclic hydrocarbon ring.
  • C x-y cycloalkenyl' refers to an unsaturated non-aromatic monocyclic hydrocarbon ring of x to y carbon atoms containing one or more carbon- carbon double bonds.
  • Examples of C 3-10 cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl and the like.
  • 'halogen' refers to a fluorine, chlorine, bromine or iodine atom.
  • 'haloC x-y alkyl' refers to a C x-y alkyl group as defined herein wherein at least one hydrogen atom is replaced with halogen.
  • haloC 1-6 alkyl groups include fluoroethyl, trifluoromethyl or trifluoroethyl and the like.
  • alkoxy' refers to a C x-y alkoxy group as herein defined wherein at least one hydrogen atom is replaced with halogen.
  • haloC ⁇ 6 alkoxy groups include difluoromethoxy or trifluoromethoxy and the like.
  • 'aryl' refers to a C 6-I2 monocyclic or bicyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl, naphthyl or tetrahydronaphthalenyl and the like.
  • heteroaryl refers to a 5-6 membered monocyclic aromatic or a fused 8-10 membered bicyclic aromatic ring, which monocyclic or bicyclic ring contains 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur.
  • Examples of such monocyclic aromatic rings include thienyl, furyl, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, triazinyl, tetrazinyl and the like.
  • fused aromatic rings include quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pteridinyl, cinnolinyl, phthalazinyl, naphthyridinyl, indolyl, isoindolyl, azaindolyl, indolizinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like.
  • heterocyclyl refers to a 4-7 membered monocyclic ring or a fused 8-12 membered bicyclic ring which may be saturated or partially unsaturated, which monocyclic or bicyclic ring contains 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur.
  • Examples of such monocyclic rings include pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, diazepanyl, azepanyl and the like.
  • bicyclic rings examples include indolinyl, isoindolinyl, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydro-1/-/-3-benzazepine, tetrahydroisoquinolinyl and the like.
  • heterocyclyl' is intended to represent any heterocyclyl group as defined above which contains a nitrogen atom.
  • R 5 represents hydrogen, C 1-6 alkyl (e.g. methyl, ethyl or i-propyl) optionally substituted by one or more (e.g. 1 , 2 or 3) halogen atoms (e.g. trifluoroethyl)or -Co- 6 alkyl-aryl (e.g. phenyl or benzyl).
  • C 1-6 alkyl e.g. methyl, ethyl or i-propyl
  • halogen atoms e.g. trifluoroethyl
  • -Co- 6 alkyl-aryl e.g. phenyl or benzyl
  • R 5 represents C 1-6 alkyl (e.g. methyl or ethyl) optionally substituted by one or more (e.g. 1 , 2 or 3) halogen atoms (e.g. trifluoroethyl). Even more particularly, R 5 represents unsubstituted C 1-6 alkyl (e.g. methyl or ethyl) particularly methyl.
  • m represents 0 or 2. In a more particular embodiment, m represents 0-1 , particularly 0.
  • R 1 represents C 1-3 alkyl (e.g. methyl).
  • n 0.
  • R 8 represents hydrogen
  • R 9 represents hydrogen or C 1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl or butyl). In a more particular embodiment, R 9 represents Ci -6 alkyl (e.g. ethyl, propyl, isopropyl or butyl), particularly ethyl.
  • R 3 represents -C 0-6 alkyl-aryl (e.g. benzyl) optionally substituted by one or two halogen atoms (e.g. chlorine or fluorine).
  • R 3 preferably represents unsubstituted benzyl, 3-chlorobenzyl, 3-fluorobenzyl or 3,5-difluorobenzyl.
  • R 3 represents unsubstituted benzyl.
  • R 4 represents C 1-10 alkyl, C 3-10 alkenyl, C 3- i 0 alkynyl, C o-6 alkylC 3- 1o cycloalkyl (i.e. C 3- i 0 cycloalkyl and/or C 1-6 alkylC 3-10 cycloalkyl), C ⁇ ocycloalkenyl, C 0 . 6 alkyl-aryl, C o-6 alkyl-heteroaryl, Coealkyl-heterocyclyl or C 2-6 alkyl-S-C 1-6 alkyl.
  • the aryl, heteroaryl and heterocyclyl groups of R 4 may optionally be substituted by one or more (e.g. 1 , 2 or 3) substituents selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl and haloC 1-6 alkoxy. More particularly, the substituents are selected from the group consisting of C 1-6 alkyl, Ci- 6 alkoxy or haloCi_ 6 alkyl.
  • the substituent is in the 3- position relative to the attachment position.
  • the alkyl, and cycloalkyl groups of R 4 may optionally be substituted by one or more (e.g. 1 to 6) substituents selected from the group consisting of halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy and C 2-6 alkynyl. More particularly, the substituents are selected from halogen, C 1-6 alkoxy, haloC 1-6 alkoxy and C 2-6 alkynyl.
  • R 4 represents:
  • C 1-10 alkyl e.g. ethyl, propyl, butyl, 1-methylpropyl, 2-ethylbutyl, 3-methyl butyl, 1- propylbutyl, 3, 3-d i methyl butyl, 1 ,5-dimethylhexyl or 1 ,1 ,5-trimethylhexyl
  • halogen e.g fluorine
  • C 1-6 alkoxy groups e.g. methoxy or propoxy
  • haloC 1-6 alkoxy groups e.g. 2,2,2-trifluoroethoxy
  • C 3-10 alkenyl e.g. propenyl, 2-methyl-2-propenyl, 3-butenyl, 3-methyl-2-butenyl;
  • C 3-I0 alkynyl e.g. propynyl, 2-butynyl, 2-pentynyl, 1 ,1-dimethyl-2-propynyl
  • C 0-6 alkylC 3 . 1o cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropylmethyl, cyclohexylethyl, tricyclodecyl or bicycloheptyl
  • optionally substituted by one or more halogen atoms e.g. fluorine
  • C 1-6 alkyl groups e.g. methyl, ethyl or propyl
  • C 2-6 alkynyl e.g. ethynyl
  • C 3-1o cycloalkenyl e.g. cyclopentenyl
  • C o-6 alkyl-aryl e.g. phenyl or benzyl
  • optionally substituted by one or more halogen e.g. chlorine
  • C 1-6 alkyl e.g. methyl
  • Ci -6 alkoxy e.g. methoxy
  • haloC-i. 6 alkyl e.g. trifluoromethyl
  • haloC 1-6 alkoxy e.g. trifluoromethoxy
  • C o-6 alkyl-heteroaryl e.g. CH 2 -thienyl, CH 2 -isoxazolyl, CH 2 -pyrazolyl or CH 2 - pyridinyl
  • C 1-6 alkyl e.g. methyl or ethyl
  • haloC-i. 6 alkyl e.g. 2,2,2-trifluoroethyl
  • Co ⁇ alkyl-heterocyclyl e.g. tetrahydropyranyl
  • C 2-6 alkyl-S-C 1-6 alkyl e.g. -ethyl-S-methyl, -ethyl-S-ethyl or -ethyl-S-tert butyl.
  • R 4 represents: C 1-10 alkyl (e.g. ethyl, propyl, butyl, 1-methylpropyl, 2-ethylbutyl, 3-methyl butyl, 1- propylbutyl, 3,3-dimethylbutyl, 1 ,5-dimethylhexyl or 1,1,5-trimethylhexyl) optionally substituted by one or more halogen (e.g.
  • fluorine atoms (to give, for example, 2- fluoroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 3-fluoropropyl, 3,3,3-trifluoropropyl or 2,2,3,3, 3-pentafluoropropyl), C 1-6 alkoxy groups (e.g. methoxy or propoxy) or haloC ⁇ 6 alkoxy groups (e.g. 2,2,2-trifluoroethoxy); C 3-10 alkynyl (e.g. propynyl);
  • C o-6 alkylC 3- io cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropylmethyl or cyclohexylethyl
  • optionally substituted by one or more halogen atoms e.g. fluorine
  • C 1-6 alkyl groups e.g. methyl, ethyl or propyl
  • C o-6 alkyl-aryl e.g. phenyl or benzyl
  • halogen e.g. chlorine
  • Ci -6 alkoxy e.g. methoxy
  • haloC-i. 6 alkyl e.g. trifluoromethyl
  • haloCi -6 alkoxy e.g. trifluoromethoxy
  • C 0-6 alkyl-heteroaryl e.g. CH 2 -thienyl, CH 2 -isoxazol, CH 2 -pyrazolyl or CH 2 - pyridinyl
  • C 1-6 alkyl e.g. methyl or ethyl
  • haloC-i. 6 alkyl e.g. 2,2,2-trifluoroethyl
  • Co ⁇ alkyl-heterocyclyl e.g. tetrahydropyranyl
  • R 4 represents heterocyclyl (e.g. tetrahydropyranyl) or C 3- - I0 alkynyl (e.g. propynyl). Most particularly, R 4 represents heterocyclyl (e.g. tetrahydropyranyl), particularly tetrahydropyran-4-yl.
  • the invention provides compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, wherein: m and n represent 0;
  • A-B represents -NR 5 -SO 2 -;
  • R 5 represents C 1-6 alkyl;
  • R 8 represents hydrogen
  • R 9 represents C 1-6 alkyl
  • R 3 represents -C 0-6 alkyl-aryl
  • R 4 represents C 1-10 alkyl, C 3- i 0 alkenyl, C 3-1o alkynyl, C 0-6 alkylC 3-1o cycloalkyl, C 3-
  • alkyl and cycloalkyl groups of R 4 may be optionally substituted by one or more (e.g. 1 to 6) halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy or C 2-
  • aryl, heteroaryl and heterocyclyl groups of R 4 may optionally be substituted by one or more (e.g. 1 , 2 or 3) halogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl and haloC 1-6 alkoxy groups.
  • the invention provides compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, wherein: m and n represent 0;
  • A-B represents -NR 5 -SO 2 -;
  • R 5 represents C 1-6 alkyl;
  • -W- represents -(CH 2 ) 2 -;
  • R 8 represents hydrogen
  • R 9 represents Ci -6 alkyl
  • R 3 represents benzyl
  • R 4 represents C 1-10 alkyl, C 3- i 0 alkynyl, C 0-6 alkylC 3-1o cycloalkyl, C o-6 alkyl-aryl, C o-6 alkyl- heteroaryl or C 0-6 alkyl-heterocyclyl; wherein the alkyl and cycloalkyl groups of R 4 may be optionally substituted by one or more (e.g. 1 to 6) halogen, C 1-6 alkyl, C 1 ⁇ aIkOXy, haloC 1-6 alkoxy or C 2-6 alkynyl groups; and wherein the aryl, heteroaryl and heterocyclyl groups of R 4 may optionally be substituted by one or more (e.g. 1 , 2 or 3) C 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkyl groups.
  • Compounds according to the invention include example E1 as shown below, or a pharmaceutically acceptable salt or solvate thereof.
  • the compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. ScL, 1977, 66, 1-19, such as acid addition salts formed with inorganic or organic acids e.g.
  • the present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
  • a pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamaic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2- naphthalenesulfonic, or hexanoic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration.
  • a suitable inorganic or organic acid such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic
  • the compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be solvated, e.g. as the hydrate.
  • the invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I) including hydrates and solvates as well as compounds containing variable amounts of solvent (e.g water).
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • compounds of formula (I) are in the form of a single enantiomer of formula (Ia):
  • R 1 , R 2 , R 3 , R 4 , m, n, A, B, W, X, Y and Z are as defined above and P 1 represents a suitable protecting group such as -COOC(CH 3 ) 3 followed by deprotection to remove the P 1 protecting group;
  • Process (a) typically comprises the use of an oxidising reagent such as Dess-Martin periodinane in an appropriate solvent such as dichloromethane at an appropriate range of temperature such as O 0 C to room temperature.
  • an oxidising reagent such as Dess-Martin periodinane
  • an appropriate solvent such as dichloromethane
  • Suitable amine protecting groups include aryl sulphonyl (e.g. tosyl), acyl (e.g. acetyl), carbamoyl (e.g. benzyloxycarbonyl or t- butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis or hydrogenolysis as appropriate.
  • aryl sulphonyl e.g. tosyl
  • acyl e.g. acetyl
  • carbamoyl e.g. benzyloxycarbonyl or t- butoxycarbonyl
  • arylalkyl e.g. benzyl
  • Suitable amine protecting groups include trifluoroacetyl (-COCF 3 ) which may be removed by base catalysed hydrolysis.
  • Suitable hydroxy protecting groups would be silyl based groups such as t-butyldimethylsilyl, which may be removed using standard methods, for example use of an acid such as trifluoroacetic or hydrochloric acid or a fluoride source such as tetra n-butylammonium fluoride.
  • Process (c) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, aromatic substitution, ester hydrolysis, amide bond formation or removal and sulphonylation.
  • Compounds of formula (II) may be prepared in accordance with procedures described in WO2005/058915 (published 30 June 2005), which claims priority from GB Patent Application 0328900.6.
  • a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use as a pharmaceutical, particularly in the treatment of patients with diseases characterised by elevated ⁇ - amyloid levels or ⁇ -amyloid deposits.
  • a compound of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of patients with diseases characterised by elevated ⁇ - amyloid levels or ⁇ -amyloid deposits.
  • a method for the treatment of a human or animal subject with diseases characterised by elevated ⁇ -amyloid levels or ⁇ -amyloid deposits comprises administering to said human or animal subject an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof.
  • composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of diseases characterised by elevated ⁇ -amyloid levels or ⁇ -amyloid deposits.
  • the compounds according to the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions for use in the therapy of diseases characterised by elevated ⁇ -amyloid levels or ⁇ -amyloid deposits, comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together, if desirable, with one or more physiologically acceptable diluents or carriers.
  • diseases characterised by elevated ⁇ -amyloid levels or ⁇ - amyloid deposits include Alzheimer's disease, mild cognitive impairment, Down's syndrome, hereditary cerebral haemorrhage with ⁇ -amyloidosis of the Dutch type, cerebral ⁇ -amyloid angiopathy and various types of degenerative dementias, such as those associated with Parkinson's disease, progressive supranuclear palsy, cortical basal degeneration and diffuse Lewis body type of Alzheimer's disease.
  • the disease characterised by elevated ⁇ -amyloid levels or ⁇ -amyloid deposits is Alzheimer's disease.
  • Compounds of formula (I) may be used in combination with other therapeutic agents.
  • suitable examples of such other therapeutic agents may be acetylcholine esterase inhibitors (such as tetrahydroaminoacridine, donepezil hydrochloride and rivastigmine), gamma secretase inhibitors, histamine H3 antagonists, 5HT4 partial agonists, antiinflammatory agents (such as cyclooxygenase Il inhibitors), antioxidants (such as Vitamin E and ginkolidesor), statins or p-glycoprotein (P-gp) inhibitors (such as cyclosporin A, verapamil, tamoxifen, quinidine, Vitamin E-TGPS, ritonavir, megestrol acetate, progesterone, rapamycin, 10,11-methanodibenzosuberane, phenothiazines, acridine derivatives such as GF120918, FK506, VX-710
  • the compounds When the compounds are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • the compounds according to the invention may, for example, be formulated for oral, inhaled, intranasal, buccal, enteral, parenteral, topical, sublingual, intrathecal or rectal administration, preferably for oral administration.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, cellulose or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, maize- starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl p- hydroxybenzoates or sorbic acid.
  • the preparations may also contain buffer salts, flavouring, colouring and/or sweetening
  • the compounds may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds according to the invention may also be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form, for instance as ampoules, vials, small volume infusions or pre-filled syringes, or in multi-dose containers with an added preservative.
  • the compositions may take such forms as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles, and may contain formulatory agents such as anti-oxidants, buffers, antimicrobial agents and/or tonicity adjusting agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • the dry solid presentation may be prepared by filling a sterile powder aseptically into individual sterile containers or by filling a sterile solution aseptically into each container and freeze-drying.
  • the compounds of the invention When the compounds of the invention are administered topically they may be presented as a cream, ointment or patch.
  • composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
  • suitable unit doses may be 0.05 to 3000 mg; and such unit doses may be administered more than once a day, for example one, two, three or four times per day (preferably once or twice); and such therapy may extend for a number of weeks, months or years.
  • Solvents A. Water + 0.05% Formic acid
  • TAMRA 5 tetramethyl rhodamine
  • TAMRA 5 tetramethyl rhodamine
  • 10 ⁇ l enzyme solution This is prepared by performing a 1 in 1750 dilution of a 3.5 ⁇ M enzyme stock in buffer B (100 mM Sodium acetate pH 4.5, 40 mM Sodium chloride, 10% (v/v) Glycerol, 0.2% (w/v) CHAPS).
  • Example E1 The compound of Example E1 was tested in the Asp-2 inhibitory assay and the Cathepsin D inhibitory assay and exhibited inhibition ⁇ 10 ⁇ M in the Asp-2 inhibitory assay and > 10 fold selectivity for Asp2 over CatD.

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Abstract

L'invention concerne de nouveaux composés de cétones de formules (I), dans laquelle, notamment, A-B représentent NR5p SO2-; W représente -CH2-, -(CH2)2-, -(CH2)3- ou -C(H)=C(H)-; X-Y-Z représentent -C=CR8-NR9-, présentant une activité d'inhibition de l'Asp2 (ß-sécrétase, BACE1 ou mémapsine 2). L'invention concerne également des procédés de préparation des composés, des compositions les contenant et leur utilisation dans le traitement de maladies caractérisées par des taux élevés de ß-amyloïde ou de dépôts de ß-amyloïdes, en particulier la maladie d'Alzheimer.
PCT/EP2005/011002 2004-10-13 2005-10-11 Composes heterocycliques de cetones pour traiter la maladie d'alzheimer WO2006040149A1 (fr)

Applications Claiming Priority (2)

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GB0422765.8 2004-10-13
GBGB0422765.8A GB0422765D0 (en) 2004-10-13 2004-10-13 Novel compounds

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