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WO2006040151A1 - Composes d'hydroxyethylamine substitues pour le traitement de la maladie d'alzheimer - Google Patents

Composes d'hydroxyethylamine substitues pour le traitement de la maladie d'alzheimer Download PDF

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Publication number
WO2006040151A1
WO2006040151A1 PCT/EP2005/011004 EP2005011004W WO2006040151A1 WO 2006040151 A1 WO2006040151 A1 WO 2006040151A1 EP 2005011004 W EP2005011004 W EP 2005011004W WO 2006040151 A1 WO2006040151 A1 WO 2006040151A1
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alkyl
cycloalkyl
heterocyclyl
aryl
heteroaryl
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PCT/EP2005/011004
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WO2006040151A8 (fr
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Emmanuel Hubert Demont
Sally Redshaw
Daryl Simon Walter
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Glaxo Group Limited
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Publication of WO2006040151A8 publication Critical patent/WO2006040151A8/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 hydroxyethylamine compounds having Asp2 ( ⁇ - 5 secretase, BACE 1 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.
  • Alzheimer's disease is a degenerative brain disorder in which extracellular deposition of 0 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, ⁇ - amyloid (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) 5 Neuron 27: 419-422).
  • a ⁇ is known to be produced through the cleavage of the beta amyloid precursor protein (also known as APP) by an aspartyl protease enzyme known as Asp2 (also known as ⁇ - 0 secretase, BACE1 or Memapsin-2) (De Strooper, B. and Konig, G. (1999) Nature 402: 471-472).
  • 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 0 ( ⁇ -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.
  • the pattern of 5 expression of Asp1 and Asp2 are quite different, 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 0 Neurosci. 4: 233-234; Roberds, S. L. et al. (2001) Hum. MoI.
  • an agent to be therapeutically useful in the treatment of Alzheimer's disease it is preferable that 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 01/70672 WO 02/02512, WO 02/02505 and WO 02/02506 (Elan Pharmaceuticals Inc.) describe a series of hydroxyethylamine compounds having ⁇ -secretase activity which are implicated to be useful in the treatment of Alzheimer's disease.
  • WO2004/094430 (Glaxo Group Ltd.; published 4 November 2004) describes a series of tricyclic indole derivatives 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 3-10 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- - I0 cycloalkyl-heterocyclyl;
  • R 8 represents hydrogen, C 1-6 alkyl or C 3- - I0 cycloalkyl;
  • R 9 represents hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3- -I 0 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- io 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- i 0 alkenyl, C 3-10 alkynyl, -C 3- - I0 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- 10 cycloalkyl, -C 3-10 cycloalkyl-aryl, -C 3- - I0 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-d.
  • R a and R b independently represent hydrogen, C 1-6 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, Ci -6 alkyl, haloCi_ 6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, Ci -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.
  • the present invention provides a compound 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 0 to 4; n represents an integer from 0 to 2; A-B represents -NR 5 -SO 2 - or -NR 5 -CO-; R 5 represents hydrogen, C 1-6 alkyl, C 3-6 alkenyl, C 3 .
  • 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- i 0 cycloalkyl-heteroaryl or - C 3-10 cycloalkyl-heterocyclyl;
  • R 3 represents Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-6 alkyl-C 3- i 0 cycloalkyl, -C 0-6 alkyl- aryl, -C 0-6 alkyl-heteroaryl or -C 0-6 alkyl-heterocyclyl;
  • R 4 represents hydrogen, Ci -10 alkyl, C 2- io alkenyl, C 2-10 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- i 0 cycloalkyl, -C 3-10 cycloalkyl-aryl, -C 3-10 cycloalkyl-heteroaryl, -C 3-10 cycloalky
  • 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 0 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 1-6 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.
  • W represents -(CH 2 ) 3 -.
  • R 4 represents hydrogen, C 1-10 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- io cycloalkyl, -C 3 .
  • A-B represents -NR 5 -SO 2 -.
  • C x-y alkyl' 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 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 hydrocarbon ring of x to y carbon atoms.
  • Examples of C 3-10 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the like.
  • 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.
  • 'halo C x-y alkoxy' refers to a C x-y alkoxy group as herein defined wherein at least one hydrogen atom is replaced with halogen.
  • halo Ci. 6 alkoxy groups include difluoromethoxy or trifluoromethoxy and the like.
  • 'aryl' as used herein refers to a C 6- i2 monocyclic or bicyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl, riaphthyl 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-1H-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 -C 0-6 alkyl-aryl (e.g. phenyl or benzyl).
  • C 1-6 alkyl e.g. methyl, ethyl or i-propyl
  • halogen atoms e.g. trifluoroethyl
  • -C 0-6 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), particularly methyl.
  • -W- represents -(CH 2 ) 3 -.
  • m represents 0-2, more particularly, 0 or 1 and most particularly 0.
  • R 1 is C 1-3 alkyl (e.g. methyl).
  • n 0.
  • R 8 represents hydrogen
  • R 9 represents hydrogen or Ci -6 alkyl (e.g. methyl, ethyl, propyl or isopropyl). In a more particular embodiment, R 9 represents C 1-6 alkyl (e.g. ethyl, propyl or isopropyl). Most particularly, R 9 represents propyl.
  • 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 may represent unsubstituted benzyl, 3-chlorobenzyl, 3-fluorobenzyl or 3,5-difluorobenzyl.
  • R 3 represents unsubstituted benzyl.
  • R 4 represents hydrogen, C 1-10 alkyl, C 3-10 alkenyl, C 3-10 alkynyl, -C 0-6 alkyl-C 3-8 cycloalkyl (i.e. -C 3- i 0 cycloalkyl and -C 1-6 alkyl-C 3-8 cycloalkyl), -C 0-6 alkyl-aryl, - C 0-6 alkyl-heteroaryl, -C 0-6 alkyl-heterocyclyl, -C(R a R b )-CONH-C 3-10 cycloalkyl or -C 3-10 cycloalkyl-aryl.
  • 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, haloCi -6 alkoxy and - CONR 22 R 23 , wherein R 22 and R 23 independently represent hydrogen or C 1-6 alkyl. More particularly, the substituents are selected from the group consisting of C 1-6 alkoxy.
  • 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 and haloC 1-6 alkoxy. More particularly, the substiutents are selected from the group consisting of halogen and C 1-6 alkoxy.
  • R 4 represents hydrogen; C 1-10 alkyl (e.g. methyl, ethyl, i-propyl, propyl, methylpropyl, dimethylethyl, butyl, 1 ,5-dimethylhexyl or 1 ,1 ,5-trimethylhexyl) optionally substituted by one or more halogen (e.g. fluoroethyl, difluoroethyl, trifluoroethyl or pentafluoropropyl) or C 1-6 alkoxy (e.g. methoxy) groups; C 3-10 alkenyl (e.g. ethenyl);
  • C 1-10 alkyl e.g. methyl, ethyl, i-propyl, propyl, methylpropyl, dimethylethyl, butyl, 1 ,5-dimethylhexyl or 1 ,1 ,5-trimethylhexyl
  • halogen e
  • C 3-10 alkynyl e.g. propynyl
  • -C 0-6 alkyl-C 3-8 cycloalkyl e.g. -CH ⁇ cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
  • halogen atoms e.g. fluorine
  • C 1-6 alkyl groups e.g. methyl
  • -C 0-6 alkyl-aryl e.g. phenyl, dihydroindenyl, benzyl, 1-methyl-1-phenylethyl, ethylphenyl or ⁇ , ⁇ -dimethylbenzyl
  • optionally substituted e.g.
  • halogen cyano, nitro, haloCi -6 alkyl (e.g. -CF 3 ), haloC 1-6 alkoxy (e.g. -OCF 3 ), C 1-6 alkyl (e.g. methyl), C 1-6 alkoxy (e.g. methoxy), C 2-6 alkynyl, C 2-6 alkenyl, amino, -NR 22 COR 23 , -CONR 22 R 23 -SO 2 R 22 , -SO 2 NR 22 R 23 , -COOR 22 , -C 1-6 alkyl-NR 22 R 23 , -C 1-6 alkanoyl or hydroxy groups;
  • -C 0-6 alkyl-heteroaryl e.g. -pyridinyl, -CH 2 -pyrazolyl, -CH 2 -pyridinyl, -CH 2 - quinoxalinyl, -CH 2 -quinolinyl, -CH 2 -thienyl, -CH 2 -pyrazinyl or -CH 2 -isoxazolyl
  • optionally substituted by one or more C 1-6 alkyl e.g. methyl or ethyl
  • halogen e.g. bromine
  • haloC 1-6 alkyl e.g. trifluoroethyl
  • -CONR 22 R 23 e.g. -CONHMe
  • -C 0-6 alkyl-heterocyclyl e.g. tetrahydropyranyl
  • C 1-6 alkyl e.g. methyl
  • R a and R b independently represent hydrogen or methyl, or R a and R b together with the carbon atom to which they are attached form a cyclopropyl or cyclohexyl group. More particularly R a and R b both represent hydrogen, both represent methyl or together with the carbon atom to which they are attached form a cyclopropyl group.
  • R 4 represents hydrogen
  • C 1-I0 alkyl e.g. methyl, ethyl, i-propyl, propyl, methylpropyl, dimethylethyl, butyl, or 1 ,1 ,5-trimethylhexyl
  • halogen e.g. fluoroethyl, difluoroethyl, trifluoroethyl or pentafluoropropyl
  • C 1-6 alkoxy e.g. methoxy
  • C 3-10 alkynyl e.g. propynyl
  • -C 0-6 alkyl-C 3-8 cycloalkyl (e.g. -CH 2 -cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) optionally substituted by one or more halogen atoms (e.g. fluorine); -C 0-6 alkyl-aryl (e.g. dihydroindenyl, benzyl, ethylphenyl or ⁇ , ⁇ -dimethylbenzyl) optionally substituted (e.g. substituted at the 3 position) by one or more haloC 1-6 alkyl (e.g. -CF 3 ), haloC 1-6 alkoxy (e.g. -OCF 3 ), C t-6 alkyl (e.g. methyl) or C 1-6 alkoxy (e.g. methoxy) groups;
  • halogen atoms e.g. fluorine
  • -Co- 6 alkyl-heteroaryl e.g. -pyridinyl, -CH 2 -pyrazolyl, -CH 2 -pyridinyl, -CH 2 - quinoxalinyl, -CH 2 -quinolinyl, -CH 2 -thienyl, -CH 2 -pyrazinyl or -CH 2 -isoxazolyl
  • C 1-6 alkyl e.g. methyl or ethyl
  • halogen e.g. bromine
  • haloC 1-6 alkyl e.g. trifluoroethyl
  • R 4 represents
  • cycloalkyl e.g. cyclopropyl
  • C 0-6 alkyl-aryl e.g. benzyl
  • optionally substituted e.g. substituted at the 3 and 5 positions
  • C 1-6 alkoxy e.g. methoxy
  • the invention provides compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, wherein:
  • A-B represents -NR 5 -SO 2 -;
  • R 5 represents hydrogen or C 1-6 alkyl optionally substituted by one or more (e.g. 1 , 2 or 3) halogen atoms;
  • -W- represents -(CH 2 ) 3 -;
  • R 8 represents hydrogen
  • R 9 represents C 1-6 alkyl
  • R 3 represents -C 0-6 alkyl-aryl optionally substituted by one or two halogen atoms
  • R 4 represents hydrogen, C 1-10 alkyl, C 3-10 alkenyl, C 3-10 alkynyl, -C 0-6 alkyl-C 3-8 cycloalkyl, - C 0-6 alkyl-aryl, -C 0-6 alkyl-heteroaryl, -C 0-6 alkyl-heterocyclyl, -C(R a R b )-CONH-C 3-10 cycloalkyl or -C 3-10 cycloalkyl-aryl;
  • R a and R b independently represent hydrogen or methyl, or R a and R b together with the carbon atom to which they are attached may form a cyclopropyl or cyclohexyl group; wherein said 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-i -6 alkoxy and haloC 1-6 alkoxy groups; and wherein said aryl, heteroaryl or heterocyclyl groups of R 4 may be optionally substituted by one or more (e.g.
  • halogen C 1-6 alkyl, Ci -6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy and -CONR 22 R 23 groups (wherein R 22 and R 23 independently represent hydrogen or C 1-6 alkyl).
  • 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 hydrogen or C 1-6 alkyl optionally substituted by one or more (e.g. 1 , 2 or 3) halogen atoms;
  • -W- represents -(CH 2 ) 3 -;
  • R 8 represents hydrogen
  • R 9 represents C 1-6 alkyl
  • R 3 represents benzyl
  • R 4 represents hydrogen, C 1-10 alkyl, C 3-10 alkynyl, -C 0-6 alkyl-C 3-8 cycloalkyl, -C 0-6 alkyl- aryl, -C 0-6 alkyl-heteroaryl or -C 0-6 alkyl-heterocyclyl; wherein said alkyl and cycloalkyl groups of R 4 may be optionally substituted by one or more (e.g. 1 to 6) halogen and C 1-6 alkoxy groups; and wherein said aryl, heteroaryl or heterocyclyl groups of R 4 may be optionally substituted by one or more (e.g.
  • Compounds according to the invention includes examples E1-E2 as shown below, or pharmaceutically acceptable salts or solvates 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. Sci., 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.
  • 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):
  • a process according to the invention for preparing a compound of formula (I) which comprises:
  • Process (a) typically comprises the use of water soluble carbodiimide, HOBT and a suitable base such as tertiary alkylamine (e.g. 4 ethyl morpholine) or pyridine in a suitable solvent such as dimethylformamide and at a suitable temperature, e.g. between O 0 C and room temperature.
  • a suitable base such as tertiary alkylamine (e.g. 4 ethyl morpholine) or pyridine
  • a suitable solvent such as dimethylformamide
  • Activated derivatives of the compound of formula (II) may be prepared by activating the carboxylic acid to an acid chloride, mixed anhydride, active ester, O-acyl-isourea or another species.
  • process (a) utilises an activated derivative, it typically comprises treatment of said activated derivative with an amine (Ogliaruso, M.A.; Wolfe, J. F. in The Chemistry of Functional Groups (Ed. Patai, S.) Suppl.
  • B The Chemistry of Acid Derivatives, Pt, 7 (John Wiley and Sons, 1979), pp 442-8; Beckwith, A.L.J, in The Chemistry of Functional Groups (Ed. Patai, S.) Suppl.
  • B The Chemistry of Amides (Ed. Zabricky, J.) (John Wiley and Sons, 1970), p 73 ff.
  • Process (b) typically comprises the use of sodium borohydride triacetate in the presence of a suitable solvent, such as ethanol, dichloromethane and 1 ,2-dichloroethane and at a suitable temperature, e.g. between O 0 C and room temperature.
  • a suitable solvent such as ethanol, dichloromethane and 1 ,2-dichloroethane and at a suitable temperature, e.g. between O 0 C and room temperature.
  • 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 (d) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, aromatic substitution, ester hydrolysis, amide bond formation or removal and sulphonylation.
  • R 1 , R 2 , R 9 m, n, A, B, X, Y and Z are as defined above
  • P 1 represents a suitable group such as C 1-6 alkyl
  • P 4 represents a suitable protecting group such as trimethylsilyl
  • L 1 , L 2 , L 3 and L 4 independently represent a suitable leaving group such as a halogen atom (e.g. chlorine or iodine) and p and q represent an integer such that p+q represents m.
  • Step (i) typically comprises treatment with Pd(OAc) 2 and LiCI in the presence of a suitable base (e.g. potassium carbonate) in a suitable solvent such as dimethylformamide at a suitable temperature such as 100°C.
  • a suitable base e.g. potassium carbonate
  • a suitable solvent such as dimethylformamide
  • Step (ii) is a deprotection step and may be carried out as described above for process (c).
  • P 4 represents a trimethylsilyl
  • this may be removed by treatment with a fluoride source such as tetra n-butylammonium fluoride (TBAF), in a suitable solvent such as tetrahydrofuran at a suitable temperature such as room temperature.
  • a fluoride source such as tetra n-butylammonium fluoride (TBAF)
  • a suitable solvent such as tetrahydrofuran
  • Step (iii) typically comprises the use of a suitable base such as sodium hydride in the presence of a suitable solvent such as DMF at a suitable temperature, such as room temperature.
  • a suitable base such as sodium hydride
  • a suitable solvent such as DMF
  • Step (iv) typically comprises the use of a suitable reducing agent such as Fe(O) in a suitable solvent such as acetic acid at a suitable temperature, such as room temperature.
  • a suitable reducing agent such as Fe(O)
  • a suitable solvent such as acetic acid
  • Step (v) typically comprises the use of a suitable base such as pyridine/DMAP in the presence of a suitable solvent such as dichloromethane at a suitable temperature, such as room temperature.
  • a suitable base such as pyridine/DMAP
  • a suitable solvent such as dichloromethane
  • Step (vi) typically comprises the use of a suitable catalyst such as tricyclohexylphosphine [1 ,3-bis(2,4,6-trimethyl-phenyl)-4,5-dihydro-imidazol-2- ylidene][benzylidine]ruthenium (IV) dichloride in the presence of a suitable solvent such as toluene at a suitable temperature such as reflux
  • a suitable catalyst such as tricyclohexylphosphine [1 ,3-bis(2,4,6-trimethyl-phenyl)-4,5-dihydro-imidazol-2- ylidene][benzylidine]ruthenium (IV) dichloride
  • a suitable solvent such as toluene at a suitable temperature such as reflux
  • Step (vii) typically comprises a standard procedure for conversion of a carboxylic ester to an acid, such as the use of an appropriate alkali metal hydroxide like lithium or sodium hydroxide in an appropriate solvent such as methanol at an appropriate temperature such as room temperature.
  • an appropriate acid such as trifluoroacetic acid in an appropriate solvent such as dichloromethane at an appropriate temperature such as O 0 C.
  • Compounds of formula (II) wherein W represents -(CH 2 ) 3 - may be prepared in an identical manner to the process described above except an additional step is required in which compounds of formula (IX) are reduced prior to step (vii).
  • This step typically comprises the use of reducing agents such as sodium borohydride in a suitable solvent such as methanol at a suitable temperature such as room temperature.
  • Compounds of formula (VIII) or formula (IX) in which R 5 is hydrogen can be converted into compounds of formula (VIII) or formula (IX) in which R 5 has an alternative definition (e.g. C 1-6 alkyl) by treatment with an alkylating agent, such as an alkyl iodide (e.g. methyl iodide) in the presence of a suitable base such as potassium carbonate in a suitable solvent such as dimethyl formamide at a suitable temperature such as room temperature.
  • an alkylating agent such as an alkyl iodide (e.g. methyl iodide) in the presence of a suitable base such as potassium carbonate in a suitable solvent such as dimethyl formamide at a suitable temperature such as room temperature.
  • R 3 and R 4 are as defined above and P 2 represents a suitable amine protecting group, such as t-butoxycarbonyl.
  • Step (i) typically comprises the reaction of a compound of formula (X) with a compound of formula NH 2 R 4 in the presence of a suitable solvent, e.g. ethanol at a suitable temperature, e.g. reflux.
  • a suitable solvent e.g. ethanol
  • a suitable temperature e.g. reflux.
  • Step (ii) typically comprises the use of suitable deprotection reactions as described above for process (c), e.g. when P 2 represents t-butoxycarbonyl, deprotection typically comprises the use of trifluoroacetic acid in the presence of a suitable solvent, such as dichloromethane at a suitable temperature, e.g. between 0 0 C and room temperature.
  • a suitable solvent such as dichloromethane
  • deprotection typically comprises the use of 4M HCI in the presence of a suitable solvent, such as methanol at a suitable temperature, e.g. room temperature.
  • Step (i) typically comprises the reaction of a compound of formula (X) in aqueous ammonia in the presence of a suitable solvent, e.g. ethanol at a suitable temperature, e.g. reflux.
  • a suitable solvent e.g. ethanol
  • a suitable temperature e.g. reflux.
  • step (ii) typically comprises the use of CICOOCH 2 -phenyl in the presence of a suitable base, e.g. triethylamine, a suitable solvent, e.g. dimethylformamide at a suitable temperature, e.g. between O 0 C and room temperature.
  • a suitable base e.g. triethylamine
  • a suitable solvent e.g. dimethylformamide
  • Step (iii) typically comprises the use of suitable deprotection reactions as described above for process (c), e.g. when P 2 represents t-butoxycarbonyl, deprotection typically comprises the use of trifluoroacetic acid in the presence of a suitable solvent, such as dichloromethane at a suitable temperature, e.g. between 0°C and room temperature. Clearly the conditions used must not cause P 3 to be removed.
  • a suitable solvent such as dichloromethane
  • Step (iv) typically comprises reacting a compound of formula (XIII) with a compound of formula (II) in the presence of water soluble carbodiimide and HOBT and a suitable base such as a tertiary alkylamine or pyridine as described above for process (a)
  • Step (v) typically comprises the use of suitable deprotection reactions as described above for process (c), e.g. when P 3 represents -COOCH 2 -phenyl, deprotection typically comprises the use of a suitable catalyst, e.g. palladium in the presence of a suitable solvent, e.g. water and ethanol and in the presence of a suitable hydrogen source, e.g. ammonium formate at a suitable temperature, e.g. 6O 0 C.
  • a suitable catalyst e.g. palladium in the presence of a suitable solvent, e.g. water and ethanol
  • a suitable hydrogen source e.g. ammonium formate at a suitable temperature,
  • 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, anti ⁇ inflammatory 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
  • 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
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • 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
  • Methyl 7-nitro-3-propyl-1 H-indole-5-carboxylate (may be prepared as described in Description 1) (2.87 g, 8.6 mmol, 1 equiv) in tetrahydrofuran (50 ml) at O 0 C was added TBAF (1 M in tetrahydrofuan, 10 ml, 10 mmol, 1.2 equiv) and the resulting red mixture was stirred for 5 min. H 2 O (2 ml) was added and the resulting mixture was partitioned between ethyl acetate and brine.
  • Methyl 7-[(ethenylsulfonyl)(methyl)amino]-1-(2-propen-1-yl)-3-propyl-1H-indole-5- carboxylate (may be prepared as described in Description 5) (300 mg, 0.82 mmol, 1 equiv) in dimethylformamide (5 ml) were added K 2 CO 3 (158 mg, 1.15 mmol, 1.4 equiv) and methyl iodide (71 ⁇ l, 1.15 mmol, 1.4 equiv) and the resulting mixture was stirred for 1.5 h then diluted with diethyl ether.
  • E1 may also be prepared using (2R,3S)-3-amino-1-(cyclopropylamino)-4-phenyl-2-butanol di-hydrochloride (may be prepared as described in Description 12) in place of (2R,3S)-3- amino-1 -(cyclopropylamino)-4-phenyl-2-butanol bis(4-methylbenzenesulfonate) salt.
  • b) 10 ⁇ l of substrate (FAM-[SEVNLDAEFK]-TAMRA ) solution in buffer A. This is prepared by diluting 2ml of a 2mM DMSO solution of the substrate into 400ml of buffer A (10OmM Sodium acetate pH 4.5, 1 I MiIIi-Q water, 0.06% Triton X-100 (0.5 ml/I) , pH adjusted to 4.5 using glacial acetic acid).
  • Aminomethyl fluorescein (FAM) and tetramethyl rhodamine (TAMRA) are fluorescent molecules which co-operate to emit fluorescence at 535nm upon cleavage of the SEVNLDAEFK peptide.
  • Blank wells (enzyme solution replaced by buffer) are included as controls on each plate.
  • Blank wells (enzyme solution replaced by buffer) are included as controls on each plate.
  • Examples E1-2 were 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

La présente invention concerne de nouveaux composés d'hydroxyéthylamine représentés par la formule (1), dans laquelle, entre autres, A-B représente -NR5-SO2, -W- représente -(CH2)3- ou -C(H)=C(H)-CH2-, et X-Y-Z représente -C=CR8 -NR9-. Ces composés présentent une activité inhibitrice de l'Asp2 (β-sécrétase, BACE1 ou mémapsine 2). L'invention concerne également des procédés de préparation de ces composés, des compositions les contenant ainsi que leur utilisation pour traiter des maladies caractérisées par des taux de β-amyloïdes élevés ou des dépôts β-amyloïdes, et notamment la maladie d'Alzheimer.
PCT/EP2005/011004 2004-10-13 2005-10-11 Composes d'hydroxyethylamine substitues pour le traitement de la maladie d'alzheimer WO2006040151A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8183252B2 (en) 2003-12-15 2012-05-22 Schering Corporation Heterocyclic aspartyl protease inhibitors

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6207664B1 (en) * 1998-11-25 2001-03-27 Pfizer Inc. Squalene synthetase inhibitor agents
WO2001070672A2 (fr) * 2000-03-23 2001-09-27 Elan Pharmaceuticals, Inc. Composes et methodes de traitement de la maladie d'alzheimer
WO2004094430A1 (fr) * 2003-04-23 2004-11-04 Glaxo Group Limited Derives d'indole tricycliques et leur utilisation dans le cadre du traitement de la maladie d'alzheimer
WO2005058915A1 (fr) * 2003-12-12 2005-06-30 Glaxo Group Limited Derives d'indole hydroxyethylamine tricycliques et leur utilisation dans le traitement de la maladie d'alzheimer

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6207664B1 (en) * 1998-11-25 2001-03-27 Pfizer Inc. Squalene synthetase inhibitor agents
WO2001070672A2 (fr) * 2000-03-23 2001-09-27 Elan Pharmaceuticals, Inc. Composes et methodes de traitement de la maladie d'alzheimer
WO2004094430A1 (fr) * 2003-04-23 2004-11-04 Glaxo Group Limited Derives d'indole tricycliques et leur utilisation dans le cadre du traitement de la maladie d'alzheimer
WO2005058915A1 (fr) * 2003-12-12 2005-06-30 Glaxo Group Limited Derives d'indole hydroxyethylamine tricycliques et leur utilisation dans le traitement de la maladie d'alzheimer

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8183252B2 (en) 2003-12-15 2012-05-22 Schering Corporation Heterocyclic aspartyl protease inhibitors

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