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WO2006103088A1 - Nouveaux composes hydroxyethylamine et cetone possedant une activite inhibitrice de asp2 - Google Patents

Nouveaux composes hydroxyethylamine et cetone possedant une activite inhibitrice de asp2 Download PDF

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WO2006103088A1
WO2006103088A1 PCT/EP2006/002953 EP2006002953W WO2006103088A1 WO 2006103088 A1 WO2006103088 A1 WO 2006103088A1 EP 2006002953 W EP2006002953 W EP 2006002953W WO 2006103088 A1 WO2006103088 A1 WO 2006103088A1
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alkyl
formula
compound
cycloalkyl
aryl
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Emmanuel Hubert Demont
Sally Redshaw
Daryl Simon Walter
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Glaxo Group Ltd
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Glaxo Group Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, 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
    • C07D515/06—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 and 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 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) 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 an 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 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.
  • WO 2004/094430 (Glaxo Group Ltd) describes a series of series of hydroxyethylamine compounds having Asp2 inhibitory activity.
  • WO 2004/014843 Takeda
  • WO 2004/043916 Merck
  • U represents -(C(H)OH)- or -(CO)-;
  • R 1 represents halogen or C 1-3 alkyl
  • R 2 represents Ci -3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen, Ci -3 alkoxy, amino, cyano or hydroxy
  • m represents an integer from 0 to 4
  • n represents an integer from 0 to 2;
  • R 3 represents -C 1-6 alkyl, -C 3-6 alkenyl, -C 3-6 alkynyl, -Ci -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, -C3-10 alkynyl, -C 3-10 cycloalkyl, -C 3-10 cycloalkenyl, -C 0-6 alkyl-aryl, -C 0-6 alkyl-heteroaryl, -C 0-6 alkyl-heterocyclyl,
  • 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- - I0 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;
  • R 5 represents -CHR 26 R 27 , wherein R 26 and R 27 independently represent hydrogen or C 1-6 alkyl; wherein said alkyl and cycloalkyl groups of R 1 , R 2 , R 3 , R 4 , R a , R b , R c or R d may be optionally substituted by one or more (e.g.
  • aryl, heteroaryl or heterocyclyl groups of R 3 , R 4 or R 5 may be optionally substituted by one or more (e.g.
  • 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.
  • 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 alkynylgroups include ethynyl, propynyl, butynyl, pentynyl or hexynyl and the like.
  • the term 'C x-y alkoxy' as used herein 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 3-10 cycloalkenyl' refers to an unsaturated non-aromatic monocyclic hydrocarbon ring of 3 to 10 carbon atoms containing one or more carbon- carbon double bonds. Examples of such groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl and the like.
  • 'halogen' refers to a fluorine, chlorine, bromine or iodine atom.
  • 'haloC 1-6 alkyl' refers to a C 1-6 alkyl group as defined herein wherein at least one hydrogen atom is replaced with halogen.
  • examples of such groups include fluoroethyl, trifluoromethyl or trifluoroethyl and the like.
  • 'halo Ci -6 alkoxy' refers to a C 1-6 alkoxy group as herein defined wherein at least one hydrogen atom is replaced with halogen. Examples of such groups include difluoromethoxy or trifluoromethoxy and the like.
  • 'Ci -6 alkanoyl' refers to a C 1-6 alkyl group as defined herein wherein the two hydrogen atoms on the carbon atom at the attachment position are replaced with an oxo group.
  • Examples of C 1-6 alkanoyl groups include methanoyl or ethanoyl and the like.
  • 'aryl' refers to a C 6-12 monocyclic or bicyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl, naphthyl or tetrahydronaphthalenyl and the like.
  • heteroaryP refers to a 5-6 membered monocyclic aromatic or a fused 8-10 membered bicyclic aromatic ring which monocyclic or bicyclic aromatic 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 is saturated or partially unsaturated and 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.
  • U represents -(C(H)OH)-.
  • -W- represents -(CH 2 )- or -(CH 2 ) 2 -, particularly -(CH 2 ) 2 -.
  • n represents 0-2. More particularly, m represents 0 or 1 , particularly 0.
  • R 1 is typically C 1-3 alkyl (e.g. methyl).
  • n 0.
  • R 3 represents -C 0 . ⁇ alkyl-aryl (e.g. benzyl) or -C 0-6 alkyl- heteroaryl optionally substituted by one or two halogen atoms (e.g. chlorine or fluorine).
  • 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 represents 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- i 0 alkynyl, -C 3-10 cycloalkyl, -C 1-6 alkyl-C 3 -io cycloalkyl, -heterocyclyl, -C 0-6 alkyl-aryl, -C 0-6 alkyl-heteroaryl, - C(R a R b )-CONH-C 3 . 1o cycloalkyl Or-C 3-10 cycloalkyl-aryl.
  • said alkyl and cycloalkyl groups of R 4 are optionally substituted by one or more (e.g. 1 to 6) substituents independently selected from halogen, Ci -6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy and haloCi -6 alkoxy groups.
  • said heterocyclyl, aryl and heteroaryl groups of R 4 are optionally substituted by one or more (e.g. 1 , 2 or 3) substituents independently selected from halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, cyano, nitro, 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 and hydroxy groups.
  • the heterocyclyl, aryl or heteroaryl groups of R 4 are 6 membered rings that are substituted by one substituent, the substituent is in the 3-position relative to the attachment position.
  • R 4 represents:
  • C 1-10 alkyl e.g. methyl, ethyl, i-propyl, propyl, sec-butyl, isobutyl, butyl, 1,5- dimethylhexyl or 1 ,1 ,5-trimethylhexyl
  • halogen e.g. fluoroethyl, difluoroethyl or pentafluoropropyl
  • C 1-6 alkoxy e.g. methoxy
  • cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
  • halogen atoms e.g. fluorine
  • C 1-6 alkyl groups e.g. methyl
  • -Ci -6 alkyl-C 3-10 cycloalkyl e.g. -CH 2 -cyclopropyl
  • -heterocyclyl e.g. tetrahydropyranyl
  • -C 0-6 alkyl-aryl e.g. phenyl or dihydroindenyl, benzyl, 1-methyl-1-phenylethyl, ethylphenyl or ⁇ , ⁇ -dimethylbenzyl
  • optionally substituted on the aryl e.g. substituted at the 3 and 5 positions
  • pyridyl optionally substituted on the heteroaryl by one or more C 1-6 alkyl (e.g. methyl or ethyl), halogen (e.g. bromine), haloC 1-6 alkyl (e.g. trifluoroethyl) Or -CONR 22 R 23 (e.g. -CONHMe) groups; -C(R a R b )-CONH-C 3-10 cycloalkyl (e.g. C(R a R b )-CONH-cyclohexyl); or
  • 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.
  • 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, -Ci -10 alkyl, -C 3-10 alkynyl, -C 3-I0 cycloalkyl, - C 1-6 alkyl-C 3- i 0 cycloalkyl, -heterocyclyl, -C 0-6 alkyl-aryl or -C 0-6 alkyl-heteroaryl.
  • said alkyl and cycloalkyl groups of R 4 are optionally substituted by one or more (e.g. 1 to 6) substituents independently selected from halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy and haloC 1-6 alkoxy groups. More particularly, said alkyl and cycloalkyl groups of R 4 are optionally substituted by one or more (e.g. 1 to 6) halogen atoms.
  • said heterocyclyl, aryl and heteroaryl groups of R 4 are optionally substituted by one or more (e.g. 1 , 2 or 3) substituents independently selected from halogen, Ci -6 alkyl, haloC 1-6 alkyl, Ci -6 alkoxy, haloCi -6 alkoxy, cyano, nitro, amino, and hydroxy groups.
  • substituents independently selected from halogen, Ci -6 alkyl, haloC 1-6 alkyl, Ci -6 alkoxy, haloCi -6 alkoxy, cyano, nitro, amino, and hydroxy groups.
  • the heterocyclyl, aryl or heteroaryl groups of R 4 are 6 membered rings that are substituted by one substituent, the substituent is in the 3-position relative to the attachment position.
  • R 4 represents:
  • C 1-I0 alkyl e.g. methyl, ethyl, i-propyl, propyl, sec-butyl, isobutyl, butyl, tert-butyl or 1 ,1 ,5-trimethylhexyl
  • halogen e.g. fluoroethyl, difluoroethyl, trifluoroethyl or pentafluoropropyl
  • -C 3-10 alkynyl e.g. propyn-2-yl
  • -C 3- io cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
  • -C 0-6 alkyl-aryl e.g. dihydroindenyl, benzyl, ethylphenyl or ⁇ , ⁇ -dimethylbenzyl
  • optionally substituted on the aryl e.g. substituted at the 3 position
  • halogen cyano, nitro, haloC 1-6 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), amino or hydroxy groups; or
  • -C 0-6 alkyl-heteroaryl e.g. pyridyl, -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. trifluoroeth
  • R 4 represents -C 3 . 10 cycloalkyl, C 3-I0 alkynyl or -C 0-6 alkyl-aryl, wherein said aryl group is optionally substituted by one or more substituents (e.g. 1 , 2 or 3) independently selected from halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy and haloC 1-6 alkoxy groups.
  • substituents e.g. 1 , 2 or 3
  • the aryl group of R 4 is a 6 membered ring that is substituted by one substituent, the substituent is in the 3-position relative to the attachment position.
  • R 4 represents:
  • -C 3-10 cycloalkyl e.g. cyclopropyl or cyclohexyl
  • -C 3- io alkynyl e.g. propyn-2-yl
  • -C 0-6 alkyl-aryl e.g. benzyl
  • aryl e.g. substituted at the 3 position
  • halo Ci -6 alkyl e.g. m-CF 3
  • R 5 represents -CHR 26 R 27 , wherein R 26 and R 27 independently represent hydrogen or C 1-6 alkyl. In one embodiment, R 26 represents hydrogen and R 27 represents hydrogen or C 1-6 alkyl. In another embodiment, R 26 and R 27 both represent C 1-6 alkyl.
  • R 5 represents methyl, ethyl, propyl or isopropyl, particularly ethyl.
  • the invention provides compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, wherein: U represents -(C(H)OH)-;
  • -W- represents -CH 2 - or -(CH 2 ) 2 -;
  • R 3 represents -C 0-6 alkyl-aryl, wherein said aryl group is optionally substituted by one or two halogen atoms;
  • R 4 represents hydrogen, -C 1-10 alkyl, -C 3-10 alkynyl, -C 3- - I0 cycloalkyl, -C 1-6 alkyl-C 3-10 cycloalkyl, -heterocyclyl, -C 0-6 alkyl-aryl or -C 0-6 alkyl-heteroaryl wherein said alkyl and cycloalkyl groups are optionally substituted by one or more substituents independently selected from halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy and haloCi -6 alkoxy groups and wherein said heterocyclyl, aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from halogen, Ci -6 alkyl, haloC 1-6 alkyl,
  • R 5 represents C 1-6 alkyl.
  • the invention provides compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, wherein:
  • U represents -(C(H)OH)-; m and n represent 0; -W- represents -(CH 2 ) 2 -;
  • R 3 represents benzyl
  • R 4 represents -C 3-10 cycloalkyl, -heterocyclyl or -C 0-6 alkyl-aryl wherein said aryl groups are optionally substituted by one or more substituents independently selected from halogen, C 1-6 alkyl, haloC 1-6 alkyl, Ci -6 alkoxy and haloCi -6 alkoxy
  • R 5 represents C 1-6 alkyl.
  • Compounds according to the invention include examples E1-E4 as shown below, or a pharmaceutically acceptable salt thereof. More particularly, compounds of the invention include example E2.
  • 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.
  • This invention includes within its scope stoichiometric solvates (e.g. hydrates) 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) where U is -(C(H)OH)- are in the form of a single enantiomer of formula (Ia):
  • a process according to the invention for preparing a compound of formula (I) where U is -(C(H)OH)- comprises:
  • R 3 and R 4 are as defined above;
  • R 1 , R 2 , R 3 , R 5 , m, n and W are as defined above, with an appropriate aldehyde or ketone; or
  • process (a) 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. 1 (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.
  • an activated derivative of the compound of formula (II) such as an acid chloride, mixed anhydride or active ester
  • process (a) typically takes place in the presence of activating agents and a suitable base such as a tertiary alkylamine (e.g. 4-ethylmorpholine) or pyridine, in a suitable solvent such as DMF or dichloromethane, at a suitable temperature eg. between 0 0 C and room temperature.
  • a suitable base such as a tertiary alkylamine (e.g. 4-ethylmorpholine) or pyridine
  • a suitable solvent such as DMF or dichloromethane
  • Process (b) typically comprises the use of sodium borohydride triacetate in the presence of a suitable solvent, such as ethanol, dichloromethane or 1 ,2-dichloroethane and at a suitable temperature, e.g. between O 0 C and room temperature.
  • a suitable solvent such as ethanol, dichloromethane or 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.
  • 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.
  • 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.
  • R 1 , R 2 , R 5 , m and n are as defined above, p is an integer from 1 to 3, P 2 represents a suitable group such as CH 2 CH 2 Si(CH 3 )3, L 1 and L 2 independently represent a suitable leaving group such as a halogen atom (eg. chlorine).
  • a suitable leaving group such as a halogen atom (eg. chlorine).
  • Step (i) typically comprises the use of a suitable base such as triethylamine in the presence of a suitable solvent such as dichloromethane at a suitable temperature, such as room temperature.
  • a suitable base such as triethylamine
  • a suitable solvent such as dichloromethane
  • Step (ii) typically comprises the use of a suitable base such as K 2 CO 3 in the presence of a suitable solvent such as DMF at a suitable temperature, such as 5O 0 C.
  • a suitable base such as K 2 CO 3
  • a suitable solvent such as DMF
  • Step (iii) typically comprises the use of a suitable fluoride salt such as TBAF in a suitable solvent such as THF at a suitable temperature such as room temperature.
  • Activated derivatives of compounds of formula (II) may then be prepared by activation of the carboxylic acid to an acid chloride, mixed anhydride or active ester.
  • Step (i) typically comprises the use of a suitable base such as triethylamine in the presence of a suitable solvent such as dichloromethane at a suitable temperature, such as room temperature.
  • a suitable base such as triethylamine
  • a suitable solvent such as dichloromethane
  • Step (ii) typically comprises the use of a suitable base such as K 2 CO 3 in the presence of a suitable solvent such as DMF at a suitable temperature, such as 5O 0 C.
  • a suitable base such as K 2 CO 3
  • a suitable solvent such as DMF
  • Step (iii) typically comprises the use of a suitable fluoride salt such as TBAF in a suitable solvent such as THF at a suitable temperature such as room temperature.
  • Activated derivatives of compounds of formula (II) may then be prepared by activation of the carboxylic acid to an acid chloride, mixed anhydride or active ester.
  • R 2 , R 5 , R 26 , R 27 , n and P 2 are as defined above
  • P 3 represents a suitable group such as Ci -6 alkyl (e.g. methyl)
  • P 4 represents a suitable protecting group such as benzyl
  • L 3 and L 4 independently represent a suitable leaving group such as an halogen atom (eg. bromine)
  • E represents an halogen (eg. bromine)
  • R 25 represents a suitable group such as C 1-6 halo-alkyl (eg. CF 3 ).
  • Step (i) typically comprises the use of a suitable base such as K 2 CO 3 in a suitable solvent such as acetone, at a suitable temperature such as reflux.
  • a suitable base such as K 2 CO 3
  • a suitable solvent such as acetone
  • Step (ii) 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 50 0 C.
  • a suitable reducing agent such as Fe(O)
  • a suitable solvent such as acetic acid
  • Step (iii) typically comprises the use of a suitable halogenating reagent such as bromine in a suitable solvent such as CH 2 CI 2 at a suitable temperature such as room temperature.
  • a suitable halogenating reagent such as bromine
  • a suitable solvent such as CH 2 CI 2
  • Step (iv) typically comprises the use of a suitable acylating agent such as trifluoroacetic acid anhydride, in the presence of a suitable base such as pyridine and a suitable solvent such as CH 2 CI 2 at a suitable temperature such as O 0 C.
  • a suitable acylating agent such as trifluoroacetic acid anhydride
  • Step (v) typically comprises the use of a suitable allylating agent such as crotyl bromide in the presence of a suitable base such as K 2 CO 3 and a suitable solvent such as CH 3 CN at a suitable temperature such as reflux.
  • a suitable allylating agent such as crotyl bromide
  • a suitable base such as K 2 CO 3
  • a suitable solvent such as CH 3 CN
  • Step (vi) typically comprises the use of a source of Pd(O) such as Pd(OAc) 2 in the presence of a suitable base such as Na 2 CO 3 and additives such as Bu 4 NCI and a suitable solvent such as DMF, at a suitable temperature such as 100 0 C.
  • a source of Pd(O) such as Pd(OAc) 2
  • a suitable base such as Na 2 CO 3
  • additives such as Bu 4 NCI
  • a suitable solvent such as DMF
  • step (vii) typically comprises the use of Pd(O) such as Pd(O) on charcoal, in the presence of a suitable source of hydrogen such as NH 4 COOH and a suitable solvent such as MeOH and H 2 O, at a suitable temperature such as 8O 0 C.
  • a suitable source of hydrogen such as NH 4 COOH
  • a suitable solvent such as MeOH and H 2 O
  • Step (viii) typically comprises a standard procedure for conversion of a carboxylic ester to an acid, such as the use of an appropriate hydroxide salt like sodium hydroxide in an appropriate solvent such as methanol at an appropriate temperature such as 6O 0 C.
  • an appropriate hydroxide salt like sodium hydroxide in an appropriate solvent such as methanol at an appropriate temperature such as 6O 0 C.
  • Step (ix) typically comprises the use of a suitable acid such as PTSA-H 2 O in a suitable solvent such as P 2 OH at a suitable temperature such as 5O 0 C.
  • Compounds of formula (Xl) are either commercially available (e.g. methyl 3-hydroxy-4- nitrobenzoate is commercially available from Avocado) or may be prepared from commercially available compounds using standard procedures.
  • Compounds of formula (III) may be prepared in accordance with procedures described in International Patent Application PCT/WO2004/050619.
  • P 5 represents a suitable amine protecting group, such as t-butoxycarbonyl and P 6 represents a suitable amine protecting group different to P 5 , such as -COOCH 2 -phenyl.
  • Step (i) typically comprises the reaction of a compound of formula (XX) 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.
  • Step (iii) typically comprises the use of suitable deprotection reactions. Examples of protecting groups and the means for their removal can be found in T. W. Greene and P.G.M. Wuts 'Protective Groups in Organic Synthesis' (J. Wiley and Sons, 3rd Ed. 1999).
  • 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 O 0 C and room temperature.
  • a suitable solvent such as dichloromethane
  • Step (iv) typically comprises reacting a compound of formula (XXIII) with a compound of formula (II) or an activated derivative of the compound of formula (II), such as an acid chloride, mixed anhydride or active ester.
  • a compound of formula (II) is a carboxylic acid
  • the reaction typically takes place in the presence of a water soluble carbodiimide and HOBT.
  • the compound of formula (II) is an activated derivative
  • the reaction typically comprises treatment of said activated derivative with an amine
  • Step (v) typically comprises the use of suitable deprotection reactions.
  • suitable deprotection reactions Examples of protecting groups and the means for their removal can be found in T. W. Greene and P.G.M. Wuts 'Protective Groups in Organic Synthesis' (J. Wiley and Sons, 3rd Ed. 1999).
  • P 6 represents -COOCH 2 -phenyl
  • deprotection typically comprises the use of a suitable catalyst, eg. 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, eg. 60 0 C.
  • Compounds of formula (XX) are either commercially available (e.g. (S)-(S)-I -oxiranyl-2- phenyl-ethyl)-carbamic acid tert-butyl ester is commercially available from Aldrich) or may be prepared from commercially available compounds using standard procedures.
  • 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.
  • 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, more particularly 100-1000mg; 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
  • Amines D19-20 were obtained in an analogous manner to the procedure described in Description 18, starting with the appropriate carbamate.
  • Examples E2-4 were obtained in an analogous manner to the procedure described in Example 1 using the appropriate amine di- tosic acid salt and acid indicated in the table. Examples E2-4 were isolated by preparative LCMS and obtained as the formic acid salts..
  • Plasmid pCDNA3.1-Fc was prepared by introducing into pCDNA3.1 an EcoR V - Xbal fragment encoding the factor Xa cleavage site (IEGR) fused in-frame via a short linker (translated sequence AAAQL) to part of the human IgGI (Fc) sequence (GenBank BC092518) encoding residues 243-469 of the IgGI polypeptide, followed by a Kemptide tag (LRRASLG).
  • the amplified BACE fragment was digested with restriction enzymes BamH I and EcoR V and cloned into pCDNA3.1-Fc to generate the expression vector pSBACE-Fc.
  • HEK-293 Human Embryonic Kidney cells
  • pSBACE-Fc Human Embryonic Kidney cells
  • Individual clones were screened for expression by monitoring levels of soluble Asp2-Fc secreted into the culture medium by western blot or ELISA using anti-human IgG antibody conjugates.
  • a productive clone was used to generate the stable cell line HEK-Asp2Fc, a high level expressor of secreted Asp2-Fc.
  • Asp2-Fc for screening applications HEK-Asp2Fc cells were cultured in a hollowfibre bioreactor (Unisyn BR1900, 1OkDa MWCO membrane).
  • Asp2-Fc protein was recovered from conditioned medium from the bioreactor by affinity capture on protein A-sepharose resin. After extensive washing to remove unbound impurities, Asp2- Fc was eluted under acidic conditions (0.1 M Glycine pH 2.7). Eluted protein was immediately neutralized and exchanged into a buffer suitable for storage at -80 0 C (20 mM MES pH 4.5, 150 mM NaCI, 0.5% (v/v) Triton X-100, 2 mM EDTA) until required for assays.
  • 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.
  • Example E1 Pharmacological Data
  • Example E1 and the formate salts of Examples E2-E4 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 Asp-2 over CatD.

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Abstract

L'invention concerne de nouveaux composés hydroxyéthylamine et cétone possédant une activité inhibitrice de Asp2 (ß-sécrétase, BACE1 ou Memapsine-2), des procédés de préparation de ces composés, des compositions contenant ces composés, ainsi que l'utilisation de ces composés pour le traitement des maladies caractérisées par des taux élevés de protéine ß- amyloïde ou par des dépôts de protéine ß-amyloïde, en particulier la maladie d'Alzheimer.
PCT/EP2006/002953 2005-03-31 2006-03-29 Nouveaux composes hydroxyethylamine et cetone possedant une activite inhibitrice de asp2 Ceased WO2006103088A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2919288A1 (fr) * 2007-07-27 2009-01-30 Sanofi Aventis Sa Derives de 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6- carboxamides, leur preparation et leur application en therapeutique.
FR2919289A1 (fr) * 2007-07-27 2009-01-30 Sanofi Aventis Sa Derives de 2,3,4,5-tetrahydropyrrolo[1,2-a][1,4]- diazepine-7-carboxamides, leur preparation et leur application en therapeutique.
WO2009044007A3 (fr) * 2007-07-27 2009-09-17 Sanofi-Aventis Dérivés de 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamides et de 2,3,4,5-tetrahydropyrrolo[1,2-a][1,4]-diazépine-7-carboxamides, leur préparation et leur application en thérapeutique
US8030320B2 (en) 2007-07-27 2011-10-04 Sanofi-Aventis Derivatives of 1-OXO-1,2-dihydroisoquinoline-5-carboxamides and of 4-OXO-3,4-dihydroquinazoline-8-carboxamides, preparation thereof and application thereof in therapeutics
CN102344485A (zh) * 2010-08-05 2012-02-08 中国人民解放军军事医学科学院毒物药物研究所 用于治疗阿尔茨海默病的肽类β分泌酶抑制剂及其用途
US8372864B2 (en) 2007-07-27 2013-02-12 Sanofi 1-oxo-isoindoline-4-carboxamide and 1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide derivatives, preparation and therapeutic use thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002002505A2 (fr) * 2000-06-30 2002-01-10 Elan Pharmaceuticals, Inc. Composes pour le traitement de la maladie d'alzheimer
WO2004080376A2 (fr) * 2003-03-14 2004-09-23 Glaxo Group Limited Nouveaux composes
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002002505A2 (fr) * 2000-06-30 2002-01-10 Elan Pharmaceuticals, Inc. Composes pour le traitement de la maladie d'alzheimer
WO2004080376A2 (fr) * 2003-03-14 2004-09-23 Glaxo Group Limited Nouveaux composes
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

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2919288A1 (fr) * 2007-07-27 2009-01-30 Sanofi Aventis Sa Derives de 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6- carboxamides, leur preparation et leur application en therapeutique.
FR2919289A1 (fr) * 2007-07-27 2009-01-30 Sanofi Aventis Sa Derives de 2,3,4,5-tetrahydropyrrolo[1,2-a][1,4]- diazepine-7-carboxamides, leur preparation et leur application en therapeutique.
WO2009044007A3 (fr) * 2007-07-27 2009-09-17 Sanofi-Aventis Dérivés de 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamides et de 2,3,4,5-tetrahydropyrrolo[1,2-a][1,4]-diazépine-7-carboxamides, leur préparation et leur application en thérapeutique
US8030320B2 (en) 2007-07-27 2011-10-04 Sanofi-Aventis Derivatives of 1-OXO-1,2-dihydroisoquinoline-5-carboxamides and of 4-OXO-3,4-dihydroquinazoline-8-carboxamides, preparation thereof and application thereof in therapeutics
US8372864B2 (en) 2007-07-27 2013-02-12 Sanofi 1-oxo-isoindoline-4-carboxamide and 1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide derivatives, preparation and therapeutic use thereof
CN102344485A (zh) * 2010-08-05 2012-02-08 中国人民解放军军事医学科学院毒物药物研究所 用于治疗阿尔茨海默病的肽类β分泌酶抑制剂及其用途

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