WO2004111022A1 - Composes de benzamide a substitution 3-(1,1-dioxotetrahydro-1,2-thiazin-2-yl) ou 3-(1,1-doxo-isothiazolidin-2yl) utilises comme inhibiteurs de l'enzyme asp2 - Google Patents

Composes de benzamide a substitution 3-(1,1-dioxotetrahydro-1,2-thiazin-2-yl) ou 3-(1,1-doxo-isothiazolidin-2yl) utilises comme inhibiteurs de l'enzyme asp2 Download PDF

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WO2004111022A1
WO2004111022A1 PCT/EP2004/006594 EP2004006594W WO2004111022A1 WO 2004111022 A1 WO2004111022 A1 WO 2004111022A1 EP 2004006594 W EP2004006594 W EP 2004006594W WO 2004111022 A1 WO2004111022 A1 WO 2004111022A1
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alkyl
formula
groups
optionally substituted
compound
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Emmanuel Hubert Demont
Sally Redshaw
Daryl Simon Walter
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Glaxo Group Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to novel hydroxyethylene compounds having Asp2 ( ⁇ - secretase, BACE1 or Memapsin) 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
  • 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. 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). In addition it has been reported that dementia correlates more closely with the levels of soluble amyloid rather than plaque burden (Naslund, J. et a/.
  • 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) (De Strooper, B. and Konig, G. (1999) Nature 402: 471-472).
  • Asp2 also known as ⁇ - secretase, BACE1 or Memapsin
  • 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. a/. (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 (Elan Pharmaceuticals Inc.) describe a series of hydroxyethylene compounds having ⁇ -secretase activity which are implicated to be useful in the treatment of Alzheimer's disease.
  • R 1 represents a group of formula Z c
  • a 3 represents CR 5a R 5b or NR 5a ;
  • n 2 represents an integer from 1 to 3;
  • R 5a and R 5b independently represent hydrogen, C 1 ⁇ alkyl optionally substituted by one or more R 11 groups, C 3-8 cycloalkyl optionally substituted by one or more R 11 groups, -C 1-2 alkyl-C 3-8 cycloalkyl or aryl;
  • R a represents halogen, C 1-3 alkyl, hydroxy or C 1-3 alkoxy
  • R c represents -C 1-6 alkyl optionally substituted by one or more R 11 groups or -C 0-6 alkyl- aryl;
  • X 1 represents N,-C(-R 6 )- or -C(-O-R 7 )-;
  • X 2 represents N,-C(-R 8 )- or -C(-Y-R 9 )-;
  • Y represents a bond, CH 2 , O, S, SO 2 , CO, NR 10 , -N(R 10 )C(O)-, -C(O)N(R 10 )-, COO, aryl, heterocyclyl or heteroaryl;
  • R 6 represents hydrogen, halogen, -C 1-6 alkyl optionally substituted by one or more R 11 groups, -C 2-6 alkenyl, -C 2-6 alkynyl -C 3-8 cycloalkyl optionally substituted by one or more R 11 groups, -C 1-2 alkyl-C 3- 8 cycloalkyl, heteroaryl, heterocyclyl or aryl; R 8 represents halogen or trifluoromethyl;
  • R 7 , R 9 and R 10 independently represent hydrogen, -Ci -6 alkyl optionally substituted by one or more R 11 groups, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl optionally substituted by one or more R 11 groups, -C 1-2 alkyl-C 3-8 cycloalkyl, heteroaryl, heterocyclyl or aryl;
  • W 1 represents CO or SO 2 ;
  • R 2 represents -C 5-8 alkyl, -Ci -6 alkyl-aryl, -C 1-6 alkyl-heteroaryl, -C 1-6 alkyl-heterocyclyl, - Ci -6 alkyl-C 3-8 cycloalkyl, -C 1-6 alkyl-S-aryl, -C 1-6 alkyl-O-aryl, -C 1-6 alkyl-S-heteroaryl or - C 1-6 alkyl-O-heteroaryl;
  • R 3 represents -C 1-6 alkyl, -C 3-8 cycloalkyl or -C 2-6 alkynyl each of which may be optionally substituted by one or more R 11 groups;
  • R 4 represents -Ci -6 alkyl optionally substituted by one or more R 11 groups, -Ci -6 alkyl-aryl, -Ci -6 alkyl-heteroaryl, -Ci -6 alkyl-heterocyclyl, -C 3-8 cycloalkyl optionally substituted by one or more R 11 groups, -Ci -6 alkyl-C 3-8 cycloalkyl or -C 2-6 alkynyl; w and y independently represent an integer from O to 2; wherein said aryl, heteroaryl or heterocyclyl groups of Y, R 2 , R 4 , R 6 , R 7 , R 9 and R 10 may be optionally substituted by one or more Ci -6 alkyl, C 2-6 alkenyl, halogen, Ci -6 alkoxy, CN, hydroxy, oxo, nitro, -NHCOCi -6 alkyl, -OCF 3 , -CF 3 ,
  • R 11 represents halogen, hydroxy, -COOH, -COOCH 3 , Ci -6 alkoxy, cyano or amino; or a pharmaceutically acceptable salt or solvate thereof.
  • R c represents -Ci -6 alkyl optionally substituted by one or more R 11 groups or -Ci, 6 alkyl- aryl;
  • Y represents a bond, CH 2 , O, S, CO, NR 10 , -N(R 10 )C(O)-, -C(O)N(R 10 )-, COO, aryl, heterocyclyl or heteroaryl;
  • R 6 represents hydrogen, halogen, -Ci -6 alkyl optionally substituted by one or more R 11 groups, -C 2-6 alkenyl, -C 3-8 cycloalkyl optionally substituted by one or more R 11 groups, - Ci -2 alkyl-C 3-8 cycloalkyl, heteroaryl, heterocyclyl or aryl; and R 7 , R 9 and R 10 independently represent hydrogen, -Ci -6 alkyl optionally substituted by one or more R 11 groups, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl optionally substituted by one or more R 11 groups, -Ci -2 alkyl-C 3-8 cycloalkyl, heteroaryl, heterocyclyl or aryl; and R 2 represents -C 5-8 alkyl, -C 1-6 alkyl-aryl, -C 1-6 alkyl-heteroaryl, -C 1-6 alky
  • R 3 represents -C 1-6 alkyl optionally substituted by one or more R 11 groups or propargyl
  • R 4 represents -Ci -6 alkyl optionally substituted by one or more R 11 groups, -C 1-6 alkyl-aryl, -C 1-6 alkyl-heteroaryl, -C 1-6 alkyl-heterocyclyl, -C 3-8 cycloalkyl optionally substituted by one or more R 11 groups, -C 1-6 alkyl-C3.s cycloalkyl or propargyl.
  • references to alkyl include references to both straight chain and branched chain aliphatic isomers of the corresponding alkyl. It will be appreciated that references to alkenyl shall be interpreted similarly.
  • references to C 3-8 cycloalkyl include references to all alicyclic (including branched) isomers of the corresponding alkyl.
  • references to 'aryP include references to monocyclic carbocyclic aromatic rings (eg. phenyl) and bicyclic carbocyclic aromatic rings (e.g. naphthyl).
  • references to 'heteroaryP include references to mono- and bicyclic heterocyclic aromatic rings containing 1-4 hetero atoms selected from nitrogen, oxygen and sulphur.
  • monocyclic heterocyclic aromatic rings include e.g. thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, tetrazolyl and the like.
  • bicyclic heterocyclic aromatic rings include eg.
  • quinolinyl isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like.
  • references to 'heterocyclyF include references to a 5-7 membered non-aromatic monocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulphur or oxygen.
  • heterocyclic non-aromatic rings examples include morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, oxathianyl, dithianyl, dioxanyl, pyrrolidinyl, dioxolanyl, oxathiolanyl, imidazolidinyl, pyrazolidinyl and the like.
  • a 3 represents CH 2 .
  • n 2 represents 1 or 2, more preferably 2.
  • Xi represents -C(-R 6 ).
  • R 6 represents halogen or hydrogen, more preferably hydrogen.
  • X 2 represents -C(-R 8 )- or -C(-Y-R 9 )-, more preferably -C(-Y-R 9 )-.
  • R 8 is preferably trifluoromethyl.
  • X 2 represents -C(-Y-R 9 )-, preferably, Y represents a bond and R 9 represents hydrogen, C 1-6 alkyl (particularly propyl) or heterocyclyl (eg. pyrrolidinyl) optionally substituted by an oxo group (eg.
  • Y represents -C(O)N(R 10 )- (particularly -C(O)N(propyl)) and R 9 represents C 1-6 alkyl (particularly propyl) or Y represents NR 10 (particularly NH) and R 9 represents C 1-6 alkyl (particularly ethyl).
  • Wi represents CO.
  • R 2 represents -C 1-6 alkyl-aryl (eg. benzyl) optionally substituted with one or more halogen atoms (eg. 3,5-difluorobenzyl), more preferably R 2 represents unsubstituted benzyl.
  • R 3 represents -Ci -6 alkyl (eg. methyl or 3-methyl butyl) or -C 2-6 alkynyl (eg. propargyl), more preferably methyl.
  • R 4 represents -C 1-6 alkyl (particularly 3,3-dimethyl butyl), -C 3-8 cycloalkyl (particularly norbornyl or cyclohexyl) Or -C 2-6 alkynyl (eg. propargyl), each of which may be optionally substituted with a COOH group. More preferably, R 4 represents -C 3-8 cycloalkyl (particularly norbornyl or cyclohexyl), most preferably norbornyl.
  • w represents O or 1 , more preferably O.
  • y represents 0 or 1 , more preferably O.
  • R a preferably represents fluorine.
  • Preferred compounds according to the invention includes examples E1-E5 as shown below, or a pharmaceutically acceptable salt 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.
  • the compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be solvated, eg. as the hydrate.
  • This invention includes within its scope stoichiometric solvates (eg. hydrates) as well as compounds containing variable amounts of solvent (eg. 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):
  • a process according to the invention for preparing a compound of formula (I) which comprises:
  • L 1 represents a suitable leaving group, eg. a halogen atom, such as bromine atom, with a compound of formula R 1 -H, wherein R 1 is as defined above, and thereafter optionally as necessary deprotecting a compound of formula (I) which is protected; or
  • R 4 -NH 2 wherein R 4 is as defined above, and thereafter optionally as necessary deprotecting a compound of formula (I) which is protected;
  • R 1 , Xi and X 2 are as defined above and L 2 represents a suitable leaving group, such as a halogen atom (eg. chlorine), and thereafter optionally as necessary deprotecting a compound of formula (I) which is protected; or
  • Process (a) typically comprises heating a compound of formula (II) and a compound R 1 - H in a suitable solvent such as 1 ,4-dioxane with a suitable base (such as caesium carbonate) with an appropriate catalyst (e.g. see Organic Letters (2000), 2, 1101-1104).
  • a suitable solvent such as 1 ,4-dioxane
  • a suitable base such as caesium carbonate
  • Process (b) typically comprises heating a mixture of compounds of formula (III) and R 4 - NH 2 .
  • Process (c) typically comprises mixing compounds of formulae (IV) and (Va) with a suitable coupling agent (such as N-cyclohexylcarbodiimide-N'-methyl polystyrene in the presence of HOBT) in a suitable solvent (such as dimethylformamide or dichloromethane) at a suitable temperature e.g. room temperature.
  • a suitable coupling agent such as N-cyclohexylcarbodiimide-N'-methyl polystyrene in the presence of HOBT
  • a suitable solvent such as dimethylformamide or dichloromethane
  • Process (d) typically comprises the use of a suitable base, eg. N-methylmorpholine or polystyrene-N-methylmorpholine in the presence of catalytic (10%) dimethylaminopyridine (DMAP) in a suitable solvent eg. dimethylformamide and/or dichloromethane.
  • a suitable base eg. N-methylmorpholine or polystyrene-N-methylmorpholine
  • DMAP dimethylaminopyridine
  • suitable solvent eg. dimethylformamide and/or dichloromethane.
  • Suitable amine protecting groups include sulphonyl (e.g. tosyl), acyl (e.g. benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis or hydrogenolysis as appropriate.
  • Other 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 (f) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic aromatic substitution, ester hydrolysis, amide bond formation, t-butoxycarbonyl group addition or removal and sulphonylation.
  • R 2 , R 3 , R 4 , X 1 and X 2 are as defined above, P 1 represents a suitable protecting group such as t-butoxycarbonyl and L 1 represents a suitable leaving group, eg. a halogen atom, such as bromine atom.
  • Step (i) typically comprises heating a compound of formula (Vl) in neat amine R 4 -NH 2 to a suitable temperature e.g. 60 0 C .
  • Step (ii) typically comprises the use of mixing a compound of formula (VII) with a suitable acid (such as trifluoroacetic acid) in a suitable solvent (such as dichloromethane) at a suitable temperature e.g. room temperature.
  • a suitable acid such as trifluoroacetic acid
  • a suitable solvent such as dichloromethane
  • Step (iii) typically comprises the use of mixing compounds of formulae (IV) and (VIII) with a suitable coupling agent (such as N-cyclohexylcarbodiimide-N'-methyl polystyrene in the presence of HOBT) in a suitable solvent (such as dichloromethane or dimethylformamide) at a suitable temperature e.g. room temperature.
  • a suitable coupling agent such as N-cyclohexylcarbodiimide-N'-methyl polystyrene in the presence of HOBT
  • a suitable solvent such as dichloromethane or dimethylformamide
  • R 1 , X 1 , X 2 , R 2 and R 3 are as defined above and P 1 represents a suitable protecting group such as t-butoxycarbonyl.
  • Step (i) typically comprises mixing a compound of formula (Vl) with a suitable acid (such as trifluoroacetic acid) in a suitable solvent (such as dichloromethane) at a suitable temperature e.g. room temperature.
  • a suitable acid such as trifluoroacetic acid
  • a suitable solvent such as dichloromethane
  • Step (ii) typically comprises mixing compounds of formulae (IX) and (Va) with a suitable coupling agent (such as N-cyclohexylcarbodiimide-N'-methyl polystyrene) in a suitable solvent (such as dimethylformamide or dichloromethane) at a suitable temperature e.g. room temperature.
  • a suitable coupling agent such as N-cyclohexylcarbodiimide-N'-methyl polystyrene
  • a suitable solvent such as dimethylformamide or dichloromethane
  • a compound of formula (1) 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 tetrahydroaminoaeridine, donepezil hydrochloride and rivastigmine), gamma secretase inhibitors, anti-inflammatory agents (such as cyclooxygenase Il inhibitors), antioxidants (such as Vitamin E and ginkolidesor) or statins.
  • P-gp p-glycoprotein
  • cyclosporin A verapamil, carvedilol, tamoxifen, quinidine, ritonavir, rapamycin, 10,11-methanodibenzosuberane, phenothiazines, FK506, VX-710, LY335979, PSC-833 and acridine derivatives such as N-[4-[2-(3,4-dihydro-6,7-dimethoxy-2(1 H)-isoquinolinyl)ethyl]phenyl]- 9,10-dihydro-5- methoxy-9-oxo-4-acridinecarboxamide (elacridar; GF120918).
  • P-gp inhibitors such as cyclosporin A, verapamil, carvedilol, tamoxifen, quinidine, ritonavir, rapamycin, 10,11-methanodibenzosuberan
  • 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
  • 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.
  • N-Ethylbenzylamine (2.9 ml, 19.5 mmol, 1.5 equiv) was then added via syringe and the resulting mixture was stirred at 90°C for 2 h then cooled to room temperature, diluted with H 2 O and AcOEt. The layers were separated, the aqueous phase diluted with saturated aqueous NaHCO 3 solution and extracted with AcOEt. The combined organic phases were dried over MgSO 4 and concentrated in vacuo.
  • N-Cyclohexylcarbodiimide-N'-methyl polystyrene 80mg @ 1.90 mmol/g; ex. Novabiochem
  • dichloromethane 0.5ml
  • 1- hydroxybenzotriazole 18 mg, 0.12 mmol
  • dichloromethane/DMF 4:1 dichloromethane/DMF
  • Examples 3-5 were prepared in an analogous manner to Example 1 using the appropriate acid and the appropriate base:
  • a) 1 ⁇ l of a DMSO solution of the test compound (IC 50 curve uses ten 1 in 2 serial dilutions from 500 ⁇ M).
  • b) 10 ⁇ l of substrate (FAM-SEVNLDAEFK-TAMRA ) solution in buffer. This is prepared by diluting 2ml of a 2mM DMSO solution of the substrate into 400ml of buffer (10OmM Sodium acetate pH 4.5, 1 I MiIIi-Q water, 0.06% Triton X-100 (0.5 ml/l) , 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.
  • FAM tetramethyl rhodamine
  • TAMRA tetramethyl rhodamine
  • Blank wells (enzyme solution replaced by buffer) are included as controls on each plate. Wells are incubated for 1h at room temperature and fluorescence read using a Tecan Ultra Fluorimeter/Spectrophotometer ( 485nm excitation, 535nm emission).
  • a) 1 ⁇ l of a DMSO solution of the test compound (IC 50 curve uses ten 1 in 2 serial dilutions from 500 ⁇ M).
  • c) 10 ⁇ l enzyme solution This is prepared by diluting 1.6ml of a 200 unit/ml (in 10 mM HCI) enzyme solution into 398.4 ml of buffer (prepared as above).
  • Blank wells (enzyme solution replaced by buffer) are included as controls on each plate. Wells are incubated for 1 h at room temperature and fluorescence read using a Tecan Ultra Fluorimeter/Spectrophotometer ( 485nm excitation, 535nm emission).
  • the compounds of E1-E5 were tested in Assays (I) and (II) and exhibited inhibition within the following range: 1-200 nM (ASp-2) and 10-3000 nM (CatD).

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

Cette invention se rapporte à des composés d'hydroxyéthylène représentés par la formule (I); ayant une action inhibitrice de l'enzyme Asp2 (ß-secrétase, BACE1 ou Mémapsine), à des procédés de préparation de ces composés, à des compositions contenant ces composés et à leur utilisation dans le traitement de maladies se caractérisant par des niveaux de ß-amyloïdes élevés ou par des dépôts de ß-amyloïdes, telles que notamment la maladie d'Alzheimer, formule dans laquelle R1 représente un groupe de formule Zc.
PCT/EP2004/006594 2003-06-19 2004-06-17 Composes de benzamide a substitution 3-(1,1-dioxotetrahydro-1,2-thiazin-2-yl) ou 3-(1,1-doxo-isothiazolidin-2yl) utilises comme inhibiteurs de l'enzyme asp2 WO2004111022A1 (fr)

Applications Claiming Priority (2)

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GB0314302.1 2003-06-19
GBGB0314302.1A GB0314302D0 (en) 2003-06-19 2003-06-19 Novel compounds

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006073366A1 (fr) * 2005-01-10 2006-07-13 Astrazeneca Ab Derives non aniliques d'isothiazol-3(2h)-one 1,1-dioxides servant de modulateurs de recepteurs nucleaires hepatiques
WO2006073363A1 (fr) * 2005-01-10 2006-07-13 Astrazeneca Ab Derives de 1,1-dioxydes d'isothiazol-3(2h)-one utilises comme modulateurs du recepteur x du foie
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
WO2003045903A1 (fr) * 2001-11-30 2003-06-05 Smithkline Beecham P.L.C. Composes d'hydroxyethylene a activite inhibitrice d'asp2
WO2003045913A1 (fr) * 2001-11-30 2003-06-05 Smithkline Beecham P.L.C. Derives de benzamide, procedes de preparation associes et utilisation pharmaceutique desdits derives
WO2003106405A1 (fr) * 2002-06-01 2003-12-24 Sunesis Pharmaceuticals, Inc. Inhibiteurs de l'aspartyl-protease
WO2004050619A1 (fr) * 2002-12-05 2004-06-17 Glaxo Group Limited Derives d'hydroxyethylamine utilises pour 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
WO2003045903A1 (fr) * 2001-11-30 2003-06-05 Smithkline Beecham P.L.C. Composes d'hydroxyethylene a activite inhibitrice d'asp2
WO2003045913A1 (fr) * 2001-11-30 2003-06-05 Smithkline Beecham P.L.C. Derives de benzamide, procedes de preparation associes et utilisation pharmaceutique desdits derives
WO2003106405A1 (fr) * 2002-06-01 2003-12-24 Sunesis Pharmaceuticals, Inc. Inhibiteurs de l'aspartyl-protease
WO2004050619A1 (fr) * 2002-12-05 2004-06-17 Glaxo Group Limited Derives d'hydroxyethylamine utilises pour le traitement de la maladie d'alzheimer

Cited By (6)

* 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
WO2006073366A1 (fr) * 2005-01-10 2006-07-13 Astrazeneca Ab Derives non aniliques d'isothiazol-3(2h)-one 1,1-dioxides servant de modulateurs de recepteurs nucleaires hepatiques
WO2006073363A1 (fr) * 2005-01-10 2006-07-13 Astrazeneca Ab Derives de 1,1-dioxydes d'isothiazol-3(2h)-one utilises comme modulateurs du recepteur x du foie
US7582629B2 (en) 2005-01-10 2009-09-01 Astrazeneca Ab Derivatives of isothiazol-3(2H)-one 1,1-dioxides as liver X receptor modulators
US7723333B2 (en) 2005-01-10 2010-05-25 Astrazeneca Ab Non-anilinic derivatives of isothiazol-3(2H)-one 1,1-dioxides as liver X receptor modulators
US7960380B2 (en) 2005-01-10 2011-06-14 Astrazeneca Ab Non-anilinic derivatives of isothiazol-3(2H)-one 1,1-dioxides as liver X receptor modulators

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