Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
  • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
• • 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
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/12—Ophthalmic agents for cataracts
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to novel heterocyclic compounds which are useful in the prevention and treatment of neurodegenerative disorders, such as Alzheimer's, Parkinson's and Huntington's diseases as well as type II diabetes.
• a number of incurable, ageing-related or degenerative diseases have been linked to a generic and fundamental pathogenic process of protein or peptide misfolding and aggregation. These include Alzheimer's, Parkinson's and Huntington's diseases and type II diabetes.
• the amyloid deposits present in these diseases consist of particular peptides that are characteristic for each of these diseases but regardless of their sequence the amyloid fibrils have a characteristic ⁇ -sheet structure and share a common aggregation pathway.
• a specific protein or peptide misfolds adopts ⁇ - strand structure and oligomerizes to form soluble aggregated intermediates en route to fibril formation ultimately forming insoluble amyloid fibres, plaques or inclusions.
• amyloid-related diseases are those in which normally soluble proteins accumulate in various tissues as insoluble deposits of fibrils that are rich in ⁇ -sheet structure and have characteristic dye-binding properties (Glenner, 1980a, 1980b). Although the specific polypeptides that comprise the deposits are different for each disease, they have several key features in common. The most prominent of these is the ability of proteins that are highly soluble in biological fluids to be gradually converted into insoluble filamentous polymers enriched in ⁇ -sheet conformation.
• Amyloid-related diseases fall into two main categories: those which affect the brain and other parts of the central nervous system and those which affect other organs or tissues around the body, outside of the brain. Examples of amyloid-related diseases which fall under these two categories are listed below in the following two sections, however many other examples of rare hereditary amyloid-related diseases are known which are not included here and more forms of amyloid-related disease are likely to be discovered in the future.
• AD/FAD Alzheimer's disease
• HSHWA hereditary cerebral hemorrhage with amyloidosis
• cerebral amyloid angiopathy cerebral amyloid angiopathy
• mild cognitive impairment and other forms of dementia are associated with the aggregation of a 40/42-residue peptide called ⁇ - amyloid, ⁇ (1-40) or ⁇ (1-42), which forms insoluble amyloid fibres and plaques in the cerebral cortex, hippocampus or elsewhere in the brain, depending on the specific disease;
• Alzheimer's disease is also associated with the formation of neurofibrillary tangles by aggregation of a hyperphosphorylated protein called tau, which also occurs in fronto temporal dementia (Pick's disease); Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are associated with the aggregation of a protein called cc-synuclein, which results in the formation of insoluble inclusions called "Lewy bodies";
• PD Parkinson's disease
• DLB dementia with Lewy bodies
• MSA multiple system atrophy
• Huntington's disease (HD), spinal and bulbar muscular atrophy (SBMA, also known as Kennedy's disease), dentatorubral pallidoluysian atrophy (DRPLA), different forms of spinocerebellar ataxia (SCA, types 1, 2, 3, 6 and 7), and possibly several other inheritable neurodegenerative diseases are associated with the aggregation of various proteins and peptides that contain abnormally expanded glutamine repeats (extended tracts of polyglutamine);
• Creutzfeldt-Jakob disease CJD
• bovine spongiform encephalopathy BSE
• GSS Gerstmann-Straussler-Scheinker disease
• GSS Gerstmann-Straussler-Scheinker disease
• ALS Amyotrophic lateral sclerosis
• MND motor neuron disease
• Familial British dementia (FBD) and familial Danish dementia (FDD) are respectively associated with aggregation of the ABri and ADan peptide sequences derived from the BRI protein;
• HCVWA Hereditary cerebral hemorrhage with amyloidosis
• Type II diabetes also known as adult-onset diabetes, or non-insulin dependent diabetes mellitus
• IAPP islet amyloid polypeptide
• Amylin islet amyloid polypeptide
• Dialysis-related amyloidosis (DRA) and prostatic amyloid are associated with the aggregation of a protein called 2-microglobulin, either in bones, joints and tendons in DRA, which develops during prolonged periods of haemodialysis, or within the prostate in the case of prostatic amyloid;
• Primary systemic amyloidosis, systemic AL amyloidosis and myeloma-associated amyloidosis are associated with the aggregation of immunoglobulin light chain (or in some cases immunoglobulin heavy chain) into insoluble amyloid deposits, which gradually accumulate in various major organs such as the liver, kidneys, heart and gastrointestinal (GI) tract;
• immunoglobulin light chain or in some cases immunoglobulin heavy chain
• GI gastrointestinal
• Reactive systemic AA amyloidosis, secondary systemic amyloidosis, familial Mediterranean fever and chronic inflammatory disease are associated with the aggregation of serum amyloid A protein, which forms insoluble amyloid deposits that accumulate in major organs such as the liver, kidneys and spleen;
• Senile systemic amyloidosis SSA
• familial amyloid polyneuropathy FAP
• familial amyloid cardiomyopathy FAC
• TTR transthyretin protein
• Familial visceral amyloidosis and hereditary non-neuropathic systemic amyloidosis are associated with misfolding and aggregation of various mutants of lysozyme, which form insoluble deposits in major organs such as the liver, kidneys and spleen;
• Finnish hereditary systemic amyloidosis is associated with aggregation of a protein called gelsolin in the eyes (particularly in the cornea);
• Fibrinogen cc-chain amyloidosis is associated with aggregation of the fibrinogen A cc- chain, which forms insoluble amyloid deposits in various organs such as the liver and kidneys;
• Insulin-related amyloidosis occurs by the aggregation of insulin at the site of injection in diabetics
• Medullary carcinoma of the thyroid is associated with the aggregation of calcitonin in surrounding tissues;
• Isolated atrial amyloidosis is associated with the aggregation of atrial natriuretic peptide (ANP) in the heart; and
• amyloid-related diseases While all these amyloid-related diseases share a common association with the pathogenic process of amyloidosis, the precise molecular mechanism by which this generic process of protein/peptide misfolding and aggregation is linked to the progressive degeneration of affected tissues is unclear. In some cases, including many of the systemic amyloid-related diseases, it is thought that the sheer mass of insoluble protein or peptide simply overwhelms the affected tissues, ultimately leading to acute organ failure. In other cases, including most of the neurodegenerative diseases listed above, it is increasingly appreciated that the toxic forms of amyloidogenic proteins are soluble oligomeric species which range in size from dimers and trimers, to much larger species comprising tens or even hundreds or thousands of protein or peptide monomers.
• the oligomers are inherently toxic to cells in vitro in the absence of insoluble aggregates, and they appear to share a common structural feature as they can all be recognised by the same antibody despite the fact that they may be formed by proteins or peptides with very different amino acid sequences (Kayed et al., 2003; Glabe, 2004; Walsh et al., 2002; Walsh and Selkoe, 2004).
• the present invention relates to chemical compounds and compositions which are inhibitors of amyloid toxicity and as such have use in the treatment of amyloid-related diseases and disorders.
• WO2007125351 describes a class of 2,5-disubstituted pyrimidine derivatives which have been shown to inhibit amyloid toxicity.
• functional groups can be grouped into clusters according to their physicochemical properties. For example, hydrophobicity ( ⁇ ), electronic ( ⁇ ) and molar refractivity properties can be used to group substituents with potentially similar biological activity. Nitrile, carboxylic acid and carboxylic acid ester functional groups fall into the same cluster and are therefore expected to show similar biological activity.
• the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof:
• R 1 is CN
• R 2 is H or F
• R 3 J and R 4" are independently hydrogen, fluorine, chlorine or OR 8 ;
• R 5 is hydrogen, C ⁇ alkyl, C 1-6 alkenyl or Q-6 alkynyl;
• R 6 and R 7 are independently hydrogen, halogen, OR 8 or NR 9 R 10 ;
• R is hydrogen or Ci_6 alkyl
• R 9 and R 10 are independently hydrogen or C 1-6 alkyl; or the groups R 9 and R 10 when they are attached to a nitrogen atom may together form a 5- or 6-membered ring which optionally contains one further heteroatom selected from NR , S and O, said 5 or 6 membered ring being optionally substituted by hydroxyl or C 1-6 alkoxy;
• R 9 and R 10 when they are attached to a nitrogen atom may together form an azetidinyl ring optionally substituted by hydroxyl or C 1-6 alkoxy.
• alkyl as used herein whether on its own or as part of a larger group includes both straight and branched chain radicals, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl and tert-butyl.
• alkyl also includes those radicals wherein one or more hydrogen atoms are replaced by fluorine, e.g. CF 3 .
• alkenyl and alkynyl as used herein includes both straight and branched chain radicals.
• halogen as used herein includes fluorine, chlorine and bromine
• Preferred compounds are:
• the present invention encompasses any salt of a compound of the present invention and, in particular, any pharmacologically acceptable salt.
• Preferred salts for the present invention include hydrohalogenates (for instance, hydrochloride salt, hydrobromide salt, hydroiodide salt and the like), inorganic acid salts (for instance, sulphate salt, nitrate salt, perchlorate salt, phosphate salt, carbonate salt, bicarbonate salt and the like), organic carboxylic acid salts (for instance, acetate salt, maleate salt, tartrate salt, fumarate salt, citrate salt and the like), organic sulfonic acid salts (for instance, methanesulfonate salt, ethane sulfonate salt, benzenesulfonate salt, toluenesulfonate salt, camphorsulfonate salt and the like), amino acid salt (for instance, aspartate salt, glutamate salt and the like), quaternary ammonium salts, alkaline metal salts (for instance, sodium salt, potassium salt and the like), alkaline earth metal salts (for instance, magnesium salt, calcium
• Salts may be prepared in a conventional manner using methods well known in the art.
• Acid addition salts of said basic compounds may be prepared by dissolving the free base compounds according to the first aspect of the invention in aqueous or aqueous alcohol solution or other suitable solvents containing the required acid.
• a base salt of said compound may be prepared by reacting said compound with a suitable base. The acid or base salt may separate directly or can be obtained by concentrating the solution e.g. by evaporation..
• the compounds of the invention may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures.
• the invention includes in particular the isomeric forms (R or S).
• the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric synthesis.
• a compound contains an alkene moiety, the alkene can be presented as a cis or trans isomer or a mixture thereof.
• an isomeric form of a compound of the invention When an isomeric form of a compound of the invention is provided substantially free of other isomers, it will preferably contain less than 5% w/w, more preferably less than 2% w/w and especially less than 1% w/w of the other isomers.
• the compounds of the invention are intended for use in pharmaceutical compositions, it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5%, e.g. 10 to 59% of a compound of the formula (I).
• a compound of formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R V are as defined for formula (I) may be prepared from a compound of formula (II)
• R 6 and R 7 are as defined in formula (I), by treatment with an appropriate aniline in the presence of a suitable catalyst such as in ' .s'(dibenzylideneacetone)- palladium(O), a phosphine ligand such as 4,5-bis , (diphenylphosphino)-9,9- dimethylxanthene and a base such as cesium carbonate in a solvent such as 1,4-dioxan with heating.
• a suitable catalyst such as in ' .s'(dibenzylideneacetone)- palladium(O)
• a phosphine ligand such as 4,5-bis , (diphenylphosphino)-9,9- dimethylxanthene
• a base such as cesium carbonate
• a compound of formula (II) wherein R 6 and R 7 are as defined in formula (I), may be prepared by treatment of 2-chloro-5-hydroxypyrimidine with one equivalent of an appropriate boronic acid of formula (III), wherein R 6 and R 7 are as defined in formula (I), in a suitable solvent such as dichloromethane in the presence of triethylamine and copper(II) acetate.
• 2-Chloro-5-hydroxypyrimidine may be prepared by methods well known to those skilled in the art.
• a compound of formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R V are as defined for formula (I) may be prepared from a compound of formula (IV) by treatment with a boronic acid of formula (III) wherein R 6 and R 7 are as defined in formula (I), in a suitable solvent such as dichloromethane in the presence of triethylamine and copper(II) acetate.
• a compound of formula (IV) can be prepared from a compound of formula (V) by de- benzylation using classical hydrogenolysis conditions of hydrogen gas in the presence of a suitable catalyst such as alladium on carbon in a suitable solvent such as ethanol.
• a compound of formula (V) can be prepared from 2-chloro-5-benzyloxypyrimidine using an appropriate aniline in the presence of a suitable catalyst such as in dibenzyl- ideneacetone)-palladium(O), a phosphine ligand such as 4,5-bis , (diphenylphosphino)- 9,9-dimethylxanthene and a base such as cesium carbonate in a solvent such as 1,4- dioxan with heating.
• a suitable catalyst such as in dibenzyl- ideneacetone)-palladium(O)
• a phosphine ligand such as 4,5-bis , (diphenylphosphino)- 9,9-dimethylxanthene
• a base such as cesium carbonate
• a solvent such as 1,4- dioxan with heating.
• the protecting groups may be removed at any stage in the synthesis of the compounds of formula (I) or may be present on the final compound of formula (I).
• a comprehensive discussion of the ways in which various labile functional groups may be protected and methods for cleaving the resulting protected derivatives is given in for example Protective Groups in Organic Chemistry, T.W. Greene and P.G.M. Wuts (Wiley- Interscience, New York, 2 nd edition, 1991). It will be appreciated by someone skilled in the art that by using the methods described above in various combinations it will be possible to synthesise other derivatives encompassed in the general formula (I).
• aniline and boronic acid building blocks used in the synthesis of compounds of general formula (I) are either commercially available or can be synthesised by methods known in the art.
• the pharmaceutically effective compounds of formula (I) may be administered in conventional dosage forms prepared by combining a compound of formula (I) ("active ingredient") with standard pharmaceutical carriers or excipients according to conventional procedures well known in the art.
• the procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, together with one or more pharmaceutically acceptable carriers or excipients.
• the active ingredient or pharmaceutical composition can be administered simultaneously, separately or sequentially with another appropriate treatment for the amyloid-related disease being treated.
• the active ingredient or pharmaceutical composition may be administered to a subject by any of the routes conventionally used for drug administration, for example they may be adapted for oral (including buccal, sublingual), nasal (including inhalation) or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) administration to mammals including humans.
• compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
• Preferred routes of administration are oral and intravenous.
• compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
• Tablets and capsules for oral administration may be in unit dose presentation form , and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidine ; filler, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
• the tablets may be coated according to methods well known in normal pharmaceutical practice.
• 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 reconstitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl /?-hydoxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
• suspending agents for example sorb
• compositions adapted for controlled or sustained release may be administered by injection, for example by the subcutaneous route.
• compositions adapted for nasal administration wherein the carrier is a solid include coarse powder having a particle size for example in the range of 20-500 microns which is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nose.
• Suitable compositions wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of an active ingredient.
• Pharmaceutical compositions adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurise aerosols, nebulizers or insufflators.
• compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti- oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
• the compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
• Extemporaneous injection solution and suspensions may be prepared from sterile powders, granules and tablets.
• fluid unit dosage forms are prepared utilising the active ingredient and a sterile vehicle, water being preferred.
• the active ingredient depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
• the active ingredient can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
• agents such as local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
• the composition can be frozen after filling into the vial and the water removed under vacuum.
• the dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
• Parenteral suspensions are prepared in substantially the same manner except that the active ingredient is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
• the active ingredient can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
• a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active ingredient.
• the pharmaceutical compositions according to the invention are preferably adapted for oral, intravenous or subcutaneous administration.
• compositions may also include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents. They may also contain therapeutically active agents in addition to the compounds of the present invention. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
• compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration.
• compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per dose.
• a unit may contain for example O. lmg/kg to lOOmg/kg, more preferably O. lmg/kg to lOmg/kg depending on the condition being treated, the route of administration and the age, weight and condition of the patient.
• Preferred unit dosage compositions are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
• the optimal quantity and spacing of individual dosages of compounds in the first and second aspects of the invention will be determined by the nature and extent of the condition being treated the form, route and site of administration, and the particular subject being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment , i.e., the number of doses of the aforementioned compounds given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
• the chemical compound or composition may be required to be coated in a material to protect it from the action of enzymes, acids and other natural conditions which may inactivate it.
• it may be coated by, or administered with, a material to prevent its inactivation.
• it may be administered in an adjuvant, co-administered with enzyme inhibitors or in liposomes.
• Adjuvants contemplated herein include resorcinols, non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether.
• Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes.
• the active chemical compound or composition may also be administered parenterally or intraperitoneally.
• Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
• compositions or formulations suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
• the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene gloycol, and the like), suitable mixtures thereof, and vegetable oils.
• the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of superfactants.
• the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thirmerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
• Sterile injectable solutions are prepared by incorporating the active chemical compound or composition in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilisation.
• dispersions are prepared by incorporating the sterilised active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
• the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile- filtered solution thereof.
• the chemical compound or composition When the chemical compound or composition is suitably protected as described above, it may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
• the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
• the tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring.
• a binder such as gum tragacanth, acacia, corn starch or gelatin
• excipients such as dicalcium phosphate
• a disintegrating agent such as corn starch, potato starch, alginic acid and the like
• a lubricant such as magnesium stearate
• a sweetening agent such as sucrose, lactose or saccharin may be added or a flavouring agent such as peppermin
• any material may be present as coatings or to otherwise modify the physical form of the dosage unit.
• tablets, pills, or capsules may be coated with shellac, sugar or both.
• a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour.
• any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
• the active compound may be incorporated into sustained-release preparations and formulations.
• pharmaceutically acceptable carrier and/or diluent includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
• the use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
• Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
• the specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such as active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired.
• the principal active ingredients are compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
• the present invention provides:
• the medicament is for the treatment of:
• AD Alzheimer's disease
• MCI mild cognitive impairment
• senile dementia any form of mild cognitive impairment (MCI) or senile dementia
• cerebral amyloid angiopathy cerebral amyloid angiopathy, inclusion body myositis, hereditary cerebral hemorrhage with amyloidosis (HCHWA, Dutch type), or age-related macular degeneration (ARMD);
• PD Parkinson' s disease
• AD Huntington's disease
• DRPLA spinocerebellar ataxia
• SBMA spinal and bulbar muscular atrophy
• h Creutzfeldt-Jakob disease
• BSE bovine spongiform encephalopathy in cows, scrapie in sheep, kuru, Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia, or any other transmissible encephalopathy that is associated with the aggregation of prion proteins
• ALS amyotrophic lateral sclerosis
• j familial British dementia (FBD) or familial Danish dementia (FDD); k) hereditary cerebral hemorrhage with amyloidosis (HCHWA, Icelandic type);
• type II diabetes adult onset diabetes, or non-insulin dependent diabetes mellitus, NIDDM
• NIDDM non-insulin dependent diabetes mellitus
• DAA dialysis-related amyloidosis
• prostatic amyloid DAA
• any form of cataract any form of cataract; and y) any other amyloid-related disease that is associated with the misfolding or aggregation of a specific target amyloid-forming protein or peptide into toxic soluble oligomers, protofibrils, ion channels, insoluble amyloid fibres, plaques or inclusions.
• a method for the treatment of an amyloid-related disease which comprises the step of administering to a subject an effective amount of a compound or pharmaceutical composition of the invention.
• a mixture of methyl methoxyacetate (104g. l.Omol) and ethyl formate (74g. l.Omol) was added dropwise to a stirred suspension of sodium (23 g. l.Omol) in toluene (300mL), the temperature being kept below 30°C. After 24h the toluene layer was decanted, to the crude, viscous methyl sodio-P-hydroxy-a-methoxyacrylate were added ethanol (150mL) and urea (60g. l.Omol). The mixture was stirred for lh. at room temperature, and then heated under reflux for 5h.
• 1,3-Dibromobenzene (50g, 0.212mol), morpholine (15.88mL, 0.191mol) and anhydrous toluene (200mL) were added to a flask by syringe under argon.
• the solution was thoroughly mixed before R-BINAP (1.32g, 0.0021mol) and iris (dibenzylideneacet one) palladium (0) (0.640g, 0.006mol) were added and finally DBU (25.83 mL, 0.1726) was added via syringe.
• the reaction mixture was stirred at 60°C.
• Sodium te/t-butoxide (30.55 g, 0.3178 mol) was added and the reaction was heated to 100°C overnight.
• the suspension was diluted with ethyl acetate and washed with water and brine.
• the organic phase was dried (MgS0 4 ) and the solvent removed under reduced pressure.
• the crude product was purified by column chromatography on silica (ethyl acetate:hexane 1: 1) to afford 2-fluoro-5-[5-(3-morpholin-4-ylphenoxy)pyrimidin-2- ylamino]benzonitrile as a light yellow solid (70mg, 35%).
• the suspension was diluted with ethyl acetate and washed with water and brine.
• the organic phase was dried (MgS0 4 ) and the solvent removed under reduced pressure.
• the crude product was purified by column chromatography on silica (ethyl acetate:hexane, 1: 1) to afford 2,6-difluoro-3-[5-(3-morpholin-4-ylphenoxy)pyrimidin-2-ylamino]benzonitrile as a solid (l lOmg, 44%).
• the suspension was diluted with ethyl acetate and washed with water and brine.
• the organic phase was dried (MgS0 4 ) and the solvent removed under reduced pressure.
• the crude product was purified by column chromatography on silica (ethyl acetate:hexane, 1: 1) to afford 2-chloro-5-[5-(3-morpholin-4-ylphenoxy)-pyrimidin-2-ylamino]benzonitrile as a solid (40mg, 16%).
• Example 6 3-Fluoro-5-[5-(3-morpholin-4-ylphenoxy)-pyrimidin-2-ylamino]- benzo-nitrile
• the suspension was diluted with ethyl acetate and washed with water and brine.
• the organic phase was dried (MgS0 4 ) and the solvent removed under reduced pressure.
• the crude product was purified by column chromatography on silica (ethyl acetate: hexane, 1: 1) to afford 3-fluoro-5-[5-(3-morpholin-4-ylphenoxy)-pyrimidin-2- ylamino]-benzonitrile as a solid (98mg, 41%).
• the suspension was diluted with ethyl acetate and washed with water and brine.
• the organic phase was dried (MgS0 4 ) and the solvent removed under reduced pressure.
• the crude product was purified by column chromatography on silica (ethyl acetate: hexane, 1: 1) to afford 2-fluoro-3-[5-(3-morpholin-4-ylphenoxy)-pyrimidin-2-ylamino]-benzonitrile as a solid (70mg, 29%).
• the suspension was diluted with ethyl acetate and washed with water and brine.
• the organic phase was dried (MgS0 4 ) and the solvent was removed under reduced pressure.
• the crude product was purified by column chromatography on silica (ethyl acetate: hexane, 1:1) to afford 2-methoxy-5-[5-(3-morpholin-4-ylphenoxy)- pyrimidin-2-ylamino]-benzonitrile as solid (113mg, 46%).
• the suspension was diluted with ethyl acetate and washed with water and brine.
• the organic phase was dried (MgS0 4 ) and the solvent removed under reduced pressure.
• the crude product was purified by column chromatography on silica (ethyl acetate: hexane, 1: 1) to afford 2-fluoro-5-[5-(3-pyrrolidin-l-ylphenoxy)-pyrimidin-2-ylamino]- benzonitrile as a solid (95mg, 46%).
• Example 11 2-Fluoro-5-[5-(3-bromophenoxy)pyrimidin-2-ylamino]-benzonitrile
• 2-fluoro-5-(5-hydroxypyrimidin-2-ylamino)-benzonitrile 0.5g, 0.00217 mol
• 3-bromophenylboronic acid 0.497g, 0.00217mol
• copper (II) acetate 0.394g
• Example 12 2-Fluoro-4-(5-(3-(3-hydroxyazetidin-l-yl)phenoxy)pyrimidin-2-yl- amino)benzonitrile
• a suspension of 2-fluoro-5-[5-(3-bromophenoxy)-pyrimidin-2-ylamino]-benzonitrile (170 mg, 0.441mmol), azetidin-3-ol hydrochloride (58mg, 0.529mmol), in ' 5'(dibenzylidene-acetone)palladium(0) (20mg, 0.022mmol), 4,5- bi5'(diphenylphosphino)-9,9-dimethyl-xanthene (26mg, 0.044mmol) and cesium carbonate (288 mg, 0.88mmol) in de-gassed 1,4-dioxane (5mL) was heated at 80°C for 2 days.
• the reaction mixture was diluted with dichloromethane and washed with water and brine.
• the organic phase was dried (MgS0 4 ) and the solvent removed under reduced pressure.
• the crude product was purified by flash chromatography, using 0- 15% ethyl acetate:hexane as eluent, to give 2-fluoro-4-(5-(3-(3-hydroxyazetidin-l-yl) phenoxy)pyrimidin-2-ylamino)benzonitrile (71mg, 44%) as a white solid.
• ⁇ (1-42) was prepared for amyloid aggregation and toxicity assays by dissolving ⁇ (1-42) HC1 salt in hexafluoroisopropanol (HFIP), with brief sonication and vortexing. This solution of the ⁇ (1-42) peptide in HFIP was stored at 4°C @ 2mM. When required, an aliquot of this stock solution was freeze-dried and dissolved in DMSO to 200 times the required final assay concentration (e.g. 2mM for a final assay concentration of 10 ⁇ ).
• HFIP hexafluoroisopropanol
• a 20mM stock solution of each test compound was prepared in DMSO, and aliquots of these solutions were used to prepare further stock solutions of each test compound in DMSO, ranging in concentration from 3 ⁇ up to lOmM. These stock solutions were prepared for use as and when required and stored at -20°C (maximum of 3 freeze-thaw cycles). The 20mM parent stock solutions were stored frozen at -20°C.
• Example 14 Cell viability assay for amyloid toxicity using MTT reduction
• the activity of compounds in protecting SH-SY5Y cells from a toxic insult of 10 ⁇ ⁇ (1-42) was assessed by using inhibition of MTT reduction as a measure of cell viability.
• An aliquot (3 ⁇ 1) of test compound [various concentrations] in DMSO is added to 294 ⁇ of Opti-Mem (containing 2% FBS, 1% Pen/Strep, 1% L-Gln) ⁇ daughter plate ⁇ . The well is mixed thoroughly. Then an aliquot (3 ⁇ ) of ⁇ (1-42) [2mM] is added to the daughter plate wells and again mixed thoroughly.
• 50 ⁇ is then aspirated and dispensed into wells containing 50 ⁇ media + SH-SY5Ycells (cells are also plated in Opti-Mem, at ⁇ 30,000 cells/well/50 ⁇ ).
• Final concentrations of compound on cells range from [50 ⁇ ] to [ ⁇ 15nM] with a final concentration of ⁇ (1- 42) ⁇ [10 ⁇ ].
• MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl- tetrazolium bromide) dye (from Promega) added to each well and the plates incubated in 5% CC"2 at 37°C for 4 hours. 100 ⁇ Stop/solubilsation solution (from Promega) was added to each well and the plates were left overnight in humidified box at room temperature. The plate was shaken and the absorbance was recorded at both 570 nm and 650 nm. ⁇ values were calculated by subtracting absorbance at 650 nm from absorbance at 570 nm, to reduce non-specific background absorbance. ⁇ values from equivalent experiments were averaged and % cell viability was determined as follows:
• % cell viability rAA(sample) - AA(dead cell control)! x 100%
• the daughter plate is sealed with silver seal and incubated at 37 °C for 24 and 48 hours for the Thioflavin T assay (LeVine and Scholten 1999).
• Example 16 Activity of compounds in inhibiting ⁇ ⁇ (1-42) aggregation using thioflavin-T fluorimetric assay
• Example 18 Activity of SEN1500 in blocking the deficit in long-term potentiation caused by toxic forms of ⁇
• LTP Long-term potentiation
• APP751 cDNA for APP
• the cells were grown to just below confluence in DMEM, containing 10% FBS and 200 ⁇ g/ml G418 (geneticin), briefly washed in DPS and incubated at 37°C with 5% C0 2 for 18 h with sufficient volume of DMEM to just cover the cells. After incubation the medium was centrifuged at 3000 g for 15 min and either used directly or snap frozen and stored at -20°C. The subsequent quantification of low-n oligomers was performed using IP/WB.
• Example 2 was prepared as 6mM stock in DMSO and stored at -20°C until use.
• 7PA2 cell conditioned medium (7PA2 CM) and wild type Chinese hamster ovary cell conditioned medium (wtCHO CM, control) were stored at -80°C until use.
• 7PA2 CM ⁇ DMSO was added to stock 7PA2 CM (lmL) and equilibrated for lh prior to the experiment.
• ⁇ ⁇ of 6mM Example 2 was added to stock 7PA2 CM. These final mixtures were diluted to 20mL in aCSF immediately prior to use. The final concentration of DMSO was 0.05% and the final concentration of Example 2 was 3 ⁇ .
• wtCHO CM control experiments l0 ⁇ L ⁇ DMSO was added to stock wtCHO CM (lmL) and equilibrated for lh prior to experiments. The final concentration of DMSO was 0.05%.
• Extracellular fEPSP recordings were made from 400 ⁇ thick transverse hippocampal slices prepared from male Sprague-Dawley rats. After a minimum 1 h recovery period slices were transferred to an interface chamber warmed to 30 ⁇ 1°C and perfused with aCSF. Schaffer collaterals were stimulated every 20 s with a concentric bipolar electrode and fEPSPs recorded from the stratum radiatum of the CAl region using a glass microelectrode. Stimulation intensity was set to evoke fEPSPs of 40-50% of the maximum amplitude.
• Amyloid deposits and amyloidosis the beta-fibrilloses. N Engl J Med 302, 1283-1292.
• Islet amyloid and type 2 diabetes from molecular misfolding to islet pathophysiology. Biochim Biophys Acta 1537, 179-203.
• Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol 155, 853-862. McLean, C. A., R. A. Cherny, F. W. Fraser, S. J. Fuller, M. J. Smith, K. Beyreuther, A. I. Bush and C. L. Masters (1999). Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol 46, 860-866.

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