Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-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
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/20—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
  • C07D487/20—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems

Definitions

• AD Alzheimer's disease
• ⁇ -amyloid angiopathy cerebral blood vessels
• Amyloidogen ⁇ c plaques and vascular amyloid angiopathy also characterize the brains of patients with Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), and other neurodegenerative disorders. Neurofibrillary tangles also occur in other dementia- inducing disorders.
• A-amyloid The family of proteins known as ⁇ -amyloid are thought to be causal for the pathology and subsequent cognitive decline in Alzheimer's disease.
• Proteolytic processing of the amyloid precursor protein (APP) generates amyloid ⁇ (A-beta) peptide; specifically, A-beta is produced by the cleavage of APP at the N-terminus by ⁇ -secretase and at the C-terminus by one or more y-secretases.
• Aspartyl protease enzyme, or ⁇ -secretase enzyme (BACE), activity is correlated directly to the generation of A-beta peptide from APP (Sinha, et al, Nature, 1999, 402, 537-540), Increasingly, studies indicate that the inhibition of the ⁇ -secretase enzyme, inhibits the production of A-beta peptide.
• the inhibition of ⁇ -secretase and consequent lowering of A-beta peptide may lead to the reduction of ⁇ -amyloid deposits in the brain and ⁇ -amylo ⁇ d levels in the cerebral blood vessels and to an effective treatment of a disease or disorder caused thereby.
• the compounds provided may also be useful to further study and elucidate the ⁇ -secretase enzyme.
• the present invention provides an imidazole amine of formula I
• Q is O, S or CH 2 ;
• VV is O 1 S or CH 2 ;
• X is N, NO, SO m , O or CH;
• Y is N, NO, SO 01 , O or CR 10 ;
• Z is N, NO 1 SO m , O or CRn with the proviso that when X is CH, Y is CR 10 and Z is CR 11 then one of Q or W must be O or S; m is 0, 1 or 2; n is 0 or 1; R 1 and R 2 are each independently H or an optionally substituted Ci-
• R 3 and R 4 are each independently H, or an optionafly substituted C 1 -C 4 alky j group or R 3 and R 4 may be taken together to form a 4- to 7- membered ring optionally containing one or two heteroatoms selected from O, N or S;
• R 5 and R 6 are each independently H, halogen, NO 2 , CN, OR 12 , CO 2 R 13 ,
• R 7 and R 8 are each independently H, halogen, NO 2 , CN, OR 15 , NR 17 R 18 or a CrC 6 alky!, C r C 6 haloaikyl, C 2 -C 6 alkenyl, C 2 -C 6 aikyny(,
• R 7 and R 8 may be taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S;
• R 9 is H, halogen, NO 2 , CN, OR 15 , NR 17 R 18 or a Ci-C 6 alkyl, d-Cghaloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
• R 10 and Rn are each independently H or a C r C 6 alkyl, C r C 6 haloalkyl,
• R 12 , Ri3, Ru and R 15 are each independently H or a C r C 6 alkyl, C 1 -
• Ri7, Ri8, Rig and R 20 are each independently H, CrC 4 alkyl, C 3 -
• Cscycloatkyl or R 17 and Ri S or R 19 and R 20 may be taken together with the atom to which they are attached to form a 5- to 7- membered ring optionally containing an additional heteroatom selected from O, N or S; and p is 0, 1 or 2; or a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
• the present invention also provides therapeutic methods and pharmaceutical compositions useful for the treatment, prevention or amelioration of a disease or disorder characterized by increased ⁇ -amyloid deposits or increased ⁇ -amyloid levels in a patient.
• AD Alzheimer's disease
• A-beta amyloid beta peptide piays a central role in the pathogenesis of the disease.
• AD Alzheimer's disease
• ⁇ -amyloid deposits and vascular ⁇ -amyloid angiopathy also characterize individuals with Downs Syndrome, Hereditary Cerebral Hemmorhage with Amyloidosis of the Dutch type and other neurodegenreative and dementia- inducing disorders.
• BACE1 amyloid precursor protein
• BACE2 a second homologous aspartyl protease named BACE2 was found to have ⁇ -secretase activity in vitro.
• Low molecular weight, non-peptide, non-substrate-related inhibitors of BACE1 or ⁇ - secretase are earnestly sought both as an aid in the study of the ⁇ -secretase enzyme and as potential therapeutic agents.
• imidazole amine compounds of formula I demonstrate inhibition of ⁇ -secretase and the selective inhibition of BACE1.
• sard imidazole amine compounds may be used as effective therapeutic agents for the treatment, prevention or amelioration of a disease or disorder characterized by elevated ⁇ -amyloid deposits or ⁇ -amyloid levels in a patient.
• the present invention provides an imidazole amine compound of formula I
• Q is O, S or CH 2 ;
• W is O, S or CH 2 ;
• X is N 1 NO, SO m , O or CH;
• Y is N, NO, SO m , O or CR 10 ;
• Z is N, NO, SO m , O or CR 11 with the proviso that when X is CH, Y is CR 10 and Z is CRn then one of Q or W must be O or S; m is 0, 1 or 2; n is O or 1; R 1 and R 2 are each independently H or an optionally substituted C 1 -
• R 3 and R 4 are each independently H, or an optionally substituted C 1 -C 4 alkyi group or R 3 and R 4 may be taken together to form a 4- to 7- membered ring optionally containing one or two heteroatoms selected from O, N or S;
• R 6 and R 6 are each independently H, halogen, NO 2 , CN, OR 12 , CO 2 R 13 , COR 14 , NR 17 Ri 8 , SOpNR 19 R 20 or a d-Cealkyl, C r C 6 haioaikyl r C 2 - C 6 alkenyL C 2 -C 6 alkynyl or C 3 -C 8 cycloalkyl group each optionally substituted;
• R 7 and R 8 are each independently H, halogen, NO 2 , CN, OR 15 , NR 17 R 18 or a C ⁇ Cealkyl, C r C 6 haloalkyl ( C 2 -C 6 alkenyl, C 2 -C 6 alkyny!, C 3 ⁇ C 8 cycloalkyl or cycloheteroalkyl group each optionally substituted or when attached to adjacent carbon atoms R 7 and R 8 may be taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S;
• R 9 is H, halogen, NO 2 , CN, OR 15 , NR 17 R 18 or a C r C 6 alkyl, C r C 6 haloalky ⁇ , C 2 -C 6 alkenyl, Ca-Cealkynyl, C 3 -C 8 cycloalkyl, cyclo
• R 10 and R 11 are each independently H or a C ⁇ Cealkyl, CrCehaloalkyl, C z -C 6 alkeny!, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, cycloheteroalkyl or aryl group each optionally substituted;
• R 12 , Ri3, R- I4 and Ri 5 are each independently H or a CrC ⁇ alkyl, C 1 - C ⁇ haloalkyi, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyi, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
• R 17 , R 18 , R 19 and R 20 are each independently H, C r C 4 alkyl, C 3 -
• Cgcycloalkyf or R 17 and R 18 or R 19 and R 20 may be taken together with the atom to which they are attached to form a 5- to 7- membered ring optionally containing an additional heteroatom selected from O 5 N or S; and p is O, 1 or 2; or a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
• halogen designates F, Cl, Br or 1
• cycloheteroalkyi designates a five- to seven-membered cycloalkyl ring system containing 1 or 2 heteroatoms, which may be the same or different, selected from N, O or S and optionally containing one double bond.
• exemplary of the cycloheteroalkyi ring systems included in the term as designated herein are the following rings wherein X 1 is NR, O or S; and R is H or an optional substituent as described hereinbeiow:
• heteroaryl designates a five- to ten-membered aromatic ring system containing 1 , 2 or 3 heteroatoms, which may be the same or different, selected from N, O or S.
• heteroaryl ring systems include pyrrolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, qu ⁇ nolinyi, isoquinoiinyl, indolyl, benzothienyl, benzofuranyl, benzisoxazolyl or the like.
• aryl designates a carbocyclic aromatic ring system, e.g., of 6-14 carbon atoms, such as phenyl, naphthy!, anthracenyl or the like.
• aryl ⁇ Ci- C 4 )alkyl designates an aryl group as defined hereinabove attached to a Ci-C 4 alkyl group which may be straight or branched.
• Said aryl(C r C 4 )alkyl groups include benzyl, phenethyl, naphthylmethyl, or the like.
• haloalkyl as used herein designates a C n H 2n+ !
• haloalkyl designates CF 3 and the term haloalkoxy designates OCF 3 .
• substituent groups which are optionally present may be one or more of those customarily employed tn the development of pharmaceutical compounds or the modification of such compounds to influence their structure/activity, persistence, absorption, stability or other beneficial property
• substituents include halogen atoms, ⁇ itro, cyano, thiocyanato, cyanato, hydroxyl, alky!, haloaikyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, al
• Pharmaceutically acceptable salts may be any acid addition salt formed by a compound of formula I and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, malonic, mandehc, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid or the like
• a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, malonic, mandehc, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid or the like
• compounds of the invention include esters, carbamates or other conventional prodrug forms, which in general, are functional derivatives of the compounds of the invention and which are readily converted to the inventive active moiety in vivo
• the method of the invention embraces the treatment of the various conditions described heremabove with a compound of formula I or with a compound which is not specifically disclosed but which, upon administration, converts to a compound of formula I in vivo
• metabolites of the compounds of the present invention defined as active species produced upon introduction of these compounds into a biological system
• Tautomers often exist in equilibrium with each other. As these tautomers interconvert under environmental and physiological conditions, they provide the same useful biological effects.
• the present invention includes mixtures of such tautomers as well as the individual tautomers of Formula I and Formula It.
• the compounds of the invention may contain one or more asymmetric carbon atoms or one or more asymmetric (chiral) centers and may thus give rise to optica! isomers and diastereomers.
• the invention includes such optical isomers and disastereomers; as well as the racemic and resolved, enantiomerically pure stereoisomers; as well as other mixtures of the R and S stereoisomers.
• one stereoisomer may be more active or may exhibit beneficial effects when enriched relative to the other stereoisomers) or when separated from the other stereoisomerfs). Additionally, the skilled artisan knows how to separate, enrich or selectively prepare said stereoisomers.
• the present invention comprises compounds of Formula 1, the stereoisomers thereof, the tautomers thereof and the pharmaceutically acceptable salts thereof.
• the compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active or enantiomerically pure form.
• the point of attachment may be via Z in which case to fulfil valency requirements R 11 is absent.
• an example of the five membered ring is pyrazoly! such as pyrazol-4-yJ (i.e., X and Y are N), which ring may be optionally substituted, e.g., 1- ethylpyrazol-4-yl or 1 -(2,2,2 ⁇ trifluoroethy)pyrazol-4-yl.
• n 1
• an example of the six membered ring is pyridyl such as pyrid-4- yl, or phenyl, which rings may be optionally substituted, e.g., 2,6-diethylpyrid-4-yl or 4-trifluromethoxyphenyl.
• Preferred compounds of the invention are those compounds of formula ! wherein R 1 and R 2 are H. Another group of preferred compounds of the invention are those compounds of formula I wherein R 9 is an optionally substituted heteroaryl group. Also preferred are those formula I compounds wherein X is N. A further group of preferred compounds of the invention are those compounds of formula I wherein R 9 is an optionally substituted heteroaryl group and is attached to the phenyl ring in the 3-position of the phenyl ring.
• More preferred compounds of the invention are those compounds of formula 1 wherein R 1 and R 2 are H and Rg is an optionally substituted heteroaryl group.
• Another group of more preferred compounds of the invention are those compounds of formula I wherein R 1 and R 2 are H; R 9 is an optionally substituted heteroaryl group; and X is N.
• a further group of more preferred compounds of the invention are those compounds of formula i wherein R 1 and R 2 are H and R 9 is an optionally substituted heteroaryl group and is attached to the phenyl ring in the 3-position of the phenyl ring.
• Preferred compounds of formula I include:
• the present invention provides a process for the preparation of a compound of formula i wherein R 9 is an optionally substituted aryl or heteroaryf group (Ia) which comprises reacting a compound of formula Il wherein Hal is Cl or Br with an optionally substituted aryl or heteroaryl group having a leaving group selected from B(OH) 2 , Sn(Bu) 3 or Sn(CH 3 ) 3 in the presence of a palladium catalyst and an inorganic base optionally in the presence of a solvent.
• A represents an optionally substituted aryl or heteroaryl group
• W is B(OH) 2 , Sn(Bu) 3 or Sn(CH 3 J 3
• Hal is Cl or Br.
• Palladium catalysts suitable for use in the process of the invention include
• Pd(O) or Pd(H) catalysts such as dichlorobis(tri-o-tolyfphosphine)palladium(ll), Pd(OCOCH 3 ) 2 /tri-o-tolylphosphine, tetrakis(triphenylphosphine)pa!ladium(0), tris(dibenzylideneacetone)dipallad!um(0)triphenylphosphine, or the like.
• Inorganic bases suitable for use in the inventive process include Na or K hydroxides, carbonates or bicarbonates, preferably Na 2 CO 3 Or K 2 CO 3 .
• Solvents suitable for use in the inventive process include polar or non-polar organic solvents such as toluene, diethoxy ethyl ether, dioxane, ethyleneglycol dimethyl ether or any non-reactive organic solvent which is capable of solubiiizing the formula Il or heteroaryl compounds.
• polar or non-polar organic solvents such as toluene, diethoxy ethyl ether, dioxane, ethyleneglycol dimethyl ether or any non-reactive organic solvent which is capable of solubiiizing the formula Il or heteroaryl compounds.
• Compounds of formula Il may be prepared using conventional synthetic methods and, if required, standard separation or isolation techniques.
• compounds of formula Il wherein R t and R 2 are H and Q and W are CH 2 (Ha) may be prepared by reacting a compound of formula IM with a diamine of formula IV to give the bicyclic compound of formula V and reacting said formula V compound with t- butyl hydroperoxide and ammonium hydroxide to give the desired formula Ma compound.
• the reaction is shown in flow diagram Il wherein Hal is Cl or Br,
• compounds of formula Il wherein R t and R 2 are H; R 3 and R 4 are H; Q is CH 2 ; and W is O (lib) may be prepared by reacting the formula III compound with 2-(aminooxy)ethanamine dihydrochloride in the presence of a base such as triethylamine and a solvent to give the bicyclic compound of formula Vl and reacting said formula Vl compound with t-butyl hydroperoxide and ammonium hydroxide to give the desired formula Mb compound.
• a base such as triethylamine and a solvent
• the reaction is shown in flow diagram III wherein Hal is Cl or Br.
• R 1 and R 2 are other than H
• Compounds of formula 1 wherein R 1 and R 2 are other than H may be prepared using standard aikylation techniques such as reacting the compound of formula ! wherein R 1 and R 2 are H with an alkyl halide, R 1 -HaI 1 to give the compound of formula I wherein R 2 is H (Id) and optionally reacting said formula Id compound with a second aikyi halide, R 2 -HaI, to give the desired formula I compound wherein R 1 and R 2 are other than H.
• the compounds of the invention are useful for the treatment, prevention or amelioration of a disease or disorder characterized by elevated ⁇ -amyloid deposits or ⁇ -amyloid levels in a patient, including Alzheimer's disease, Downs Syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type or other neurodegenerative or dementia-inducing disorders.
• the present invention provides a method for the treatment, prevention or amelioration of a disease or disorder characterized by elevated ⁇ -amyloid deposits or ⁇ -amyloid levels in a patient which comprises providing said patient with a therapeutically effective amount of a compound of formula I as described hereinabove.
• the compound may be provided by oral or parenteral administration or in any common manner known to be an effective administration of a therapeutic agent to a patient in need thereof.
• providing designates either directly administering such a compound or substance, or administering a prodrug, derivative or analog which forms an equivalent amount of the compound or substance within the body.
• CNS disorder may vary according to the specific condition(s) being treated, the size, age and response pattern of the patient, the severity of the disorder, the judgment of the attending physician and the like.
• effective amounts for daily oral administration may be about 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg and effective amounts for parenteral administration may be about 0.1 to 100 mg/kg, preferably about 0.5 to 50 mg/kg.
• the compounds of the invention are provided by administering the compound or a precursor thereof in a solid or liquid form, either neat or in combination with one or more conventional pharmaceutical carriers or excipients. Accordingly, the present invention provides a pharmaceutical composition which comprises a pharmaceuticaliy acceptable carrier and an effective amount of a compound of formula I as described hereinabove.
• Solid carriers suitable for use in the composition of the invention include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aides, binders, tablet-disintegrating agents or encapsulating materials.
• the carrier may be a finely divided solid which is in admixture with a finely divided compound of formula I.
• the formula I compound may be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Said powders and tablets may contain up to 99% by weight of the formula I compound.
• Solid carriers suitable for use in the composition of the invention include calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrroiidine, low melting waxes and ion exchange resins.
• any pharmaceutically acceptable liquid carrier suitable for preparing soiutions, suspensions, emulsions, syrups and elixirs may be employed in the composition of the invention.
• Compounds of formula f may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a pharmaceutically acceptable oil or fat, or a mixture thereof.
• Said liquid composition may contain other suitable pharmaceuticai additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers, osmo-regulators, or the like.
• liquid carriers suitable for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) or their derivatives, or oils (e.g., fractionated coconut oil and arachis oil).
• the carrier may also be an oily ester such as ethyl ofeate or isopropyl myristate.
• compositions of the invention which are sterile solutions or suspensions are suitable for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously.
• Inventive compositions suitable for oral administration may be in either liquid or solid composition form.
• sustained delivery is defined as delaying the release of an active agent, i.e., a compound of the invention, until after placement in a delivery environment, followed by a sustained release of the agent at a later time.
• active agent i.e., a compound of the invention
• sustained delivery devices include, e.g., hydrogels (see, e.g., US Patent Nos. 5,266,325; 4,959,217; and 5,292,515), an osmotic pump, such as described by Alza (US Patent Nos. 4,295,987 and 5,273,752) or Merck (European Patent No.
• hydrophobic membrane materials such as ethyienemethacryiate (EMA) and ethylenevinylacetate (EVA); bioresorbable polymer systems (see, e.g., International Patent Publication No. WO 98/44964, Bioxid and Celiomeda; US Patent Nos. 5,756,127 and 5,854,388); other bioresorbable impiant devices have been described as being composed of, for example, polyesters, poiyanhydrides, or lactic acid/g!ycoiic acid copolymers (see, e.g., US Patent No. 5,817,343 (Alkermes Inc.) ⁇ .
• the compounds of the invention may be formulated as described herein.
• the invention provides a pharmaceutical kit for delivery of a product.
• the kit contains packaging or a container with the compound formulated for the desired delivery route.
• the kit may contain a suspension containing a compound of the invention formulated for aerosol or spray delivery of a predetermined dose by inhalation.
• the kit may further contain instructions for monitoring circulating levels of product and materials for performing such assays including, e.g., reagents, well plates, containers, markers or labels, and the like.
• Such kits are readily packaged in a manner suitable for treatment of a desired indication.
• the kit may also contain instructions for use of the spray pump or other delivery device.
• kits will be readily apparent to one of skill in the art, taking into consideration the desired indication and the delivery route.
• the doses may be repeated daily, weekly, or monthly, for a predetermined length of time or as prescribed.
• a mixture of potassium terf-butoxide (0.355 g, 3.16 mrnol) in tetrahydrofuran at -78 0 C was treated dropwise with a solution of 1 (0.665 g, 2.53 mmol) in tetrahydrofuran, stirred for 10 mtn, treated with carbon disulfide (0.635 g, 8,34 mmol), allowed to warm to room temperature slowly and stirred for 1 h at room temperature.
• the reaction mixture was cooled to -78 0 C 1 treated with di-2-pyridyl-thiocarbonate (0.880 g, 3.79 mmol), allowed to warm to room temperature, stirred overnight at room temperature and concentrated in vacuo.
• reaction mixture was treated with anhydrous methanol, cooled to 0 0 C, treated with sodium borohydride (0.991 g, 26.2 mmol), warmed to room temperature, stirred for 1 h at to room temperature, cooled to 0 0 C and quenched by the careful addition of saturated ammonium chloride until gas evolution had ceased and ail precipitates had dissolved.
• the reaction mixture was diluted with methylene chloride and water. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo.
• a mixture of potassium f-butoxtde (0.04 g, 0.37 mmo! in tetrahydrofuran at -78 0 C was treated dropwise over a period of 2 min. with a solution of 2 (0.11 g, 0.34 mmol) and carbon disulfide (0.04 g, 0.51 mmol) in tetrahydrofuran, stirred at -78 0 C for 0.5 h, slowly warmed to room temperature, stirred at room temperature for 1 h and diluted with methylene chloride and water. The phases were separated.
• Assay Conditions 10 nM human BACE1 (or 10 nM Murine BACE1 , 1.5 nM human BACE2) 25 ⁇ M substrate (WABC-6, MW 1549.6, from AnaSpec); final buffer conditions:50 mM Na-Acetate, pH 4.5, 0.05% CHAPS, 25% PBS; temperature: room temperature; reagent information: Na-Acetate: Aldrich, Cat. # 24,124-5 CHAPS: Research Organics, Cat.
• Fluorescence Readings Readings at ⁇ ex 320 nm and ⁇ em 420 nm are taken every 40-sec for 30 min at room temperature to determine the linear slope for substrate cleavage rate (v,).
• Fluorescent Kinetic Assay for human recombinant BACE 2 This assay is used to provide kinetic and selectivity parameters for the analyses of the tested compounds.
• final assay conditions 10 nM human BACE1 (or 10 nM Murine BACE1 , 1.5 nM human BACE2) 25 ⁇ M Substrate (WABC-6, MW 1549.6, from AnaSpec).
• Final buffer conditions 50 mM Na-Acetate, pH 4.5, 0.05% CHAPS, 25% PBS. Temperature: room temperature.
• Reagent Information Na- Acetate: Aldrich, Cat.# 24,124-5 CHAPS: Research Organics, Cat. # 1304C 1X PBS: Mediatech (Cellgro), Cat# 21 -031 -CV Peptide Substrate AbzSEVNLDAEFRDpa: AnaSpec, Peptide Name: WABC-6
• V 0 substrate cleavage rate in the absence of inhibitor
• IC 5O value represents the value obtained at 100% inhibition.
• the compounds of the invention are potent and selective inhibitors of BACE1.

Landscapes

• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Hospice & Palliative Care (AREA)
• Psychiatry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=38988046

Family Applications (1)

Country Status (9)

Families Citing this family (21)

Family Cites Families (5)

• 2007
  • 2007-07-24 TW TW096126963A patent/TW200817406A/zh unknown
  • 2007-08-07 CL CL200702288A patent/CL2007002288A1/es unknown
  • 2007-08-07 PE PE2007001049A patent/PE20080744A1/es not_active Application Discontinuation
  • 2007-08-10 CA CA002660441A patent/CA2660441A1/en not_active Abandoned
  • 2007-08-10 JP JP2009524746A patent/JP2010500999A/ja not_active Withdrawn
  • 2007-08-10 EP EP07840855A patent/EP2054414A2/en not_active Withdrawn
  • 2007-08-10 MX MX2009001699A patent/MX2009001699A/es not_active Application Discontinuation
  • 2007-08-10 WO PCT/US2007/075690 patent/WO2008022024A2/en active Application Filing
  • 2007-08-16 AR ARP070103654A patent/AR062409A1/es unknown

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events