WO2018162445A1 - Inhibiteurs de bêta-sécrétase - Google Patents

Inhibiteurs de bêta-sécrétase Download PDF

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Publication number
WO2018162445A1
WO2018162445A1 PCT/EP2018/055403 EP2018055403W WO2018162445A1 WO 2018162445 A1 WO2018162445 A1 WO 2018162445A1 EP 2018055403 W EP2018055403 W EP 2018055403W WO 2018162445 A1 WO2018162445 A1 WO 2018162445A1
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WIPO (PCT)
Prior art keywords
3alkyl
halo
3alkyloxy
group
formula
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PCT/EP2018/055403
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English (en)
Inventor
Sven Franciscus Anna Van Brandt
Henricus Jacobus Maria Gijsen
Ann Marleen VOS
Daniel Oehlrich
Original Assignee
Janssen Pharmaceutica Nv
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Publication date
Application filed by Janssen Pharmaceutica Nv filed Critical Janssen Pharmaceutica Nv
Priority to EP18710001.1A priority Critical patent/EP3592752A1/fr
Priority to KR1020197028606A priority patent/KR20190126346A/ko
Priority to CN201880016097.1A priority patent/CN110382506A/zh
Priority to CA3051779A priority patent/CA3051779A1/fr
Priority to US16/489,910 priority patent/US20190389882A1/en
Priority to EA201992055A priority patent/EA201992055A1/ru
Priority to AU2018229723A priority patent/AU2018229723A1/en
Priority to MX2019010653A priority patent/MX2019010653A/es
Priority to JP2019548451A priority patent/JP2020509064A/ja
Publication of WO2018162445A1 publication Critical patent/WO2018162445A1/fr

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Classifications

    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to tricyclic inhibitors of beta-secretase having the structure shown in Formula (I) and (II)
  • the present invention is directed to compounds of Formula (I) and (II)
  • R 1 is selected from the group consisting of C3- 6 cycloalkyl, Ar, Het, Ar-CH 2 -,
  • R 2 is hydrogen or Ci-3alkyl
  • Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above.
  • An illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier.
  • Illustrating the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.
  • an example of the invention is a method of treating a disorder selected from the group consisting of Alzheimer's disease, mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with stroke, dementia associated with Parkinson's disease, dementia associated with beta-amyloid, and age-related macular degeneration, preferably Alzheimer's disease, type 2 diabetes and other metabolic disorders, comprising administering to a subject in need thereof, a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
  • a disorder selected from the group consisting of Alzheimer's disease, mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with stroke, dementia associated with Parkinson's disease, dementia associated with beta-amyloid, and age-related macular degeneration, preferably Alzheimer's disease, type 2 diabetes and other metabolic disorders, comprising administering to a subject in need thereof, a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
  • the present invention is directed to compounds of formula (I) and (II) as defined hereinbefore, and pharmaceutically acceptable addition salts and solvates thereof.
  • the compounds of formula (I) are inhibitors of the beta-secretase enzyme (also known as beta-site cleaving enzyme, BACE, BACE1 , Asp2 or memapsin 2, or
  • R la is H or Ci_3alkyl, and R 1 is selected from the group consisting of C3- 6 cycloalkyl, Ar, and Het-; or
  • Het is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl, each of which being optionally substituted with 1 , 2, or 3 substituents, each independently selected from the group consisting of halo, cyano, Ci-3alkyl, poly-halo- Ci_3alkyl, and Ci-3alkyloxy; and
  • R and R 2 are as defined herein.
  • R 1 is selected from the group consisting of C3- 6 cycloalkyl, Ar, Het, Ar-CH 2 -, Het-CH 2 -, and 4-morpholinyl-CH 2 -; and R and R 2 are as defined herein.
  • R 1 is selected from the group consisting of C3- 6 cycloalkyl, Ar, Het, and 4- morpholinyl-CH 2 -; wherein
  • Ar is phenyl or phenyl substituted with 1 , 2 or 3 substituents each independently selected from the group consisting of of halo, cyano, Ci_3alkyl, mono-halo-Ci_3alkyl, poly-halo-Ci_3alkyl, C3- 6 cycloalkyl, Ci-3alkyloxy, mono-halo-Ci-3alkyloxy- and polyhalo-Ci-3alkyloxy; and
  • Het is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl, each of which being optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of halo, cyano, Ci-3alkyl, poly-halo- Ci_3alkyl, and Ci-3alkyloxy; and
  • the invention relates to compounds of Formula (I) and (II) as defined herein, wherein
  • R is phenyl substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halo, Ci-3alkyloxy, cyano, 2-cyano-pyridin-5-yl, 3-cyano- pyridin-5-yl, and pyrimidin-5-yl; and
  • L 1 , R and R 1 are as defined herein.
  • R 2 is Ci-3alkyl, in particular methyl.
  • the invention relates to compounds of Formula ( ⁇ ) and ( ⁇ ") and compounds of Formula ( ⁇ ) and ( ⁇ ") as represented below, wherein the tricyclic core is in the plane of the drawing and H and R are projected above the plane of the drawing (with the bond shown with a bold wedge ) in ( ⁇ ) and (IF) or wherein the tricyclic core is in the plane of the drawing and H and R are projected below the plane of the
  • Halo shall denote fluoro, chloro and bromo;
  • C 1-3 alky 1 shall denote a straight or branched saturated alkyl group having 1 , 2 or 3 carbon atoms carbon atoms, respectively e.g.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • the absolute configuration is specified according to the Cahn-Ingold-Prelog system.
  • the configuration at an asymmetric atom is specified by either R or S.
  • Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
  • stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other isomers.
  • a compound of formula (I) is for instance specified as (R)
  • a compound of formula (I) is for instance specified as E
  • E this means that the compound is substantially free of the Z isomer
  • a compound of formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.
  • addition salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable addition salts".
  • Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable addition salts.
  • Suitable pharmaceutically acceptable addition salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable addition salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • acids which may be used in the preparation of pharmaceutically acceptable addition salts include, but are not limited to, the following: acetic acid, 2,2- dichloroactic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, (+)- camphoric acid, camphorsulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, beta- oxo-glutaric acid, glycolic acid, hippuric
  • Representative bases which may be used in the preparation of pharmaceutically acceptable addition salts include, but are not limited to, the following: ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, dimethylethanolamine, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylene-diamine, N-methyl-glucamine, hydrabamine, IH-imidazole, L- lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide,
  • a particular salt is the trifluoroacetic acid addition salt.
  • Final compounds according to Formula (I) and (II) can be prepared by deprotecting intermediate compounds of Formula (III) and (IV) wherein Q represents a base labile (e.g. an acyl) or acid labile (e.g. a trityl) protecting group (Reaction Scheme 1). Such reactions can be performed under art-known reaction conditions.
  • Q represents a base labile (e.g. an acyl) or acid labile (e.g. a trityl) protecting group
  • Intermediates of Formula (IV) wherein R 2 is Ci_3alkyl herein referred to as intermediates of Formula (IV-a) can be prepared by reaction the corresponding intermediates of Formula (III) wherein R 2 is methyl, herein referred to as intermediates of Formula (Ill-a) with Ci_3alkyl iodide (Reaction Scheme 2).
  • the reaction can be performed under thermal conditions such as, for example, heating the reaction mixture at 100 °C.
  • Reaction Scheme 2 all variables are defined as in Formula (I).
  • Intermediate compounds of Formula (III) wherein R 2 is hydrogen herein referred to as (Ill-b) can be prepared from an intermediate compound of Formula (III- a), following art-known O-demethylation procedures. Said transformation may conveniently be conducted by treatment of intermediate (Ill-a) with a suitable O- demethylating agent, such as, trimethylchlorosilane, in the presence of a suitable additive such as, sodium iodide, in a suitable inert solvent such as, acetonitrile, under suitable reaction conditions, such as at a convenient temperature, typically 50 °C, for a period of time to ensure the completion of the reaction.
  • a suitable O- demethylating agent such as, trimethylchlorosilane
  • a base such as triethylamine
  • a peptide coupling reagent such as HBTU
  • Intermediate compounds of Formula (Ill-d) can be prepared from an intermediate compound of Formula ( ⁇ -e) by art-known reduction procedures, such as, for example, treating intermediate compound ( ⁇ -e), dissolved in a suitable solvent, such as THF, with a reducing agent, such as lithium aluminium hydride, at a convenient temperature, such as room temperature, for a period of time to ensure the completion of the reaction.
  • a suitable solvent such as THF
  • a reducing agent such as lithium aluminium hydride
  • a base such as triethylamine
  • a peptide coupling reagent such as HBTU
  • Intermediate compounds of Formula (Ill-h) and ( ⁇ -i) can be prepared from the corresponding intermediates of Formula (Ill-f) following art-known palladium- catalyzed carbonylation procedures.
  • Said carbonylation may conveniently be conducted by stirring an intermediate compound of Formula (Ill-f) under a carbon monoxide atmosphere in the presence of a suitable palladium catalyst, such as, for example, palladium acetate, a suitable ligand, such as, 1,3- bis(diphenylphosphino)propane and a suitable base, such as, potassium acetate in a suitable reaction solvent or mixtures of solvents such as, for example, THF/EtOH.
  • Reaction may be carried out in an autoclave at a suitable pressure such as, for example, 30 bar, at a convenient temperature, typically 120 °C, for a period of time to ensure the completion of the reaction.
  • a suitable pressure such as, for example, 30 bar
  • bromination may conveniently be conducted by treatment of the corresponding intermediate compounds of Formula (Ill-j) with a brominating agent such as, for example, N-bromosuccinimide in a suitable inert solvent such as, for example, acetonitrile and the like at a suitable temperature such as, for example, room
  • Intermediates compound of Formula (Ill-j) may need to be protected by a protecting group PG such as, for example, tert-butoxycarbonyl group, following art- known procedures.
  • Said reaction can conveniently be conducted by treatment of intermediate compound (Ill-j) with di-tert-butyl dicarbonate, in the presence of a suitable catalyst, such as, 4-(dimethylamino)pyridine (DMAP), in a suitable inert solvent such as, THF, under suitable reaction conditions, such as at a convenient temperature, typically r.t., for a period of time to ensure the completion of the reaction.
  • a suitable catalyst such as, 4-(dimethylamino)pyridine (DMAP)
  • DMAP 4-(dimethylamino)pyridine
  • the protected intermediate (Ill-k) may then be brominated as described above to yield (III-l) which than may be deprotected by treatment with a suitable acid, such as for example, trifluoroacetic acid of formic acid in a suitable solvent, or neat, at ambient temperature to yield intermediate (Ill-f).
  • a suitable acid such as for example, trifluoroacetic acid of formic acid in a suitable solvent, or neat
  • Said cyclization may conveniently be conducted by treatment of an intermediate compound of Formula (V) with a suitable reagent, such as l-chloro-N,N-2- trimethylpropenylamine, in a suitable reaction solvent, such as for example DCM under suitable reaction conditions, such as at a convenient temperature, typically r.t., for a period of time to ensure the completion of the reaction.
  • a suitable reagent such as l-chloro-N,N-2- trimethylpropenylamine
  • a suitable inert solvent such as, for example, DCM
  • reaction can be performed in a suitable reaction inert solvent, such as, THF under suitable reaction conditions, such as at a suitable temperature, typically in a range between -78 °C and room temperature, for a period of time to ensure the completion of the reaction.
  • a suitable reaction inert solvent such as, THF
  • suitable reaction conditions such as at a suitable temperature, typically in a range between -78 °C and room temperature, for a period of time to ensure the completion of the reaction.
  • An intermediate compound of Formula (IX) can be obtained commercially or synthesized according to literature procedures.
  • Intermediate compounds of Formula (X) can be prepared by reacting the intermediate compounds of Formula (XI) following art-known coupling procedures. Said transformation may be conveniently conducted by conversion of an intermediate compound of Formula (XI) to the corresponding cyanocuprate reagent in the presence of a suitable metalation reagent, such as, isopropylmagnesium chloride lithium chloride complex, and a suitable organocuprate precursor, such as, for example, copper(I) cyanide di(lithium chloride) complex solution, followed by addition of a suitable halide, such as allyl bromide. Reaction may be performed in a suitable inert solvent, such as, for example, THF and the like solvents, at a convenient temperature, typically -70 °C-r.t. for a period of time to ensure the completion of the reaction.
  • a suitable metalation reagent such as, isopropylmagnesium chloride lithium chloride complex
  • a suitable organocuprate precursor such as, for example, copper(I) cyan
  • the flow synthesis system utilized the Vapourtec® R4 reactors and R2 pump modules with integrated valves and reagent loops controlled by FlowCommanderTM software. Up to four reactors, pumps and valves were used depending on the complexity of the chemistry.
  • the output from the final reactor flowed into a HPLC injection valve enabling an aliquot of product to be injected onto the purification system. Loss of material due to dispersion in the synthesis system was minimized in several ways. Firstly small bore tubing was used throughout the system as this minimised dispersion. Secondly, the reagent loop sizes were selected to ensure a steady state concentration of reactants and product was achieved in the reactor. Finally, the injection to HPLC was timed to ensure that an aliquot was taken at the point of maximum product
  • concentration i.e. under steady state conditions.
  • the use of fresh bottles of reagents and/or generating reagents in situ may improve the synthetic outcome.
  • the amide formation is typically conducted in flow using NMP as solvent at 40°C for 20 min to give the protected product.
  • the protecting group for instance trityl group
  • the protecting group can be removed according to known procedures, for instance by using 33% TFA in NMP. This is then added to the outflow of the first reaction and the subsequent mixture is heated, typically at 120 °C for 15 min.
  • all variables are as defined in Formula (I).
  • an appropriate coupling reagent such as for example, HBTU
  • the compounds of the present invention and the pharmaceutically acceptable compositions thereof inhibit BACE and therefore may be useful in the treatment or prevention of Alzheimer's Disease (AD), mild cognitive impairment (MCI), senility, dementia, dementia with Lewy bodies, cerebral amyloid angiopathy, multi-infarct dementia, Down's syndrome, dementia associated with Parkinson's disease, dementia of the Alzheimer's type, vascular dementia, dementia due to HIV disease, dementia due to head trauma, dementia due to Huntington's disease, dementia due to Pick's disease, dementia due to Creutzfeldt- Jakob disease, frontotemporal dementia, dementia pugilistica, dementia associated with beta-amyloid and age related macular
  • treatment is intended to refer to all processes, wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disease or an alleviation of symptoms, but does not necessarily indicate a total elimination of all symptoms.
  • treatment does not necessarily indicate a total elimination of all symptoms, but may also refer to symptomatic treatment in any of the disorders mentioned above.
  • a method of treating subjects such as warm-blooded animals, including humans, suffering from or a method of preventing subjects such as warm-blooded animals, including humans, suffering from any one of the diseases mentioned hereinbefore.
  • Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of a therapeutically effective amount of a compound of Formula (I), a stereoisomeric form thereof, a pharmaceutically acceptable addition salt or solvate thereof, to a subject such as a warm-blooded animal, including a human.
  • the invention also relates to a method for the prevention and/or treatment of any of the diseases mentioned hereinbefore comprising administering a therapeutically effective amount of a compound according to the invention to a subject in need thereof.
  • a method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day.
  • the compounds according to the invention are preferably formulated prior to
  • the compounds of the present invention may be administered alone or in combination with one or more additional therapeutic agents.
  • Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of Formula (I) and one or more additional therapeutic agents, as well as administration of the compound of Formula (I) and each additional therapeutic agent in its own separate pharmaceutical dosage formulation.
  • a compound of Formula (I) and a therapeutic agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.
  • the present invention also provides compositions for preventing or treating diseases in which inhibition of beta-secretase is beneficial, such as Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with stroke, dementia associated with AD
  • AD Alzheimer's disease
  • the present invention further provides a pharmaceutical composition comprising a compound according to the present invention, together with a pharmaceutically acceptable carrier or diluent.
  • a pharmaceutically acceptable carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
  • compositions of this invention may be prepared by any methods well known in the art of pharmacy.
  • a therapeutically effective amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like.
  • Injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • transdermal patch e.g., as a transdermal patch, as a spot-on or as an ointment.
  • Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
  • the pharmaceutical composition will comprise from 0.05 to 99% by weight, preferably from 0.1 to 70%> by weight, more preferably from 0.1 to 50% by weight of the active ingredient, and, from 1 to 99.95% by weight, preferably from 30 to 99.9% by weight, more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
  • the present compounds can be used for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like.
  • the compounds are preferably orally administered.
  • the exact dosage and frequency of administration depends on the particular compound according to formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art.
  • said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
  • a typical dosage can be one 1 mg to about 100 mg tablet or 1 mg to about 300 mg taken once a day, or, multiple times per day, or one time-release capsule or tablet taken once a day and containing a proportionally higher content of active ingredient.
  • the time-release effect can be obtained by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure, or by any other known means of controlled release.
  • compositions, methods and kits provided above, one of skill in the art will understand that preferred compounds for use in each are those compounds that are noted as preferred above. Still further preferred compounds for the compositions, methods and kits are those compounds provided in the non-limiting Examples below.
  • DBU l,8-diazabicyclo[5.4.0]undec- 7-ene
  • SQD Single Quadrupole Detector
  • MSD Mass Selective Detector
  • BEH bridged ethylsiloxane/silica hybrid
  • DAD Diode Array Detector
  • HSS High Strength silica.
  • Q-Tof Quadrupole Time- of- flight mass spectrometers
  • CLND means ChemiLuminescent Nitrogen Detector
  • ELSD means Evaporative Light Scanning Detector.
  • the r.m. was diluted with sat. NaHC0 3 sol. (0.1 L) and the layers were separated.
  • the organic layer was dried over MgSC ⁇ , filtered and transferred to a 1 L 4 neck flask, equipped with a mechanical stirrer and cooled to 0 °C (internal temperature).
  • sodium hypochlorite 210 mL, 470 mmol
  • the r.m. was allowed to come to r.t. and stirring was continued at r.t. overnight.
  • the layers were separated and the aq. layer was extracted with DCM (0.2 L).
  • the combined organic layers were dried over MgSC ⁇ , filtered and concentrated in vacuo to give a solid which was recrystallized from DIPE (0.1 L) to afford intermediate 4 (8.64 g, 44%).
  • Gilson FC204 fraction collector set to take 100 x 16 mm tubes
  • Tables 1 and 2 below list the compounds of Formula (I) and (II) that were exemplified (*Ex. No.) and prepared by analogy to one of the above Examples (indicated by the Ex. No.). In case no salt form is indicated, the compound was obtained as a free base.
  • 'Ex. No.' refers to the Example number according to which protocol the compound was synthesized.
  • 'Co. No.' means compound number.
  • HPLC High Performance Liquid Chromatography
  • MS Mass Spectrometer
  • tune parameters e.g. scanning range, dwell time. ..
  • ions allowing the identification of the compound's nominal mono isotopic molecular weight (MW).
  • Data acquisition was performed with appropriate software.
  • Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H] + (protonated molecule) and/or [M-H] ⁇ (deprotonated molecule).
  • the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used.
  • Values are either peak values or melt ranges, and are obtained with experimental uncertainties that are commonly associated with this analytical method.
  • Base assay buffer was prepared by adding a 50 mM solution of citric acid (1.00244; Merck Biosciences) to stirring solution of 50 mM trisodium citrate (1.06448; Merck Biosciences) until a final pH of 5.0 was achieved.
  • Assay buffer was prepared by adding DMSO to base buffer to a final concentration of 1% (vol./vol).
  • ⁇ -secretase I (18.64 ⁇ ; "BACEl”
  • ⁇ -secretase II (4.65 ⁇ ; "BACE2”
  • BACEl ⁇ -secretase I
  • BACE2 ⁇ -secretase II
  • assay buffer typically 12.5 ⁇ of assay buffer was dispensed to rows B to P of the assay plate.
  • To row A was added 18.75 ⁇ of test compound diluted appropriately in assay buffer.
  • a 6.25 ⁇ aliquot of sample was transferred from row A to row B and the sample mixed three times by pipette. The process was repeated down the plate and 6.25 ⁇ of solution discarded at row N post-mix.
  • Rows O and P were designated as the positive and negative controls.
  • To row P was added 6.25 ⁇ base buffer.
  • 6.25 ⁇ enzyme freshly prepared 40 nM BACE1 or 40 nM BACE2 diluted in base buffer.
  • the CyclOps bioassay module consisted of a fraction collection station, a reagent station, liquid handling robotics, plate store and an integrated plate reader
  • the fraction collection station composed of a 384 well collection plate (P-384-240SQ- C; Axygen, Union City, CA, USA) mounted on a H-portal carriage (Festo AG & Co. KG, Esslingen, Germany), a syringe drive and a two-way six port injection valve fitted with a 200 ⁇ loop (VICI AG International, Schenkon Switzerland). The output of the injection valve was addressable to all the positions of a 384 well collection plate.
  • the reagent station consisted of hydraulically cooled (10-12°C) aluminium segments; each manufactured to house a SBS microtiter plate footprint.
  • ThermoFisher :methanol (M/4058/17; ThermoFisher) contained in a covered reagent reservoir (390007; Porvair Sciences Ltd., Leatherhead, UK).
  • the liquid handling system composed of a LISSY system (Zinsser Analytik GmbH, Frankfurt, Germany) equipped with gripper arm and single teflon-coated stainless steel probe. Between every liquid handling step the teflon-coated stainless steel probe was washed with probe wash solution followed by system liquid (water). Control of the bioassay system was achieved using WinLISSY software (Zinsser Analytik) and SoftMax Pro (which was under WinLISSY automation command control).
  • a plate store housed a stack of assay plates (Costar 4514). Input and output relays enabled contact closure control and feedback between the bioassay module and the CyclOps control software.
  • the plate store was an aluminium rack that accommodated a stack of assay plates which could be accessed by the liquid handling system.
  • the output of the dilution module flowed through the collection station injection valve set in the 'load' position.
  • WinLISSY set to input polling mode contact closure by the CyclOps control software initiated the bioassay protocol.
  • the first action triggered the injection valve to the 'inject' position, isolating the loop contents, and the fraction collection system dispensed the loop contents to an addressable well on the collection plate.
  • the liquid handling system delivered an assay plate to an assay station on the liquid handling bed. Onto columns of the assay plate the liquid handling system dispensed 12.5 ⁇ assay buffer down two columns of the assay plate from row B to row P. To row A was added 18.75 ⁇ of test compound from the respective well of the collection plate.
  • a 6.25 ⁇ aliquot of sample from row A was transferred to row B. The process was repeated down the plate for both columns and 6.25 ⁇ reagent discarded at row N. Rows O and P were designated as the positive and negative controls.
  • To row P was added 6.25 ⁇ assay buffer.
  • To rows A to O of the first column was added 6.25 ⁇ 40 nM BACE1 stored in base buffer.
  • For the BACE2 enzyme addition 17.5 ⁇ of 400 nM BACE2 was diluted with 157.5 ⁇ base buffer. This was mixed by pipetting 175 ⁇ of solution five times in the designated receiving Eppendorf tube and then 6.25 ⁇ of the diluted BACE2 was added up the respective column.
  • MCA substrate 30.8 ⁇ of 1 mM MCA substrate in 100% DMSO was diluted with 385 ⁇ HPLC water. This was mixed by pipetting 400 ⁇ five times in the designated receiving Eppendorf tube and 6.25 ⁇ added up the respective columns. The assay plate was then transferred to the plate reader carriage, the drawer closed and the assay incubation initiated. After 60 min. WinLISSY executed a sub-routine that instructed the plate reader to load and execute a protocol file which read the fluorescence intensity. This protocol file contained the parameters required to read the microtiter plate and write the corresponding data as a text file.
  • Fluorescence intensity was read at 360/405 nm (excitation/emission) utilising a nine reads per well protocol (50 ms integration; density of 3, 0.25 mm spacing) and outputted the median value of the nine reads as a text file.

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Abstract

La présente invention concerne des inhibiteurs tricycliques de bêta-sécrétase ayant la structure représentée par la formule (I) et (II), dans laquelle les radicaux sont tels que définis dans la description. L'invention concerne en outre des compositions pharmaceutiques comprenant ces composés, des procédés de préparation de ces composés et compositions et l'utilisation de ces composés et compositions pour la prévention et le traitement de troubles dans lesquels la bêta-sécrétase est impliquée, tels que la maladie d'Alzheimer (MA), le trouble cognitif léger, la sénilité, la démence, la démence à corps de Lewy, le syndrome de Down, la démence associée à un accident vasculaire cérébral, la démence associée à la maladie de Parkinson, la démence associée à la bêta-amyloïde, la dégénérescence maculaire liée à l'âge, le diabète de type 2 et d'autres troubles métaboliques.
PCT/EP2018/055403 2017-03-07 2018-03-06 Inhibiteurs de bêta-sécrétase WO2018162445A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
EP18710001.1A EP3592752A1 (fr) 2017-03-07 2018-03-06 Inhibiteurs de bêta-sécrétase
KR1020197028606A KR20190126346A (ko) 2017-03-07 2018-03-06 베타 세크레타제의 억제제
CN201880016097.1A CN110382506A (zh) 2017-03-07 2018-03-06 β-分泌酶的抑制剂
CA3051779A CA3051779A1 (fr) 2017-03-07 2018-03-06 Inhibiteurs de beta-secretase
US16/489,910 US20190389882A1 (en) 2017-03-07 2018-03-06 Inhibitors of beta secretase
EA201992055A EA201992055A1 (ru) 2017-09-07 2018-03-06 Ингибиторы бета-секретазы
AU2018229723A AU2018229723A1 (en) 2017-03-07 2018-03-06 Inhibitors of beta secretase
MX2019010653A MX2019010653A (es) 2017-03-07 2018-03-06 Inhibidores de beta secretasa.
JP2019548451A JP2020509064A (ja) 2017-03-07 2018-03-06 βセクレターゼ阻害剤

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US201762468070P 2017-03-07 2017-03-07
US62/468070 2017-03-07
EP17189778 2017-09-07
EP17189778.8 2017-09-07

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110009395A1 (en) * 2009-07-09 2011-01-13 Eli Lilly And Company Bace inhibitors
WO2017051276A1 (fr) * 2015-09-24 2017-03-30 Pfizer Inc. N-[2-(2-amino-6,6-disubstitués-4,4a,5,6-tétrahydropyrano[3,4-d][1,3]thiazin-8a(8h)-yl)-1,3-thiazol-4-yl]amides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110009395A1 (en) * 2009-07-09 2011-01-13 Eli Lilly And Company Bace inhibitors
WO2017051276A1 (fr) * 2015-09-24 2017-03-30 Pfizer Inc. N-[2-(2-amino-6,6-disubstitués-4,4a,5,6-tétrahydropyrano[3,4-d][1,3]thiazin-8a(8h)-yl)-1,3-thiazol-4-yl]amides

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GONZALEZ-MUNOZ G C ET AL: "Old phenothiazine and dibenzothiadiazepine derivatives for tomorrow's neuroprotective therapies against neurodegenerative diseases", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 45, no. 12, 2010, pages 6152 - 6158, XP027526586, ISSN: 0223-5234, [retrieved on 20101125] *
MOTULSKY, H.J.; BROWN, R.E., BMC BIOINFORMATICS, vol. 7, 2006, pages 123

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