WO2013182638A1 - 2-aminothiazinylhétéroaryles en tant qu'inhibiteurs de bace1 pour le traitement de la maladie d'alzheimer - Google Patents

2-aminothiazinylhétéroaryles en tant qu'inhibiteurs de bace1 pour le traitement de la maladie d'alzheimer Download PDF

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WO2013182638A1
WO2013182638A1 PCT/EP2013/061691 EP2013061691W WO2013182638A1 WO 2013182638 A1 WO2013182638 A1 WO 2013182638A1 EP 2013061691 W EP2013061691 W EP 2013061691W WO 2013182638 A1 WO2013182638 A1 WO 2013182638A1
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compound
compounds
anyone
methyl
optionally substituted
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PCT/EP2013/061691
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Karsten Juhl
Lena TAGMOSE
Mauro Marigo
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H. Lundbeck A/S
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention is directed to novel compounds which inhibit BACE1.
  • Separate aspects of the invention are directed to pharmaceutical compositions comprising said compounds and uses of the compounds to treat Alzheimer's disease.
  • AD Alzheimer's disease
  • AD is a degenerative brain disorder characterized by impairment of memory, cognition, temporal and local orientation, judgment and reasoning but also severe emotional disturbances. In many instances, Alzheimer's disease gradually leads to severe mental deterioration.
  • Amyloid plaques occur in the extracellular space of cerebral tissue and vascular tissue. Amyloid deposits in the vasculature are commonly observed in the brains of patients beyond a certain age with Down's Syndrome (Trisomy 21) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA- D). A component of amyloid deposits characteristic of AD and the other mentioned disorders are peptides designated as amyloid-beta ( ⁇ ).
  • ⁇ -peptides are a group of proteolytic fragments derived from the ⁇ -amyloid precursor protein (APP) by a series of proteolytic cleavage steps (Selkoe, et al., Annu Rev Cell Biol, 1994. 10, 373-403).
  • APP ⁇ -amyloid precursor protein
  • proteolytic cleavage steps Several forms of APP have been identified of which the most abundant are proteins of 695, 751 and 770 amino acids length. They all arise from a single gene through differential splicing.
  • the ⁇ -peptides are derived from the same domain of the APP but differ at their N- and C-termini, the main species are of 40 and 42 amino-acid length.
  • ⁇ peptides are produced from APP through the sequential action of 2 proteolytic enzymes termed ⁇ - and ⁇ -secretase.
  • ⁇ -Secretase cleaves first in the extracellular domain of APP approximately 28 amino acids outside of the trans-membrane domain (TM) to produce a C- terminal fragment of APP containing the TM- and the cytoplasmatic domain ( ⁇ ).
  • TM trans-membrane domain
  • ⁇ cytoplasmatic domain
  • ⁇ is the substrate for ⁇ -secretase which cleaves at several adja- cent positions within the TM to produce the ⁇ -peptides and the cytoplasmic fragment.
  • the ⁇ -secretase is a complex of at least 4 different proteins, its catalytic subunit is likely a presenilin protein (PSEN1, PSEN2).
  • ⁇ -secretase is an asparryl protease beta-site APP-cleaving enzyme 1 (BACE1; Asp2) which is anchored into the membrane by a transmembrane domain (Vassar et al., Science, 1999, 286, 7353).
  • BACE1 is expressed in many tissues in humans but its level is especially high in the CNS.
  • BACE1 co- localizes with its substrate APP in Golgi and endocytic compartments (Willem M, et al. Semin.Cell Dev. Biol, 2009, 20, 175-182). Knock-out studies in mice have demonstrated the absence of amyloid peptide formation while the animals are healthy and fertile (Ohno M, et al. Neurobiol.
  • the present invention relates to novel cyclic amidines having BACEl inhibitory activity, to their preparation, to their medical use and to medicaments comprising them.
  • BACEl knock-out mice are seen to have markedly enhanced clearance of axonal and myelin debris from degenerated fibers, accelerated axonal regeneration, and earlier reinnervation of neuromuscular junctions, compared with littermate controls. These observations were reproduced in part by pharmacological inhibition of BACEl . Thus, the data suggest BACEl inhibition as a therapeutic approach to accelerate regene- ration and recovery after peripheral nerve damage (Farah MH, et al., J Neurosci. 2011 Apr 13;31(15):5744- 54).
  • BACEl inhibitors are presently known but appear to have a range of non-specific effect, or can only achieve limited access to the central nervous system where the BACEl enzyme is abundantly expressed. Thus, it would be beneficial to identify and provide BACEl inhibitors. It would further be particularly beneficial if such compounds can provide improved efficacy of treatment while reducing adverse effects associated with compounds targeting neuronal nicotinic receptors by selectively inhibiting BACEl.
  • An objective of the present invention is to provide compounds that inhibit BACEl . Accordingly, the to compounds of Formula I.
  • Ar is selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, thiophenyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, 1,3,4- thiadiazolyl, isothiazolyl, 1,3,4-oxadiazolyl and 1,2,4-thiadiazolyl and where the Ar is optionally substituted with one or more halogen, CN, C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C r C 6 fluoroalkyl, C r C 3 alkyl(0)C r C 3 or C r C 6 alkoxy; wherein n is 0-2;
  • each Y 1 and Y 2 is independently N or CR 3 with the proviso that at least one Y is N; wherein R 1 is C r C 3 alkyl or C r C 3 fluoroalkyl;
  • each R 2 is independently hydrogen, fluorine, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl with the proviso that only one R 2 may be hydroxyl or C -C3 alkoxy;
  • each R 3 is independently hydrogen, halogen, C1-C6 alkyl or C1-C6 fluoroalkyl; and or a pharmaceutically acceptable salt thereof.
  • the compound is selected from one of the specific compounds disclosed in the Experimental Section.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier.
  • the present invention also provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier.
  • the present invention provides a method of treating a subject suffering from Alzheimer's disease comprising administering to the subject a therapeutically effective amount of a compound of Formula I.
  • the present invention is directed to the use of a compound as defined in Formula I for the manufacture of a medicament for treating Alzheimer's disease.
  • n 0.
  • n 1 or 2.
  • Y 1 is N.
  • Y 2 is N.
  • R 1 is methyl or trifluoromethyl.
  • each R 2 is independently hydrogen or fluorine.
  • Ar is optionally substituted phenyl. In one embodiment, Ar is optionally substituted pyrimidyl. In one embodiment, Ar is optionally substituted pyrazinyl. In one embodiment, Ar is optionally substituted imidazolyl. In one embodiment, Ar is optionally substituted pyrazolyl. In one embodiment, Ar is optionally substituted 1,2,4-triazolyl. In one embodiment, Ar is optionally substituted thiophenyl. In one embodiment, Ar is optionally substituted furanyl. In one embodiment, Ar is optionally substituted thiazolyl. In one embodiment, Ar is optionally substituted oxazolyl. In one embodiment, Ar is optionally substituted isoxazolyl.
  • Ar is optionally substituted 1,3,4-thiadiazolyl. In one embodiment, Ar is optionally substituted 1,3,4-oxadiazolyl. In one embodiment, the compound is selected from the group consisting of (S)-4-[2-(4-Bromo-thiophen-2- ylmethyl) Wazol-5-yl]-4-methyl-5,6-dihydro-4H-[l,3]tWazin-2-ylamine; (S)-4-[5-(4-Bromo-thiophen-2- ylmethyl) Wazol-2-yl]-4-methyl-5,6-dihydro-4H 1,3]thiazin-2-ylamine; (S)-4-Methyl-4-[2-(5-prop-l- ynyl-pyridin-3-ylmethyl) Wazol-5-yl]-5,6-dihydro-4H-[l,3]thiazin-2-ylamine; (S)-4-[2-(5-Chloro-pyri
  • isotopically labelled compounds which are identical to those claimed in formula I, where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, 13 C, U C, 14 C, 15 N, 18 0, 17 0, 35 S, 18 F, 36 C1 and 125 I, respectively.
  • Certain isotopically labelled compounds of the invention, such as those with radioactive isotopes incorporated including but not limited to 3 H and 14 C, are useful in drug and/or substrate tissue distribution assays.
  • the present invention is based on the discovery that the compounds of Formula I are inhibitors of BACE1, and as such, are useful for the treatment of Alzheimer's disease. Additionally, certain aspects of the invention are explained in greater detail below but this description is not intended to be a detailed catalog of all the different ways in which the invention may be implemented, or all the features that may be added to the instant invention. Hence, the following specification is intended to illustrate some embodiments of the invention, and not to exhaustively specify all permutations, combinations and variations thereof.
  • One aspect of this invention is all tautomeric forms of the compounds of the present invention. It is understood by those practicing the art that compounds of formula I can exist in tautomeric forms, as depicted in Figure A. When any reference in this application to one of the specified tautomers of formula I mixtures thereof.
  • Ci-Ce alkyl refers to a straight chained or branched saturated hydrocarbon having from one to six carbon atoms inclusive.
  • substituents include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-l -propyl, n-pentyl and n-hexyl.
  • straight chained or branched C 1 -C3 alkyl refers to a saturated hydrocarbon having from one to three carbon atoms inclusive. Examples of such substituents include, but are not limited to, methyl, ethyl and n-propyl.
  • Ci-Ce alkoxy refers to a straight chained or branched saturated alkoxy group having from one to six carbon atoms inclusive with the open valency on the oxygen. Examples of such substituents include, but are not limited to, methoxy, ethoxy, n-butoxy, t-butoxy and n-hexyloxy.
  • the "Cp alkoxy” is optionally substituted with one or more fluorine atoms.
  • C r C 3 alkyl(0)Ci-C 3 alkyl refers to substituents which include, but are not limited to, methoxymethyl, ethoxymethyl and ethoxyethyl.
  • Ci-Ce fluoroalkyl refers to a straight chained or branched saturated hydrocarbon having from one to six carbon atoms inclusive substituted with one or more fluorine atoms.
  • substituents include, but are not limited to, trifluoromethyl, pentafluoroethyl, 1-fluoroethyl, mono- fluoromethyl, difluoromethyl, 1 ,2-difluoroethyl and 3,4 difluorohexyl.
  • straight chained or branched C -C3 fluoroalkyl refers to a saturated hydrocarbon having from one to three carbon atoms inclusive substituted with one or more fluorine atoms per carbon atom.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • C 2 _6-alkenyl refers to a branched or unbranched alkenyl group having from two to six carbon atoms and one double bond, including but not limited to ethenyl, propenyl, and butenyl.
  • C 2 -6-alkynyl shall mean a branched or unbranched alkynyl group having from two to six carbon atoms and one triple bond, including but not limited to ethynyl, propynyl and butynyl.
  • the phrase "effective amount” when applied to a compound of the invention is intended to denote an amount sufficient to cause an intended biological effect.
  • the phrase "therapeutically effective amount” when applied to a compound of the invention is intended to denote an amount of the compound that is sufficient to ameliorate, palliate, stabilize, reverse, slow or delay the progression of a disorder or disease state, or of a symptom of the disorder or disease.
  • the method of the present invention provides for administration of combinations of compounds. In such instances, the "effective amount” is the amount of the combination sufficient to cause the intended biological effect.
  • treatment means ameliorating or reversing the progress or severity of a disease or disorder, or ameliorating or reversing one or more symptoms or side effects of such disease or disorder.
  • Treatment or “treating”, as used herein, also means to inhibit or block, as in retard, arrest, restrain, impede or obstruct, the progress of a system, condition or state of a disease or disorder.
  • treatment or “treating” further means an approach for obtaining beneficial or desired clinical results, where "beneficial or desired clinical results” include, without limitation, alleviation of a symptom, diminishment of the extent of a disorder or disease, stabilized (i.e., not worsening) disease or disorder state, delay or slowing of a disease or disorder state, amelioration or palliation of a disease or disorder state, and remission of a disease or disorder, whether partial or total, detectable or undetectable.
  • the present invention also provides a method of treating a disease or disorder, the method comprises administering a therapeutically effective amount of at least one compound of formula I or a pharma- ceutically acceptable salt thereof to a mammal in need thereof, wherein the disease or disorder is a neurodegenerative or cognitive disease or disorder.
  • the neurodegenerative or cognitive disease or disorder is Alzheimer's disease, mild cognitive impairment, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-DT), degenerative dementia, amyotrophic lateral sclerosis, traumatic brain injury or stroke.
  • the disease or disorder is a peripheral amyloidosis, such as amyloid neuropathy or pancreatitis.
  • the disease or disorder is a peripheral nerve damage.
  • the present invention provides a method of treating Alzheimer's disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of formula I.
  • the present invention further provides a method of inhibiting BACE1 in a patient comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of formula I.
  • the present invention also provides a method of inhibiting ⁇ -secretase mediated cleavage of amyloid precursor protein comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of formula I.
  • the present invention provides the use of a compound of formula I for the manufacture of a medicament for the treatment of Alzheimer's disease.
  • the present invention also provides the use of a compound of formula I for the manufacture of a medicament for the inhibition of BACE1.
  • the present invention further provides the use of a compound of formula I for the manufacture of a medicament for the inhibition of production or accumulation of ⁇ peptide.
  • the invention also provides a compound of formula I for use in therapy of a patient, for example, in the treatment of Alzheimer's disease or to slow the progression of a patient's mild cognitive impairment to Alzheimer's disease.
  • the invention provides a pharmaceutical formulation adapted for any of the above treatments and uses.
  • the mammal of the method of the invention is a human. In other embodiments, the patient of the method of the invention is a human patient.
  • At least one symptom of the neurodegenerative or cognitive disease or disorder is treated.
  • the present invention also comprises salts of the present compounds, typically, pharmaceutically acceptable salts.
  • Such salts include pharmaceutically acceptable acid addition salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic,
  • pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in S. M. Berge, et al., J. Pharm. Sci., 1977, 66, 2.
  • the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
  • Racemic forms may be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Separation of such diastereomeric salts can be achieved, e.g. by fractional crystallization.
  • the optically active acids suitable for this purpose may include, but are not limited to d- or 1- tartaric, mandelic or camphorsulfonic acids. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix.
  • the compounds of the present invention may also be resolved by the formation and chromatographic separation of diastereomeric derivatives from chiral derivatizing reagents, such as, chiral alkylating or acylating reagents, followed by cleavage of the chiral auxiliary. Any of the above methods may be applied either to resolve the optical antipodes of the compounds of the invention per se or to resolve the optical antipodes of synthetic intermediates, which can then be converted by methods described herein into the optically resolved final products which are the compounds of the invention.
  • Optically active compounds can also be prepared from optically active starting materials.
  • the present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one of the specific compounds disclosed in the Experimental Section and a pharmaceutically acceptable carrier.
  • the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • compositions may be specifically formulated for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It will be appreciated that the route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient.
  • compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, the compositions may be prepared with coatings such as enteric coatings or they may be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
  • Other suitable administration forms include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants.
  • Typical oral dosages range from about 0.001 to about 100 mg kg body weight per day. Typical oral dosages also range from about 0.01 to about 50 mg kg body weight per day. Typical oral dosages further range from about 0.05 to about 10 mg/kg body weight per day. Oral dosages are usually administered in one or more dosages, typically, one to three dosages per day. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration may contain from about 0.01 to about 1000 mg, from about 0.05 to about 500 mg, or from about 0.5 to about 200 mg.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is an acid addition salt of a compound having the utility of a free base.
  • a compound of Formula I contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of Formula I with a molar equivalent of a pharmaceutically acceptable acid.
  • suitable organic and inorganic acids are described above.
  • solutions of the compounds of Formula I in sterile aqueous solution aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the compounds of Formula I may be readily incorporated into known sterile aqueous media using standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical compositions formed by combining the compounds of Formula I and a pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy. If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it may be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will range from about 25 mg to about 1 g per dosage unit. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • Schemes 1-7 describe the use of selective protecting groups during the synthesis of the compounds of the invention.
  • One skilled in the art would be able to select the appropriate protecting group for a particular reaction.
  • Methods for protection and deprotection of such groups are well known in the art, and may be found in T. Green, et al., Protective Groups in Organic Synthesis, 1991, 2 nd Edition, John Wiley & Sons, New York.
  • Method A LC-MS were run on a Sciex APIl 50EX equipped with APPI-source operating in positive ion mode.
  • the HPLC consisted of Shimadzu LClO-ADvp LC pumps, SPD-M20A PDA detector (operating at 254 nM) and SCL-IOA system controller.
  • Autosampler was Gilson 215, Colomn oven was a Jones Chromatography 7990R and ELS detector was a Sedere Sedex 85.
  • LC-conditions The column was a Waters Symmetry C-l 8, 4.6 x 30 mm, 3.5 ⁇ operating at 60°C with 3.0 rnl/min of a binary gradient consisting of water + 0.05 % trifluoroacetic acid (A) and methanol + 0.05 % trifluoroacetic acid. Gradient: 0.01 min 17% B
  • the retention times (t R ) are expressed in minutes.
  • Method B LC-MS were run on Waters Aquity UPLC-MS consisting of Waters Aquity including column mager, binary solvent manager, sample organizer, PDA detector (operating at 254 tiM), ELS detector, and TQ-MS equipped with APPI-source operating in positive ion mode.
  • LC-conditions The column was Acquity UPLC BEH CI 8 1.7 ⁇ ; 2.1x50mm operating at 60°C with 1.2 ml/min of a binary gradient consisting of water + 0.05 % trifluoroacetic acid (A) and acetonitrile + 5% water + 0.05 % trifluoroacetic acid.
  • the retention times (t R ) are expressed in minutes.
  • Method C LC-MS were run on Waters Aquity UPLC-MS consisting of Waters Aquity including column mager, binary solvent manager, sample organizer, PDA detector (operating at 254 nM), ELS detector, and SQ-MS equipped with APPI-source operating in positive ion mode.
  • LC-conditions The column was Acquity UPLC BEH CI 8 1.7 ⁇ ; 2.1x50mm operating at 60°C with 1.2 ml/min of a binary gradient consisting of water + 0.1 % formic acid (A) and acetonitrile + 5%> water + 0.1 % formic acid.
  • R ⁇ Y 1 and Y 2 are as defined under formula I
  • PG is an alcohol protection group such as a dimethyl- tert-butylsilyl group and M is MgBr, MgCl, Li or another metal.
  • Compounds of the general formula IV may be prepared by reacting compounds of the general formula II with a strong base such as tert-butyllithium or LDA (Lithium diisopropylamide) followed by addition of a Weinreb amide of general formula III.
  • Compounds of the general formula VI may be prepared by reacting compounds of the general formula IV with a sulfinamide such as Va in the presence of a Lewis acid/drying agent such as titanium tetraethoxide.
  • Compounds of the general formula VII may be prepared by reacting compounds of the general formula VI with an alkyllithium reagent or alkylmagnesium reagent.
  • Compounds of the general formula VIII are obtained by treatment of compounds of the general formula VII with an acid such as hydrochloric acid.
  • R 1 , Y 1 , Y 2 and n are as defined under formula I and Q is phenyl, methyl or an alkoxy group such as ethoxy.
  • Treatment of compounds of the general formula XI with an aqueous acid such as aqueous hydrochloric acid gives compounds of the general formula XII.
  • R 1 , Y 1 , Y 2 and n are as defined under formula I.
  • Compounds of the general formula XTV may be prepared by reacting compounds of the general formula XIII with a sulfinamide such as Vb in the presence of a Lewis acid/drying agent such as titanium tetraethoxide.
  • Compounds of the general formula XVI may be prepared by reacting compounds of the general formula XTV with compounds of the general formula XV in the presence of zinc. Reduction of the ester moiety of compounds of the general formula XVI gives compounds of the general formula XVII.
  • Compounds of the general formula XVIII are obtained by treatment of compounds of the general formula XVII with an acid such as hydrochloric acid.
  • R 1 , Y 1 , Y 2 and n are as defined under formula I and Q is phenyl, methyl or an alkoxy group such as ethoxy.
  • R 1 , Y 1 , Y 2 , Ar and n are as defined under formula I
  • M is MgBr, MgCl, Li or another metal
  • Q is an alkoxy group such as ethoxy or tert-butoxy.
  • Compounds of the general formula XXII (Scheme 5) may be prepared by reacting compounds of the general formula XII with compounds of the general formula XXI.
  • Compounds of the general formula I may be prepared by reacting compounds of the general formula XXII with an acid such as trifluoroacetic acid and a silane such as triethyl silane, followed by removal of the carbamate protection group from the amino moiety with conditions known to persons skilled in the art.
  • R 1 , Y 1 , Y 2 , Ar and n are as defined under formula I, M is MgBr, MgCl, Li or another metal and Q is an alkoxy group such as ethoxy or tert-butoxy.
  • R 1 , Y 1 , Y 2 , Ar and n are as defined under formula I and Q is an alkoxy group such as ethoxy or tert- butoxy.
  • Compounds of the general formula XXII (Scheme 5) may be prepared by reacting compounds of the general formula XX with a bromine-magnesium exchange reagent such as isopropyl magnesium chloride followed by reaction with aldehydes of the general formula XXVII.
  • Compounds of the general formula I may be prepared by reacting compounds of the general formula XXII with an acid such as trifluoroacetic acid and a silane such as triethyl silane, followed by removal of the carbamate protection group from the amino moiety with conditions known to persons skilled in the art.
  • an acid such as trifluoroacetic acid and a silane such as triethyl silane
  • the crude product was flash chromatographed on silica gel (eluent: heptane/ethyl acetate) using the Combi-Flash Rf to obtain 3.68g of a mixture of product (3-(tert- butyl-dimethyl-silanyloxy)-l-(2-l,3-dioxolan-2-yl-thiazol-5-yl)-propan-l-one) and starting material (2- [l,3]dioxolan-2-yl-thiazole).
  • Titanium(rV) ethoxide (3.0 mL, 14 mmol) was added to (S)- 2-methyl-2-propanesulfinamide (1.01 g, 8.33mmol) and 3-(tert-butyl-dimethyl-silanyloxy)-l-(2-l,3-dioxolan-2-yl-thiazol-5-yl)-propan-l-one (3.68 g, 65%o pure, 6.96 mmol) in tetrahydrofuran (36 mL). The reaction mixture was stirred at 65 °C overnight in a sealed tube and was cooled to room temperature. Water (1.0 mL, 55 mmol) was added.
  • Step l
  • Trifluoroacetic Acid (0.50 mL, 6.5 mmol) was added to ((S)-4- ⁇ 2-[(4-bromo-thiophen-2-yl)-hydroxy- methyl] Wazol-5-yl ⁇ -4-methyl-5,6-dihydro-4H-l,3-thiazin-2-yl)-carbamic acid ethylester (19 mg, 0.040 mmol)) and triethylsilane (23 uL, 0.14 mmol) in methylene chloride (0.50 mL, 7.8 mmol). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was poured into saturated NaHCOs (aq).
  • Step l
  • the binding assay was performed as filter-based assay using membranes isolated from CHO cells transiently transfected with the cDNA encoding human BACE1.
  • the binding assay was run in a 50 mM sodium acetate buffer, pH 4.5 containing 50 mM NaCl and 0.0025% pluriol.
  • the membrane suspension was preheated at 32 °C for 2 hours in 50 mM sodium acetate buffer, pH 4.5 containing 50 mM NaCl and 0.01%) pluriol before 25 ⁇ (1.5 ⁇ g membrane) was added to each well (Corning 3363 plates) containing 25 ⁇ of a high-affinity [ 3 H]-BACE1 compound ([3H]-N-((lS,2R)-l-Benzyl-3-cyclopropylamino-2-hydroxy- propyl)-5-(methanesulfonyl-methyl-amino)-N-((R)-l-phenyl-ethyl)-isophthalamide at 6 nM final) and 50 ⁇ of a given concentration of test compound.
  • a high-affinity [ 3 H]-BACE1 compound [3H]-N-((lS,2R)-l-Benzyl-3-cyclopropylamino-2-hydroxy- propyl)-5-(methanes
  • the plates are incubated at room temperature for 60 minutes under agitation.
  • the assay was terminated by rapid filtration through GF B UniFilters presoaked with 0, 1 %> polyethyleneimine using a Tomtec harvester.
  • the filters are washed 3 times with ice-cold 50 mM sodium acetate buffer, pH 4.5 containing 50 mM NaCl, dried and added 50 ⁇ scintillant counting in a Wallac scintillation counter. Total and non-specific binding are determined using buffer and 10 ⁇ of a high affinity BACE1 inhibitor, respectively.
  • the binding assay was performed as SPA-based assay using membranes isolated from CHO cells transiently transfected with the cDNA encoding human BACEl .
  • the binding assay was run in a 50 mM sodium acetate buffer, pH 4.5 containing 50 mM NaCl and 0.03% Tween-20 in a white clear bottom 384 plates (Corning #3653).
  • 1.5 tiM ligand [ 3 H]-N-((1S,2R)-1-Benzyl- 3-cyclopropylarnino-2-hydroxy-propyl)-5-(m
  • the activity assay was performed as a SPA-based assay using BACEl enzyme purified form sf9 cells infected with cDNA encoding human BACEl .
  • the activity assay was run in 50 mM sodium acetate, pH 4.5 containing, 50 mM NaCl, 0.01% tween and 0.1% BSA in a 384w OptiPlate (#6007290, PerkinElmer). 200 mU BACEl enzyme was mixed with test compound and 50 nM substrate

Abstract

La présente invention concerne de nouveaux inhibiteurs de l'enzyme BACE1. Des aspects séparés de l'invention concernent des compositions pharmaceutiques comprenant lesdits composés et des utilisations des composés pour traiter des troubles pour lesquels la réduction de dépôts de Aβ est bénéfique, tels que la maladie d'Alzheimer.
PCT/EP2013/061691 2012-06-08 2013-06-06 2-aminothiazinylhétéroaryles en tant qu'inhibiteurs de bace1 pour le traitement de la maladie d'alzheimer WO2013182638A1 (fr)

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US9096615B2 (en) 2013-07-30 2015-08-04 Amgen Inc. Bridged bicyclic amino thiazine dioxide compounds as inhibitors of beta-secretase and methods of use thereof
WO2016022724A1 (fr) 2014-08-08 2016-02-11 Amgen Inc. Composés thiazin-2-amine fusionnée à un groupement cyclopropyle utilisés en tant qu'inhibiteurs de la bêta-secrétase et leurs procédés d'utilisation
US9296734B2 (en) 2013-03-01 2016-03-29 Amgen Inc. Perfluorinated 5,6-dihydro-4H-1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
US9309263B2 (en) 2013-01-29 2016-04-12 Amgen Inc. Fused multi-cyclic sulfone compounds as inhibitors of beta-secretase and methods of use thereof
US9611261B2 (en) 2013-03-08 2017-04-04 Amgen Inc. Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
WO2018112083A1 (fr) 2016-12-15 2018-06-21 Amgen Inc. Dérivés de thiazine en tant qu'inhibiteurs de bêta-sécrétase et procédés d'utilisation
WO2018112084A1 (fr) 2016-12-15 2018-06-21 Amgen Inc. Dérivés de thiazine et d'oxazine bicycliques en tant qu'inhibiteurs de bêta-sécrétase et procédés d'utilisation
WO2018112086A1 (fr) 2016-12-15 2018-06-21 Amgen Inc. Derivés thiazine fusionnés à un cyclopropyle utilisés en tant qu'inhibiteurs de la bêta-sécrétase et procédés d'utilisation
WO2018112081A1 (fr) 2016-12-15 2018-06-21 Amgen Inc. Dérivés d'oxazine en tant qu'inhibiteurs de bêta-sécrétase et procédés d'utilisation
WO2018112094A1 (fr) 2016-12-15 2018-06-21 Amgen Inc. Dérivés de dioxyde de 1,4-thiazine et de dioxyde de 1,2,4-thiadiazine en tant qu'inhibiteurs de bêta-sécrétase et procédés d'utilisation
US10246429B2 (en) 2015-08-06 2019-04-02 Amgen Inc. Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9309263B2 (en) 2013-01-29 2016-04-12 Amgen Inc. Fused multi-cyclic sulfone compounds as inhibitors of beta-secretase and methods of use thereof
US9296734B2 (en) 2013-03-01 2016-03-29 Amgen Inc. Perfluorinated 5,6-dihydro-4H-1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
US9611261B2 (en) 2013-03-08 2017-04-04 Amgen Inc. Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
US9096615B2 (en) 2013-07-30 2015-08-04 Amgen Inc. Bridged bicyclic amino thiazine dioxide compounds as inhibitors of beta-secretase and methods of use thereof
WO2016022724A1 (fr) 2014-08-08 2016-02-11 Amgen Inc. Composés thiazin-2-amine fusionnée à un groupement cyclopropyle utilisés en tant qu'inhibiteurs de la bêta-secrétase et leurs procédés d'utilisation
US9550762B2 (en) 2014-08-08 2017-01-24 Amgen, Inc. Cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
US10246429B2 (en) 2015-08-06 2019-04-02 Amgen Inc. Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
WO2018112086A1 (fr) 2016-12-15 2018-06-21 Amgen Inc. Derivés thiazine fusionnés à un cyclopropyle utilisés en tant qu'inhibiteurs de la bêta-sécrétase et procédés d'utilisation
WO2018112084A1 (fr) 2016-12-15 2018-06-21 Amgen Inc. Dérivés de thiazine et d'oxazine bicycliques en tant qu'inhibiteurs de bêta-sécrétase et procédés d'utilisation
WO2018112081A1 (fr) 2016-12-15 2018-06-21 Amgen Inc. Dérivés d'oxazine en tant qu'inhibiteurs de bêta-sécrétase et procédés d'utilisation
WO2018112094A1 (fr) 2016-12-15 2018-06-21 Amgen Inc. Dérivés de dioxyde de 1,4-thiazine et de dioxyde de 1,2,4-thiadiazine en tant qu'inhibiteurs de bêta-sécrétase et procédés d'utilisation
WO2018112083A1 (fr) 2016-12-15 2018-06-21 Amgen Inc. Dérivés de thiazine en tant qu'inhibiteurs de bêta-sécrétase et procédés d'utilisation
US10889579B2 (en) 2016-12-15 2021-01-12 Amgen Inc. Thiazine derivatives as β-secretase inhibitors and methods of use
US10889581B2 (en) 2016-12-15 2021-01-12 Amgen Inc. Cyclopropyl fused thiazine derivatives as beta-secretase inhibitors and methods of use
US10947223B2 (en) 2016-12-15 2021-03-16 Amgen Inc. Substituted oxazines as beta-secretase inhibitors
US11021493B2 (en) 2016-12-15 2021-06-01 Amgen Inc. 1,4-thiazine dioxide and 1,2,4-thiadiazine dioxide derivatives as beta-secretase inhibitors and methods of use
US11548903B2 (en) 2016-12-15 2023-01-10 Amgen Inc. Bicyclic thiazine and oxazine derivatives as beta-secretase inhibitors and methods of use

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