Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
  • A61P33/06—Antimalarials
• • 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

Definitions

• the present invention relates to the use of substituted piperidines as beta-secretase-, cathepsin D-, plasmepsin II- and/or HIV-protease-inhibitors.
• beta-secretase-, cathepsin D-, plasmepsin II- and/or HlV-protease- inhibition there is still a need for highly potent active ingredients.
• the improvement of the pharmacokinetic properties is at the forefront. These properties directed towards better bioavailability are, for example, absorption, metabolic stability, solubility or lipophilicity.
• Alzheimer Disease aspartyl protease Beta-Secretase
• AD Alzheimer's disease
• the symptoms of AD include progressive memory loss, language difficulty and ultimately loss of basic neural function and death.
• the biomarkers in the central nervous system for AD include amyloid plaques, intracellular neurofibrillary tangles and activated microglia. The appearance of these three markers is likely to contribute to the neuronal cell death and memory loss observed in AD.
• Beta-amyloid is a defining feature of AD and now believed to be a causative precursor in the development of the disease.
• Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with Amloidosis of the Dutch-Type (HCHWA-D) and other neurodegenerative disorders.
• Beta-amyloid plaques are predominantly composed of amyloid beta peptide (A-beta, also sometimes designated betaA4).
• the A-beta peptide is derived by proteolysis of the beta amyloid precursor protein (APP).
• Beta-APP is processed by three distinct ordered enzymatic activities.
• the bulk of beta-APP is processed via alpha-secretase in a non-amyloidogenic pathway.
• a small fraction of beta-APP is cleaved by beta- secretase activity to generate the membrane-bound C-terminal fragment C99.
• Gamma-secretase cleaves C99 to generate the amyloidogenic A-beta peptide of 39-42 amino acids.
• the aspartyl protease activity of beta-secretase has been disclosed using varied nomenclature, including BACE (beta-site APP cleaving enzyme), Asp and memapsin.
• beta-secretase cleavage of beta-APP as a critical step in the generation of AD is underscored by the observation that human mutations at the beta-secretase cleavage subsites (Swedish mutations) of beta-APP lead to increased A-beta production and early onset familial AD. Furthermore, BACE1 - knockout mice fail to produce A-beta peptide and present a normal phenotype. When crossed with transgenic mice that overexpress APP, the progeny show reduced amounts of A-beta in brain extracts as compared with control animals.
• Beta-secretase inhibiting compounds as discussed by Thompson et al. (2005) in Curr. Pharm. Des. 11 , 3383-3404 are therefore useful to treat or to prevent diseases that are characterized by amyloid beta deposits or plaques such as AD.
• the present invention also relates to methods of treating subjects who have, or in preventing subjects from developing a disease or condition selected from the group consisting of AD, for helping prevent or delay the onset of AD, for helping to slow the proression of AD, for treating subjects with mild cognitive impairment (MCI) and preventing or delaying the onset of AD in those who could progress form MCI to AD, for treating Down's syndrome, for treating humans who have HCHWAD, for treating cerebral amyloid angiopathy, and for treating degenerative dementias Alzheimer's Disease aspartyl protease: Cathepsin D
• Human cathepsin D is an intracellular aspartic peptidase found mainly in lysosomes. It has a number of housekeeping functions, including the degradation of cellular and phagocytosed proteins. The enzymes may be involved in a variety of disease states, including cancer and Alzheimer's disease (AD). Clinical studies have shown that cathepsin D is overexpressed in breast cancer cells and this seems to be associated with an increased risk for metastasis due to enhanced cell growth. Cathepisn D is also thought to be involved in formation of the beta-amyloid peptide in AD. Recently, several genetic association studies linked cathepsin D with amyloid pathology and Alzheimer's disease as described for example by Davidson et al., (2006) in J. Neurol. Neurosurg. Psychiatry 77, 515-517. The availability of selective and potent inhibitors will help to further define the role of cathepsin D in disease and possibly lead to therapeutic agents.
• Plasmodium falciparum Malaria is considered as one of the most serious infectious diseases in the world, affecting approximately 500 million people. The disease is spread by the anopheles mosquito that is mostly found in tropical regions. The species Plasmodium falciparum is responsible for more than 95% of malaria-related morbidity and mortality. Increasingly, Plasmodium falciparum is becoming resistant to existing therapies such as chloroquine, mefloquine and sulfadoxime/ pyrimethamine. Thus there is an urgent need for new treatments.
• the parasite In the erythrocytic stage of the parasite's life cycle the parasite invades the red blood cells of its host consuming up to 80% of the hemoglobin as a source of nutrients for growth and development. Hemoglobin degradation takes place in an acidic vacuole of the parasite and many of the current antimalarial drugs appear to disrupt important vacuolar functions.
• the food vacuole contains aspartic, cysteine and metallo- proteases, which are all considered to play a role in the process of hemoglobin degradation. At least 10 genes encoding aspartic proteases have been identified in the Plasmodium genome.
• plasmepsin I, II, IV and HAP plasmepsin I, II, IV and HAP
• Inhibitors of plasmepsin I and Il have shown efficacy in cell and animal models of malaria, indicating that these enzymes may represent targets for drug discovery as described for example by Coombs et al. (2001 ) Trends Parasitol 17, 532-537.
• a non-selective inhibitor of aspartic proteases, pepstatin inhibits the growth of Plasmodium falciparum in vitro.
• the present invention relates to the identification of low molecular weight, non- peptidic inhibitors of the Plasmodium falciparum protease plasmepsin Il or other related aspartic proteases to treat and/or to prevent malaria.
• HIV aspartyl protease HIV-1 peptidase
• AIDS Acquired immunodeficiency syndrome
• Gag and Gag-Pol Two polyprotein precursors, Gag and Gag-Pol.
• the 55-kDa Gag precursor contains the structural proteins and the 160-kDa Gag-Pol polyprotein contains the functional viral enzymes protease, reverse transcriptase, and integrase.
• Gag and Gag-Pol polyproteins are transported to the plasma membrane where assembly of type-C retroviruses and lentiviruses typically occurs.
• the viral protease cleaves the Gag and Gag-Pol precursors into the structural and functional proteins required for viral replication.
• the protease activity within the cytoplasma of infected cells allows for the formation of virions which can be released from the cell in the last stages of budding.
• the mature HIV-1 protease is an obligatory dimer of identical 11 -kDa subunits, each contributing one of the two catalytic aspartic residues.
• the cell-derived members of the aspartic protease family are monomehc enzymes with two Asp-Thr- Gly-containing domains.
• the unique dimeric structure of the retroviral protease is mainly stabilized by an antiparallel beta-sheet formed by the interdigitation of the amino- and carboxyl-terminal beta-strands of each monomer.
• HIV-1 protease i.e. the dimerization and autocatalytic release from Gag-Pol
• Inhibition of protease activation causes a severe defect in Gag polyprotein processing and a complete loss of viral infectivity.
• the viral protease has become a target for HIV therapeutics, resulting in many HIV protease inhibitors reaching clinical trials as reviewed by Rana et al. (1999) in Pharmacotherapy 19, 35-59 and Morse et al., (2006) in Lancet Infect. Dis. 6, 215-225.
• Most of these drugs are substrate-based inhibitors, whose design has been facilitated by an abundance of crystal structure data for both the native enzyme and enzyme- inhibitor complexes. Additionally, there are now extensive biochemical data detailing both the catalytic mechanism and the molecular basis for substrate selection.
• the present invention relates to compounds of the general formula
• R 1 is straight-chain Ci-s-alkanoyloxy, straight-chain Ci-s-alkoxy, straight-chain Ci-S- alkoxy-straight-chain-Ci-s-alkoxy, straight-chain Ci-s-alkoxycarbonylamino, straight- chain Co-8-alkylcarbonylamino, optionally N-mono- or N,N-di-Ci-8-alkylated amino or hydroxy or straight-chain omega-hydroxy-Ci-s-alkyl.
• straight-chain Ci-s-alkanoyloxy is straight-chain Co-7-alkylcarbonyloxy such as formyloxy, acetyloxy, propionyloxy and butyryloxy.
• straight-chain Ci- 8 -alkyl are methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl respectively.
• Examples of straight-chain omega-hydroxy-Ci-s-alkyl are hydroxymethyl, 2-hydroxy- ethyl, 3-hydroxy-n-propyl, 4-hydroxy-n-butyl, 5-hydroxy-n-pentyl and 6-hydroxy-n-hexyl respectively.
• Examples of straight-chain Ci-s-alkoxy are radicals such as methoxy, ethoxy, n-propoxy and n-butoxy.
• Examples of straight-chain Co-Cs-alkylcarbonylamino are for example formylamino (formamido), acetylamino, propionylamino and butylcarbonylamino.
• N-mono- or N,N-di-Ci-8-alkylated amino is preferably optionally N-mono- or N,N-di-straight-chain-Ci-8-alkylated amino and may, for example, be amino, methylamino, dimethylamino, ethylamino, methylethylamino, n-propylamino, n-butylamino, n-pentylamino or n-hexylamino.
• the compounds of the formula (I) have at least three asymmetric carbon atoms and may therefore exist in the form of optically pure diastereomers, mixtures of diastereomers, diastereomehc racemates, mixtures of diastereomeric racemates or as meso compounds.
• the invention encompasses all these forms.
• Mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates can be fractionated by conventional methods, e.g. by column chromatography, thin-layer chromatography, HPLC and the like.
• Salts are primarily the pharmaceutically acceptable or nontoxic salts of compounds of formula (I).
• pharmaceutically acceptable salts encompasses salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
• Salts of compounds having salt-forming groups are in particular acid addition salts, salts with bases, or, in the presence of a plurality of salt-forming groups, in some cases also mixed salts or internal salts.
• Such salts are formed, for example, from compounds of formula (I) with an acidic group, for example a carboxyl or sulfonyl group, and are, for example, the salts thereof with suitable bases such as non-toxic metal salts derived from metals of group Ia, Ib, Ha and Hb of the Periodic Table of the Elements, for example alkali metal, in particular lithium, sodium, or potassium, salts, alkaline earth metal salts, for example magnesium or calcium salts, and also zinc salts and ammonium salts, including those salts which are formed with organic amines, such as optionally hydroxy-substituted mono-, di- or trialkylamines, in particular mono-, di- or tri(lower alkyl)amines, or with quaternary ammonium bases, e.g.
• suitable bases such as non-toxic metal salts derived from metals of group Ia, Ib, Ha and Hb of the Periodic Table of the Elements, for example alkali metal, in particular
• methyl-, ethyl-, diethyl- or triethylamine mono-, bis- or tris(2-hydroxy(lower alkyl))amines, such as ethanol-, diethanol- or triethanolamine, tris(hydroxymethyl)methylamine or 2-hydroxy-tert- butylamine, N,N-di(lower alkyl)-N-(hydroxy(lower alkyl))amine, such as N,N-di-N- dimethyl-N-(2-hydroxyethyl)amine, or N-methyl-D-glucamine, or quaternary ammonium hydroxides such as tetrabutyl ammoniumhydroxide.
• the compounds of formula (I) having a basic group, for example an amino group may form acid addition salts, for example with suitable inorganic acids, e.g. hydrohalic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid with replacement of one or both protons, phosphoric acid with replacement of one or more protons, e.g. ortho- phosphoric acid or metaphosphohc acid, or pyrophosphohc acid with replacement of one or more protons, or with organic carboxylic, sulfonic or phosphonic acids or N-substituted sulfamic acids, e.g.
• suitable inorganic acids e.g. hydrohalic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid with replacement of one or both protons, phosphoric acid with replacement of one or more protons, e.g. ortho- phosphoric acid or metaphosphohc acid, or pyrophosphohc acid with replacement of one or more protons, or with organic carboxylic, sulf
• Salts obtained may be converted to other salts in a manner known per se, acid addition salts, for example, by treating with a suitable metal salt such as a sodium, barium or silver salt, of another acid in a suitable solvent in which an inorganic salt which forms is insoluble and thus separates out of the reaction equilibrium, and base salts by release of the free acid and salt reformation.
• a suitable metal salt such as a sodium, barium or silver salt
• the compounds of formula (I), including their salts may also be obtained in the form of hydrates or include the solvent used for the crystallization.
• Prodrug derivatives of the compounds described herein are derivatives thereof which on in vivo use liberate the original compound by a chemical or physiological process.
• a prodrug may for example be converted into the original compound when a physiological pH is reached or by enzymatic conversion.
• Possible examples of prodrug derivatives are esters of freely available carboxylic acids, S- and O-acyl derivatives of thiols, alcohols or phenols, the acyl group being defined as herein.
• Preferred derivatives are pharmaceutically acceptable ester derivatives which are converted by solvolysis in physiological medium into the original carboxylic acid, such as, for example, lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or disubstituted lower alkyl esters such as lower omega-(amino, mono- or dialkylamino, carboxy, lower alkoxycarbonyl) - alkyl esters or such as lower alpha-(alkanoyloxy, alkoxycarbonyl or dialkylaminocarbonyl) - alkyl esters; conventionally, pivaloyloxymethyl esters and similar esters are used as such.
• lower alkyl esters such as, for example, lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or disubstituted lower alkyl esters such as lower omega-(amino, mono- or dial
• a particular compound in this invention also includes its prodrug derivative and salt form, where this is possible and appropriate.
• the definitions mentioned apply within the scope of general chemical principles such as, for example, the usual valencies of atoms.
• the compounds of the formula (I) also include those compounds in which one or more atoms are replaced by their stable, non-radioactive isotopes; for example, a hydrogen atom by deuterium.
• a preferred group of compounds of the formula (I) and the pharmaceutically acceptable salts thereof are compounds in which R 1 is hydroxy or straight-chain onnega-hydroxy-Ci-s-alkyl, more preferably hydroxy or straight-chain omega-hydroxy-Ci -4 -alkyl.
• a further preferred group of compounds of the formula (I) and the pharmaceutically acceptable salts thereof, are compounds in which
• R 1 is straight-chain Ci-s-alkoxy or straight-chain Ci-s-alkoxy-straight-chain-Ci-s- alkoxy, more preferably straight-chain Ci -4 -alkoxy or straight-chain Ci -4 -alkoxy- straight-chain-Ci -4 -alkoxy.
• a further preferred group of compounds of the formula (I) and the pharmaceutically acceptable salts thereof, are compounds in which
• R 1 is straight-chain Ci-s-alkanoyloxy, more preferably straight-chain Ci -4 -alkanoyloxy.
• a further preferred group of compounds of the formula (I) and the pharmaceutically acceptable salts thereof, are compounds in which
• R 1 is straight-chain Co-8-alkylcarbonylamino, more preferably straight-chain C0-3- alkylcarbonylamino.
• a further preferred group of compounds of the formula (I) and the pharmaceutically acceptable salts thereof, are compounds in which
• R 1 is optionally N-mono- or N,N-di-Ci-8-alkylated amino, more preferably optionally N- mono- or N,N-di-Ci -4 -alkylated amino,.
• a further preferred group of compounds of the formula (I) and the pharmaceutically acceptable salts thereof, are compounds in which
• R 1 is optionally N-mono- or N,N-di-straight-chain-Ci-8-alkylated amino, more preferably optionally N-mono- or N,N-di-straight-chain-Ci -4 -alkylated amino.
• R 1 is very particularly preferably hydroxy, methoxy, 2-methoxy-ethoxy, acetyloxy formamido, methylcarbonylamino or ethylcarbonylamino.
• the compound groups mentioned above are not to be regarded as closed, but rather parts of these compound groups may be exchanged with one another or with the definitions given above or omitted in a sensible manner, for example to replace general by more specific definitions.
• the definitions are valid in accordance with general chemical principles, such as, for example, the common valences for atoms.
• the compounds of formula (I) can be prepared in an analogous manner to preparation processes disclosed in the literature. Similar preparation processes are described for example in WO 97/09311. Details of the specific preparation variants can be found in the examples.
• the compounds of formula (I) may also be prepared in optically pure form.
• the separation into antipodes can be effected by procedures known per se, either preferably at an earlier synthetic stage by salt formation with an optically active acid, for example (+)- or (-)-mandelic acid and separation of the diastereomehc salts by fractional crystallization, or preferably at a relatively late stage by dehvatizing with a chiral auxiliary building block, for example (+)- or (-)-camphanoyl chloride, and separation of the diastereomeric products by chromatography and/or crystallization and subsequent cleavage of the bonds to give the chiral auxiliary.
• the pure diastereomeric salts and derivatives may be analysed to determine the absolute configuration of the pipehdine present with common spectroscopic procedures, and X-ray spectroscopy on single crystals constitutes a particularly suitable procedure.
• the compounds of formula (I), and their pharmaceutically acceptable salts reveal inhibitory activities on the enzymes beta-secretase, cathepsin D, plasmepsin Il and/or HIV-protease.
• the activitiy of inhibitors of beta-secretase, cathepsin D, plasmepsin Il and/or HIV protease can be assessed experimentally with following in vitro assays.
• the protease inhibitory activity of compounds can be tested with an assay kit using the fluorescence resonance energy transfer (FRET) technology and a recombinant i.e. baculovirus expressed enzyme preparation.
• FRET fluorescence resonance energy transfer
• the FRET is used to monitor the cleavage of the peptide substrate.
• the principle of the assay is as follows relies on a measurable energy difference, quantitatively depending on the presence of a peptide sequence.
• the peptide substrate is synthesized with two terminal fluorophores, a fluorescent donor and quenching acceptor.
• the distance between these two groups is selected so that upon light excitation, the donor fluorescence energy is significantly quenched by the acceptor through resonance energy transfer. Upon cleavage by the protease, the fluorophore is separated from the quenching group, restoring the fluorescence yield of the donor.
• a weakly fluorescent peptide substrate becomes highly fluorescent upon enzymatic cleavage; the increase in fluorescence is linearly related to the rate of proteolysis.
• the FRET assay was performed in white polysorp plates.
• the assay buffer consisted of 50 mM sodium acetate pH 5, 392 mM sodium chloride, 12.5% glycerol and 0.1 % BSA.
• the incubates per well were composed of 160 ⁇ l buffer, 10 ⁇ l inhibitor in DMSO, 10 ⁇ l peptide substrate in DMSO and 20 ⁇ l enzyme-solution. The inhibitors are tested in a concentration range of 1 pM to 1 mM.
• the fluorescently marked donor and acceptor peptide substrates are generated by solid phase peptide synthesis (Applied Biosystems).
• the beta-secretase peptide substrate Rh-GIu-VaI- Asn-Leu-Asp-Ala-Glu-Phe-Lys-Quencher is obtained from Invitrogen, Carlsbad, CA, USA.
• the cathepsin D peptide substrate of the sequence DABCYL-Pro-Thr-Glu- Phe-Phe-Arg-Leu-OXL, the plasmepsin peptide substrate of the sequence DABCYL- Glu-Arg-Nle-Phe-Leu-Ser-Phe-Pro-OXL and the HIV protease peptide substrate of the sequence DABCYL-His-Lys-Ala-Arg-Val-Leu-Tyr-Glu-Ala-Nle-Ser-EDANS are all obtained from AnaSpec Inc, San Jose, CA, USA.
• the recombinantly expressed enzyme preparations are added in various amounts to the assay systems eg the beta-sectrase concentration is 1 unit/ml incubation volume, the cathepsin D concentration is 100 ng/ml, the HIV protease concentration is 500 ng/ml and the plasmepsin Il concentration is 50 ng/ml.
• the reaction is started upon addition of the enzyme solution. The incubation occurs at 37°C over 30-120 min ie specifically the beta-secretase incubation lasts 60 min, the cathepsin D incubation 120 min, the plasmepsin Il incubation 40 min and the HIV protease incubation 40 min.
• the reactions are stopped by the addition of 20 ⁇ l of a 1.0 M Tris Base solution.
• the enzymatic substrate to product conversion is assessed by fluorescence measurements at 460 nm wave length.
• the compounds of the present invention revealed structure-dependent and enzyme- specific inhibitory activities.
• the inhibitory activities were measured as IC50 values.
• the beta-secretase inhibitory activity ranged between 1 pM and 1 mM;
• the values for cathepsin D ranged between 1 pM and 1 mM, for plasmepsin Il between 1 pM and 1 mM and for HIV-protease between 1 pM and 1 mM.
• the compounds of the formula (I) and the pharmaceutically acceptable salts thereof may find use as medicines, for example in the form of pharmaceutical preparations.
• the pharmaceutical preparations may be administered enterally, such as orally, for example in the form of tablets, coated tablets, sugar-coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions, nasally, for example in the form of nasal sprays, rectally, for example in the form of suppositories, or trans- dermally, for example in the form of ointments or patches.
• the administration may also be parenteral, such as intramuscular or intravenous, for example in the form of injection solutions.
• the compounds of the formula (I) and pharmaceutically usable salts thereof may be processed with pharmaceutically inert, inorganic or organic excipients.
• excipients used for example for tablets, coated tablets and hard gelatine capsules, may be lactose, corn starch, or derivatives thereof, talc, stearic acid or salts thereof etc.
• Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols, etc.
• Suitable excipients for preparing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.
• Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, bile acids, lecithin, etc.
• Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols, etc.
• the pharmaceutical preparations may additionally also comprise preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavourings, salts for altering the osmotic pressure, buffers, coatings or antioxidants. They may also comprise other therapeutically valuable substances.
• Subject of the present invention is also the use of the compounds of formula (I), and their pharmaceutically acceptable salts for the prevention, delay of progression or the treatment of Alzheimer Disease, malaria or HIV infection.
• Subject of the present invention is also the use of the compounds of formula (I), and their pharmaceutically acceptable salts for the manufacture of a medication for the prevention, delay of progression or the treatment of Alzheimer Disease, malaria or HIV infection.
• Subject of the present invention is also the method for the prevention, delay of progression or the treatment of Alzheimer Disease, malaria or HIV infection, whereby a therapeutically effective dose of a compound of the general formula (I) or a pharmaceutically acceptable salt thereof is applied.
• Subject of the present invention is also a pharmaceutical preparation that contains for the inhibition of beta-secretase, cathepsin D, plasmepsin and/or HIV-protease a compound of the general formula (I), or a pharmaceutically acceptable salt thereof as well as commonly used ingredients.
• Subject of the present invention is also a pharmaceutical preparation for the prevention, delay of progression or treatment of Alzheimer Disease, malaria and HIV infection that contains a compound of the general formula (I), or a pharmaceutically acceptable salt thereof as well as commonly used ingredients.
• the dose may vary within wide limits and has of course to be adapted to the individual circumstances in each individual case.
• the reaction mixture is quenched by addition of 10 ml of methanol and concentrated under reduced pressure.
• the title compound is obtained from the residue by means of flash chromatography (SiO 2 60F).
• the starting material(s) is(are) prepared as follows: a) (3S,4R,5R)-3-Hvdroxymethyl-4-r4-((S)-3-methoxy-2-methyl-propoxymethyl)- phenyl1-5-r4-(3-methoxy-propyl)-3,4-dihvdro-2H-benzo ⁇ ,41oxazin-6-ylmethoxy1- piperidine-1 -carboxylic acid benzyl ester
• reaction mixture After overnight stirring, the reaction mixture is cooled to 10 0 C and successively treated dropwise with a solution of 251.871 mmol of potassium hydroxide in 60 ml of water and then with 86.852 mmol of hydrogen peroxide (30%/water). The reaction mixture is slowly warmed to 65°C, stirred for 3 hours and then re-cooled to room temperature. The reaction mixture is partitioned between tert-butyl methyl ether and ice-water - the organic layer is washed with brine. The combined aqueous layers are extracted with tert-butyl methyl ether (2X) - the combined organic layers are dried with sodium sulfate and evaporated.
• reaction mixture After 2 hours, the reaction mixture is cooled to room temperature and then a solution of 125.214 mmol of 1 -benzyl-3-thtyloxymethyl- piperidin-4-one [234757-27-8] in 170 ml of tetrahydrofuran is slowly added, taking care to keep the internal reaction temperature under 40°C. After overnight stirring at room temperature, the reaction mixture is quenched with saturated aqueous ammonium chloride solution. Ethyl acetate is added to the reaction mixture and the phases separated - the organic phase is washed successively with water and brine. The combined aqueous phases are back-extracted with ethyl acetate - the combined organic phases are dried with sodium sulfate and evaporated.
• thisopropyl-(3-methoxy-2(S)-methylpropoxy)silane is used to afford the title compound as a yellow oil.
• Rf 0.42 (dichloromethane- diethylether 1 :1 ).
• the starting material(s) is(are) prepared as follows: a) (3R,4R,5R)-3-(Acetylamino-methyl)-4-[4-((S)-3-methoxy-2-methyl- propoxymethyl)-phenvH-5-[4-(3-methoxy-propyl)-3,4-dihvdro-2H- benzo[1 ,41oxazin-6-ylmethoxy1-piperidine-1 -carboxylic acid benzyl ester 5.936 mmol of acetyl chloride are added to a solution of 5.396 mmol of (3R,4R,5R)-3- aminomethyl-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy- propyl)-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-piperidine-1 -car
• the starting material(s) is(are) prepared as follows: a) (3S,4R,5R)-3-Methoxymethyl-4-r4-((S)-3-methoxy-2-methyl-propoxymethyl)- phenyl1-5-r4-(3-methoxy-propyl)-3,4-dihvdro-2H-benzo ⁇ ,41oxazin-6-ylmethoxy1- piperidine-1 -carboxylic acid benzyl ester
• the starting material(s) is(are) prepared as follows: a) (3S,4R,5R)-3-Acetoxymethyl-4-r4-((S)-3-methoxy-2-methyl-propoxymethyl)- phenyl1-5-r4-(3-methoxy-propyl)-3,4-dihvdro-2H-benzo ⁇ ,41oxazin-6-ylmethoxy1- piperidine-1 -carboxylic acid benzyl ester

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• 2009
  • 2009-04-01 BR BRPI0910991A patent/BRPI0910991A2/pt not_active Application Discontinuation
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  • 2009-04-01 EP EP09728288A patent/EP2271644A1/en not_active Withdrawn
  • 2009-04-01 EA EA201001517A patent/EA201001517A1/ru unknown
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  • 2009-04-01 JP JP2011502382A patent/JP2011516453A/ja active Pending

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