WO2009121914A1

WO2009121914A1 - Substituted piperidines as therapeutic compounds

Info

Publication number: WO2009121914A1
Application number: PCT/EP2009/053898
Authority: WO
Inventors: Peter Herold; Robert Mah; Stefan Stutz; Vincenzo Tschinke; Aleksandar Stojanovic; Dirk Behnke; Stjepan Jelakovic
Original assignee: Novartis Ag
Priority date: 2008-04-02
Filing date: 2009-04-01
Publication date: 2009-10-08
Also published as: KR20110002459A; CN101970431A; EP2271644A1; AU2009232012A1; MX2010010876A; EA201001517A1; JP2011516453A; BRPI0910991A2; CA2719070A1

Abstract

Described are compounds of the general formula (I), and pharmaceutically acceptable salt thereof, in which R¹ has the definitions illustrated in detail in the description, as beta-secretase, cathepsin D, plasmepsin II and/or HIV protease inhibitors.

Description

Substituted piperidines as therapeutic compounds

Field of the Invention

The present invention relates to the use of substituted piperidines as beta-secretase-, cathepsin D-, plasmepsin II- and/or HIV-protease-inhibitors.

Background of the Invention

With regard to beta-secretase-, cathepsin D-, plasmepsin II- and/or HlV-protease- inhibition, there is still a need for highly potent active ingredients. In this context, 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

Alzheimer's disease (AD) is a progressive degenerative disease of the brain. 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.

The significance of 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. This evidence supports the proposal that inhibition of beta-secretase activity and reduction of A-beta peptide deposits in the brain provides a therapeutic strategy for the treatment of AD and other beta amyloid disorders as described by Verdile et al. (2004) in Pharmacol. Res 50, 397-409.

Compounds that are effective inhibitors of beta-secretase may inhibit beta-secretase- mediated cleavage of APP and the production of A-beta peptide. The pharmacological inhibition of A-beta peptide generation may reduce amyloid beta deposits, respectively the formation of plaques. 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.

Malaria Aspartyl Protease: Plasmepsin I and Il

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.

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. Four of the aspartic proteases have been localized in the acidic food vacuole of the parasite, namely plasmepsin I, II, IV and HAP, a histo- aspartic protease. 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. Indeed, a non-selective inhibitor of aspartic proteases, pepstatin, inhibits the growth of Plasmodium falciparum in vitro. Similar results have been obtained with analogs of pepstatin or with immunodeficiency virus protease inhibitors indicating that inhibition of aspartic proteases interferes with the life cycle of Plasmodium falciparum as noted for example by Andrews et al. (2006) in Antimicrob. Agents Chemother 50, 639-648.

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

First reported in 1981 in a small number of patients, Acquired immunodeficiency syndrome (AIDS) has now become a major epidemic with more than 38 million people infected worldwide, including approximately 1 million in the United States, 580,000 in Western Europe and more than 25 million in Sub-Saharan Africa (http://www.unaids.org). Since AIDS was first clinically identified, scientific and therapeutic progress has been extraordinary. However, AIDS remains out of control, especially in developing countries.

The prognosis of AIDS patients who have full access to current therapies has completely changed since the first cases of AIDS were reported. Today, the median survival for HIV-positive patients receiving treatment exceeds 8 years. The life expectancy for AIDS patients was less than 1 year before AZT was introduced in 1987. This dramatic change is due to the development of effective therapies, to early detection of HIV-positive individuals, and to a sustained effort to analyze and understand viral-resistance mechanisms, which can be overcome by rational drug development and combination therapy. FDA-approved therapies target three steps of the HIV life cycle: reverse transcription, proteolytic maturation and fusion. Triple therapy, commonly referred to as HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART), is now the standard for treatment. It consists of a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor in combination with two nucleoside reverse transcriptase inhibitors.

Translation of human immunodeficiency virus type-1 (HIV-1 ) genomic RNA results in the production of 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. During particle assembly, 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. In contrast, 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.

The activation of HIV-1 protease i.e. the dimerization and autocatalytic release from Gag-Pol, is a critical step in the viral life cycle. Inhibition of protease activation causes a severe defect in Gag polyprotein processing and a complete loss of viral infectivity. As such, 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. Detailed Description of the Invention

Firstly, the present invention relates to compounds of the general formula

(I) for the inhibition of beta-secretase, cathepsin D, plasmepsin Il and/or HIV-protease and their pharmaceutically acceptable salts, in which

R¹ 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.

A straight-chain is also sometimes referred to in the literature as linear or un-branched. As used herein, straight-chain Ci-s-alkanoyloxy is straight-chain Co-7-alkylcarbonyloxy such as formyloxy, acetyloxy, propionyloxy and butyryloxy. Examples of 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. Optionally 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). The term "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. 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. acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid, isonicotinic acid, and also amino acids, for example the alpha-amino acids mentioned above, and also methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1 ,2- disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene-2- sulfonic acid, 2- or 3-phosphoglycerate, glucose 6-phosphate, N-cyclohexylsulfamic acid (with formation of the cyclamates) or with other acidic organic compounds such as ascorbic acid. Compounds of formula (I) having acidic and basic groups may also form internal salts.

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. 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.

Pharmaceutically unsuitable salts may also be used for isolation and purification.

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.

Because of the close relationship between a free compound, a prodrug derivative and a salt compound, 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 R¹ 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

R¹ 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.

R¹ is straight-chain Ci-s-alkanoyloxy, more preferably straight-chain Ci_-4-alkanoyloxy.

R¹ is straight-chain Co-8-alkylcarbonylamino, more preferably straight-chain C0-3- alkylcarbonylamino.

R¹ 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,.

R¹ 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.

R¹ 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. 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. Thus 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 μl buffer, 10 μl inhibitor in DMSO, 10 μl peptide substrate in DMSO and 20 μl 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 μl of a 1.0 M Tris Base solution. The enzymatic substrate to product conversion is assessed by fluorescence measurements at 460 nm wave length.

In vitro enzyme inhibitory activities

The compounds of the present invention revealed structure-dependent and enzyme- specific inhibitory activities. The inhibitory activities were measured as IC50 values. Thus 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.

To prepare tablets, coated tablets, sugar-coated tablets and hard gelatine capsules, the compounds of the formula (I) and pharmaceutically usable salts thereof may be processed with pharmaceutically inert, inorganic or organic excipients. Such 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. In general, for oral administration, a daily dose of about 3 mg to about 3 g, preferably about 10 mg to about 1 g, for example about 300 mg, per adult (70 kg), divided into preferably 1-3 individual doses which may, for example, be of equal size, may be appropriate, although the upper limit specified may also be exceeded if this should be found to be appropriate; typically, children receive a lower dose according to their age and body weight.

Examples

The following examples illustrate the present invention. All temperatures are stated in degrees Celsius and pressures in mbar. Unless mentioned otherwise, the reactions take place at room temperature. The abbreviation "Rf = xx (A)" means for example that the Rf is found in solvent system A to be xx. The ratio of amounts of solvents to one another is always stated in parts by volume. Chemical names for final products and intermediates have been generated on the basis of the chemical structural formulae with the aid of the AutoNom 2000 (Automatic Nomenclature) program.

HPLC gradients on Hypersil BDS C-18 (5 urn); column: 4 x 125 mm

I 90% water^*/10% acetonitrile^* to 0% water7100% acetonitrile^* in 5 minutes +

2.5 minutes (1.5 ml/min)

II 95% water75% acetonitrile^* to 0% water7100% acetonitrile^* in 40 minutes (0.8 ml/min)

^* contains 0.1 % trifluoroacetic acid

The following abbreviations are used:

Rf ratio of distance migrated by a substance to the distance of the solvent front from the starting point in thin-layer chromatography Rt retention time of a substance in HPLC (in minutes) m.p. melting point (temperature)

Thin-film chromatography eluent systems: A dichloromethane-methanol-25% ammonia cone. = 200:20:1 B dichloromethane-methanol-25% ammonia cone. = 200:10:1 C dichloromethane-methanol-25% ammonia cone. = 200:30:1 D dichloromethane-methanol-25% ammonia cone. = 100:10:1

General procedure A: (N-Cbz-deprotection, N-(1 -phenyl-ethyl)-deprotection or N- benzyl-deprotection)

To a stirred solution of 1 mmol of "N-protected derivative" in 15 ml of tetrahydrofuran

(or methanol) are added 0.1 mmol Pd/C 10% and the reaction mixture is hydro- genated at room temperature. The reaction mixture is filtered and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound.

General procedure B: (N-Tos-deprotection)

To a stirred solution of 0.09 mmol "tosylamide" in 10 ml of methanol are added 0.44 mmol sodium dihydrogenphosphate and 0.90 mmol of sodium amalgam (10% Na) at room temperature. The reaction mixture is stirred for 2-18 hours, diluted with water and extracted with ethyl acetate (3X). The organic phases are combined, washed with brine and dried over sodium sulfate. The solvent is concentrated under reduced pressure and the residue is purified by flash chromatography (SiO2 60F) to afford the title compound.

General procedure C: (Bhh-reduction)

To a stirred solution of 1 mmol of "lactam" in 3 ml of tetrahydrofuran is admixed with

2-4 mmol of borane tetrahydrofuran (1 M in tetrahydrofuran) and heated to 50⁰C for

2-8 hours.

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 (SiO₂ 60F).

General procedure D: (O-alkylation I)

1.2 mmol mmol of sodium hydride (60% dispersion in oil) and 0.1 mmol of tetrabutyl- ammonium iodide are added to a solution of 1 mmol of "alcohol" and 1.1 mmol of "benzyl halide" in 2.0 ml of N,N-dimethylformamide while stirring at -10⁰C. The reaction mixture is stirred at -10°C for 1 hour and at room temperature for 18 hours. The mixture is poured into 1 M aqueous sodium bicarbonate solution and extracted with tert-butyl methyl ether (2X). The organic phases are washed successively with water and brine, dried with sodium sulfate and evaporated. The title compound is obtained from the residue by means of flash chromatography (SiO₂ 60F).

General Method E: (O-alkylation II)

1.1 mmol of sodium hydride (60% dispersion in oil) are added to a solution of 1 mmol of "alcohol" and 1.0-2.0 mmol of "benzyl halide" in 2.0 ml of N,N-dimethylformamide while stirring at -10⁰C. The reaction mixture is stirred at -10°C for 1 hour and at room temperature for 18 hours. The mixture is poured into 1 M aqueous sodium bicarbonate solution and extracted with tert-butyl methyl ether (2X). The combined organic phases are washed successively with water and brine, dried with sodium sulfate and evaporated. The title compound is obtained from the residue by flash chromatography (SiO₂ 60F). General Method F: (alcohol desilylation)

A solution of 1 mmol of "silyl ether" in 5 ml of tetrahydrofuran is mixed with

1.5-2.0 mmol of tetrabutylammonium fluoride (1 M solution in tetrahydrofuran) and the solution is stirred at room temperature for 1-2 hours. The reaction solution is then diluted with water and extracted with tert-butyl methyl ether (2X). The combined organic phases are dried with sodium sulfate and evaporated. The title compound is obtained from the residue by flash chromatography (SiO2 60F).

Example 1

{(3S,4R,5R)-4-r4-((S)-3-Methoxy-2-methyl-propoxymethyl)-phenyl1-5-r4-(3-methoxy- propyl)-3,4-dihvdro-2H-benzori ,41oxazin-6-ylmethoxy1-piperidin-3-yl)-methanol According to general procedure A, (3S,4R,5R)-3-hydroxymethyl-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 -carboxylic acid benzyl ester is used to afford the title compound.

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-benzoπ ,41oxazin-6-ylmethoxy1- piperidine-1 -carboxylic acid benzyl ester

According to general procedure C, (3S,4R,5R)-3-hydroxymethyl-4-[4-((S)-3-methoxy- 2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-piperidine-1 -carboxylic acid benzyl ester is used to afford the title compound as a turbid oil. Rf = 0.15 (EtOAc-heptane 2:1 ); Rt = 5.22 (gradient I).

b) (3S,4R,5R)-3-Hvdroxymethyl-4-r4-((S)-3-methoxy-2-methyl-propoxymethyl)- phenvπ-5-[4-(3-methoxy-propyl)-3-oxo-3,4-dihvdro-2H-benzo[1 ,41oxazin-6- ylmethoxyi-piperidine-1-carboxylic acid benzyl ester

A solution of 8.526 mmol of (3R,4R,5S)-4-[4-((S)-3-methoxy-2-methyl-propoxy- methyl)-phenyl]-3-[4-(3-methoxy-propyl)-3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-6- ylmethoxy]-5-thtyloxymethyl-piperidine-1-carboxylic acid benzyl ester in 20 ml of tetrahydrofuran and 80 ml of methanol is treated with 12.789 mmol of toluene-4- sulfonic acichmonohydrate. After stirring for 15 hours, the reaction mixture is basified with saturated aqueous sodium bicarbonate solution and concentrated under reduced pressure to remove most of the methanol and tetrahydrofuran. The residue is extracted with dichloromethane (3X) - the combined organic layers are washed successively with water and brine, dried with sodium sulfate and evaporated. The title compound is obtained as a yellow oil from the residue by flash chromatography (SiO2 60F). Rt = 4.86 (gradient I).

c) (3R,4R,5S)-4-r4-((S)-3-Methoxy-2-methyl-propoxymethyl)-phenyll-3-r4-(3- methoxy-propyl)-3-oxo-3,4-dihvdro-2H-benzo[1 ,41oxazin-6-ylmethoxy1-5- trityloxymethyl-piperidine-i-carboxylic acid benzyl ester

According to general procedure D, (3R,4R,5S)-3-hydroxy-4-[4-((S)-3-methoxy-2- methyl-propoxymethyl)-phenyl]-5-thtyloxymethyl-piperidine-1 -carboxylic acid benzyl ester and 6-chloromethyl-4-(3-methoxy-propyl)-4H-benzo[1 ,4]oxazin-3-one [857272- 02-7] are used to afford the title compound as a yellow oil. Rt = 6.58 (gradient I).

d) (3R,4R,5S)-3-Hvdroxy-4-r4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl1-5- trityloxymethyl-piperidine-i-carboxylic acid benzyl ester

8.478 mmol of benzyl chloroformate are added dropwise to a mixture of 8.478 mmol of (3R,4R,5S)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-thtyloxy- methyl-piperidin-3-ol (L)-(+)-mandelate in 150 ml of ethyl acetate and 150 ml of saturated aqueous sodium bicarbonate solution at 0⁰C. After 1 hour, the reaction mixture is partitioned between saturated aqueous sodium carbonate solution and ethyl acetate - the organic layer is washed successively with water and brine. The combined aqueous layers are back-extracted with ethyl acetate - the combined organic layers are dried with sodium sulfate and evaporated. The crude title compound is obtained as a white foam. Rt = 6.14 (gradient I).

e) (3R,4R,5S)-4-r4-((S)-3-Methoxy-2-methyl-propoxymethyl)-phenyl1-5- trityloxymethyl-piperidin-3-ol (L)-(+)-mandelate

According to general procedure A, (3R,4R,5S)-1 -benzyl-4-[4-((S)-3-methoxy-2- methyl-propoxymethyl)-phenyl]-5-thtyloxymethyl-piperidin-3-ol (L)-(+)-mandelate is used to afford the title compound as a white foam. Rt = 4.92 (gradient I). f) (3R,4R,5S)-1 -Benzyl-4-r4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl1-5- trityloxymethyl-piperidin-3-ol (L)-(+)-mandelate

2.36 mmol of (L)-(+)-mandelic acid are added to a solution of 5.90 mmol of (rac- 3R,4R,5S)-1-benzyl-4-[4-((S)-3-methoxy-2-nnethyl-propoxynnethyl)-phenyl]-5-tntyloxy- methyl-piperidin-3-ol in 36 ml of tetrahydrofuran at 60⁰C (oil bath temperature). 36 ml of n-hexane are slowly added dropwise at 60⁰C. The mixture is slowly cooled to room temperature over the course of 3 hours and, after a brief treatment in an ultrasonic bath, then cooled at 0°C for 2 hours. The precipitate is filtered off and washed with 1 :4 tetrahydrofuran/n-hexane to afford the title compound as a white solid. Rt = 5.36 (gradient I).

For analytical purposes, a small amount of the salt is dissolved in ethyl acetate and washed with saturated aqueous sodium carbonate solution (2X). The organic phase is washed with brine, dried with sodium sulfate and evaporated to afford the title compound as the free base (white solid). HPLC; Rt = 12.81 (Daicel Chiralpak AD 0.46 x 25 cm; 95% hexane/5% isopropanol; 0.7 ml/minute for 60 minutes).

g) (rac-3R,4R,5S)-1-Benzyl-4-r4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl1- 5-trityloxymethyl-piperidin-3-ol

86.852 mmol of a solution of borane-tetrahydrofuran (1 M/THF) are added dropwise to a solution of 43.426 mmol of 1 -benzyl-4-[4-((S)-3-methoxy-2-methyl-propoxy- methyl)-phenyl]-3-(R,S)-thtyloxymethyl-1 ,2,3,6-tetrahydro-pyhdine in 220 ml of tetrahydrofuran at room temperature. After overnight stirring, the reaction mixture is cooled to 10⁰C 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. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound as a yellow oil. Rf = 0.15 (EtOAc-heptane 1 :1 ); Rt = 5.36 (gradient I). h) 1 -Benzyl-4-r4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl1-3-(R,S)- trityloxymethyl-1 ,2,3,6-tetrahvdro-pyridine

102.636 mmol of thionyl chloride are slowly added to a solution of 85.53 mmol of 1 -benzyl-4-[4-((S)-3-methoxy-2-methyl-propoxynnethyl)-phenyl]-3-(R,S)-tntyloxy- methyl-piperidin-4-(R,S)-ol in 250 ml of pyridine at 0⁰C, taking care that the internal temperature stays below 10⁰C. After 5 minutes, the reaction mixture is quenched by adding 50 ml of 4N NaOH solution and concentrated under reduced pressure. The residue is dissolved in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and brine, dried with sodium sulfate and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound as a yellow oil. Rf = 0.28 (EtOAc-heptane-25% ammonia cone. 100:200:1 ); Rt = 5.64 (gradient I).

i) 1 -Benzyl-4-r4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl1-3-(R,S)-thtyloxy- methyl-piperidin-4-(R, S)-Ol

2.32 mmol of 1 ,2-dibromoethane are added to a suspension of 156.518 mmol of magnesium in 20 ml of tetrahydrofuran under argon at room temperature. The reaction mixture is warmed until the magnesium starts to react and then 3 ml of a solution of 151.509 mmol of 1 -bromo-4-((S)-3-methoxy-2-methyl-propoxymethyl)- benzene in 170 ml of tetrahydrofuran, followed by the rest of the solution, is added while maintaining a gentle reflux. 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. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound as a yellow oil. Rf = 0.30 (EtOAc-heptane-25% ammonia cone. 100:100:1 ); Rt = 5.43 (gradient I). j) 1 -Bromo-4-((S)-3-methoxy-2-methyl-propoxymethyl)-benzene According to general method E, 1 -bromo-4-chloromethyl-benzene [589-17-3] and (R)-3-methoxy-2-methyl-propan-1-ol are used to afford the title compound as a yellow oil. Rf = 0.44 (EtOAc-heptane 1 :6); Rt = 5.29 (gradient I).

k) (R)-3-Methoxy-2-methyl-propan-1-ol

According to general method F, 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 ).

I) Thisopropyl-((S)-3-methoxy-2-methylpropoxy)silane

3.09 g of sodium hydride (60% dispersion in oil) are added to a solution of 9.55 g of (S)-2-methyl-3-triisopropylsilanyloxypropan-1-ol [256643-28-4] and 7.3 ml of methyl iodide in 70 ml of N,N-dimethylformamide at 0⁰C. After 60 hours at room temperature, the reaction mixture is diluted with tert-butyl methyl ether and washed successively with water and brine, dried with sodium sulfate and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title as a yellow oil. Rf = 0.51 (EtOAc-heptane 1 :10).

Example 2

N-{(3S,4R,5R)-4-r4-((S)-3-Methoxy-2-methyl-propoxymethyl)-phenyl1-5-[4-(3- methoxy-propyl)-3,4-dihvdro-2H-benzo[1 ,41oxazin-6-ylmethoxy1-piperidin-3-ylmethyl)- acetamide

According to general procedure A, (3R,4R,5R)-3-(acetylamino-methyl)-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 -carboxylic acid benzyl ester is used to afford the title compound.

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 -carboxylic acid benzyl ester and 6.475 mmol of triethylamine in 80 ml of dichloromethane under argon at 0⁰C. After 30 minutes, the reaction mixture is quenched with saturated aqueous sodium bicarbonate solution and extracted with tert-butyl methyl ether (2X). The combined organic layers are washed successively with water and brine, dried with sodium sulfate and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound as a yellow oil. Rt = 4.98 (gradient I).

b) (3R,4R,5R)-3-Aminomethyl-4-r4-((S)-3-methoxy-2-methyl-propoxymethyl)- phenyl1-5-r4-(3-methoxy-propyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6-ylmethoxy1- piperidine-1 -carboxylic acid benzyl ester

7.128 mmol of thphenylphosphine are added to a solution of 5.940 mmol of (3S,4R,5R)-3-azidomethyl-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 - carboxylic acid benzyl ester in 20 ml of methanol, 20 ml of tetrahydrofuran, 5 ml of water and 3.56 ml of concentrated aqueous ammonia (25%) at room temperature. After overnight stirring, the reaction mixture is partitioned between tert-butyl methyl ether and 5:1 water/saturated aqueous sodium bicarbonate solution. The aqueous layer is extracted with tert-butyl methyl ether - the combined organic layers are washed successively with water and brine, dried with sodium sulfate and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound as a yellow oil. Rf = 0.42 (dichloromethane-methanol-25% ammonia cone. 200:20:1 ); Rt = 4.64 (gradient I).

c) (3S,4R,5R)-3-Azidomethyl-4-r4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl1- 5-[4-(3-methoxy-propyl)-3_,4-dihvdro-2H-benzo[1 _,41oxazin-6-ylmethoxy1- piperidine-1 -carboxylic acid benzyl ester

31.265 mmol of sodium azide are added to a solution of 6.253 mmol of (3R,4R,5S)-4- [4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-3-[4-(3-methoxy-propyl)-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-5-(toluene-4-sulfonyloxymethyl)- piperidine-1 -carboxylic acid benzyl ester in 50 ml of 1 ,3-dimethyl-tetrahydro- pyrimidin-2-one (DMPU) under argon at 45°C. After 5 hours, the reaction mixture is cooled to room temperature, diluted with tert-butyl methyl ether, washed with water and brine, dried with sodium sulfate and evaporated. The crude title compound is obtained as a yellow oil. Rf = 0.58 (EtOAc-heptane 2:1 ); Rt = 5.96 (gradient I).

d) (3R,4R,5S)-4-r4-((S)-3-Methoxy-2-methyl-propoxymethyl)-phenyll-3-r4-(3- methoxy-propyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6-ylmethoxy1-5-(toluene-4- sulfonyloxymethyl)-piperidine-1 -carboxylic acid benzyl ester 7.077 mmol of 4-methyl-benzenesulfonyl chloride are added to a solution of 6.583 mmol of (3S,4R,5R)-3-hydroxymethyl-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 -carboxylic acid benzyl ester (Example 1 a), 9.875 mmol of thethylamine and 0.329 mmol of dimethyl-pyhdin-4-yl-amine in 65 ml of dichloromethane under argon at 0⁰C. After overnight stirring at room temperature, the reaction mixture is diluted with tert-butyl methyl ether, washed successively with saturated aqueous sodium bicarbonate solution, water and brine, dried with sodium sulfate and evaporated. The crude title compound is obtained as a yellow oil. Rf = 0.44 (EtOAc- heptane 2:1 ); Rt = 5.94 (gradient I).

According to the procedures described in example 2, the following compounds are prepared in an analogous manner:

3 N-{(3S,4R,5R)-4-r4-((S)-3-Methoxy-2-methyl-propoxymethyl)-phenyll-5-r4-(3- methoxy-propyl)-3,4-dihvdro-2H-benzori ,41oxazin-6-ylmethoxy1-piperidin-3- ylmethvD-propionamide using propionyl chloride instead of acetyl chloride in step a.

7 N-{(3S,4R,5R)-4-r4-((S)-3-Methoxy-2-methyl-propoxymethyl)-phenyll-5-r4-(3- methoxy-propyl)-3,4-dihvdro-2H-benzori ,41oxazin-6-ylmethoxy1-piperidin-3- ylmethylMormamide replacing step a with the following procedure: 1.4 mmol of 4-nitrophenylformiate are added to a solution of 1 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 -carboxylic acid benzyl ester (example 2b) in 10 ml of dichloromethane under argon followed by the addition of 1 mmol of thethylamine. After 60 minutes, the reaction mixture is evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound, which is identified based on the Rf value.

Example 4

6-{(3R,4R,5S)-5-Methoxymethyl-4-r4-((S)-3-methoxy-2-methyl-propoxymethyl)- phenyl1-piperidin-3-yloxymethyl)-4-(3-methoxy-propyl)-3,4-dihvdro-2H- benzoH ,41oxazine

According to general procedure A, (3S,4R,5R)-3-methoxymethyl-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 -carboxylic acid benzyl ester is used to afford the title compound.

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-benzoπ ,41oxazin-6-ylmethoxy1- piperidine-1 -carboxylic acid benzyl ester

2.568 mmol of methyl iodide are added to a suspension of 0.642 mmol of (3S,4R,5R)-3-hydroxymethyl-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- carboxylic acid benzyl ester (Example 1 a) and 0.963 mmol of sodium hydride (60% dispersion in oil) under argon at 0⁰C. After stirring for 1 hour at 0⁰C and 1 hour at room temperature, the reaction mixture is partitioned between tert-butyl methyl ether and saturated aqueous sodium bicarbonate solution. The aqueous layer is extracted with tert-butyl methyl ether (2X) - the combined organic layers are washed successively with water and brine, dried with sodium sulfate and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound as a yellow oil. Rf = 0.41 (EtOAc-heptane 1 :1 ); Rt = 5.87 (gradient I). According to the procedures described in example 4, the following compound is prepared in an analogous manner:

6 6-{(3R,4R,5S)-5-(2-Methoxy-ethoxymethyl)-4-r4-((S)-3-methoxy-2-methyl- propoxymethyl)-phenyl1-piperidin-3-yloxymethyl)-4-(3-methoxy-propyl)-3,4- dihydro-2H-benzo[1 ,41oxazine using 1 -bromo-2-methoxy-ethane (instead of methyl iodide) and 1 equivalent of tetrabutylammonium iodide in step a.

Example 5

Acetic acid (3S,4R,5R)-4-r4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl1-5-r4-(3- methoxy-propyl)-3,4-dihvdro-2H-benzori ,41oxazin-6-ylmethoxy1-piperidin-3-yl methyl ester

According to general procedure A, (3S,4R,5R)-3-acetoxymethyl-4-[4-((S)-3-methoxy-

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-benzoπ ,41oxazin-6-ylmethoxy1- piperidine-1 -carboxylic acid benzyl ester

Analogously to Example 2a, (3S,4R,5R)-3-hydroxymethyl-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 -carboxylic acid benzyl ester (Example 1 a) and acetyl chloride are used to afford the title compound as a colorless oil. Rf = 0.20 (EtOAc-heptane 1 :1 ); Rt = 5.69 (gradient I).

Claims

1. A compound of formula

(I) for the inhibition of beta-secretase, cathepsin D, plasmepsin Il and/or HIV-protease or its pharmaceutically acceptable salt, in which

2. Compound according to claim 1 wherein

R¹ is hydroxy or straight-chain omega-hydroxy -Ci-s-alkyl.

3. Compound according to claim 1 wherein R¹ is straight-chain Ci-s-alkanoyloxy.

4. Compound according to claim 1 wherein R¹ is straight-chain Co-8-alkylcarbonylamino.

5. Compound according to claim 1 wherein

R¹ is optionally N-mono- or N,N-di-straight-chain-Ci-8-alkylated amino.

6. Compound according to claim 1 wherein

R¹ is hydroxy, methoxy, 2-methoxy-ethoxy, acetyloxy, formamido, methylcarbonylamino or ethylcarbonylamino.

7. A compound of the general formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6 for the prevention, delay of progression or treatment of Alzheimer Disease, malaria or HIV infection.

8. A pharmaceutical preparation for the prevention, delay of progression or treatment of Alzheimer disease, malaria or HIV infection, whereby said preparation contains a compound of the general formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, as well as commonly used ingredients.