WO2005058822A1

WO2005058822A1 - Substituted amino-cycloalkanes

Info

Publication number: WO2005058822A1
Application number: PCT/EP2004/014144
Authority: WO
Inventors: Christoph Boss; Thomas Weller; Corinna Grisostomi; Oliver Corminboef
Original assignee: Actelion Pharmaceuticals Ltd
Priority date: 2003-12-17
Filing date: 2004-12-13
Publication date: 2005-06-30

Abstract

Novel substituted 4-aminopiperidine derivatives of the formula (I) wherein R1, R2, R3, R4 and (A) are as defined in claim 1, and optically pure enantiomers, mixtures of enantiomers, racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of dia stereomeric racemates and the meso-form thereof as well as pharmaceutically acceptable salts, solvent complexes and morphological forms thereof, exhibit useful parasitic aspartic proteases inhibiting properties and thus, can be used in the form of pharmaceutical compositions as antimalarial medicines. They can be prepared according to known methods.

Description

SUBSTITUTED AMINO-AZA-CYCLOALKANES The present invention relates to novel substituted 4-aminopiperidine derivatives of the general formula I below. The invention also concerns related aspects including pharmaceutical compositions containing one or more compounds of general formula I and especially their use as inhibitors of the plasmodium falciparum protease plasmepsin II or related aspartic proteases such as plasmepsin I, plasmepsin IV or HAP (Histoaspartic protease). Malaria is one of the most serious and complex health problems affecting humanity in the 21^st century [C. Boss et al., Curr. Med. Chem., 2003, 10, 883-907; Rosenthal, P. J., Ed., Antimalarial Chemotherapy: Mechanism of Action, Resistance, and New Directions in Drug Discovery; Humana Press: New Jersey, 2001; Wiesner J. et al., Angew. Chem., 2003, 115, 5432-5451.; D. F. Wirth, Malaria: A Third World Disease in Need of First World Drug Development, Annual Reports in Medicinal Chemistry, 34, 1999, 349-358.; J. A. Radding, Development of Anti-Malarial Inhibitors of Hemoglobinases, Annual Reports in Medicinal Chemistry, 34, 1999, 159-168.]. The disease affects about 300 million people worldwide, killing 1 to 1.5 million people every year. Malaria is an infectious disease caused by four species of the protozoan parasite Plasmodium, P. falciparum being the most severe of the four. All attempts to develop vaccines against P. falciparum have failed so far. Therefore, therapies and preventive measures against malaria are confined to drugs. However, resistance to many of the currently available antimalarial drugs is spreading rapidly and new drugs are needed.

P. falciparum enters the human body by way of bites of the female anophelino mosquito. The plasmodium parasite initially populates the liver, and during later stages of the infectious cycle reproduces in red blood cells. During this stage, the parasite degrades hemoglobin and uses the degradation products as nutrients for growth [Goldberg, D. E., Slater, A. F., Beavis, R., Chait, B., Cerami, A., Henderson, G. B., Hemoglobin degradation in the human malaria pathogen Plasmodium falciparum: a catabolic pathway initiated by a specific aspartic protease, J. Exp. Med., 1991 , 173, 961 - 969]. Hemoglobin degradation is mediated by serine proteases and aspartic proteases. Aspartic proteases have been shown to be indispensable to parasite growth. A non-selective inhibitor of aspartic proteases, Pepstatin, inhibits the growth of P. falciparum in red blood cells in vitro. The same results have been obtained with analogs of pepstatin [Francis,

S. E., Gluzman, I. Y., Oksman, A., Knickerbocker, A., Mueller, R., Bryant, M. L., Sherman, D. R., Russell, D. G., Goldberg, D. E., Molecular characterization and inhibition of a Plasmodium falciparum aspartic hemoglobinase, Embo. J., 1994, 13, 306 - 317; Moon, R. P., Tyas, L., Certa, U., Rupp, K., Bur, D., Jaquet, H., Matile, H., Loetscher, H., Grueninger-Leitch, F., Kay, J., Dunn, B. M., Berry, C, Ridley, R. G., Expression and characterization of plasmepsin I from Plasmodium falciparum, Eur. J. Biochem., 1997, 244, 552 - 560.]. These results show that inhibition of parasite aspartic proteases interferes with the life cycle of P. falciparum. Consequently, aspartic proteases are targets for antimalarial drug development. Today plasmepsin II inhibitor has enterd human clinical trials or is in advanced stage of clinical development. The scientific literature reports a certain number of peptidomimetic or substrate-derived plasmepsin II inhibitors [Hallberg, A., Samuelsson, B. et al., J. Med. Chem., 2003, 46, 734-746; ibid, Bioorg. Med. Chem., 2003, 11, 1235-1246; ibid, Bioorg. Med. Chem., 2003, 11, 827-841 ; Nόteberg, D., Larhed, M. et al., J. Comb. Chem., 2003, 5, 456-464; Nezami, A., Freire, E. et al., Biochemistry, 2002, 41, 2273-2280; Haque, T. S., Ellman, J. A. et al., J. Med. Chem., 1999, 42, 1428-1440 ; Brinner, K. M., Ellamn, J. A. et al., Bioorg. Med. Chem., 2002, 10, 3649-3661 ; Dolle R. E. et al.; Bioorg. Med. Chem. Lett, 1998, 8, 2315-2320; Dolle R. E. et al., Bioorg. Med. Chem: Lett.7 1998, 8, 3203-3206; US Patent 5,734,054 (Pharmacopeia Inc., Dolle R. E. et al.)] which according to the reported data show reasonable inhibitory activity towards the isolated enzyme, but very often fail to conserve this activity in cell based assays or in animal models of malaria. It is of general knowledge that peptidomimetic drugs are potentially metabolically of limited stability and very often might exhibit unfavourable pharmacokinetic properties preventing them from being active in in vivo situations.

There are some reports of non-peptidic or non-peptidomimetic plasmepsin II inhibitors in the scientific literature [Carcache, D. A., Diederich F. et al., ChemBioChem, 2002, 11, 1137-1141 ; Carcache, D. A., Diederich, F. et al., Helv. Chim. Ada, 2003, 86, 2173-2191 ; Carcache, D. A., Diederich, F. et al., Helv. Chim. Ada, 2003, 86, 2192-2209.]. But these compounds show a rather low activity in the isolated enzyme assay and are therefore not suitable as drugs.

Another class of non-peptidic and non-substrate derived inhibitors of plasmepsin II are disclosed in WO 02/38534 (Actelion Pharmaceuticals Ltd; Boss C. et al.). Another group of plasmepsin II inhibitors is described in WO 02/24649 A1 (Actelion Pharmaceuticals Ltd, Boss, C. et al.), in C. Boss et al., Curr. Med. Chem., 2003, 10, 883-907 and in R. Mueller, M. Huerzeler and C. Boss, Molecules, 2003, 8, 556-564. These publications describe clearly non-pepti- domimetic, low-molecular weight plasmepsin II inhibitors and can be considered as the most closely related prior art to the present invention. Although highly active on the isolated enzyme, these molecules suffer from substantial drawbacks with respect to their physicochemical properties such as lipophilicity and solubility in aqueous solutions or under physiological conditions, which prevents them from transforming their substantial in vitro activity into physiological situations. With respect to physicochemical properties (solubility, lipophilicity) the compounds of the present invention are clearly superior to the compounds described in the prior art. This fact manifestates in the results obtained from cellular assays and in in vivo models with compounds contained in the present application as compared to compounds described in prior art documents. The compounds of general formula I were tested in the assay described below against plasmepsin II, human cathepsin D, and human cathepsin E in order to determine their biological activity and their selectivity profile.

The fluorescence resonance energy transfer (FRET) assay for plasmepsin II, human cathepsin D and human cathepsin E.

The assay conditions were selected according to reports in the literature [Peranteau, A. G., Kuzmic, P., Angell, Y., Garcia-Echeverria, C, Rich, D. H., (1995), Increase in fluorescence upon the hydrolysis of tyrosine peptides: application to proteinase assays, Anal Biochem; 227(1 ), 242 - 245; Gulnik, S. V., Suvorov, L. I., Majer, P., Collins, J., Kane, B. P., Johnson, D. G., Erickson, J. W., (1997), Design of sensitive fluorogenic substrates for human cathepsin D, FEBS Lett. 413(2), 379 - 384; Robinson, P. S., Lees, W. E., Kay, J., Cook, N. D., (1992), Kinetic parameters for the generation of endothelins-1 , -2 and -3 by human cathepsin E, Biochem J. 284 (Pt 2), 407 - 409.]. The FRET assay was performed in white polysorp plates (Fluoronunc, cat n° 437842 A). The assay buffer consisted of 50 mM Na acetate pH 5, 12,5% glycerol, 0.1% BSA.

The incubates per well were composed of: - 160 μl buffer - 10 μl inhibitor (in DMSO) - 10 μl of the corresponding substrate in DMSO (see table A) to a final concentration of 1 μM - 20 μl of enzyme to a final amount of x ng per assay tube (x = 10 ng/assay tube plasmepsin II, x = 10 ng/assay tube human cathepsin E and x = 20 ng/assay tube human cathepsin D)

The reactions were initiated by addition of the enzyme. The assay was incubated at 37°C for 30 min (for human cathepsin E), 40 min (for plasmepsin II) or 120 min (for human cathepsin D). The reactions were stopped by adding 10% (v/v) of a 1 M solution of Tris-base. Product-accumulation was monitored by measuring the fluorescence at 460 nm.

Auto-fluorescence of all the test substances is determined in assay buffer in the absence of substrate and enzyme and this value was subtracted from the final signal.

In order to show the above mentioned superiority of the class of compounds claimed herein, one representative compound of the present invention, i.e. the compound of present Example 59 having the formula

has been compared in two assays with the structurally most related prior art compound of the formula

which is known from WO 02/24649 A1 (Actelion Pharmaceuticals Ltd).

The comparative data can be summarized as follows:

The ICso-values determined in the isolated enzyme assay of the two compounds given above are very similar, namely 5.7 nM for the prior art compound and 20 nM for the compound of present Example 59. The ICso-values determined in the cell based assay [a description of this assay can be found in: Desjardin R. E. et al.;

Antimicrob. Agents Chemother., 1979, 16, 710], however, show clear differences.

Thus, the IC50-values in this assay are 2020 nM for the prior art compound and much more favorable 100 nM for the compound of present Example 59. Moreover and more importantly, the IC₅o shift from the isolated enzyme assay towards the cell based assay (which is much closer to the situation in vivo) is of a factor of

354.4 for the prior art compound and of a factor of only 5 for the compound claimed herein. This is also reflected in the very good solubility profile of the compound claimed herein (cf. Figure 1 on page 53) which clearly indicates superior physicochemical properties and therefore more efficient transformation of in vitro activities into cell based systems or in in vivo systems.

Description of the Invention: The present invention relates to low molecular weight organic compounds, in particular to substituted 4-aminopiperidines of the general formula I: General Formula I

wherein R¹ represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl-lower alkyl, aryl-lower alkyl, heteroaryl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, carboxyl-lower alkyl, lower alkoxy-carbonyl-lower alkyl, 2,2-diphenyl-ethyl, 2-phenyl-propyl or 1- [2,6,6-trimethyl-cyclohex-1-enyl)-methyl; R² represents propyl, butyl, pentyl or hexyl;

R³ and R⁴ represent hydrogen, lower alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, aryl-lower alkyl, heteroaryl-lower alkyl, cycloalkyl-lower alkyl, heterocyclyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl or bis-lower alkyl-amino-lower alkyl and may be the same or different; or R³ and R⁴ can form together a 5 to 7-memberd aza-cycloalkyl system which may be substituted by amino, lower alkyl-amino, bis lower alkyl-amino, hydroxy or lower alkoxy; a 4-N- piperazinyl ring system which may be substituted at the second nitrogen atom by lower alkyl, aryl, heteroaryl, cycloalkyl, aryl-lower alkyl, heteroaryl-lower alkyl or cycloalkyl-lower alkyl; or a morpholinyl or thiomorpholinyl ring system; and

represents

In a preferred embodiment also the following forms are encompassed: optically pure enantiomers, mixtures of enantiomers, racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form thereof as well as pharmaceutically acceptable salts, solvent complexes and morphological forms thereof.

These substituted 4-aminopiperidines are novel and exhibit useful pharmaco- dynamic properties. Objects of the present invention are the 4-aminopiperidines of the formula I above, their optically pure enantiomers, mixtures of enantiomers, racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and meso-form as well as their pharmaceutically acceptable salts, solvent complexes and morphological forms as such and for use as therapeutically active compounds, pharmaceutical compositions containing same and the preparation of such pharmaceutical compositions as well as the use of such compounds and compositions for the treatment and/or prevention of diseases demanding the inhibition of parasitic aspartic proteases. The expression lower alkyl - alone or in combination - as used in the present specification means straight and branched chain saturated hydrocarbon groups with 1 to 7, preferably 3 to 6, carbon atoms, such as methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, tert.-butyl, n-pentyl, 2-methyl-propyl, 3,3- dimethyl-propyl, n-hexyl, n-heptyl and the like. The expression lower alkoxy - alone or in combination - means alkyl ether groups in which alkyl has the meaning given above, such as methoxy, ethoxy, propoxy, iso-propoxy; iso-butoxy, sec.-bu- toxy, tert.-butoxy and the like. The expression lower alkenyl means straight and branched chain unsaturated hydrocarbon groups with 2 to 7, preferably 3 to 6, carbon atoms, such as vinyl, allyl, 2-butenyl or 3-butenyl. The expression lower alkynyl means straight and branched chain hydrocarbon groups with 2 to 7, preferably 3 to 6, carbon atoms, which contain a triple bond, such as ethinyl, propynyl, butynyl, pentynyl, hexynyl and the like, and which may be substituted with hydroxy or lower alkoxy. The expression lower alkanoylamino means an amino group in which one hydrogen atom is replaced with a straight or branched chain alkylcarbonyl group with 2 to 7, preferably 2 to 4, carbon atoms, such as acetylamino, n-propanoylamino and n-butanoylamino. The expression lower alkenylen means straight and branched chain unsaturated divalently bond hydrocarbon groups with 2 to 7, preferably 2 to 4, carbon atoms, such as vinylen, allylen, propenylen and butenylen. The expression cycloalkyl - alone or in combination - means a saturated cyclic hydrocarbon ring system with 3 to 6 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, which may be mono- or di- substituted with lower alkyl, lower alkoxy; aryl-lower alkoxy; heteroaryl-lower alkoxy, aryl-lower alkyl-amino, heteroaryl-lower alkyl-amino, lower alkyl-amino, bis-(lower alkyl)-amino, aryl-lower alkoxy-lower alkyl, heteroaryl-lower alkoxy-lower alkyl, aryl-lower alkyl-amino-lower alkyl, heteroaryl-lower alkyl-amino-lower alkyl, aryl-sulfonyl-amino-lower alkyl, heteroaryl-sulfonyl-amino-lower alkyl, cycloalkyl-sulfonyl-amino-lower alkyl, heterocyclyl-sulfonylamino-lower alkyl, aryl-lower alkyl-sulfonyl-amino-lower alkyl, heteroaryl-lower alkyl-sulfonyl-amino-lower alkyl, cycloalkyl-lower alkyl-sulfonyl- amino-lower alkyl, heterocyclyl-lower alkyl-sulfonylamino-lower alkyl, lower alkyl- sulfonyl-amino-lower alkyl, aryl amino-carbonyl-lower alkyl, heteroaryl-amino- carbonyl-lower alkyl, cycloalkyl-amino-carbonyl-lower alkyl, heterocyclyl-amino- carbonyl-lower alkyl, lower alkyl-amino-carbonyl-lower alkyl, aryl-ureido-lower alkyl, heteroaryl-ureido-lower alkyl, cycloalkyl-ureido-lower alkyl, lower alkyl- ureido-lower alkyl or aryl-lower alkyl-ureido-lower alkyl.

The expression cycloalkenyl means an unsaturated cyclic hydrocarbon ring system with 5 to 7 carbon atoms, i.e. cyclopentenyl, cyclohexenyl and cyclohep- tenyl which may be substituted with lower alkyl or lower alkoxy. The expression heterocyclyl - alone or in combination - means a saturated or unsaturated five-, six- or seven-membered ring containing one or two heteroatoms chosen from nitrogen, oxygen or sulfur which may be the same or different and which rings may be substituted with lower alkyl, lower alkenyl, aryl, heteroaryl, aryl-lower alkoxy, aryl-lower alkoxy-lower alkyl, aryl-oxy; heteroaryl-lower alkoxy, heteroaryl-lower alkoxy-lower alkyl, heteroaryl-oxy; amino, bis-(lower alkyl)-amino, alkanoyl-amino, halogen, hydroxy, hydroxy-lower alkyl, lower alkoxy or phenoxy. Examples of such rings are morpholinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, 1 ,4-dioxanyl, pyrrolidinyl, tetrahydrofuranyl, dihydropyrrolyl, imidazolidinyl, dihydropyrazolyl, pyrazolidinyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and the like, and substituted derivatives of such type rings with substituents as outlined hereinbefore. The expression heteroaryl - alone or in combination - means six-membered aromatic rings containing one to four nitrogen atoms, benzofused six-membered aromatic rings containing one to three nitrogen atoms, five-membered aromatic rings containing one oxygen, one nitrogen or one sulfur atom and benzo-fused derivatives thereof, five-membred aromatic rings containing two nitrogen atoms and benzo-fused derivatives thereof, five membered aromatic rings containig one oxygen and one nitrogen atom and benzo-fused derivatives thereof, five membred aromatic rings containing one sulfur and one nitrogen atom and benzo fused derivatives thereof, five membered aromatic rings containing three nitrogen atoms and benzo fused derivatives thereof or the tetrazolyl ring. Examples of such rings are furanyl, thienyl, pyrrolyl, pyridinyl (such as 2-pyridinyl, 3-pyridinyl or 4- pyridinyl), indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazinyl, thiazinyl, pyrazolyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuran, and the like, whereby such ring systems may be mono-, di- or tri-substituted with heterocyclyl, heterocyclyl-lower alkyl-amino, cycloalkyl, cycloalkyl-amino, cycloalkyl-lower alkyl- amino, aryl; heteroaryl, aryloxy; aryl-lower alkoxy, heteroaryl-lower alkoxy; aryl- lower alkyl-amino, heteroaryl-lower alkyl-amino, lower alkyl, lower alkenyl, lower alkynyl, lower alkyl-carbonyl, amino, lower alkyl-amino, aryl-amino, heteroaryl- amino, bis-(lower-alkyl)-amino, bis-aryl-amino, (aryl)(heteroaryl)-amino, lower alkanoyl-amino, aryl-carbonyl-amino, heteroaryl-carbonyl-amino, lower alkyl- sulfonyl-amino, aryl-sulfonyl-amino, heteroaryl-sulfonyl-amino, aryl-lower alkyl- sulfonyl-amino, heteroaryl-lower alkyl-sulfonyl-amino, ω-amino-lower alkyl, halogen, hydroxy, carboxyl, lower alkoxy-carbonyl, lower alkoxy, vinyloxy, allyloxy; ω-hydroxy-lower alkyl, cyano, amidino, trifluoromethyl, lower alkyl-sulfonyl and the like. Examples of substituted heteroaryl are 2,6-dichloro-pyridin-4-yl or 3,5- dfchloro pyridin-4-yl The expression aryl - alone or in combination - means six membered aromatic rings like phenyl, and condensed systems like naphthyl or indenyl and the like, whereby such ring systems may be mono-, di- or tri-substituted with cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, aryl-lower alkoxy, heteroaryl-lower alkoxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkenylen, lower alkyl-carbonyl, aryl- carbonyl, heteroaryl-carbonyl, cycloalkyl-carbonyl, heterocyclyl-carbonyl, amino, lower alkyl-amino, aryl-amino, heteroaryl-amino, bis-(lower-alkyl)-amino, bis-aryl- amino, lower alkanoyl-amino, aryl-carbonyl-amino, heteroaryl-carbonyl-amino, lower alkyl-sulfonyl-amino, cycloalkyl-sulfonyl-amino, cycloalkyl-lower alkyl- sulfonyl-amino, aryl-sulfonyl-amino, heteroaryl-sulfonyl-amino, aryl-lower alkyl- sulfonyl-amino, ω-amino-lower alkyl, halogen, hydroxy; carboxyl, lower alkoxy- carbonyl, lower alkoxy, vinyloxy, allyloxy, ω-hydroxy-lower alkyl, ω-hydroxy-lower alkoxy, cyano, amidino, trifluoromethyl, lower alkyl-sulfonyl and the like.

Examples for substituted aryl are for example phenoxy (preferred 4- phenoxy), benzoic acid (preferred 4-benzoic acid), benzyl-oxy-phenyl.

The expression aryloxy means aryl ether groups in which aryl has the meaning given above.

The expression halogen means fluorine, chlorine, bromine and iodine with fluorine, chlorine and bromine being preferred. The expression cycloalkyl-lower alkyl refers to a cycloalkyl group as defined above which is substituted with a lower alkyl group as defined above.

The expression aryl-lower alkyl refers to aryl group as defined above which is substituted with a lower alkyl group as defined above.

The expression heteroaryl-lower alkyl means refers to a heteroalkyl group as defined above which is substituted with a lower alkyl group as defined above. An example for heteroaryl-lower alkyl is pyridinyl-ethyl, such as 2- pyridinyl-ethyl.

The expression hydroxy-lower alkyl refers to a hydroxy group, which is substituted with a lower alkyl group as defined above.

The expression lower alkoxy-lower alkyl refers to a lower alkoxy group as defined above which is substituted with a lower alkyl group as defined above.

The expression carboxyl-lower alkyl refers to a carboxyl group, which is substituted with a lower alkyl group as defined above.

The term lower alkylcarbonyl refers to a -CO-lower alkyl group wherein lower alkyl is as defined above. The term lower alkoxy-carbonyl refers to a -CO-lower alkoxy group wherein lower alkoxy is as defined above.

The expression lower alkoxy-carbonyl-lower alkyl refers to a lower alkoxy- carbonyl as defined above which is substituted with a lower alkyl group as defined above. The expression heterocyclyl-lower alkyl refers to a heterocyclyl as defined above group, which is substituted with a lower alkyl group as defined above. An example for heterocyclyl-lower alkyl is N-ethyl-pyrrolidine. The expression bis-lower alkyl-amino refers to a group (lower alkyl)₂N-, wherein lower alkyl is as defined and both lower alkyl group may be differten or the same.

The expression bis-lower alkyl-amino-lower alkyl refers to a bis-lower alkyl- amino group as defined above which is substituted with a lower alkyl group as defined above.

It is understood that the substituents outlined relative to the expressions cycloalkyl, heterocyclyl, heteroaryl and aryl have been omitted in the definitions of the general formulae I to VI and in claims 1 to 15 for clarity reasons but the definitions in formulae I to VI and in claims 1 to 15 should be read as if they are included therein.

The expression pharmaceutically acceptable salts encompasses either salts with inorganic acids or organic acids like hydrochloric or hydrobromic acid; sulfuric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, methylsulfonic acid, p- toluolsulfonic acid and the like or in case the compound of formula I is acidic in nature with an inorganic base like an alkali or earth alkali base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide etc.

The compounds of the general formula I can contain one or more asymmetric carbon atoms and may be prepared in form of optically pure enantiomers, dia- stereomers, mixtures of diastereomers, diastereomeric racemates and mixtures of diastereomeric racemates. The present invention encompasses all these forms. Mixtures may be separated in a manner known per se, i.e. by column chromatography, thin layer chromatography, HPLC, crystallization etc. Preferred are compounds of formula I above wherein R¹ represents hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, cycloalkyl-lower alkyl, aryl- lower alkyl, heteroaryl-lower alkyl, hydroxy-lower alkyl, 2,2-diphenyl-ethyl, 2- phenyl-propyl or 1-[2,6,6-trimethyl-cyclohex-1-enyl)-methyl, preferably methyl, ethyl, propyl, butyl, 2-methyl-propyl, 3,3-dimethyl-propyl, cyclopropyl-methyl, aryl- methyl, pyridyl-methyl or imidazolyl-methyl, more preferably methyl, ethyl, propyl, butyl, 2-methyl-propyl or 3,3-dimethyl-propyl , most preferably 2-methyl-propyl. The preferred meaning of R² is pentyl or hexyl, more preferred pentyl. R³ represents preferably hydrogen or lower alkyl, more preferably hydrogen or methyl. R⁴ represents preferably pyrrolidinyl-lower alkyl, piperidinyl-lower alkyl, morpholinyl-lower alkyl, 4-N-methyl-piperazinyl-lower alkyl, benzyl, pyridyl-ethyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or quinolinyl, whereby these aryl and heteroaryl rings may be mono-, di-, tri-, or tetra-substituted with methyl, methoxy, fluorine, chlorine or trifluoromethyl. More preferred R⁴ represents pyrrolidinyl-ethyl, benzyl, pyridyl-ethyl, 2-pyridyl, 3-pyridyl or 4-pyridyl which rings can be mono- or di-substituted with methyl, methoxy or chlorine. Preferably, R³ and R⁴ together form a pyrrolidine-, piperidine-, morpholine-, thiomorpholine- , 4-N-methyl- piperazine- or 4-N-(2-pyridyl)-piperazine-ring, more preferably a pyrrolidine-,

piperidine-, morpholine- or 4-N-methyl-piperazine-ring.

represents preferably

more preferably

A particular group of compounds of formula I above are those wherein R¹ represents hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, hydroxy-lower alkyl or 2,2-diphenyl-ethyl; R² represents pentyl; R³ represents hydrogen or lower alkyl; R⁴ represents pyrrolidinyl-lower alkyl, benzyl, pyridyl-ethyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or quinolinyl, whereby the heteroaryl rings may be mono- or di-substituted with methyl, methoxy or chlorine; or R³ and R⁴ together form a morpholine-, thiomorpholine- , 4-N-methyl-piperazine- or 4-N-(2-pyridyl)-

piperazine-ring; and

represents

From the above it follows that a preferred subgroup of compounds of formula I above are those of the general formula II Formula II

wherein 1 1 A \ ^A

R , R , R and ^ — ^/ are as defined in general formula I above,

and optically pure enantiomers, mixtures of enantiomers, such as racemates, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form as well as pharmaceutically acceptable salts, solvent complexes and morphological forms thereof.

Particular compounds of formula II are those wherein ΛΛ is as defined in general formula I above; R¹ represents methyl, ethyl, propyl, butyl, 2-methyl- propyl, 3,3-dimethyl-propyl, cyclopropyl, aryl, pyridyl or imidazolyl; R³ represents hydrogen or lower alkyl and R⁴ represents pyrrolidinyl-lower alkyl, piperidinyl-lower alkyl, morpholinyl-lower alkyl, 4-N-methyl-piperazinyl-lower alkyl, benzyl, pyridyl- methyl, phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, whereby these aryl and heteroaryl rings may be mono-, di, tri-, or tetra-substituted with methyl, methoxy, fluorine, chlorine or trifluoromethyl; or R³ and R⁴ together form a a pyrrolidine-, piperidine-, morpholine- or 4-N-methyl-piperazine-ring; and optically pure enantiomers, mixtures of enantiomers, such as racemates, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form as well as pharmaceutically acceptable salts, solvent complexes and morphological forms thereof.

Another group of particular compounds of formula II are those wherein

represents

R¹ represents methyl, ethyl, propyl, butyl, 2-methyl-propyl, 3,3-dimethyl-propyl, cyclopropyl, aryl, pyridyl or imidazolyl; R³ represents hydrogen or lower alkyl and

R⁴ represents pyrrolidinyl-lower alkyl, piperidinyl-lower alkyl, morpholinyl-lower alkyl, 4-N-methyl-piperazinyl-lower alkyl, benzyl, pyridyl-methyl, phenyl, 2-pyridyl,

3-pyridyl or 4-pyridyl, whereby these aryl and heteroaryl rings may be mono-, di-, tri-, or tetra-substituted with methyl, methoxy, fluorine, chlorine or trifluoromethyl; or R³ and R⁴ together form a pyrrolidine-, piperidine-, morpholine- or 4-N-methyl- piperazine-ring; and optically pure enantiomers, mixtures of enantiomers, such as racemates, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form as well as pharmaceutically acceptable salts, solvent complexes and morphological forms thereof. A further preferred subgroup of compounds of formula I above are those of the general formula III

Formula III

wherein

R¹, R³ and R⁴ are as defined in general formula I above, and optically pure enantiomers, mixtures of enantiomers, such as racemates, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form as well as pharmaceutically acceptable salts, solvent complexes and morphological forms thereof.

Particular compounds of formula III are those wherein R¹ represents methyl, ethyl, propyl, butyl, 2-methyl-propyl, 3,3-dimethyl-propyl, cyclopropyl, aryl, pyridyl or imidazolyl; R³ represents hydrogen or lower alkyl and R⁴ represents pyrrolidinyl- lower alkyl, piperidinyl-lower alkyl, morpholinyl-lower alkyl, 4-N-methyl-piperazinyl- lower alkyl, benzyl, pyridyl-methyl, phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, whereby these aryl and heteroaryl rings may be mono-, di-, tri-, or tetra-substituted with methyl, methoxy, fluorine, chlorine or trifluoromethyl; or R³ and R⁴ together form a a pyrrolidine-, piperidine-, morpholine- or 4-N-methyl-piperazine-ring; and optically pure enantiomers, mixtures of enantiomers, such as racemates, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form as well as pharmaceutically acceptable salts, solvent complexes and morphological forms thereof.

Another preferred subgroup of compounds of formula I above are those of the general formula IV

Formula IV

wherein

Particular compounds of formula IV are those wherein R¹ represents methyl, ethyl, propyl, butyl, 2-methyl-propyl, 3,3-dimethyl-propyl, cyclopropyl, aryl, pyridyl or imidazolyl; R³ represents hydrogen or lower alkyl and R⁴ represents pyrrolidinyl- lower alkyl, piperidinyl-lower alkyl, morpholinyl-lower alkyl, 4-N-methyl-piperazinyl- lower alkyl, benzyl, pyridyl-methyl, phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, whereby these aryl and heteroaryl rings may be mono-, di-, tri-, or tetra-substituted with methyl, methoxy, fluorine, chlorine or trifluoromethyl; or R³ and R⁴ together form a a pyrrolidine-, piperidine-, morpholine- or 4-N-methyl-piperazine-ring; and optically pure enantiomers, mixtures of enantiomers, such as racemates, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form as well as pharmaceutically acceptable salts, solvent complexes and morphological forms thereof. Still another preferred subgroup of compounds of formula I above are those of the general formula V Formula V

wherein R¹, R³ and R⁴ are as defined in general formula I above, and optically pure enantiomers, mixtures of enantiomers, such as racemates, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form as well as pharmaceutically acceptable salts, solvent complexes and morphological forms thereof. Particular compounds of formula V are those wherein R¹ represents methyl, ethyl, propyl, butyl, 2-methyl-propyl, 3,3-dimethyl-propyl, cyclopropyl, aryl, pyridyl or imidazolyl; R³ represents hydrogen or lower alkyl and R⁴ represents pyrrolidinyl- lower alkyl, piperidinyl-lower alkyl, morpholinyl-lower alkyl, 4-N-methyl-piperazinyl- lower alkyl, benzyl, pyridyl-methyl, phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, whereby these aryl and heteroaryl rings may be mono-, di-, tri-, or tetra-substituted with methyl, methoxy, fluorine, chlorine or trifluoromethyl; or R³ and R⁴ together form a a pyrrolidine-, piperidine-, morpholine- or 4-N-methyl-piperazine-ring; and optically pure enantiomers, mixtures of enantiomers, such as racemates, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form as well as pharmaceutically acceptable salts, solvent complexes and morphological forms thereof. Especially preferred compounds of the general formula I above are those of the general formula VI Formula VI

wherein

R³ and R⁴ and ^-^ are as defined in general formula I above, and optically pure enantiomers, mixtures of enantiomers, such as racemates, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form as well as pharmaceutically acceptable salts, solvent complexes and morphological forms thereof.

A Particular compounds of formula VI are those wherein — ^/ is as defined in general formula I above; R³ represents hydrogen or lower alkyl and R⁴ represents pyrrolidinyl-lower alkyl, piperidinyl-lower alkyl, morpholinyl-lower alkyl, 4-N-methyl- piperazinyl-lower alkyl, benzyl, pyridyl-methyl, phenyl, 2-pyridyl, 3-pyridyl or 4- pyridyl, whereby these aryl and heteroaryl rings may be mono-, di-, tri-, or tetra- substituted with methyl, methoxy, fluorine, chlorine or trifluoromethyl; or R³ and R⁴ together form a a pyrrolidine-, piperidine-, morpholine- or 4-N-methyl-piperazine- ring; and optically pure enantiomers, mixtures of enantiomers, such as racemates, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form as well as pharmaceutically acceptable salts, solvent complexes and morphological forms thereof.

Another group of particular compounds of formula VI are those wherein ΛΛ⁾

represents

R³ represents hydrogen or methyl and R⁴ represents 2-pyridyl, 3-pyridyl or 4- pyridyl, whereby these pyridyl-rings may be mono-, di-, tri-, or tetra-substituted with methyl, methoxy, fluorine, chlorine or trifluoromethyl; and optically pure enantiomers, mixtures of enantiomers, such as racemates, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form as well as pharmaceutically acceptable salts, solvent complexes and morphological forms thereof.

Another group of particular compounds of formula VI are compounds wherein

( Λ7-Λ) represents

The compounds of the general formula I of the present invention can be prepared according to the general sequences of reactions outlined below in Reaction

schemes 1 to 3, wherein R¹, R², R³, R⁴ and ΛΛ are as defined in general formula I above (for simplicity and clarity reasons, only parts of the synthetic possibilities which lead to compounds of formulae i to VI are described). For general methods of certain steps see also pages 22 and 28-32.

All chemical transformations can be performed according to well-known standard methodologies as described in the literature or as described in the typical procedures.

Scheme 1 : Preparation of final compounds (General pathway): a) MeOH

The final compounds can be prepared by refluxing commercially available N-Boc-

4-aminopiperidine (Neosystems) (1) and the appropriate halogen-substituted ΛΛ carbaldehyde (2) in dry methanol for 4 hours, followed by the addition of sodium borohydride at room temperature and stirring for another 15 minutes [Mueller, R. et al., Molecules, 2003, 8, 556-564]. Usual aqueous workup yielded compound 3, which subsequently was acylated by 4-lower alkyl substituted benzoic acid chlorides (4) in dichloromethane and triethylamine as the base to give derivative 5 [Mueller, R. et al., Molecules, 2003, 8, 556-564]. Boc-deprotection generally was achieved by stirring compounds 5 in 4 M HCI in dioxane for 1 h at room temperature followed by evaporation to dryness [T. W. Greene, P. G. M. Wuts, Protective groups in organic synthesis, Wiley-lnterscience, 1991 ; P. J. Kocienski,

Protecting Groups, Thieme, 1994; Mueller, R. et al., Molecules, 2003, 8, 556-564].

Reductive amination of compounds 6 by aldehydes 7 in either dichloromethane or acetonitrile with sodium tri-acetoxyborohydride resulted in compounds 8 [Mueller,

R. et al., Molecules, 2003, 8, 556-564; Abdel-Magid, A. F. et al., J. Org. Chem.,

1996, 61, 3849-3862] which were then transformed to final compounds 10 by

Buchwald-Hartwig-Aryl-Amination conditions. The aryl-amination reactions were usually performed in an inert atmosphere (Argon or N₂-gas) with a suitable catalyst like SK-CC01-A or SK-CC02-A [commercially available from Solvias AG or eventually Fluka and especially designed for aryl-aminations, see Anita Schnyder et al., Angew. Chem. Int. Ed., 2003, 41, 3668-3671 ; Ricci, A. (Editor); Modern

Amination Methods; Wiley- VCH, Germany, 2000, especially Chapter 7, pp195 -

262 and references cited there.] at elevated temperatures for 2 to 6 h and a 2 fold excess of the amine.

Scheme 2: Preparation of Example 11

1 11

Example 11 Scheme 3: Preparation of Example 1 :

The compounds of the general formula I and their pharmaceutically acceptable salts may be used as therapeutics e.g. in form of pharmaceutical compositions. They may especially be used to in prevention or treatment of malaria. These compositions may be administered in enteral or oral form e.g. as tablets, dragees, gelatine capsules, emulsions, solutions or suspensions, in nasal form like sprays or rectally in form of suppositories. These compounds may also be administered in intramuscular, parenteral or intraveneous form, e.g. in form of injectable solutions. These pharmaceutical compositions may contain the compounds of formula I as well as their pharmaceutically acceptable salts in combination with inorganic and/or organic excipients which are usual in the pharmaceutical industry like lactose, maize or derivatives thereof, talcum, stearinic acid or salts of these materials.

For gelatine capsules vegetable oils, waxes, fats, liquid or half-liquid polyols etc. may be used. For the preparation of solutions and sirups e.g. water, polyols saccharose, glucose etc. are used. Injectables are prepared by using e.g. water, polyols, alcohols, glycerin, vegetable oils, lecithin, liposomes etc. Suppositories are prepared by using natural or hydrogenated oils, waxes, fatty acids (fats), liquid or half-liquid polyols etc. The compositions may contain in addition preservatives, stability improving substances, viscosity improving or regulating substances, solubility improving substances, sweeteners, dyes, taste improving compounds, salts to change the osmotic pressure, buffer, anti-oxidants etc.

The compounds of formula I may also be used in combination with one or more other therapeutically useful substances e. g. with other antimalarials like quinine, chloroquine, amodiaquine, mefloquine, primaquine, tafenoquine, artemisinin and artemisinine-derivatives like artemether, arteether or artesunat, pyrimethamine- sulfadoxine (Fansidar), mepacrine, halofantrine, proguanil, chloroproguanil, lumefantrine, pyronaridine, atovaquone and the like and / or antibiotics like rifampicine, doxycycline, clindamycine or azithromycine and the like. The dosage may vary within wide limits but should be adapted to the specific situation. In general the dosage given in oral form should daily be between about 3 mg and about 3 g, peferably between about 10 mg and about 1 g, especially preferred between 5 mg and 300 mg, per adult with a body weight of about 70 kg. The dosage should be administered preferably in 1 to 3 doses per day which are of equal weight. As usual, children should receive lower doses which are adapted to body weight and age.

The following examples illustrate the invention but do not limit the scope thereof. All temperatures are given in °C.

List of abbreviations:

Boc or boc tert.-butyloxycarbonyl

DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene(1 ,5-5)

DCM dichloromethane DIPEA di-isopropyl-ethyl-amine (Hϋnigs base)

DMF dimethylformamide

DMSO dimethylsulfoxide

EtOAc ethyl acetate

HCI hydrochloric acid

MeOH methanol

NEt₃ triethylamine

NMM N-methyl-morpholine

N₂ nitrogen as protective gas/inert atmosphere

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography rt room temperature min. minutes h hours tR retention time (in minutes)

General Procedures and Examples:

All solvents were stored over molecular sieves. All reagents were used without further purification as received from commercial sources.

All compounds were characterized by ¹H-NMR (300MHz) and occasionally by ¹³C- NMR (75MHz) (Varian Oxford, 300MHz;), by LC-MS (Finnigan AQA/HP 1100;

Column: Develosil C30 Aqua, 50x4.6mm, 5μm; Gradient: 5-95% acetonitrile in water, 1 min, with 0.03% TFA, flow:4.5 ml/min.), by TLC (TLC-plates from Merck,

Silica gel 60 F₂₅₄).

Preparative HPLC-System: Column: Zorbax SB-AQ 5mM, 21.2x50mm; flow: 40 ml/min; Gradient: 10-95% acetonitirle in water, 3.5 min, with 0.5% formic acid; detection by UV/ELSD.

a) General Procedures:

Typical procedure A) for the reductive amination: The amine and the aldehyde (0.97 eq.) (which are used as starting materials, are known compounds), are mixed in anhydrous MeOH and stirred under reflux for 4 h. The reaction mixture is cooled to rt followed by the addition of sodium borohydride (1.5 eq.). Stirring is continued for 15 min.. Small amounts of water are carefully added and the methanol is removed under reduced pressure. Water is added to the residue which is then extracted 3x with EtOAc. The combined organic layers are washed with brine, dried over sodium sulfate, filtered and the solvent is evaporated. The secondary amine is usually obtained in high purity and can be used in subsequent transformations without further purification. In case purification seems to be necessary, either flash chromatography over silicagel with solvent mixtures like DCM / MeOH = 9/1 or HPLC-purifications were performed.

Typical procedure B) for the acylation:

To a solution of the amine in anhydrous EtOAc (or acetonitirle or DCM) is added a base like NEt₃ (or DIPEA, or NMM) followed by the addition of the carboxylic acid chloride (1.2 eq.). The reaction mixture is stirred for 2 to 14 h at rt, followed by standard aqueous work-up and purification, either by flash chromatography over silicagel with an appropriate solvent mixture (usually EtOAc / hexane) or by HPLC, to give the amide intermediate. The carboxylic acid chlorides {Rr(CO)-CI} may be obtained in situ from the corresponding carboxylic acid as described in the literature (i. e.: Devos, A.,

Remion, J., Frisque-Hesbain, A.-M., Colens.A., Ghosez, L., J. Chem. Soc, Chem.

Commun. 1979, 1180).

Typical procedure C) for the Boc-deprotection:

The Boc-protected intermediate is dissolved in dioxane followed by the addition of 4M HCI in dioxane (commercially available from Aldrich) at rt. Stirring is continued for 1 to 2 h. The reaction mixture is evaporated to dryness. [In case of very sensitive intermediates, the Boc-protected compound is dissolved in DCM followed by the addition of TFA at rt. Stirring is usually continued for 3 to 4 h followed by evaporation to dryness [Kocienski, P. J., Protecting Groups, Thieme Verlag Stuttgart, 1994; Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, Wiley-lnterscience, 2^nd Edition, 1991.].

Typical procedure D) for the second reductive amination:

The amine and the aldehyde (1.5 eq.) are mixed in anhydrous dichloromethane (or THF, or acteonitirle) and sodium triacetoxyborohydride (1.3 eq.) is added. After stirring the solution for 48 h, methanol is added and the reaction mixture is treated in the same manner as described in procedure A).

Typical Procedure E) for the aryl/heteroaryl-amination reaction: [see also: Ricci, A. (Editor), Modern Amination Methods, Wiley-VCH, Germany, 2000, especially Chapter 7, pp195 - 262 and references cited there.] In a dry reaction flask, toluene is degassed for 30 min with N2. The aryl-halo- genide or the heteroaryl-halogenide, the amine and sodium tert.-butoxide are added. The mixture is heated to 100°C for 30 min followed by the addition of the appropriate palladium-catalyst (e.g. SK-CC01 A or SK-CC02-A from Solvias AG; M. Thommen et al., sp2, September 2003, p32-35, www.sp2.uk.com and references cited therein) suspended in toluene. Stirring at 100°C was continued for 2 to 8 h followed by standard aqueous work up and purification of the compounds by preparative TLC or by HPLC. All chemical transformations can be performed according to well known standard methodologies as described in the literature or as described in the typical procedures above.

b) Examples:

Example 1 : a) 4-(4-Bromo-benzylamino)-piperidine-1 -carboxylic acid tert-butyl ester:

According to typical procedure A), 5 g of 4-bromobenzaldehyde, 6.39 g of 4- amino-piperidine-1 -carboxylic acid tert.-butyl ester hydrochloride and 4.6 ml DIPEA was refluxed in dry MeOH for 4 h, cooled to rt followed by the addition of 1.02 g sodium borohydride and stirring was continued for additional 15 min. Standard aqueous work up resulted in 9.62 g of the title compound which could be used for further transformations without purification. LC-MS: tR = 0.76; [M+H]⁺ = 369.12.

b) 4-[(4-Bromo-benzyl)-(4-pentyl-benzoyl)-amino]-piperidine-1 -carboxylic acid tert- butyl ester:

According to typical procedure B), 3.0 g 4-(4-bromo-benzylamino)-piperidine-1- carboxylic acid tert-butyl ester was dissolved in 100 ml DCM followed by the addition of 7 ml DIPEA. The mixture was cooled to 0°C and 2 ml 4-pentyl-benzoyl chloride was slowly added. Stirring was continued for 16 h at rt. Standard aqueous work up resulted in 3.63 g of the title compound as a white solid. LC-MS: tR 1.18; [M+H]⁺ = 543.5.

c) N-(4-Bromo-benzyl)-4-pentyl-N-piperidin-4-yl-benzamide hydrochloride:

According to typical procedure C), 2.1 g 4-[(4-bromo-benzyl)-(4-pentyl-benzoyl)- amino]-piperidine-1 -carboxylic acid tert-butyl ester was dissolved in 50 ml dioxane followed by the addition of 20 ml of 4 M HCI in dioxane. Stirring was continued for 90 min. The reaction mixture was evaporated to dryness to give 2 g of the title compound. LC-MS: tR = 0.69; [M+H]⁺ = 443.42.

d) N-(4-Bromo-benzyl)-N-[1-(3-methyl-butyl)-piperidin-4-yl]4-pentylbenzamide:

According to typical procedure D), 1.61 g N-(4-Bromo-benzyl)-4-pentyl-N-piperidin- 4-yl-benzamide hydrochloride was dissolved in 30 ml DCM. 300 mg of isovaleraldehyde and 200 mg of sodium triacetoxy borohydride were added and stirring continued for 16 h at room temperature. Standard aqueous work up followed by column chromatographic purification (Silicagel; EtOAc/ hexane = 1 :1 gave 1.55 g of the title compound. LC-MS: tR = 0.97; [M+H]⁺ = 515.20.

e) N-[1 -(3-Methyl-butyl)-piperidin-4-yl]-4-pentyl-N-[4-(2-pyrrolidin-1 -yl-ethyl-amino)- benzyl]-benzamide:

According to typical procedure E), 1.5 ml toluene was degassed with N₂, followed by the addition of 77 mg N-(4-bromo-benzyl)-N-[1-(3-methyl-butyl)-piperidin-4-yl]4- pentylbenzamide, 21 mg 2-pyrrolidin-1-yl-ethylamine and 20 mg sodium tert.- butoxide. The mixture was heated to 100°C for 30 min, then 2.0 mg of the Pd- catalyst SK-CC01-A (2'-(Dimethylamino)-2-biphenylyl-palladium(ll) chloride dinorbornyl-phosphine complex; Fluka 36037 or from Solvias AG). Stirring at 100°C was continued for 4 h followed by standard aqueous work up and HPLC- purification to give 15 mg of the title compound. LC-MS: tR = 0.80; [M+H]⁺ = 547.3.

In the following tables Examples 2 to 60 are depicted which can all be prepared according to the typical procedures and the procedures described for the preparation of Example 1 above and the sequences outlined in schemes 1 to 3:

Table 1:

Table 2:

Table 3:

Table 4:

Table 5:

Table 6:

Table 7:

Table 8:

Table 9:

Table 10:

Table 11:

Table 12:

Claims

1. Substituted 4-aminopiperidine derivatives of the general formula I:

General Formula I

wherein

R¹ represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl-lower alkyl, aryl-lower alkyl, heteroaryl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, carboxyl-lower alkyl, lower alkoxy-carbonyl-lower alkyl, 2,2-diphenyl-ethyl, 2-phenyl-propyl or 1- [2 , 6 ,6-trimethyl-cyclohex- 1 -enyl )-methyl ; R² represents propyl, butyl, pentyl or hexyl;

R³ and R⁴ represent hydrogen, lower alkyl, aryl; heteroaryl, cycloalkyl, heterocyclyl, aryl-lower alkyl, heteroaryl-lower alkyl, cycloalkyl-lower alkyl, heterocyclyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl or bis-lower alkyl-amino-lower alkyl and may be the same or different; or R³ and R⁴ can form together a 5 to 7-memberd aza-cycloalkyl system which may be substituted by amino, lower alkyl-amino, bis lower alkyl-amino, hydroxy or lower alkoxy; a 4-N- piperazinyl ring system which may be substituted at the second nitrogen atom by lower alkyl, aryl, heteroaryl, cycloalkyl, aryl-lower alkyl, heteroaryl-lower alkyl or cycloalkyl-lower alkyl; or a morpholinyl or thiomorpholinyl ring system; and

represents and optically pure enantiomers, mixtures of enantiomers, racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of dia- stereomeric racemates and the meso-form thereof as well as pharmaceutically acceptable salts, solvent complexes and morphological forms thereof.

2. Compounds according to any one of claims 1 wherein R¹ represents hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, hydroxy-lower alkyl or 2,2-diphenyl-ethyl; R² represents pentyl; R³ represents hydrogen or lower alkyl; R⁴ represents pyrrolidinyl-lower alkyl, benzyl, pyridyl-ethyl, 2-pyridyl, 3-pyridyl, 4- pyridyl or quinolinyl, whereby the heteroaryl rings may be mono- or di-substituted with methyl, methoxy or chlorine; or R³ and R⁴ together form a morpholine-, thiomorpholine- , 4-N-methyl-piperazine- or 4-N-(2-pyridyl)-piperazine-ring; and

Λ- Λ represents

3. Compounds according to any one of claims 1 to 2, wherein R¹ represents methyl, ethyl, propyl, butyl, 2-methyl-propyl, 3,3-dimethyl-propyl, cyclopropyl, aryl, pyridyl or imidazolyl; R³ represents hydrogen or lower alkyl and R⁴ represents pyrrolidinyl-lower alkyl, piperidinyl-lower alkyl, morpholinyl-lower alkyl, 4-N-methyl- piperazinyl-lower alkyl, benzyl, pyridyl-methyl, phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, whereby these aryl and heteroaryl rings may be mono-, di-, tri-, or tetra-substituted with methyl, methoxy, fluorine, chlorine or trifluoromethyl; or R³ and R⁴ together form a a pyrrolidine-, piperidine-, morpholine- or 4-N-methyl-piperazine- ring.

4. Compounds according to claim 1 of the general formula II

Formula II

wherein

R¹, R³, R⁴ and are as defined in general formula I, and optically pure enantiomers, mixtures of enantiomers, such as racemates, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form as well as pharmaceutically acceptable salts, solvent complexes and morphological forms thereof.

5. Compounds according to claim 1 of the general formula III

Formula III

wherein

R¹, R³ and R⁴ are as defined in general formula I,

6. Compounds according to claim 1 of the general formula IV

Formula IV

wherein

R »1 , D R3 a „„nd.J D R4 are as defined in general formula I, and optically pure enantiomers, mixtures of enantiomers, such as racemates, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form as well as pharmaceutically acceptable salts, solvent complexes and morphological forms thereof.

7. Compounds according to claim 1 of the general formula V

Formula V

wherein

R¹, R³ and R⁴ are as defined in general formula I, and optically pure enantiomers, mixtures of enantiomers, such as racemates, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form as well as pharmaceutically acceptable salts, solvent complexes and morphological forms thereof.

8. Compounds according to claim 1 of the general formula VI

Formula VI

wherein

R³ and R⁴ and ---^/ are as defined in general formula I, and optically pure enantiomers, mixtures of enantiomers, such as racemates, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form as well as pharmaceutically acceptable salts, solvent complexes and morphological forms thereof.

9. A compound as described as end product in any one of Examples 1 to 60.

10. A compound according to any one of claims 1 to 9 for use as medicament.

11. Use of a compound as claimed in any one of claims 1 to 9 for the preparation of a pharmaceutical composition for treatment of diseases demanding the inhibition of parasitic aspartic proteases.

12. Pharmaceutical compositions containing one or more compounds as claimed in any one of claims 1 to 9 and inert excipients.