WO2004105738A2 - Utilisation de derives de tetrahydropyridine - Google Patents

Utilisation de derives de tetrahydropyridine Download PDF

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Publication number
WO2004105738A2
WO2004105738A2 PCT/EP2004/005064 EP2004005064W WO2004105738A2 WO 2004105738 A2 WO2004105738 A2 WO 2004105738A2 EP 2004005064 W EP2004005064 W EP 2004005064W WO 2004105738 A2 WO2004105738 A2 WO 2004105738A2
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Prior art keywords
mmol
compound
treatment
pharmaceutical compositions
parasitic
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PCT/EP2004/005064
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English (en)
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WO2004105738A3 (fr
Inventor
Daniel Bur
Walter Fischli
Lubos Remen
Sylvia Richard-Bildstein
Thomas Weller
Christoph Boss
Christoph Binkert
Solange Meyer
Olivier Bezencon
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Actelion Pharmaceuticals Ltd
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Publication of WO2004105738A2 publication Critical patent/WO2004105738A2/fr
Publication of WO2004105738A3 publication Critical patent/WO2004105738A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • these compounds can be regarded as inhibitors of other aspartyl proteases and might, therefore, be useful as inhibitors of plasmepsin I, plasmepsin IV or histo-aspartic protease (HAP) to treat malaria and as inhibitors of Candida albicans secreted aspartyl proteases to treat fungal infections.
  • HAP histo-aspartic protease
  • Malaria is one of the most serious and complex health problems affecting civilization in the 21 st century. 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.
  • 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 [1].
  • 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 [2], [3].
  • the present invention relates to the identification of low molecular weight, non- peptidic inhibitors of the plasmodium falciparum protease plasmepsin II or other related aspartic proteases to treat and/or prevent malaria.
  • Plasmepsin inhibitors based on a peptidomimetic or substrate-analogue approach are described in the following patents: US-05734054 (Pharmacopeia Inc), US- 05892038 (Pharmacopeia Inc.), WO-00114331 (University of California, Berkley), WO-02074719 (Johns Hopkins University), and publications: D. N ⁇ teberg, E. Hamelink, J. Hulten, M. Wahlgren, L. Vrang, B. Samuelsson, A. Hallberg, J. Med. Chem., 2003, 46, 734-746. K. Oscarsson, S. Oscarson, L. Vrang, E. Hamelink, A. Hallberg, B.
  • Non- peptidomimetic plasmepsin II inhibitors are described in the following publications: WO-00224649 (Actelion Pharmaceuticals Ltd.), WO-00238543 (Actelion Pharmaceuticals Ltd.) and WO-09912532 (F. Hoffmann-LaRoche Ltd.).
  • the compounds of general formula I were tested against plasmepsin II, HIV- protease, human cathepsin D, human cathepsin E and human renin in order to determine their biological activity and their selectivity profile.
  • FRET fluorescence resonance energy transfer
  • the FRET assay was performed in white polysorp plates (Fluoronunc, cat n°
  • the assay buffer consisted of 50 mM sodium acetate pH 5, 12,5% glycerol, 0.1% BSA + 392 mM NaCl (for HIV-protease).
  • the incubates per well were composed of: - 160 ⁇ l buffer
  • 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 and HIV- protease) 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.
  • the present invention relates to pharmaceutical compositions for treating diseases demanding the inhibition of parasitic aspartic proteases containing one or more compounds of the general formula I,
  • X and W represent independently a nitrogen atom or a CH-group
  • V represents -(CH 2 ) ; -A-(CH 2 ) S -; -CH 2 -A-(CH 2 ) r ; -(CH 2 ) S -A- -(CH 2 ) 2 -A-(CH 2 ) U -; -A-(CH 2 ) V -B-; -CH 2 -CH 2 -CH 2 -A-CH 2 -; -A-CH 2 -CH 2 -B-CH 2 - -CH 2 -A-CH 2 -CH 2 -B-; -CH 2 -CH 2 -CH 2 -CH 2 -A-CH 2 -CH 2 -; -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -A-CH 2 -CH 2 -; -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -A-CH 2 -CH 2 -; -CH 2 -CH 2 -CH 2
  • a and B independently represent -O-; -S-; -SO-; -SO 2 -;
  • U represents aryl; heteroaryl;
  • T represents -CONR 1 -; -(CH 2 ) p OCO-; -(CH 2 ) p N(R 1 )CO-; -(CH 2 ) p N(R 1 )SO 2 -; COO-; -(CH ⁇ pOCONR 1 -; -(CH 2 ) p N(R 1, )CONR 1 -;
  • Q represents lower alkylene; lower alkenylene;
  • M represents hydrogen; cycloalkyl; aryl; heterocyclyl; heteroaryl; R 1 and R 1 ' independently represent hydrogen; lower alkyl; lower alkenyl; lower alkinyl; cycloalkyl; aryl; cycloalkyl - lower alkyl;
  • enantiomers such as racemates, 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 and suitable carrier materials.
  • lower alkyl in the definitions of general formula I - if not otherwise stated - the term lower alkyl, alone or in combination with other groups, means saturated, straight and branched chain groups with one to seven carbon atoms, preferably one to four carbon atoms that can be optionally substituted by halogens.
  • lower alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl and heptyl.
  • the methyl, ethyl and isopropyl groups are preferred.
  • lower alkoxy refers to a R-O group, wherein R is a lower alkyl.
  • R is a lower alkyl.
  • lower alkoxy groups are methoxy, ethoxy, propoxy, iso-propoxy, iso- butoxy, sec-butoxy and tert-butoxy.
  • lower alkenyl alone or in combination with other groups, means straight and branched chain groups comprising an olefinic bond and two to seven carbon atoms, preferably two to four carbon atoms, that can be optionally substituted by halogens.
  • Examples of lower alkenyl are vinyl, propenyl or butenyl.
  • lower alkinyl alone or in combination with other groups, means straight and branched chain groups comprising a triple bond and two to seven carbon atoms, preferably two to four carbon atoms, that can be optionally substituted by halogens.
  • Examples of lower alkinyl are ethinyl, propinyl orbutinyl.
  • lower alkylene alone or in combination with other groups, means straight and branched divalent chain groups with one to seven carbon atoms, preferably one to four carbon atoms that can be optionally substituted by halogens.
  • Examples of lower alkylene are ethylene, propylene or butylene.
  • lower alkenylene alone or in combination with other groups, means straight and branched divalent chain groups comprising an olefinic bond and two to seven carbon atoms, preferably two to four carbon atoms, that can be optionally substituted by halogens.
  • Examples of lower alkenylene are vinylene, propenylene and butenylene.
  • lower alkylenedioxy refers to a lower alkylene substituted at each end by an oxygen atom.
  • Examples of lower alkylenedioxy groups are preferably methylenedioxy and ethylenedioxy.
  • lower alkylenoxy refers to a lower alkylene substituted at one end by an oxygen atom.
  • Examples of lower alkylenoxy groups are preferably ethylenoxy and propylenoxy.
  • halogen means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine.
  • cycloalkyl alone or in combination, means a saturated cyclic hydrocarbon ring system with 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which can be optionally mono-, di-, or trisubstituted independently by lower alkyl, lower alkenyl, lower alkenylene, lower alkoxy, lower alkylenoxy, lower alkylenedioxy, hydroxy, halogen, -CF 3 , - N ⁇ R 1 ', -NR 1 C(O)R 1 ', -NR ⁇ O ⁇ R 1 ', -CIO ⁇ R 1 *, lower alkylcarbonyl, -COOR 1 , -SR 1 , -SOR 1 , -SO 2 R 1 , -SOzNR 1 ⁇ '.
  • the cyclopropyl group is a preferred group.
  • aryl alone or in combination, relates to the phenyl, the naphthyl or the indanyl group, preferably the phenyl group, which can be optionally mono-, di-, tri-, tetra- or pentasubstituted independently by lower alkyl, lower alkenyl, lower alkinyl, lower alkenylene or lower alkylene forming with the aryl ring a five- or six-membered ring, lower alkoxy, lower alkylenedioxy, lower alkylenoxy, hydroxy, hydroxy-lower alkyl, halogen, cyano, -CF 3 , -OCF 3 , -M ⁇ R 1 ', -NR ⁇ 1 ' - lower alkyl, -NR 1 C(O)R 1 ' 5 -NR 1 S(O) 2 R 1» , -C(O)NR 1 R 1» , -NO 2 , lower alkylcarbonyl, -CO
  • aryloxy refers to an Ar-O group, wherein Ar is an aryl.
  • An example of aryloxy groups is phenoxy.
  • heterocyclyl alone or in combination, means saturated or unsaturated (but not aromatic) five-, six- or seven-membered rings containing one or two nitrogen, oxygen or sulfur atoms which may be the same or different and which rings can be optionally substituted with lower alkyl, hydroxy, lower alkoxy and halogen.
  • the nitrogen atoms, if present, can be substituted by a COOR group.
  • rings are piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl, pyrrolidinyl, tetrahydrofuranyl, dihydropyrrolyl, imidazolidinyl, dihydropyrazolyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl.
  • 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; benzofused five- membered aromatic rings containing one oxygen, one nitrogen or one sulfur atom; five-membered aromatic rings containing one oxygen and one nitrogen atom and benzofused derivatives thereof; five-membered aromatic rings containing a sulfur and a nitrogen or an oxygen atom and benzofused derivatives thereof; five- membered aromatic rings containing two nitrogen atoms and benzofused derivatives thereof; five-membered aromatic rings containing three nitrogen atoms and benzofused derivatives thereof, or a tetrazolyl ring.
  • Examples of such ring systems are furanyl, thiophenyl, pyrrolyl, pyridinyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazinyl, thiazinyl, thiazolyl, isothiazolyl, pyridazinyl, pyrazolyl, oxazolyl, isoxazolyl, coumarinyl, benzothiophenyl, quinazolinyl, quinoxalinyl.
  • Such rings may be adequatly substituted with lower alkyl, lower alkenyl, lower alkinyl, lower alkylene, lower alkenylene, lower alkylenedioxy, lower alkyleneoxy, hydroxy-lower alkyl, lower alkoxy, hydroxy, halogen, cyano, -CF 3 , -OCF 3 , -NR'R 1 ', -NR ⁇ - lower alkyl, -N ⁇ COR 1 , - S(O) 2 R ! , -SO 2 NR 1 R 1 ', another aryl, another heteroaryl or another heterocyclyl and the like.
  • heteroaryloxy refers to a Het-O group, wherein Het is a heteroaryl.
  • salts encompasses either salts with inorganic acids or organic acids like hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like that are non toxic to living organisms 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 and the like.
  • inorganic acids or organic acids like hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like that are non toxic to living organisms or in case the compound of formula I is acidic in nature
  • 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, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, and the meso-form and pharmaceutically acceptable salts therof.
  • 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 or crystallization.
  • the compounds of general formula I and their pharmaceutically acceptable salts may be used as therapeutics e.g. in form of pharmaceutical compositions. These pharmaceutical compositions may particularly be used for treatment of disorders associated with the role of plasmepsin II and which require inhibition of plasmepsin II for treatment. They may especially be used for treatment and/or prevention of malaria or diseases caused by protozoal infection. These pharmaceutical compositions may also contain aside of one or more compounds of the general formula I a known plasmepsin II inhibitor, a known antimalarial or known HIV protease inhibitor.
  • compositions may also be used for treatment or prevention of diseases demanding the inhibition of parasitic aspartic proteases, and particularly for malaria or protozoal infections.
  • the invention also relates to the use of pharmaceutical compositions as defined above for the treatment or prevention of diseases demanding the inhibition of parasitic aspartic proteases in combination with a known plasmepsin II inhibitor, a known antimalarial or a known HIV protease inhibitor or another known anti-HIV treatment.
  • compounds of formula I are useful for the preparation of a medicament for the treatment or prevention of diseases demanding the inhibition of parasitic aspartic proteases, particularly malaria or protozoal infection. These compounds are more particularly useful for diseases demanding the inhibition of parasitic aspartic proteases in combination with a known plasmepsin II inhibitor, a known antimalarial or a known HIV protease inhibitor or another known anti-HIV treatment.
  • Another aspect of the invention concerns a method of treating a patient suffering from a disease requiring the inhibition of parasitic aspartic proteases by administering a pharmaceutical composition comprising a compound of the general formula I.
  • the dosage of compounds of formula I can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage between 1 mg and 1000 mg, particularly between 50 mg and 500 mg, comes into consideration.
  • the pharmaceutical preparations conveniently contain between 1 mg and 500 mg, preferably between 5 mg and 200 mg of a compound of formula I.
  • a further aspect of the invention concerns a process for the preparation of the above-mentioned pharmaceutical composition by mixing one or more active ingredients of formula I with inert excipients in a manner known per se.
  • the compounds of formula I may also be used in combination with one or more other therapeutically useful substances. All forms of prodrugs leading to an active component comprised in general formula I are included in the present invention.
  • the compounds of general formula I can be manufactured by the methods given in another patent application filed by the applicant (Actelion Pharmaceuticals Ltd).
  • the compounds of formula I and their pharmaceutically acceptable acid addition salts can be used as medicaments, e. g. in the form of pharmaceutical preparations for enteral, parenteral, or topical administration. They can be administered, for example, perorally, e. g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e. g. in the form of suppositories, parenterally, e. g. in the form of injection solutions or infusion solutions, or topically, e. g. in the form of ointments, creams or oils.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula I and their pharmaceutically acceptable acid addition salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants in a manner known per se.
  • Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials.
  • lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules.
  • Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers are, however, required in the case of soft gelatine capsules).
  • Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like.
  • Suitable carrier materials for injections are, for example, water, alcohols, polyols, glycerols and vegetable oils.
  • Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.
  • Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
  • Usual stabilizers preservatives, wetting and emulsifying agents, consistency- improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
  • the dosage of compounds of formula I can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 mg to about 1000 mg, especially about 50 mg to about 500 mg, comes into consideration. For children the dosage has to be adapted to the body weight and age.
  • the pharmaceutical preparations conveniently contain about 1 - 500 mg, preferably 5 - 200 mg of a compound of formula I.
  • the compounds of general formula I can be manufactured by the methods given below, by the methods given in the examples of WO 04/002957 Al (Actelion Pharmaceuticals Ltd.) or by analogous methods. Synthetic Approaches for the preparation of compounds of general formula I:
  • Precursors are compounds that were prepared as key intermediates and/or building blocks and which were suitable for further transformations in parallel chemistry.
  • Ideal starting materials are any commercially available 4-oxo-piperidine-3- carboxylic acid ester derivatives, for instance l-benzyl-4-oxo-piperidine-3- carboxylic acid methyl ester, possibly as a salt.
  • a transesterif ⁇ cation for instance according to Seebach D., et al, Synthesis, 1982, 138
  • another ester derivative A wherein R a is optionally a lower alkyl, a lower alkenyl, or a benzyl group
  • PG all abreviations are outlined at the beginning of the chapter Examples
  • R b is a linker ending with a silanyl ether
  • compounds of type D are deprotected to compounds of type E, then coupled to a phenol or aromatic alcohol using a Mitsunobu reaction, leading to derivatives of type F wherein V and U have the meaning given in general formula I above (Scheme 3).
  • the ester F is optionally then be cleaved by any suitable method to lead to precursor G.
  • a compound of type D may be reduced with DIB AL to a compound of type M that can be then oxidized to a compound of type N with e.g. the Dess-Martin periodinane (Scheme 4).
  • Aldehyde N may then be transformed to a compound of type O by reductive amination, which can be acylated to a derivative of type Q' wherein Q and M have the meaning given in general formula I above.
  • compounds of type M can be then acylated following standard procedures to esters or carbamates of type P.
  • a precursor of type T can be prepared in three steps from a compound of type D, by saponification (compound of type R), amide coupling (compound of type S) and finally desilylation.
  • a compound of type G can be coupled to the amine to yield amides of type L wherein V, U and M have the meaning given in general formula I above. Removal of the N-protecting group (PG) leads to a final compound, wherein V, U, Q and M have the meaning given in general formula I above (Scheme 7).
  • HP110 binary pump column: Develosil RP -AQUEOUS, 5 ⁇ M, 4.6 mm x 50 mm; gradient: 5 - 95% methanol in water (0.04% TFA), 1 min, 95% methanol in water
  • EDCHC1 Ethyl-N.N-dimethylaminopropylcarbodiimide hydrochloride
  • EDC-HC1 (1.10 eq.), HOBt (cat. amount), DMAP (cat. amount) and DIPEA (2.00 eq.) in CH2CI 2 (20 mL/g of acid) was stirred at rt overnight.
  • the reaction mixture was either washed over diatomic earth (Isolute Sorbent Technology, Johnson, C. R., et al, Tetrahedron, 1998, 54, 4097), or washed with aq. 1M HC1, and the org. extracts were evaporated under reduced pressure. The residue was used without further purification.
  • the starting material was dissolved in CH 2 CI 2 (10 mL/g of starting material) and the sol. was cooled to 0°C. 4M HC1 in dioxane (same volume as CH 2 CI 2 ) was added and the reaction mixture was left for 90 min at rt. The solvents were removed under reduced pressure. Purification of the residue by HPLC led to the desired compound.
  • Cyclopropyl-(3-trifluoromethoxybenzyl)amine Synthesized according to typical procedure E from 3-trifluoromethoxy- benzaldehyde and cyclopropylamine.
  • Example 8 Preparation of Example 8 is given in a detailed description.
  • the other examples depicted in Table 1 can be prepared in analoguous procedures.
  • Activity class A IC 50 (Plasmepsin II) ⁇ 100 nM
  • Activity class B 100 nM ⁇ IC 50 (Plasmepsin II) ⁇ 10 ⁇ M

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés de tétrahydropyridine et des composés associés, et leur utilisation comme ingrédients actifs dans la préparation de compositions pharmaceutiques. L'invention se rapporte également à des aspects connexes, par exemple à des procédés de préparation desdits composés et de compositions pharmaceutiques contenant un ou plusieurs des composés précités et, en particulier, à leur utilisation comme inhibiteurs de la plasmepsine II.
PCT/EP2004/005064 2003-05-30 2004-05-12 Utilisation de derives de tetrahydropyridine WO2004105738A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005068427A1 (fr) * 2004-01-14 2005-07-28 Takeda Pharmaceutical Company Limited Derive de carboxamide et son utilisation

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004002957A1 (fr) * 2002-06-27 2004-01-08 Actelion Pharmaceuticals Ltd Nouveaux derives de tetrahydropyridine en tant qu'inhibiteurs de renine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004002957A1 (fr) * 2002-06-27 2004-01-08 Actelion Pharmaceuticals Ltd Nouveaux derives de tetrahydropyridine en tant qu'inhibiteurs de renine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BOSS C ET AL: "INHIBITORS OF THE PLASMODIUM FALCIPARUM PARASITE ASPARTIC PROTEASE PLASMEPSIN II AS POTENTIAL ANTIMALARIAL AGENTS" CURRENT MEDICINAL CHEMISTRY, BENTHAM SCIENCE PUBLISHERS BV, BE, vol. 10, no. 11, 2003, pages 883-907, XP009036752 ISSN: 0929-8673 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005068427A1 (fr) * 2004-01-14 2005-07-28 Takeda Pharmaceutical Company Limited Derive de carboxamide et son utilisation
JPWO2005068427A1 (ja) * 2004-01-14 2007-09-06 武田薬品工業株式会社 カルボキサミド誘導体およびその用途

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