EP1322612A1 - Amino-aza-cycloalcanes substitues utiles contre la malaria - Google Patents

Amino-aza-cycloalcanes substitues utiles contre la malaria

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Publication number
EP1322612A1
EP1322612A1 EP01972013A EP01972013A EP1322612A1 EP 1322612 A1 EP1322612 A1 EP 1322612A1 EP 01972013 A EP01972013 A EP 01972013A EP 01972013 A EP01972013 A EP 01972013A EP 1322612 A1 EP1322612 A1 EP 1322612A1
Authority
EP
European Patent Office
Prior art keywords
mixtures
compounds
diastereomers
typical procedure
lower alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01972013A
Other languages
German (de)
English (en)
Inventor
Christoph Boss
Walter Fischli
Solange Meyer
Sylvia Richard-Bildstein
Thomas Weller
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Actelion Pharmaceuticals Ltd
Original Assignee
Actelion Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Priority to EP01972013A priority Critical patent/EP1322612A1/fr
Priority claimed from PCT/EP2001/010272 external-priority patent/WO2002024649A1/fr
Publication of EP1322612A1 publication Critical patent/EP1322612A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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

  • the invention relates to novel compounds which are substituted amino-aza- cycloalkane derivatives of the general formula I.
  • the invention also concerns related aspects including processes for the preparation of the compounds, 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.
  • 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 novel low molecular weight, non-peptidic inhibitors of the plasmodium falciparum protease plasmepsin II or other related aspartic proteases to treat and/or prevent malaria.
  • 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 assay conditions were selected according to reports in the literature [4 - 7].
  • 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 + 392 mM NaCl (for HIV-protease).
  • the incubates per well were composed of: - 160 ⁇ l buffer - 10 ⁇ l inhibitor (in DMSO)
  • 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 enzymatic in vitro assay was performed in polypropylene plates (Nunc, Cat No 4-42587A).
  • the assay buffer consisted of 100 mM sodium phosphate, pH 7.4, including 0.1% BSA.
  • the incubates were composed of 190 ⁇ L per well of an enzyme mix and 10 ⁇ L of renin inhibitors in DMSO.
  • the enzyme mix was premixed at 4°C and composed as follows:
  • Angiotensin I was detected by an enzyme immunoassay (EIA). 10 ⁇ L of the incubates or standards were transferred to immuno plates which were previously coated with a covalent complex of Angiotensin I and bovine serum albumin (Ang I - BSA). 190 ⁇ L of Angiotensin l-antibodies were added and a primary incubation made at 4°C over night. The plates were washed 3 times and then incubated for one hour at room temperature with a biotinylated anti-rabbit antibody. Thereafter, the plates were washed and incubated at room temperature for 30 min with a streptavidin-peroxidase complex.
  • EIA enzyme immunoassay
  • the peroxidase substrate ABTS (2.2'-Azino-di-(3-ethyl- benzthiazolinsulfonate), was added and the plates incubated for 10-30 min at room temperature. After stopping the reaction with 0.1 M citric acid pH 4.3 the plate is evaluated in a microplate reader at 405 nm.
  • the present invention relates to novel, low molecular weight organic compounds, which are substituted amino-aza-cycloalkanes of the general formula I:
  • Q represents -S0 2 -R 1 ; -CO-R 1 ; -CO-NH-R 1 ; -CO-N(R )(R 2 ); -CO-OR 1 ;
  • X represents -S0 2 -R 1 ; -CO-R 1 ; -CO-NH-R 1 ; -CO-N(R 1 )(R 2 ); -CO-OR 1 ; -(CH 2 )p-R 1 ; -(CH 2 ) P -CH(R 1 )(R 2 ); hydrogen;
  • R 1 , R 2 and R 3 represent lower alkyl; lower alkenyl; aryl; heteroaryl; cycloalkyl; heterocyclyl; aryl-lower alkyl; heteroaryl-Iower alkyl; cycloalkyl-lower alkyl; heterocyclyl-lower alkyl; aryl-lower alkenyl; heteroaryl-Iower alkenyl; cycloalkyl- lower alkenyl; heterocyclyl-lower alkenyl;
  • R 4 represents hydrogen; -CH 2 -OR 5 ; -CO-OR 5 ;
  • R 5 represents hydrogen, lower alkyl; cycloalkyl; aryl; heteroaryl; heterocyclyl; cycloalkyl-lower alkyl; aryl-lower alkyl; heteroaryl-Iower alkyl; heterocyclyl-lower alkyl;
  • t represents the whole numbers 0 (zero) or 1 and in case t represents the whole number 0 (zero), R 4 is absent;
  • n represents the whole numbers 2, 3 or 4;
  • n the whole numbers 1 or 2;
  • p represents the whole numbers 0 (zero), 1 or 2;
  • lower means straight and branched chain groups with one to seven carbon atoms, preferably 1 to 4 carbon atoms which may optionally be substituted with hydroxy or lower alkoxy.
  • lower alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl.
  • lower alkoxy groups are methoxy, ethoxy, propoxy, iso-butoxy, sec.-butoxy and tert.-butoxy etc.
  • Lower alkylendioxy-groups as substituents of aromatic rings onto two adjacent carbon atoms are preferably methylen-dioxy and ethylen-dioxy.
  • Lower alkylen-oxy groups as substituents of aromatic rings onto two adjacent carbon atoms are preferably ethylen-oxy and propylen-oxy.
  • Examples of lower alkanoyl-groups are acetyl, propanoyl and butanoyl.
  • Lower alkenylen means e.g. vinylen, propenylen and butenylen.
  • cycloalkyl alone or in combination, means a saturated cyclic hydrocarbon ring system with 3 to 6 carbon atoms , e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl which may be substituted with lower alkyl groups.
  • 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 may be substituted with lower alkyl, lower alkenyl, aryl, aryl- lower alkyloxy, aryl-oxy, amino, bis-(lower alkyi)-amino, alkanoyl-amino, halogen, nitro, hydroxy, lower alkoxy, phenoxy;
  • examples of such rings are morpholinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, 1 ,4-dioxanyl, pyrrolidinyl, tetrahydrofuranyl, dihydropyrrolyl, imidazolidinyl, dihydropyrazolyl, pyrazolidinyl etc. and substituted derivatives of such type rings with substituents as outlined hereinbefore
  • 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; benzo-fused five- termed aromatic rings containing one oxygen, one nitrogen or one sulfur atom; five membered aromatic rings containig one oxygen and one nitrogen atom and benzo fused derivatives thereof; five termed aromatic rings containing a sulfur and nitrogen or oxygen 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, indolyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquino
  • ring systems may be mono-, di- or tri- substituted with aryl; aryloxy, aryl-lower alkyl-oxy, lower alkyl; lower alkenyl; lower alkyl-carbonyl; amino; lower alkyl-amino; bis-(lower-alkyl)-amino; lower alkanoyl-amino; ⁇ -amino-lower alkyl; halogen; hydroxy; carboxyl; lower alkoxy; vinyloxy; allyloxy; ⁇ -hydroxy-lower alkyl; nitro; cyano; amidino; trifluoromethyl; lower alkyl-sulfonyl etc.
  • aryl alone or in combination, means six membered aromatic rings and condensed systems like naphthyl or indenyl etc. whereby such ring systems may be mono-, di- or tri-substituted with aryl, aryloxy, aryl-lower alkyloxy, lower alkyl, lower alkenylen, lower alkyl-carbonyl, aryl-carbonyl, amino, lower alkyl-amino, aryl-amino, bis-(lower-alkyl)-amino, lower alkanoyl-amino, ⁇ - amino-lower alkyl, halogen, hydroxy, carboxyl, lower alkoxy, vinyloxy, allyloxy, ⁇ - hydroxy-lower alkyl, ⁇ -hydroxy-lower alkoxy, nitro, cyano, amidino, trifluoromethyl, lower alkyl-sulfonyl etc.
  • 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, diastereomers, 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.
  • 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.
  • 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.
  • vegetable oils, waxes, fats, liquid or half-liquid polyols etc. may be used.
  • 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.
  • 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 quinolines (quinine, chloroquine, amodiaquine, mefloquine, primaquine, tafenoquine etc), peroxide antimalarials (artemisinin derivatives), pyrimethamine- sulfadoxine antimalarials (e.g. Fansidar etc), hydroxynaphtoquinones (e.g. atovaquone etc.), acroline-type antimalarials (e. g. pyronaridine etc) etc.
  • other antimalarials like quinolines (quinine, chloroquine, amodiaquine, mefloquine, primaquine, tafenoquine etc), peroxide antimalarials (artemisinin derivatives), pyrimethamine- sulfadoxine antimalarials (e.g. Fansidar
  • the dosage may vary within wide limits but should be adapted to the specific situation.
  • 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.
  • Preferred compounds are compounds of the formula II
  • the compounds of the general formula I of the present invention may be prepared according to the general sequences of reactions outlined below, wherein R 1 , R 2 , R 3 , R 4 , R 5 , Q, X, t, m, n and p 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 V are described). For general methods of certain steps see also pages 19 - 23.
  • Scheme 1 Preparation of substituted 4-amino-N-benzyl-piperidines:
  • the carboxylic acid chlorides ⁇ R (CO)-CI ⁇ may be obtained in situ from the corresponding carboxylic acid as described in the literature (i. e.: Devos, A.;
  • the urea derivatives 4 are obtained by reaction of the amines 2 in dichloromethane, with one equivalent isocyanate.
  • the N-Boc protected 4-amino-piperidine 7 (Scheme 2) can be prepared in a two step procedure starting by reacting 4-hydroxy-N-Boc-piperidine with methanesulfonylchloride in an inert solvent like DCM in the presence of a base like TEA to generate 4-mesyloxy-N-Boc-piperidine.
  • the mesyloxy group is substituted with sodium azide followed by reduction of the azide functionality to the amino group to give 7.
  • the amine 7 is transformed to the secondary amine 8 via the typical procedure for the reductive amination described above.
  • the synthesis of compounds 9, 10, 11 and 12 can also be performed via the typical procedures described above.
  • Boc-deprotection is achieved either with hydrochloric acid in a solvent like diethylether or dioxane or with TFA in DCM.
  • the second reductive amination step of the derivatives 13, 14, 15 and 16 to the fully derivatized final compounds 17, 18, 19 and 20 can be performed according to the typical procedure described above.
  • Compounds 13, 14, 15 and 16 could also be transformed with acylating reagents like isocyanates, acid chlorides or sulfonyl chlorides to yield products with an urea-, amide- or sulfonamide functionality instead of the amine functionality at the ring nitrogen atom.
  • the amine and the aldehyde (1.5 eq.) (which are used as starting materials, are known compounds or the synthesis is described above or below, respectively), are mixed in anhydrous methanol and stirred for 6 h. The mixture is then treated with sodium borohydride (1.5 eq.) and stirred for 2 h. Purified Amberiyst 15 or another suitable scavenger is added and the suspension is shaken for 12 h. The resin is then separated by filtration and washed with methanol. The secondary amine is removed from the resin by adding a 2 M methanolic ammonia solution. The resin is drained after 30 min and washed with methanol. The filtrate is evaporated to yield the pure secondary amine. Typical procedure B) for the acylation:

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés qui sont des dérivés amino-aza-cycloalcane substitués de formule générale I. Elle concerne aussi des réalisations s'y rapportant notamment des procédés de préparation de ces composés, des compositions pharmaceutiques contenant un ou plusieurs composé de formule générale I et spécialement leurs utilisations en tant qu'inhibiteurs de plasmepsine II protéase de Plasmodium falciparum ou de protéases aspartiques associées.
EP01972013A 2000-09-25 2001-09-06 Amino-aza-cycloalcanes substitues utiles contre la malaria Withdrawn EP1322612A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP01972013A EP1322612A1 (fr) 2000-09-25 2001-09-06 Amino-aza-cycloalcanes substitues utiles contre la malaria

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
WOPCT/EP00/09328 2000-09-25
EP0009328 2000-09-25
EP01972013A EP1322612A1 (fr) 2000-09-25 2001-09-06 Amino-aza-cycloalcanes substitues utiles contre la malaria
PCT/EP2001/010272 WO2002024649A1 (fr) 2000-09-25 2001-09-06 Amino-aza-cycloalcanes substitues utiles contre la malaria

Publications (1)

Publication Number Publication Date
EP1322612A1 true EP1322612A1 (fr) 2003-07-02

Family

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Family Applications (1)

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EP01972013A Withdrawn EP1322612A1 (fr) 2000-09-25 2001-09-06 Amino-aza-cycloalcanes substitues utiles contre la malaria

Country Status (1)

Country Link
EP (1) EP1322612A1 (fr)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0224649A1 *

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