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WO2013018069A1 - Combination of antimalarial agents - Google Patents

Combination of antimalarial agents Download PDF

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Publication number
WO2013018069A1
WO2013018069A1 PCT/IB2012/053984 IB2012053984W WO2013018069A1 WO 2013018069 A1 WO2013018069 A1 WO 2013018069A1 IB 2012053984 W IB2012053984 W IB 2012053984W WO 2013018069 A1 WO2013018069 A1 WO 2013018069A1
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Prior art keywords
benzyl
piperazin
ethyl
oxo
acetyl
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French (fr)
Inventor
Christoph Boss
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Actelion Pharmaceuticals Ltd
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Actelion Pharmaceuticals Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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

  • the present invention relates to a combination comprising a compound of the formula I and one or more other antimalarial agent, especially for use as a medicament to treat or prevent malaria infections or to treat or prevent other protozoal diseases like sleeping sickness, Chagas disease, amebiasis, giardiasis, trichomoniasis, toxoplasmosis, and leishmaniasis.
  • a compound of the formula I especially for use as a medicament to treat or prevent malaria infections or to treat or prevent other protozoal diseases like sleeping sickness, Chagas disease, amebiasis, giardiasis, trichomoniasis, toxoplasmosis, and leishmaniasis.
  • 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.
  • P. falciparum enters the human body by way of bites of the female anophelino mosquito (it may also be transmitted by blood transfusion from asymptotic donors; almost all infected blood components including red cells, platelet concentrates, white cells, cryoprecipitates and fresh plasma can transmit malaria).
  • 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.
  • the present invention relates to low molecular weight, non-peptidic, non-quinoline compounds of formula I in combination with one or more other antimalarial agent which combinations are useful in the treatment and/or prevention of protozoal infections, especially in the treatment and/or prevention of malaria, in particular Plasmodium falciparum malaria.
  • the present invention relates to a combination comprising a compound of the formula I:
  • ⁇ X is CH or N
  • R represents -N0 2 , -N(CH 3 ) 2 , or -NCH 3 (CH 2 CH 2 OH);
  • R 2 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyano, halogen, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, methylsulfonyl, acetyl, or acetylamino; or
  • ⁇ X is CH, R is hydrogen, and R 2 is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, methylsulfonyl, acetylamino, or methoxycarbonyl; or
  • ⁇ X is CH, R is cyano, and R 2 is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methylsulfonyl, or acetylamino; or
  • ⁇ X is CH, R is chloro, and R 2 is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, difluoromethoxy, methylsulfonyl, or acetylamino; or
  • ⁇ X is CH, R is methoxy or isopropoxy, and R 2 is trifluoromethyl; or
  • ⁇ X is CH, R is methylsulfonyl or ethylsulfonyl, and R 2 is trifluoromethyl, ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, or difluoromethoxy, such as especially trifluoromethyl, tert-butyl, n-propoxy, or isopropoxy;
  • a further embodiment of the invention relates to the combination according to embodiment i), wherein in addition to a compound of formula I, the combination contains only one other antimalarial agent.
  • a further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is selected from the group consisting of:
  • a further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is selected from the group consisting of:
  • a further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is selected from the group consisting of:
  • a further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is selected from the group consisting of:
  • a further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is selected from the group consisting of:
  • a further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is (S)-N-[4-(4-acetyl-piperazin-1 -yl)- benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-tert-butyl-phenyl)- acrylamide or a salt thereof.
  • a further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is (S)-N-[4-(4-acetyl-piperazin-1 -yl)- benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-propoxy-phenyl)- acrylamide or a salt thereof.
  • a further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is (S)-N-[4-(4-acetyl-piperazin-1 -yl)- benzyl]-N- ⁇ 1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl]-2-oxo-ethyl ⁇ -3-(4-ethoxy-phenyl)- acrylamide or a salt thereof.
  • a further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is (S)-N-[4-(4-acetyl-piperazin-1 -yl)- benzyl]-N- ⁇ 1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl]-2-oxo-ethyl ⁇ -3-(4-tert-butyl- phenyl)-acrylamide or a salt thereof.
  • a further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is (S)-N-[4-(4-acetyl-piperazin-1 -yl)- benzyl]-N-[1 -benzyl-2-(4- ⁇ 4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl ⁇ -piperazin-1 -yl)-2-oxo- ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide or a salt thereof.
  • a further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is (S)-N-[4-(4-acetyl-piperazin-1 -yl)- benzyl]-N-[1 -benzyl-2-(4- ⁇ 4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl ⁇ -piperazin-1 -yl)-2-oxo- ethyl]-3-(4-isopropoxy-phenyl)-acrylamide or a salt thereof.
  • a further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of Quinine and other related antimalarials (interfering with heme-polymerization / parasite detoxification pathways) from the 4-aminoquinoline- and the arylaminoalcohol class such as Quinidine, Chloroquine, Amodiaquine, Mefloquine, Halofantrine, Lumefantrine (Benflumetol), Desbutyllumefantrine, Pyronaridine, Piperaquine, Mepacrine, Sontoquine, AQ13, F2Bu, Tebuquine, Isoquine, FAQ4, and Naphthoquine.
  • Quinine and other related antimalarials interfering with heme-polymerization / parasite detoxification pathways
  • the 4-aminoquinoline- and the arylaminoalcohol class such as Quinidine
  • a further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of antifolate-agents, for example dihydrofolate reductase inhibitors such as Pyrimethamine, Proguanil / Cycloguanil, Chloroproguanil / Chlorocycloguanil, and PS-15 / Cyclo-PS-15.
  • antifolate-agents for example dihydrofolate reductase inhibitors such as Pyrimethamine, Proguanil / Cycloguanil, Chloroproguanil / Chlorocycloguanil, and PS-15 / Cyclo-PS-15.
  • a further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of dihydropteroate-synthase inhibitors such as sulfadoxine and dapsone.
  • the other antimalarial agent is selected from the group consisting of trimethoprime, WR99210, and JPC-2056.
  • a further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of Artemisinine and derivatives thereof, such as Artemisinine, Dihydroartemisinine, Artemether, Arteether, Artesunate, Artelinate, Artemisone, Artelinic acid and further compounds as described in J. Wiesner et al., Angewandte Chemie, 2003, 115, 5432-5451 , specifically pages 5443-5444, chapter 5.2).
  • the other antimalarial agent is selected from the group consisting of Artemisinine and derivatives thereof, such as Artemisinine, Dihydroartemisinine, Artemether, Arteether, Artesunate, Artelinate, Artemisone, Artelinic acid and further compounds as described in J. Wiesner et al., Angewandte Chemie, 2003, 115, 5432-5451 , specifically pages
  • a further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of RKA 182 and related compounds (J. Chadwick et al. ChemMedChem, 2011 ; DOI: 10.1002/cmdc.201 100196).
  • the other antimalarial agent is selected from the group consisting of antibiotics active against malaria parasites such as Rifampicine, Doxycycline, Clindamycin, and Azithromycin.
  • a further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of inhibitors of mitochondrial electrone transfer such as Atovaquone, Lapinone, Menoctone, Pravaquone, BW58C80, and Buparvaquone.
  • the other antimalarial agent is selected from the group consisting of 8-aminoquinoline based compounds such as Pamaquine, Tafenoquine, Primaquine, Quinocide, NCP1 161 B, and Bulaquine.
  • a further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of inhibitors of the mevalonate independent isoprenoide biosynthesis such as Fosmidomycine, FR900098 and produgs of FR900098.
  • the other antimalarial agent is selected from the group consisting of inhibitors of the mevalonate independent isoprenoide biosynthesis such as Fosmidomycine, FR900098 and produgs of FR900098.
  • a further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of antimalarials interfering with heme-polymerization / parasite detoxification pathways such as WR-243251 , Floxacrine, 2,7-Dibromocryptolepine, Ro 06-9075, and Ro 22-8014.
  • the other antimalarial agent is selected from the group consisting of antimalarials interfering with heme-polymerization / parasite detoxification pathways such as WR-243251 , Floxacrine, 2,7-Dibromocryptolepine, Ro 06-9075, and Ro 22-8014.
  • a further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of endoperoxides such as Yingzhaosu A, Arteflen, OZ277 / Arterolane and related synthetic trioxolane based compounds, and OZ439 and related synthetic trioxolane based compounds.
  • the other antimalarial agent is selected from the group consisting of trioxaquines such as DU-1 102.
  • a further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of protease inhibitors (e.g. falcipain inhibitors or plasmepsin inhibitors), inhibitors of fatty acid synthesis (e.g. triclosan and analogues), inhibitors of choline uptake (e.g. ammonium salts such as E10 or bis-ammonium salts such as G25 or MS1 ), farnesyl- transferase inhibitors (e.g. FTI-2153 and Schl-41 16), glycolysis inhibitors (e.g.
  • protease inhibitors e.g. falcipain inhibitors or plasmepsin inhibitors
  • inhibitors of fatty acid synthesis e.g. triclosan and analogues
  • inhibitors of choline uptake e.g. ammonium salts such as E10 or bis-ammonium salts such
  • a further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is ferroquine.
  • a further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of Quinidine, Chloroquine, Amodiaquine, Mefloquine, Halofantrine, Lumefantrine (Benflumetol), Desbutyllumefantrine, Pyronaridine, Piperaquine, Mepacrine, Sontoquine, AQ13, F2Bu, Tebuquine, Isoquine, FAQ4, Naphthoquine, Pyrimethamine, Proguanil / Cycloguanil, Chloroproguanil / Chlorocycloguanil, PS-15 / Cyclo-PS-15, sulfadoxine, dapsone, trimethoprime, WR99210, JPC-2056, Artemisinine, Dihydroartemisinine, Artemether, Arteether, Artesunate, Artelinate,
  • a further embodiment of the invention relates to a combination according to embodiment i) comprising a compound of formula I as defined in any one of embodiments i) to xiii), or a salt thereof, and two or more (preferably two or three and most preferably two) other antimalarial agents independently selected from the antimalarial agents listed in any one of embodiments xiv) to xxix).
  • xxxi) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xxx), for use as a medicament.
  • xxxii) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xxx), for use in the treatment and/or prevention of protozoal infections.
  • a further embodiment of the invention relates to the combination according to any one of embodiments i) to xxx), for use in the treatment and/or prevention of malaria.
  • xxxiv) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xxx) for use according to any one of embodiments xxxi) to xxxiii), wherein the compound of formula I and the one or more other antimalarial agent are administered simultaneously, concurrently, separately or sequentially.
  • xxxv) A further embodiment of the invention relates to a pharmaceutical composition comprising the combination according to any one of embodiments i) to xxx) and a pharmaceutically acceptable carrier. Based on the dependencies of the different embodiments i) to xxix) as disclosed hereinabove, the following embodiments are thus possible and intended and herewith specifically disclosed in individualized form:
  • salts refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. 1986, 33, 201 -217.
  • the term "combination" means a fixed combination with defined amounts of the combination partners or it means a "kit of parts" in the sense that the combination partners as defined herein can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners, i.e., simultaneously, concurrently, separately or sequentially.
  • the parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • the total amounts and the ratio of the total amounts of the combination partners to be administered can be varied, e.g.
  • the present invention also includes isotopically labelled, especially 2 H (deuterium) labelled compounds of formula I, which compounds are identical to the compounds of formula I except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopically labelled, especially 2 H (deuterium) labelled compounds of formula I and salts thereof are within the scope of the present invention.
  • the compounds of formula I are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula I are not isotopically labelled at all. Isotopically labelled compounds 1 of formula I may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
  • the combinations of the present invention can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such as especially oral) or parenteral (including topical application or inhalation) administration, and are suitable for the treatment and/or prevention of the diseases mentioned herein, such as especially malaria.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21 st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula I or their pharmaceutically acceptable salts or the other antimalarial agents, or a compound of formula I in combination with one or more other antimalarial agent according to the invention (fixed combinations), into a galenical administration form together with suitable, non-toxic, inert, pharmaceutically acceptable solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • antimalarial agents which according to the present invention can be used in combination with the compounds of formula I, are either commercially available or can be prepared as described in the literature. Alternatively, they can be prepared according to processes analogous to those known in the literature. These other antimalarial agents can be used either in free form or in the form of a pharmaceutically acceptable salt. Also, where appropriate, a prodrug, or - if present - an active metabolite of such other antimalarial agent can be used as combination partners according to the present invention.
  • In vitro antimalarial activity Plasmodium falciparum in vitro assay
  • the plates are incubated for a further 24 h under the same conditions then harvested with a Betaplate cell harvester (Wallac) and washed with distilled water.
  • the dried filters are inserted into a plastic foil with 10 mL of scintillation fluid, and counted in a Betaplate liquid scintillation counter.
  • IC 50 values are calculated from sigmoidal inhibition curves using Microsoft Excel.
  • In vivo antimalarial activity of the combinations of the present invention can be assessed for groups of three female NMRI mice (20-22 g) intravenously infected on day 0 with P. berghei strain GFP-ANKA (0.2 mL heparinized saline suspension containing 2 x 10 7 parasitized erythrocytes). In control mice, parasitemia typically rises to approximately 40% by day 3 after infection.
  • the compounds of the combination are formulated in Tween 80/ethanol (7%/3%) usually at concentrations of 10 mg/mL.
  • the compounds of the combination are administered in a volume of 10 mL/kg orally as single doses (1x100 mg/kg, 24 h after infection).

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Abstract

The present invention relates to a combination comprising a compound of the formula I and one or more other antimalarial agent, especially for use as a medicament to treat or prevent malaria infections or to treat or prevent other protozoal diseases like sleeping sickness, Chagas disease, amebiasis, giardiasis, trichomoniasis, toxoplasmosis, and leishmaniasis.

Description

COMBINATION OF ANTIMALARIAL AGENTS The present invention relates to a combination comprising a compound of the formula I and one or more other antimalarial agent, especially for use as a medicament to treat or prevent malaria infections or to treat or prevent other protozoal diseases like sleeping sickness, Chagas disease, amebiasis, giardiasis, trichomoniasis, toxoplasmosis, and leishmaniasis. Background of the invention:
Numerous serious diseases affecting humans as well as domestic and livestock animal are caused by protozoal organisms such as kinetoplastida, apicomplexa, anaerobic protozoa, microsporidia and Plasmodium, for example. The clinically most relevant of these diseases is malaria.
Malaria is one of the most serious and complex health problems affecting humanity in the 21st 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. Various classes of antimalarial drugs exist. The most widely used are the quinoline antimalarials, e.g. chloroquine which has been an especially effective drug for both prophylaxis and therapy. However, resistance to many of the currently available antimalarial drugs is spreading rapidly, threatening people in areas where malaria is endemic. Reports of multi-drug resistant strains of malaria parasites render the search for new antimalarial agents especially urgent. P. falciparum enters the human body by way of bites of the female anophelino mosquito (it may also be transmitted by blood transfusion from asymptotic donors; almost all infected blood components including red cells, platelet concentrates, white cells, cryoprecipitates and fresh plasma can transmit malaria). 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.
The limitations of the current antiprotozoal chemotherapeutic arsenal underscore the need for new drugs in this therapeutic area. The present invention relates to low molecular weight, non-peptidic, non-quinoline compounds of formula I in combination with one or more other antimalarial agent which combinations are useful in the treatment and/or prevention of protozoal infections, especially in the treatment and/or prevention of malaria, in particular Plasmodium falciparum malaria.
Detailed description of the invention:
i) The present invention relates to a combination comprising a compound of the formula I:
Figure imgf000003_0001
wherein
♦ X is CH or N;
R represents -N02, -N(CH3)2, or -NCH3(CH2CH2OH); and
R2 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyano, halogen, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, methylsulfonyl, acetyl, or acetylamino; or
♦ X is CH, R is hydrogen, and R2 is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, methylsulfonyl, acetylamino, or methoxycarbonyl; or
♦ X is CH, R is cyano, and R2 is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methylsulfonyl, or acetylamino; or
♦ X is CH, R is chloro, and R2 is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, difluoromethoxy, methylsulfonyl, or acetylamino; or
♦ X is CH, R is methoxy or isopropoxy, and R2 is trifluoromethyl; or
♦ X is CH, R is methylsulfonyl or ethylsulfonyl, and R2 is trifluoromethyl, ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, or difluoromethoxy, such as especially trifluoromethyl, tert-butyl, n-propoxy, or isopropoxy;
or a salt of such compound;
and one or more, preferably one, other antimalarial agent. ii) A further embodiment of the invention relates to the combination according to embodiment i), wherein in addition to a compound of formula I, the combination contains only one other antimalarial agent. iii) A further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is selected from the group consisting of:
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(6-methoxy-pyridin-3-yl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(6-ethoxy-pyridin-3-yl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-ethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-methanesulfonyl-phenyl)-acrylamide,
(S)-3-(4-acetylamino-phenyl)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4- dimethylamino-benzyl)-piperazin-1 -yl]-2-oxo-ethyl}-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-propoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-isopropoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-ethyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-difluoromethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-isopropyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide, (S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(6-trifluoromethyl-pyridin-3-yl)-aCT^
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(6-methoxy-pyridin-3-yl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(6-ethoxy-pyridin-3-yl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-ethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-methanesulfonyl-phenyl)-acrylam
(S)-3-(4-acetylamino-phenyl)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4^ hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-propoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-isopropoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-ethyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-difluoromethoxy-phenyl)-acrylam
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-isopropyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-tert-butyl-phenyl)-acrylamide, and
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-nitro-benzyl)-piperazin-1 -yl]-2- oxo-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide,
or a salt of such compound. iv) A further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is selected from the group consisting of:
(S)-N-[4-(4-acetyl-piperazin-1 -yl)benzyl]-N-{1 -(4-(4-(dimethylamino)benzyl)piperazin-1 -yl)-1 - oxo-3-phenylpropan-2-yl}cinnamamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)benzyl]-N-{1 -[4-(4-(dimethylamino)benzyl)piperazin-1 -yl]-1 - oxo-3-phenylpropan-2-yl}-3-(p-tolyl)acrylamide, (S)-N-[4-(4-acetyl-piperazin-1 -yl)benzyl]-N-{1 -(4-(4-(dimethylamino)benzyl)piperazin-1 -yl)-1 - oxo-3-phenylpropan-2-yl}-3-(4-propylphenyl)acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)benzyl]-N-{1 -(4-(4-(dimethylamino)benzyl)piperazin-1 -yl)-1 - oxo-3-phenylpropan-2-yl}-3-(4-methoxyphenyl)acrylamide,
(S)-3-(4-acetyl-phenyl)-N-[4-(4-acetyl-piperazin-1 -yl)benzyl]-N-{1 -(4-(4-
(dimethylamino)benzyl)piperazin-1 -yl)-1 -oxo-3-phenylpropan-2-yl}acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)benzyl]-3-(4-cyanophenyl)-N-{1 -(4-(4-
(dimethylamino)benzyl)piperazin-1 -yl)-1 -oxo-3-phenylpropan-2-yl}acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)benzyl]-N-{1 -(4-(4-(dimethylamino)benzyl)piperazin-1 -yl)-1 - oxo-3-phenylpropan-2-yl}-3-(4-fluorophenyl)acrylamide, and
(S)-N-[4-(4-acetyl-piperazin-1 -yl)benzyl]-3-(4-chlorophenyl)-N-{1 -(4-(4-
(dimethylamino)benzyl)piperazin-1 -yl)-1 -oxo-3-phenylpropan-2-yl}acrylamide,
or a salt of such compound. v) A further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is selected from the group consisting of:
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-ethyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-tert-butyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-ethoxy-phenyl)-acrylamide,
(S)-4-(2-{[4-(4-acetyl-piperazin-1 -yl)-benzyl]-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-carbamoyl}-vinyl)-benzoic acid methyl ester,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-methanesulfonyl-phenyl)-acrylamide,
(S)-3-(4-acetylamino-phenyl)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl- piperazin-1 -yl)-2-oxo-ethyl]-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-propoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-isopropoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-isopropyl-phenyl)-acrylamide, (S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin 2-oxo-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin 2-oxo-ethyl}-3-(4-ethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin 2-oxo-ethyl}-3-(4-methanesulfonyl-phenyl)-acrylamide,
(S)-3-(4-acetylamino-phenyl)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4 cyano-benzyl)-piperazin-1 -yl]-2-oxo-ethyl}-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin 2-oxo-ethyl}-3-(4-propoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin 2-oxo-ethyl}-3-(4-isopropoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin 2-oxo-ethyl}-3-(4-ethyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin 2-oxo-ethyl}-3-(4-difluoromethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin 2-oxo-ethyl}-3-(4-isopropyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin 2-oxo-ethyl}-3-(4-trifluoromethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin 2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-chloro-benzyl)-piperazin- 2-oxo-ethyl}-3-(4-ethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-chloro-benzyl)-piperazin- 2-oxo-ethyl}-3-(4-methanesulfonyl-phenyl)-acrylamide,
(S)-3-(4-acetylamino-phenyl)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4 chloro-benzyl)-piperazin-1 -yl]-2-oxo-ethyl}-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-chloro-benzyl)-piperazin- 2-oxo-ethyl}-3-(4-propoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-chloro-benzyl)-piperazin- 2-oxo-ethyl}-3-(4-isopropoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-chloro-benzyl)-piperazin- 2-oxo-ethyl}-3-(4-ethyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-chloro-benzyl)-piperazin- 2-oxo-ethyl}-3-(4-difluoromethoxy-phenyl)-acrylamide, (S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-chloro-benzyl)-piperazin-1 -yl]- 2-oxo-ethyl}-3-(4-isopropyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-chloro-benzyl)-piperazin-1 -yl]- 2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-methoxy-benzyl)-piperazin-1 - yl]-2-oxo-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide, and
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-isopropoxy-benzyl)-piperazin-
1 -yl]-2-oxo-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide,
or a salt of such compound. vi) A further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is selected from the group consisting of:
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-(methylsulfonyl)-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-isopropoxyphenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-(methylsulfonyl)-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-(methylsulfonyl)-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-propoxyphenyl)-acrylamide,
(S)-N-(4-(4-acetylpiperazin-1 -yl)benzyl)-N-(1 -(4-(4-(methylsulfonyl)benzyl)piperazin-1 -yl)-1 - oxo-3-phenylpropan-2-yl)-3-(4-(trifluoromethyl)phenyl)acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-(ethylsulfonyl)-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-propoxyphenyl)-acrylamide, and
(S)-N-(4-(4-acetylpiperazin-1 -yl)benzyl)-N-(1 -(4-(4-(ethylsulfonyl)benzyl)piperazin-1 -yl)-1 - oxo-3-phenylpropan-2-yl)-3-(4-(trifluoromethyl)phenyl)acrylamide,
or a salt of such compound. vii) A further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is selected from the group consisting of:
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-tert-butyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-ethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-propoxy-phenyl)-acrylamide, (S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-isopropoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-isopropyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-ethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-ethyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl]- 2-oxo-ethyl}-3-(4-ethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl]- 2-oxo-ethyl}-3-(4-difluoromethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl]- 2-oxo-ethyl}-3-(4-isopropyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl]- 2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-trifluorom
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-propoxy-phenyl)-acrylamide, and
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-isopropoxy-phenyl)-acrylamide,
or a salt of such compound. viii) A further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is (S)-N-[4-(4-acetyl-piperazin-1 -yl)- benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-tert-butyl-phenyl)- acrylamide or a salt thereof. ix) A further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is (S)-N-[4-(4-acetyl-piperazin-1 -yl)- benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-propoxy-phenyl)- acrylamide or a salt thereof. x) A further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is (S)-N-[4-(4-acetyl-piperazin-1 -yl)- benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl]-2-oxo-ethyl}-3-(4-ethoxy-phenyl)- acrylamide or a salt thereof. xi) A further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is (S)-N-[4-(4-acetyl-piperazin-1 -yl)- benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl]-2-oxo-ethyl}-3-(4-tert-butyl- phenyl)-acrylamide or a salt thereof. xii) A further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is (S)-N-[4-(4-acetyl-piperazin-1 -yl)- benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide or a salt thereof. xiii) A further embodiment of the invention relates to the combination according to embodiment i) or ii), wherein the compound of formula I is (S)-N-[4-(4-acetyl-piperazin-1 -yl)- benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-isopropoxy-phenyl)-acrylamide or a salt thereof. xiv) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of Quinine and other related antimalarials (interfering with heme-polymerization / parasite detoxification pathways) from the 4-aminoquinoline- and the arylaminoalcohol class such as Quinidine, Chloroquine, Amodiaquine, Mefloquine, Halofantrine, Lumefantrine (Benflumetol), Desbutyllumefantrine, Pyronaridine, Piperaquine, Mepacrine, Sontoquine, AQ13, F2Bu, Tebuquine, Isoquine, FAQ4, and Naphthoquine. xv) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of antifolate-agents, for example dihydrofolate reductase inhibitors such as Pyrimethamine, Proguanil / Cycloguanil, Chloroproguanil / Chlorocycloguanil, and PS-15 / Cyclo-PS-15. Λ„
10 xvi) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of dihydropteroate-synthase inhibitors such as sulfadoxine and dapsone. xvii) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of trimethoprime, WR99210, and JPC-2056. xviii) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of Artemisinine and derivatives thereof, such as Artemisinine, Dihydroartemisinine, Artemether, Arteether, Artesunate, Artelinate, Artemisone, Artelinic acid and further compounds as described in J. Wiesner et al., Angewandte Chemie, 2003, 115, 5432-5451 , specifically pages 5443-5444, chapter 5.2). xix) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of RKA 182 and related compounds (J. Chadwick et al. ChemMedChem, 2011 ; DOI: 10.1002/cmdc.201 100196). xx) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of antibiotics active against malaria parasites such as Rifampicine, Doxycycline, Clindamycin, and Azithromycin. xxi) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of inhibitors of mitochondrial electrone transfer such as Atovaquone, Lapinone, Menoctone, Pravaquone, BW58C80, and Buparvaquone. xxii) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of 8-aminoquinoline based compounds such as Pamaquine, Tafenoquine, Primaquine, Quinocide, NCP1 161 B, and Bulaquine. Λ Λ
1 1 xxiii) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of inhibitors of the mevalonate independent isoprenoide biosynthesis such as Fosmidomycine, FR900098 and produgs of FR900098. xxiv) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of antimalarials interfering with heme-polymerization / parasite detoxification pathways such as WR-243251 , Floxacrine, 2,7-Dibromocryptolepine, Ro 06-9075, and Ro 22-8014. xxv) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of endoperoxides such as Yingzhaosu A, Arteflen, OZ277 / Arterolane and related synthetic trioxolane based compounds, and OZ439 and related synthetic trioxolane based compounds. xxvi) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of trioxaquines such as DU-1 102. xxvii) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of protease inhibitors (e.g. falcipain inhibitors or plasmepsin inhibitors), inhibitors of fatty acid synthesis (e.g. triclosan and analogues), inhibitors of choline uptake (e.g. ammonium salts such as E10 or bis-ammonium salts such as G25 or MS1 ), farnesyl- transferase inhibitors (e.g. FTI-2153 and Schl-41 16), glycolysis inhibitors (e.g. Gossypol, Dioncophyllin, Febrifugin, WR182393 and the like), and diamidines such as pentamidine, stilbamidine, furamidine or propamidine and the like. xxviii) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is ferroquine. xxix) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xiii), wherein the other antimalarial agent is selected from the group consisting of Quinidine, Chloroquine, Amodiaquine, Mefloquine, Halofantrine, Lumefantrine (Benflumetol), Desbutyllumefantrine, Pyronaridine, Piperaquine, Mepacrine, Sontoquine, AQ13, F2Bu, Tebuquine, Isoquine, FAQ4, Naphthoquine, Pyrimethamine, Proguanil / Cycloguanil, Chloroproguanil / Chlorocycloguanil, PS-15 / Cyclo-PS-15, sulfadoxine, dapsone, trimethoprime, WR99210, JPC-2056, Artemisinine, Dihydroartemisinine, Artemether, Arteether, Artesunate, Artelinate, Artemisone, Artelinic acid, RKA 182, Rifampicine, Doxycycline, Clindamycin, Azithromycin, Atovaquone, Lapinone, Menoctone, Pravaquone, BW58C80, Buparvaquone, Pamaquine, Tafenoquine, Primaquine, Quinocide, NCP1 161 B, Bulaquine, Fosmidomycine, FR900098, WR-243251 , Floxacrine, 2,7- Dibromocryptolepine, Ro 06-9075, Ro 22-8014, Yingzhaosu A, Arteflen, OZ277 / Arterolane, OZ439, DU-1 102, triclosan, E10, G25, MS1 , FTI-2153, Schl-41 16, Gossypol, Dioncophyllin, Febrifugin, WR182393, pentamidine, stilbamidine, furamidine, propamidine, and ferroquine. xxx) A further embodiment of the invention relates to a combination according to embodiment i) comprising a compound of formula I as defined in any one of embodiments i) to xiii), or a salt thereof, and two or more (preferably two or three and most preferably two) other antimalarial agents independently selected from the antimalarial agents listed in any one of embodiments xiv) to xxix). xxxi) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xxx), for use as a medicament. xxxii) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xxx), for use in the treatment and/or prevention of protozoal infections. xxxiii) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xxx), for use in the treatment and/or prevention of malaria. xxxiv) A further embodiment of the invention relates to the combination according to any one of embodiments i) to xxx) for use according to any one of embodiments xxxi) to xxxiii), wherein the compound of formula I and the one or more other antimalarial agent are administered simultaneously, concurrently, separately or sequentially. xxxv) A further embodiment of the invention relates to a pharmaceutical composition comprising the combination according to any one of embodiments i) to xxx) and a pharmaceutically acceptable carrier. Based on the dependencies of the different embodiments i) to xxix) as disclosed hereinabove, the following embodiments are thus possible and intended and herewith specifically disclosed in individualized form:
i), ii)+i), iii)+i), iii)+ii)+i), iv)+i), iv)+ii)+i), v)+i), v)+ii)+i), vi)+i), vi)+ii)+i), vii)+i), vii)+ii)+i), viii) +i), viii)+ii)+i), ix)+i), ix)+ii)+i), x)+i), x)+ii)+i), xi)+i), xi)+ii)+i), xii)+i), xii)+ii)+i), xiii)+i), xiii) +ii)+i), xiv)+i), xiv)+ii)+i), xiv)+iii)+i), xiv)+iii)+ii)+i), xiv)+iv)+i), xiv)+iv)+ii)+i), xiv)+v)+i), xiv) +v)+ii)+i), xiv)+vi)+i), xiv)+vi)+ii)+i), xiv)+vii)+i), xiv)+vii)+ii)+i), xiv)+viii)+i), xiv)+viii)+ii)+i), xiv) +ix)+i), xiv)+ix)+ii)+i), xiv)+x)+i), xiv)+x)+ii)+i), xiv)+xi)+i), xiv)+xi)+ii)+i), xiv)+xii)+i), xiv)+xii)+ii)+i), xiv)+xiii)+i), xiv)+xiii)+ii)+i), xv)+i), xv)+ii)+i), xv)+iii)+i), xv)+iii)+ii)+i), xv) +iv)+i), xv)+iv)+ii)+i), xv)+v)+i), xv)+v)+ii)+i), xv)+vi)+i), xv)+vi)+ii)+i), xv)+vii)+i), xv)+vii)+ii)+i), xv)+viii)+i), xv)+viii)+ii)+i), xv)+ix)+i), xv)+ix)+ii)+i), xv)+x)+i), xv)+x)+ii)+i), xv) +xi)+i), xv)+xi)+ii)+i), xv)+xii)+i), xv)+xii)+ii)+i), xv)+xiii)+i), xv)+xiii)+ii)+i), xvi)+i), xvi) +ii)+i), xvi)+iii)+i), 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xxvi)+x)+ii)+i), xxvi)+xi)+i), xxvi)+xi)+ii)+i), xxvi) +xii)+i), xxvi)+xii)+ii)+i), xxvi)+xiii)+i), xxvi)+xiii)+ii)+i), xxvii)+i), xxvii)+ii)+i), xxvii)+iii)+i), xxvii) +iii)+ii)+i), xxvii)+iv)+i), xxvii)+iv)+ii)+i), xxvii)+v)+i), xxvii)+v)+ii)+i), xxvii)+vi)+i), xxvii)+vi)+ii)+i), xxvii)+vii)+i), xxvii)+vii)+ii)+i), xxvii)+viii)+i), xxvii)+viii)+ii)+i), xxvii)+ix)+i), xxvii)+ix)+ii)+i), xxvii)+x)+i), xxvii)+x)+ii)+i), xxvii)+xi)+i), xxvii)+xi)+ii)+i), xxvii)+xii)+i), xxvii) +xii)+ii)+i), xxvii)+xiii)+i), xxvii)+xiii)+ii)+i), xxviii)+i), xxviii)+ii)+i), xxviii)+iii)+i), xxviii) +iii)+ii)+i), xxviii)+iv)+i), xxviii)+iv)+ii)+i), xxviii)+v)+i), xxviii)+v)+ii)+i), xxviii)+vi)+i), xxviii)+vi)+ii)+i), xxviii)+vii)+i), xxviii)+vii)+ii)+i), xxviii)+viii)+i), xxviii)+viii)+ii)+i), xxviii)+ix)+i), xxviii) +ix)+ii)+i), xxviii)+x)+i), xxviii)+x)+ii)+i), xxviii)+xi)+i), xxviii)+xi)+ii)+i), xxviii)+xii)+i), xxviii)+xii)+ii)+i), xxviii)+xiii)+i), xxviii)+xiii)+ii)+i), xxix)+i), xxix)+ii)+i), xxix)+iii)+i), xxix) +iii)+ii)+i), xxix)+iv)+i), xxix)+iv)+ii)+i), xxix)+v)+i), xxix)+v)+ii)+i), xxix)+vi)+i), xxix)+vi)+ii)+i), xxix)+vii)+i), xxix)+vii)+ii)+i), xxix)+viii)+i), xxix)+viii)+ii)+i), xxix)+ix)+i), xxix)+ix)+ii)+i), xxix)+x)+i), xxix)+x)+ii)+i), xxix)+xi)+i), xxix)+xi)+ii)+i), xxix)+xii)+i), xxix)+xii)+ii)+i), xxix)+xiii)+i), and xxix)+xiii)+ii)+i).
In the list above the numbers refer to the embodiments according to their numbering provided hereinabove whereas "+" indicates the dependency from another embodiment. The different individualized embodiments are separated by commas. I n other words, "iii)+ii)+i)" for example refers to embodiment iii ) depending on embodiment ii) depending on embodiment i), i.e. embodiment "iii)+ii)+i)" corresponds to embodiment i) further limited by the features of embodiments ii) and iii). The term "halogen" as used herein means fluorine, chlorine, bromine or iodine, such as especially fluorine or chlorine. Any reference hereinbefore or hereinafter to a compound of formula I is to be understood as referring also to salts, especially pharmaceutically acceptable salts, of a compound of formula I, as appropriate and expedient.
The term "pharmaceutically acceptable salts" refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. 1986, 33, 201 -217.
In particular the term "combination" according to the present invention means a fixed combination with defined amounts of the combination partners or it means a "kit of parts" in the sense that the combination partners as defined herein can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners, i.e., simultaneously, concurrently, separately or sequentially. The parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts. The total amounts and the ratio of the total amounts of the combination partners to be administered can be varied, e.g. in order to cope with the needs of a patient sub-population to be treated or the needs of the single patient which different needs can be due to the particular disease, severity of the disease, age, sex, body weight, etc. of the patients. The present invention also includes isotopically labelled, especially 2H (deuterium) labelled compounds of formula I, which compounds are identical to the compounds of formula I except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially 2H (deuterium) labelled compounds of formula I and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In one embodiment of the invention, the compounds of formula I are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula I are not isotopically labelled at all. Isotopically labelled compounds 1 of formula I may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
The combinations of the present invention can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such as especially oral) or parenteral (including topical application or inhalation) administration, and are suitable for the treatment and/or prevention of the diseases mentioned herein, such as especially malaria.
The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21 st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula I or their pharmaceutically acceptable salts or the other antimalarial agents, or a compound of formula I in combination with one or more other antimalarial agent according to the invention (fixed combinations), into a galenical administration form together with suitable, non-toxic, inert, pharmaceutically acceptable solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
The preparation of the compounds of formula I and their medicinal use are described in the published PCT application WO 201 1/083413.
The other antimalarial agents, which according to the present invention can be used in combination with the compounds of formula I, are either commercially available or can be prepared as described in the literature. Alternatively, they can be prepared according to processes analogous to those known in the literature. These other antimalarial agents can be used either in free form or in the form of a pharmaceutically acceptable salt. Also, where appropriate, a prodrug, or - if present - an active metabolite of such other antimalarial agent can be used as combination partners according to the present invention. In vitro antimalarial activity: Plasmodium falciparum in vitro assay
In vitro activity of the combinations of the present invention against erythrocytic stages of P. falciparum in human red blood cells can be determined using a [3H] hypoxanthine incorporation assay. One strain sensitive to all known drugs (P. falciparum NF54) is used in this assay and all tested combinations are compared for activity with the standard drugs chloroquine (sigma C6628) and artesunate (sigma 36, 159-3). The compounds of the combination, tested in duplicates, are serially diluted with screening medium [RPMI 1640 Λ
17 medium, supplemented with HEPES (5.94 g/L), NaHC03 (2.1 g/L), neomycin (100 U/mL), and Albumax (5 g/L) or human serum (50% final concentration)] in 96-well microtiter plates within an appropriate concentration range. Thereafter, the parasite cultures incubated in screening medium containing washed human red blood cells at 2.5% hematocrit (0.3% parasitemia) are added to the serially diluted compounds and incubated in a humidifying atmosphere at 37°C, 4% C02, 3% 02, and 93% N2. After 48 h, [3H] hypoxanthine (0.5 μθϊ) is added to each well of a plate. The plates are incubated for a further 24 h under the same conditions then harvested with a Betaplate cell harvester (Wallac) and washed with distilled water. The dried filters are inserted into a plastic foil with 10 mL of scintillation fluid, and counted in a Betaplate liquid scintillation counter. IC50 values are calculated from sigmoidal inhibition curves using Microsoft Excel.
In vivo antimalarial efficacy studies
In vivo antimalarial activity of the combinations of the present invention can be assessed for groups of three female NMRI mice (20-22 g) intravenously infected on day 0 with P. berghei strain GFP-ANKA (0.2 mL heparinized saline suspension containing 2 x 107 parasitized erythrocytes). In control mice, parasitemia typically rises to approximately 40% by day 3 after infection. The compounds of the combination are formulated in Tween 80/ethanol (7%/3%) usually at concentrations of 10 mg/mL. The compounds of the combination are administered in a volume of 10 mL/kg orally as single doses (1x100 mg/kg, 24 h after infection). 48 h after drug treatment (day 3 post-infection), 1 μΙ tail blood is taken, resuspended in 1 mL PBS buffer and parasitemia determined with a FACScan (Becton Dickinson) by counting 100Ό00 red blood cells. Activity is calculated as the difference between the mean value of the control group and treated groups expressed as a percent relative to the control group.

Claims

Claims:
1. A combination comprising a compound of the formula I:
Figure imgf000019_0001
wherein
♦ X is CH or N;
R represents -N02, -N(CH3)2, or -NCH3(CH2CH2OH); and
R2 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyano, halogen, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, methylsulfonyl, acetyl, or acetylamino; or
♦ X is CH, R is hydrogen, and R2 is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, methylsulfonyl, acetylamino, or methoxycarbonyl; or
♦ X is CH, R is cyano, and R2 is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methylsulfonyl, or acetylamino; or
♦ X is CH, R is chloro, and R2 is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, difluoromethoxy, methylsulfonyl, or acetylamino; or
♦ X is CH, R is methoxy or isopropoxy, and R2 is trifluoromethyl; or
♦ X is CH, R is methylsulfonyl or ethylsulfonyl, and R2 is trifluoromethyl, ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, or difluoromethoxy;
or a salt of such a compound;
and one or more other antimalarial agent.
2. The combination according to claim 1 , wherein in addition to a compound of formula I, the combination contains only one other antimalarial agent.
3. The combination according to claim 1 or 2, wherein the compound of formula I selected from the group consisting of:
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(6-methoxy-pyridin-3-yl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(6-ethoxy-pyridin-3-yl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-ethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-methanesulfonyl-phenyl)-acrylamide,
(S)-3-(4-acetylamino-phenyl)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4- dimethylamino-benzyl)-piperazin-1 -yl]-2-oxo-ethyl}-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-propoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-isopropoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-ethyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-difluoromethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-isopropyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(6-methoxy-pyridin-3-yl)-acrylamide, (S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(6-ethoxy-pyridin-3-yl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-ethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-methanesulfonyl-phenyl)-acrylam
(S)-3-(4-acetylamino-phenyl)-N-[4-(4^
hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-propoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-isopropoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-ethyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-difluoromethoxy-phenyl)-acrylam
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-isopropyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-tert-butyl-phenyl)-acrylamide, and
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-nitro-benzyl)-piperazin-1 -yl]-2 oxo-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide,
or a salt of such compound.
4. The combination according to claim 1 or 2, wherein the compound of formula I selected from the group consisting of:
(S)-N-[4-(4-acetyl-piperazin-1 -yl)benzyl]-N-{1 -(4-(4-(dimethylamino)benzyl)piperazin-1 -yl)-1 oxo-3-phenylpropan-2-yl}cinnamamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)benzyl]-N-{1 -[4-(4-(dimethylamino)benzyl)piperazin-1 -yl]-1 oxo-3-phenylpropan-2-yl}-3-(p-tolyl)acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)benzyl]-N-{1 -(4-(4-(dimethylamino)benzyl)piperazin-1 -yl)-1 oxo-3-phenylpropan-2-yl}-3-(4-propylphenyl)acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)benzyl]-N-{1 -(4-(4-(dimethylamino)benzyl)piperazin-1 -yl)-1 oxo-3-phenylpropan-2-yl}-3-(4-methoxyphenyl)acrylamide,
(S)-3-(4-acetyl-phenyl)-N-[4-(4-acetyl-piperazin-1 -yl)benzyl]-N-{1 -(4-(4- (dimethylamino)benzyl)piperazin-1 -yl)-1 -oxo-3-phenylpropan-2-yl}acrylamide, (S)-N-[4-(4-acetyl-piperazin-1 -yl)benzyl]-3-(4-cyanophenyl)-N-{1 -(4-(4- (dimethylamino)benzyl)piperazin-1 -yl)-1 -oxo-3-phenylpropan-2-yl}acrylamide
(S)-N-[4-(4-acetyl-piperazin-1 -yl)benzyl]-N-{1 -(4-(4-(dimethylamino)benzyl)piperazin-1 -yl)-1 oxo-3-phenylpropan-2-yl}-3-(4-fluorophenyl)acrylamide, and
(S)-N-[4-(4-acetyl-piperazin-1 -yl)benzyl]-3-(4-chlorophenyl)-N-{1 -(4-(4- (dimethylamino)benzyl)piperazin-1 -yl)-1 -oxo-3-phenylpropan-2-yl}acrylamide,
or a salt of such compound.
5. The combination according to claim 1 or 2, wherein the compound of formula I selected from the group consisting of:
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-ethyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-tert-butyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-ethoxy-phenyl)-acrylamide,
(S)-4-(2-{[4-(4-acetyl-piperazin-1 -yl)-benzyl]-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-carbamoyl}-vinyl)-benzoic acid methyl ester,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-methanesulfonyl-phenyl)-acrylamide,
(S)-3-(4-acetylamino-phenyl)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl piperazin-1 -yl)-2-oxo-ethyl]-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-propoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-isopropoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-isopropyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl]- 2-oxo-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl]- 2-oxo-ethyl}-3-(4-ethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl]- 2-oxo-ethyl}-3-(4-methanesulfonyl-phenyl)-acrylamide,
(S)-3-(4-acetylamino-phenyl)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4- cyano-benzyl)-piperazin-1 -yl]-2-oxo-ethyl}-acrylamide, (S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl] 2-oxo-ethyl}-3-(4-propoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl] 2-oxo-ethyl}-3-(4-isopropoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl] 2-oxo-ethyl}-3-(4-ethyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl] 2-oxo-ethyl}-3-(4-difluoromethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl] 2-oxo-ethyl}-3-(4-isopropyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl] 2-oxo-ethyl}-3-(4-trifluoromethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl] 2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-chloro-benzyl)-piperazin-1 -yl] 2-oxo-ethyl}-3-(4-ethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-chloro-benzyl)-piperazin-1 -yl] 2-oxo-ethyl}-3-(4-methanesulfonyl-phenyl)-acrylamide,
(S)-3-(4-acetylamino-phenyl)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4- chloro-benzyl)-piperazin-1 -yl]-2-oxo-ethyl}-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-chloro-benzyl)-piperazin-1 -yl] 2-oxo-ethyl}-3-(4-propoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-chloro-benzyl)-piperazin-1 -yl] 2-oxo-ethyl}-3-(4-isopropoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-chloro-benzyl)-piperazin-1 -yl] 2-oxo-ethyl}-3-(4-ethyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-chloro-benzyl)-piperazin-1 -yl] 2-oxo-ethyl}-3-(4-difluoromethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-chloro-benzyl)-piperazin-1 -yl] 2-oxo-ethyl}-3-(4-isopropyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-chloro-benzyl)-piperazin-1 -yl] 2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-methoxy-benzyl)-piperazin-1 - yl]-2-oxo-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide, and
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-isopropoxy-benzyl)-piperazin 1 -yl]-2-oxo-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide, or a salt of such compound.
6. The combination according to claim 1 or 2, wherein the compound of formula I selected from the group consisting of:
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-(methylsulfonyl)-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-isopropoxyphenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-(methylsulfonyl)-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-(methylsulfonyl)-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-propoxyphenyl)-acrylamide,
(S)-N-(4-(4-acetylpiperazin-1 -yl)benzyl)-N-(1 -(4-(4-(methylsulfonyl)benzyl)piperazin-1 -yl)-1 oxo-3-phenylpropan-2-yl)-3-(4-(trifluoromethyl)phenyl)acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-(ethylsulfonyl)-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-propoxyphenyl)-acrylamide, and
(S)-N-(4-(4-acetylpiperazin-1 -yl)benzyl)-N-(1 -(4-(4-(ethylsulfonyl)benzyl)piperazin-1 -yl)-1 - oxo-3-phenylpropan-2-yl)-3-(4-(trifluoromethyl)phenyl)acrylamide,
or a salt of such compound.
7. The combination according to claim 1 or 2, wherein the compound of formula I selected from the group consisting of:
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-tert-butyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-ethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-propoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-isopropoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo- ethyl]-3-(4-isopropyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-ethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-ethyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-dimethylamino-benzyl)- piperazin-1 -yl]-2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide, (S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl]- 2-oxo-ethyl}-3-(4-ethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl]- 2-oxo-ethyl}-3-(4-difluoromethoxy-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl]- 2-oxo-ethyl}-3-(4-isopropyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl]- 2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide,
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-trifluorom
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-propoxy-phenyl)-acrylamide, and
(S)-N-[4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl- amino]-benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-isopropoxy-phenyl)-acrylamide,
or a salt of such compound.
8. The combination according to claim 1 or 2, wherein the compound of formula I is (S)-N [4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo-ethyl]-3- (4-tert-butyl-phenyl)-acrylamide or a salt thereof.
9. The combination according to claim 1 or 2, wherein the compound of formula I is (S)-N [4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-benzyl-piperazin-1 -yl)-2-oxo-ethyl]-3- (4-propoxy-phenyl)-acrylamide or a salt thereof.
10. The combination according to claim 1 or 2, wherein the compound of formula I is (S)-N [4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl]-2-oxo- ethyl}-3-(4-ethoxy-phenyl)-acrylamide or a salt thereof.
1 1. The combination according to claim 1 or 2, wherein the compound of formula I is (S)-N [4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-{1 -benzyl-2-[4-(4-cyano-benzyl)-piperazin-1 -yl]-2-oxo- ethyl}-3-(4-tert-butyl-phenyl)-acrylamide or a salt thereof.
12. The combination according to claim 1 or 2, wherein the compound of formula I is (S)-N [4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]- benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide or a salt thereof.
13. The combination according to claim 1 or 2, wherein the compound of formula I is (S)-N- [4-(4-acetyl-piperazin-1 -yl)-benzyl]-N-[1 -benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]- benzyl}-piperazin-1 -yl)-2-oxo-ethyl]-3-(4-isopropoxy-phenyl)-acrylamide or a salt thereof.
14. The combination according to any one of claims 1 to 13, wherein the other antimalarial agent is selected from the group consisting of Quinine and other related antimalarials (interfering with heme-polymerization / parasite detoxification pathways) from the 4- aminoquinoline- and the arylaminoalcohol class such as Quinidine, Chloroquine, Amodiaquine, Mefloquine, Halofantrine, Lumefantrine (Benflumetol), Desbutyllumefantrine, Pyronaridine, Piperaquine, Mepacrine, Sontoquine, AQ13, F2Bu, Tebuquine, Isoquine, FAQ4, and Naphthoquine.
15. The combination according to any one of claims 1 to 13, wherein the other antimalarial agent is selected from the group consisting of antifolate-agents, for example dihydrofolate reductase inhibitors such as Pyrimethamine, Proguanil / Cycloguanil, Chloroproguanil / Chlorocycloguanil, and PS-15 / Cyclo-PS-15.
16. The combination according to any one of claims 1 to 13, wherein the other antimalarial agent is selected from the group consisting of dihydropteroate-synthase inhibitors such as sulfadoxine and dapsone.
17. The combination according to any one of claims 1 to 13, wherein the other antimalarial agent is selected from the group consisting of trimethoprime, WR99210, and JPC-2056.
18. The combination according to any one of claims 1 to 13, wherein the other antimalarial agent is selected from the group consisting of Artemisinine and derivatives thereof, such as Artemisinine, Dihydroartemisinine, Artemether, Arteether, Artesunate, Artelinate, Artemisone, Artelinic acid and further compounds as described in J. Wiesner et al., Angewandte Chemie, 2003, 115, 5432-5451 , specifically pages 5443-5444, chapter 5.2).
19. The combination according to any one of claims 1 to 13, wherein the other antimalarial agent is selected from the group consisting of RKA 182 and related compounds (J. Chadwick et al. ChemMedChem, 2011 ; DOI: 10.1002/cmdc.201 100196).
20. The combination according to any one of claims 1 to 13, wherein the other antimalarial agent is selected from the group consisting of antibiotics active against malaria parasites such as Rifampicine, Doxycycline, Clindamycin, and Azithromycin.
21. The combination according to any one of claims 1 to 13, wherein the other antimalarial agent is selected from the group consisting of inhibitors of mitochondrial electrone transfer such as Atovaquone, Lapinone, Menoctone, Pravaquone, BW58C80, and Buparvaquone.
22. The combination according to any one of claims 1 to 13, wherein the other antimalarial agent is selected from the group consisting of 8-aminoquinoline based compounds such as
Pamaquine, Tafenoquine, Primaquine, Quinocide, NCP1 161 B, and Bulaquine.
23. The combination according to any one of claims 1 to 13, wherein the other antimalarial agent is selected from the group consisting of inhibitors of the mevalonate independent isoprenoide biosynthesis such as Fosmidomycine, FR900098 and produgs of FR900098.
24. The combination according to any one of claims 1 to 13, wherein the other antimalarial agent is selected from the group consisting of antimalarials interfering with heme- polymerization / parasite detoxification pathways such as WR-243251 , Floxacrine, 2,7- Dibromocryptolepine, Ro 06-9075, and Ro 22-8014.
25. The combination according to any one of claims 1 to 13, wherein the other antimalarial agent is selected from the group consisting of endoperoxides such as Yingzhaosu A, Arteflen, OZ277 / Arterolane and related synthetic trioxolane based compounds, and OZ439 and related synthetic trioxolane based compounds.
26. The combination according to any one of claims 1 to 13, wherein the other antimalarial agent is selected from the group consisting of trioxaquines such as DU-1 102.
27. The combination according to any one of claims 1 to 13, wherein the other antimalarial agent is selected from the group consisting of protease inhibitors (e.g. falcipain inhibitors or plasmepsin inhibitors), inhibitors of fatty acid synthesis (e.g. triclosan and analogues), inhibitors of choline uptake (e.g. ammonium salts such as E10 or bis-ammonium salts such as G25 or MS1 ), farnesyl-transferase inhibitors (e.g. FTI-2153 and Schl-41 16), glycolysis inhibitors (e.g. Gossypol, Dioncophyllin, Febrifugin, WR182393 and the like), and diamidines such as pentamidine, stilbamidine, furamidine or propamidine and the like.
28. The combination according to any one of claims 1 to 13, wherein the other antimalarial agent is ferroquine.
29. The combination according to any one of claims 1 to 13, wherein the other antimalarial agent is selected from the group consisting of Quinidine, Chloroquine, Amodiaquine, Mefloquine, Halofantrine, Lumefantrine (Benflumetol), Desbutyllumefantrine, Pyronaridine, Piperaquine, Mepacrine, Sontoquine, AQ13, F2Bu, Tebuquine, Isoquine, FAQ4, Naphthoquine, Pyrimethamine, Proguanil / Cycloguanil, Chloroproguanil / Chlorocycloguanil, PS-15 / Cyclo-PS-15, sulfadoxine, dapsone, trimethoprime, WR99210, JPC-2056, Artemisinine, Dihydroartemisinine, Artemether, Arteether, Artesunate, Artelinate, Artemisone, Artelinic acid, RKA 182, Rifampicine, Doxycycline, Clindamycin, Azithromycin, Atovaquone, Lapinone, Menoctone, Pravaquone, BW58C80, Buparvaquone, Pamaquine, Tafenoquine, Primaquine, Quinocide, NCP1 161 B, Bulaquine, Fosmidomycine, FR900098, WR-243251 , Floxacrine, 2,7-Dibromocryptolepine, Ro 06-9075, Ro 22-8014, Yingzhaosu A, Arteflen, OZ277 / Arterolane, OZ439, DU-1 102, triclosan, E10, G25, MS1 , FTI-2153, Schl- 41 16, Gossypol, Dioncophyllin, Febrifugin, WR182393, pentamidine, stilbamidine, furamidine, propamidine, and ferroquine.
30. A combination according to claim 1 comprising a compound of formula I as defined in any one of claims 1 to 13, or a salt thereof, and two or more (preferably two or three and most preferably two) other antimalarial agents independently selected from the antimalarial agents listed in any one of claims 14 to 29.
31. The combination according to any one of claims 1 to 30 for use as a medicament.
32. The combination according to any one of claims 1 to 30 for use in the treatment and/or prevention of protozoal infections.
33. The combination according to any one of claims 1 to 30 for use in the treatment and/or prevention of malaria.
34. The combination according to any one of claims 1 to 30 for use according to any one of claims 31 to 33, wherein the compound of formula I and the one or more other antimalarial agent are administered simultaneously, concurrently, separately or sequentially.
35. A pharmaceutical composition comprising the combination according to any one claims 1 to 30 and a pharmaceutically acceptable carrier.
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