EP2097081A1 - Cholestérylamines pour le traitement et la prévention de maladies infectieuses - Google Patents

Cholestérylamines pour le traitement et la prévention de maladies infectieuses

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Publication number
EP2097081A1
EP2097081A1 EP07847023A EP07847023A EP2097081A1 EP 2097081 A1 EP2097081 A1 EP 2097081A1 EP 07847023 A EP07847023 A EP 07847023A EP 07847023 A EP07847023 A EP 07847023A EP 2097081 A1 EP2097081 A1 EP 2097081A1
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EP
European Patent Office
Prior art keywords
use according
virus
compound
spp
compounds
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.)
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EP07847023A
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German (de)
English (en)
Inventor
Hans-Joachim KNÖLKER
Sameer Agarwal
Georg Schlechtingen
Tobias Braxmeier
Cornelia Schroeder
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Technische Universitaet Dresden
Jado Technologies GmbH
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Technische Universitaet Dresden
Jado Technologies GmbH
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Priority to EP07847023A priority Critical patent/EP2097081A1/fr
Publication of EP2097081A1 publication Critical patent/EP2097081A1/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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 the use of cholesterylamines in the preparation of pharmaceutical compositions.
  • These pharmaceutical compositions are to be used in the medical intervention of infectious diseases, in particular diseases caused by a virus or a bacterium.
  • the lipid bilayer that forms cell membranes is a two dimensional liquid the organization of which has been the object of intensive investigations for decades by biochemists and biophysicists.
  • the bulk of the bilayer has been considered to be a homogeneous fluid, there have been repeated attempts to introduce lateral heterogeneities, lipid microdomains, into our model for the structure and dynamics of the bilayer liquid (Glaser, Curr. Opin. Struct. Biol. 3 (1993), 475-481 ; Jacobson, Comments MoI. Cell Biophys. 8 (1992), 1-144; Jain, Adv. Lipid Res. 15 (1977), 1-60; Winchil, Curr. Opin. Struct. Biol. 3 (1993), 482-488).
  • Lipid rafts are lipid platforms of a special chemical composition (rich in sphingomyelin and cholesterol in the outer leaflet of the cell membrane) that function to segregate membrane components within the cell membrane.
  • Rafts are understood to be relatively small (30 to 50 nm in diameter, estimates of size varying considerably depending on the probes used and cell types analysed) but they can be coalesced under certain conditions. Their specificity with regard to lipid composition is reminiscent of phase separation behavior in heterogeneous model membrane systems.
  • lipid rafts for their purposes (Van der Goot, Semin. Immunol. 13 (2001), 89-97) to infect host cells.
  • viral infections caused by influenza virus, HIV-1 , measles virus, respiratory syncytial virus, filoviridae such as Ebola virus and Marburg virus, papillomaviridae and polyomaviridae, Epstein-Barr virus, hepatitis C virus, and Echovirus 1 represent diseases for which rafts and/or raft proteins are targets.
  • bacterial infections caused by Escherichia coli, Mycobacterium tuberculosis and bovis, Campylobacter jejuni, Vibrio cholerae, Clostridium difficile, Clostridium tetani, Streptococci species, Salmonella, and Shigella involve pathological processes related to rafts (Simons, J. Clin. Invest. 110 (2002), 597-603).
  • influenza virus (Scheiffele, J. Biol. Chem. 274 (1999), 2038-2044; Scheiffele, EMBO J. 16 (1997), 5501-5508).
  • the virus contains two integral glycoproteins, hemagglutinin and neuraminidase, both of which are raft- associated as judged by cholesterol-dependent detergent resistance (Zhang, J. Virol. 74 (2000), 4634-4644). Cholesterol and the integrity of rafts are essential to the transport of hemagglutinin to the plasma membrane (Keller, J. Cell Biol. 140 (1998), 1357-1367). Influenza virus buds out from the apical membrane of epithelial cells, which is enriched in lipid rafts.
  • influenza virus envelope is formed from coalesced rafts during budding, a process in which assemblies of M proteins form a layer at the cytosolic leaflet of the nascent viral envelope which drives raft clustering (Zhang, J. Virol. 74 (2000), 4634-4644).
  • the viral M2 protein a peripheral raft protein, promotes the pinching-off of mature influenza virus particles (Schroeder, Eur. Biophys. J. 34 (2005), 52-66).
  • HIV-1 which likewise incorporates host raft lipids and proteins into its envelope, employs rafts for at least four key events in its life cycle: passage across a new host's mucosa, viral entry into immune cells, signaling of changes in host cell functions as well as viral exit from cells, and dispersion through the host's vascular system.
  • Viruses, bacteria, and parasites may enter or interact with a host cell by changing the cellular state of signaling. This is also the case during HIV infection.
  • Nef an early HIV gene product, promotes infectivity of the virus via lipid rafts (Zheng, Curr. Biol. 11 (2001), 875-879), and infection with HIV-1 virions lacking Nef does not progress to AIDS (Kirchhoff, N. Engl. J. Med. 332 (1995), 228-232).
  • Nef oligomerization may aid in organizing the T-cell signaling complex and the HIV budding site (Zheng, Curr. Biol. 11 (2001), 875-879; Wang, Proc. Natl.
  • HIV exit from the cell another raft-dependent step, depends critically on the viral Gag protein (Ono, Proc. Natl. Acad. Sci. USA 98 (2001), 13925-13930; Lindwasser, J. Virol. 75 (2001), 7913-7924): Gag proteins specifically bind to rafts containing HIV spike proteins, which cluster rafts together to promote virus assembly. The interaction between HIV-1 protein and lipid rafts may cause a conformational change in Gag required for envelope assembly (Campbell, J. Clin. Virol. 22 (2001), 217-227).
  • raft clustering is the pathogenic mechanism of pore-forming toxins, which are secreted by Clostridium, Streptococcus, and Aeromonas species, among other bacteria (Lesieur, MoI. Membr. Biol. 14 (1997), 45-64). These toxins may cause diseases ranging from mild cellulites to gaseous gangrene and pseudomembranous colitis. Best studied is the toxin aerolysin from the marine bacterium Aeromonas hydrophila. Aerolysin is secreted and binds to a GPI-anchored raft protein on the surface of the host cell.
  • the toxin is incorporated into the membrane after proteolysis and then heptamerizes in a raft-dependent manner to form a raft-associated channel through which small molecules and ions flow to trigger the pathogenic changes.
  • the oligomerization of aerolysin can be triggered in solution but occurs at more than 10 5 - fold lower toxin concentration at the surface of the living cell. This enormous increase in efficiency is due to activation by raft binding and by concentration into raft clusters, which is driven by the oligomerization of the toxin. Again, a small change can lead to a huge effect by amplification of raft clustering (Lesieur, MoI. Membr. Biol. 14 (1997), 45- 64; Abrami, J. Cell Biol. 147 (1999), 175-184).
  • bacterial cell membrane domains are functionally and to an extent structurally analogous to mammalian lipid rafts.
  • antimicrobial peptides were differentially toxic to bacteria with a high phosphoethanolamine content in their membranes, emphasizing the potential importance of the lipid composition of the cell surface in determining selective toxicity of antimicrobial agents (Epand, Biochim Biophys Acta. 1758 (2006), 1343-1350).
  • WO 01/22957 describes the use of gangliosides for the modulation of sphingolipid/cholesterol microdomains.
  • a problem underlying the present invention is the provision of means and methods for clinical and/or pharmaceutical intervention in infectious diseases/disorders, in particular those linked to and/or associated with biological/biochemical processes regulated by lipid rafts.
  • cholesterylamines are surprisingly superior to other cholesteryl derivatives, in particular cholesteryl sulfate, in the medical management of infectious diseases, in particular disorders or diseases caused by viral agents and bacteria.
  • the term “cholesterylamine” is intended to also cover compounds which are sometimes referred to as “aminocholesteryl derivatives” and compounds which are sometimes referred to as “aminocholestane and aminocholestene derivatives”.
  • the term “cholesterylamine” is intended to also cover derivatives of cholesterol, wherein the A ring has been replaced by a nitrogen-containing heterocycle as shown in formula 2 below.
  • the present invention provides for the use of a compound of the following formula 1:
  • Said disorders or diseases may be caused by a virus or bacterium.
  • R 1 , R 2 , R 3 , R 4 and R 5 is an amine-containing group selected from X(CH 2 ) n NH 2 , X(CH 2 J n NH(C 1-4 alkyl), X(CH 2 J n N(C 1-4 alkyl) 2 , X(CH 2 J n N(C 1-4 alkyl) 3 + .
  • R 5 is the amine-containing group.
  • X is a direct bond or a phosphorous-containing group selected from OP(O)(OC 1-4 alkyl)O, OP(O)(O-)CH 2 O or OP(O)(OC 1-4 alkyl)CH 2 O.
  • X is a direct bond.
  • X is OP(O)(OC 1-4 alkyl)O.
  • X is OP(O)(O-)CH 2 O.
  • X is OP(O)(OCi -4 alkyl)CH 2 O.
  • n is an integer from O to 2. In one embodiment, n is O. In another embodiment, n is 1. In yet another embodiment, n is 2. In one preferred group of compounds, n is O or 1. In another preferred group of compounds, n is 1 or 2.
  • n is an integer from 2 to 6, preferably 2.
  • R 5 is the amine-containing group
  • R 4 is absent.
  • R 1 , R 2 , R 3 and R 4 are independently H or OH.
  • R 6 is H.
  • X is a direct bond and n is 1 or 2, R 6 can also be OH.
  • R 6 is H.
  • R 1 is the amine-containing group
  • R 2 and R 6 are independently H or OH.
  • R 3 and R 6 are independently H or OH.
  • R 3 is the amine-containing group
  • R 2 and R 6 are independently H or OH.
  • the compound of formula 1 contains one to four hydroxyl groups.
  • the hydroxyl groups increase solubility of the cholesterylamines in an amphiphilic or polar medium which can be advantageous in medical applications.
  • the compound of formula 1 contains 0 or 1 hydroxyl groups. In another embodiment, the compound of formula 1 does not contain any hydroxyl group.
  • Compounds 1e and 11 represent cations, which can be used in combination with any pharmaceutically acceptable anion, such as e.g. halogenides, phosphate, sulfate and acetate.
  • Said disorders or diseases may be caused by a virus or bacterium.
  • Y is NH, N(Ci -4 alkyl) or N(C 1-4 alkyl) 2 + , preferably NH.
  • p is an integer from 0 to 2 and q is an integer of 1 or 2, provided that if p is 2, then q is 1.
  • p is 0 and q is 2.
  • such amines can be prepared via reductive amination strategies: e.g. substituted amines by using alkylamines or dialkylamines as reagents or primary amines by using hydroxylamine as reagent followed by treatment with Raney-Nickel.
  • Amines can be obtained either as free bases or as the corresponding hydrochlorides by precipitation with HCI as solution in diethyl ether.
  • the corresponding hydroxy-decorated derivatives can be prepared from 4-cholesten-3-one or 1 ,4-cholestadien-3-one, which are both commercially available, using epoxidations followed by ring-opening with hydride or by osmium-mediated bishydroxylation strategies.
  • Aminomethyl derivatives are available by treatment of a ketone with tosylmethylisocyanide (TosMIC) as described in Oldenziel, J. Org. Chem. 42 (1977), 3114-3118.
  • Aminoethyl-decorated cholesteryl derivatives can be prepared starting from the corresponding ketone using a Horner- Wadsworth-Emmons (HWE) approach with commercial cyanomethylphosphonate as reagent according descriptions documented in various literature protocols (Drefahl, Chem. Ber. 97 (1964), 2011-2013; Kargiozov, Synth. Commun. 34 (2004), 871-888; Shen, Bioorg. Med. Chem. Lett. 15 (2005), 4564-4569). Subsequent hydrogenation of the formed double bond followed by hydride-mediated reduction of the nitrile provides the aminoethyl-substituted cholesteryl derivatives.
  • the corresponding ketone can be used as synthetic precursor, which can be produced by various alternative literature-known procedures (Barillier, Tetrahedron 50 (1994), 5413-5424; Penz, Monatshefte fuer Chemie 112 (1981), 1045-1054; Lightner, Steroids 35 (1980), 189-207; Nakai, Tetrahedron Lett. (1979), 531-534). Subsequent introduction of the amine-containing group can be achieved by the general strategies described above for 3-cholestanone. The same principle can be used for 4- cholestanone (available as described in Nakai, Tetrahedron Lett.
  • Compounds of the general formula 1, wherein X is a direct bond and which have a primary amino function at position 1, 2 or 4 can be prepared from the corresponding ally) amines.
  • epoxidation and subsequent opening or bishydroxylation of the double bond would result in the described hydroxy-decorated compounds.
  • Said allyl amines can be prepared from 2 ⁇ ,3 ⁇ -epoxy-5 ⁇ -cholestane via ring opening of the epoxy moiety with benzylamine followed by debenzylation or via treatment with mesylchloride followed by treatment with azide and subsequent lithium aluminium hydride reduction.
  • 2 ⁇ ,3 ⁇ -Epoxy-5 ⁇ -cholestane is, for example, available via meta- chloroperbenzoic acid mediated epoxidation of 5 ⁇ -cholestan-2-ene which itself can be prepared as described in the literature (Cruz Silva, Tetrahedron 61 (2005), 3065- 3073).
  • Compounds of the general formula 1 , wherein X is a O-alkylphosphate can be prepared from the corresponding cholesterols or dihydrocholesterols (available as described above) using the literature-known phosphoramidite methodology (Beaucage, S. L.; J. Org. Chem. 2007, 72(3), 805-815; Noyori, R.; J. Am Chem. Soc. 2001, 723(34), 8165-8176; Hayakawa, Y.; Bull. Chem. Soc. Jpn. 2001 , 74(9), 1547- 1565; Noyori, R.; Tetrahedron Lett. 1986, 27(35), 4191-4194; Reviews: Bannwarth W.; HeIv. Chim.
  • X is a phosphonate or O- alkylphosphonate
  • X is a phosphonate or O- alkylphosphonate
  • the resulting phosphonates can be O-alkylated using Ci -4 alkyl halides in standard protocols known to the skilled person.
  • Synthetic methods to prepare 4-aza-cholesteryl derivatives without expanding the steroidal A-ring utilize a twofold strategy of oxidative A-ring opening (Bo ⁇ cza-Tomaszewski, Z.; Tetrahedron Lett. 1986, 27, 3767-3770) to obtain the corresponding seco-cholesteryl derivatives and subsequent ring closing in the presence of a nitrogen source (Doorenbos, N. J.; J. Org. Chem. 1961 , 26, 2546- 2548) followed by reduction of the resulting lactame derivatives to the corresponding amines (Shoppee, C.W.; J. Chem. Soc. 1962, 2275-2285 and Kim, J.C.; Bull. Korean Chem. Soc.
  • A-Nor-azasteroids can be obtained, for example, by a Favorski-type ring contraction of the corresponding 4-aza-steroids (Edwards, O. E.; Can. J. Chem. 1997, 75(6), 857-872) or by an amination-cyclocondensation sequence using seco-cholesteryl derivatives described above as substrates (Chupina, L.N.; Khimiko-Farmatsevticheskii Zhurnal 1982, 16(5), 563-567 and Rulin, V.A.; Zhumal Organicheskoi Khimii 1975, 11(8), 1763-1766).
  • the compounds provided herein are useful in the treatment (as well as prevention and/or amelioration) of infectious diseases or disorders, like viral diseases or bacterial infections.
  • Compounds provided herein have been evaluated in corresponding cell- based disease/disorder models.
  • Viral diseases to be treated in accordance with the present invention include diseases induced by a virus selected from the group consisting of influenza, HIV, Hepatitis virus (A, B, C, D), Rotavirus, Respiratory syncytial virus, Herpetoviridae (e.g. Herpes simplex virus, Epstein-Barr virus), Echovirus 1 , measles virus, Picornaviridae (e.g. Enterovirus, Coxsackievirus), Filoviridae (e.g. Ebolavirus, Marburgvirus), Papillomaviridae and Polyomaviridae.
  • the virus is influenza virus.
  • Bacterial infections to be treated in accordance with the present invention include infections induced by, inter alia, Gram-positive bacilli, Gram-positive cocci, Gram- negative bacilli and Gram-negative cocci.
  • Gram-positive bacilli are, for example, Clostridium spp., Bacillus anthracis, Erysipelothrix rhusiopathiae, Listeria monocytogenes, Nocardia spp., Corynebacterium diphtheriae and Propionibacterium acnes.
  • Gram-positive cocci are, for example, Staphylococcus aureus, and Streptococcus spp.
  • Gram-negative bacilli are, for example, Escherichia coli, Heliobacter pylori, Brucella spp., Aeromonas hydrophila, Shigella spp., Vibrio spp., Yersinia pestis, Salmonella spp., Klebsiella pneumoniae, Burkhoideria cepacia, Enterobacter spp., Pseudomonas aeruginosa, Campylobacter jejuni and Legionella pneumophila.
  • Gram-negative cocci are, for example, Neisseria gonorrhoeae and Moraxella catarrhalis
  • Bacterial infections to be treated in accordance with the present invention also include infections induced by clinical bacteria for which the Gram stain is not applicable.
  • These bacteria are, for example, Borrelia spp., Bartonella Quintana, Chlamydia pneumoniae, Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium leprae, Mycobacterium ulcerans, Mycobacterium kanasasii, Mycobacterium avium, Mycobacterium paratuberculosis, Mycobacterium scrofulaceam, Rickettsia spp. and Treponema spp.
  • a "mycobacteria-induced disease” may comprise an disorder/disease elucidated and/or related to an infection with, inter alia, M. tuberculosis, M. bovis, M. avium, M. africanum, M. kanasasii, M. intracellular, M. ulcerans, M. paratuberculosis, M. simiae, M. scrofulaceam, M. szulgai, M. xenopi, M. fortuitum, M. chelonei M. leprae and M. marinum.
  • the present invention is not limited to the treatment/prevention of a disorder caused by the pathogen agent (e.g. bacterium) per se, but comprises also the medical amelioration of a disorder caused by products produced by said pathogens, like, e.g. toxins.
  • the pathogen agent e.g. bacterium
  • the present invention is not limited to the treatment/prevention of a disorder caused by the pathogen agent (e.g. bacterium) per se, but comprises also the medical amelioration of a disorder caused by products produced by said pathogens, like, e.g. toxins.
  • Mycobacteria-induced diseases to be treated in accordance with the present invention include, inter alia, tuberculosis, leprosy, tropical skin ulcer, ulceration, abscess, pulmonary disease, granulomatous (skin) disease, opportunistic infections with non- tuberculous mycobacteria as well as diseases elicited by atypical mycobacteria such as M. avium including pulmonary disease, lymphadenitis, cutaneous and disseminated diseases, e.g. in immunocompromised patients.
  • the use is not restricted to mycobacteria-induced diseases in humans, but comprises also the use of the present invention in animal diseases, like bovine tuberculosis.
  • the mycobacteria-induced disease is tuberculosis as also documented in the appended examples.
  • biochemical/biophysical pathological process occurring on, in or within lipid rafts, accordingly, means for example, pathogen-induced abnormal raft clustering upon viral or bacterial infections, the formation of oligomeric structures of (bacterial) toxins in lipid rafts upon infection with pathogens, or the enhanced activity of signaling molecules in lipid rafts caused by a virus or bacterium. Also a tighter than normal packing of lipid rafts/lipid raft components is considered a "biochemical/biophysical pathological process" in accordance with this invention.
  • cholesterylamines as defined herein above which are believed to be capable of interfering with biological processes, in particular pathological processes taking place in, on, or within lipid rafts of cells, preferably diseased cells. These molecules may be considered as "raft modulators”.
  • Toxicity assays are well known in the art and may, inter alia, comprise lactate dehydrogenase (LDH) or adenylate kinase (AK) assays or an apoptosis assay. Yet, these (cyto)-toxicity assays are, as known by the skilled artisan, not limited to these assays.
  • the present invention provides in particular for the use of the compounds as shown in formulae 1a to 11 as well as 2a and 2b in a medical setting for the treatment of disorders and diseases which are caused by a viral or bacterial infection.
  • disorders and diseases which are caused by a viral or bacterial infection.
  • influenza infections and tuberculosis are, however, influenza infections and tuberculosis.
  • the cholesterylamines described in this invention can be applied to 1) modulate raft formation and interfere with the transport of hemagglutinin and neuraminidase to the cell surface, 2) prevent the clustering of rafts containing the spike glycoproteins induced by M proteins and, thus, interfere with virus assembly, or 3) by increasing the size/volume of lipid rafts or 4) prevent the fission of the budding pore (pinching-off) which occurs at the phase boundary of raft (viral membrane) and non-raft (plasma membrane).
  • Particularly preferred compounds in this regard are compounds 1a, 1b, 1g, 1h, 1i, 1j, 1k, 2a and 2b, and compounds 1a, 1i, 1k and 2b represent an even more preferred embodiment within the context of the present invention.
  • Corresponding experimental evidence is provided in the appended examples.
  • raft clustering is involved in the virus assembly process.
  • the compounds 1a to 11 as well as 2a and 2b have an effect in a virus replication assay.
  • the structural feature underlying this effect is thought to be represented by the combination of an amine-substitution inside the steroidal A ring and the presence of cholesteryl-type B, C, D ring including the cholesteryl-type side chain.
  • Using a 3-aminomethy! or 3-aminoethy! substitution in the A-ring results in increased potency of compound 1i or 1k, thus indicating the 3-aminomethyl or 3- aminoethyl substitution pattern as an even more preferred embodiment.
  • the above compounds can also be used in the treatment of HIV infections and in the medical management of HIV-related diseases, in particular AIDS.
  • viral diseases which may be approached with the above compounds or derivatives thereof are herpes, Ebola, enterovirus, coxsackievirus, hepatitis C, rotavirus and respiratory syncytial virus. Accordingly, particularly preferred compounds as well as preferred compounds provided herein in context of a specific (viral) assay or test system may also be considered useful in the medical intervention and/or prevention of other infectious diseases, in particular viral infections.
  • the compounds described herein may also be employed in the treatment of bacterial infections or toxicoses induced by secreted bacterial toxins.
  • Bacterial toxins such as cholera, aerolysin, anthrax and helicobacter toxin form oligomeric structures in the raft, crucial to their function.
  • the raft is targeted by binding to raft lipids such as ganglioside GM 1 for cholera.
  • prevention of oligomerization is considered to be equivalent to prevention of raft clustering, hence the same or similar compounds as those used for viral infection should be able to inhibit the activity of bacterial toxins.
  • Tuberculosis is an example of a bacterial infectious disease involving rafts.
  • Complement receptor type 3 is a receptor able to internalize zymosan and C3bi-coated particles and is responsible for the nonopsonic phagocytosis of Mycobacterium kansasii in human neutrophils.
  • CR3 has been found associated with several GPI-anchored proteins localized in lipid rafts of the plasma membrane. Cholesterol depletion markedly inhibits phagocytosis of M. kansasii, without affecting phagocytosis of zymosan or serum-opsonized M. kansasii.
  • CR3 when associated with a GPI protein, relocates in cholesterol-rich domains where M. kansasii are internalized. When CR3 is not associated with a GPI protein, it remains outside of these domains and mediates phagocytosis of zymosan and opsonized particles, but not of M. kansasii isopentenyl pyrophosphate (IPP), a mycobacterial antigen that specifically stimulates Vgamma9Vdelta2 T cells. Accordingly, the present invention also provides for the use of the compounds disclosed herein in the treatment and/or amelioration of an Mycobacterium infection, preferably of a Mycobacterium tuberculosis infection.
  • IPP isopentenyl pyrophosphate
  • compositions comprising as an active ingredient a compound of formula 1 or 2, in particular one of the formulae 1a to 11 as well as 2a and 2b as defined above.
  • the pharmaceutical compositions may optionally comprise pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives or antioxidants.
  • compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in Remington's
  • compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, rectal, nasal, topical, aerosol or vaginal administration.
  • dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets.
  • Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration.
  • Dosage forms for rectal and vaginal administration include suppositories and ovula.
  • Dosage forms for nasal administration can be administered via inhalation and insufflation, for example by a metered inhaler.
  • Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.
  • exemplary base addition salts comprise, for example, alkali metal salts such as sodium or potassium salts; alkaline-earth metal salts such as calcium or magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, diethanol amine salts or ethylenediamine salts; aralkyl amine salts such as N, N-dibenzylethylenediamine salts; heterocyclic aromatic amine salts such as pyridin salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salt
  • Exemplary acid addition salts comprise acetate, adipate, alginate, ascorbate, benzoate, benzenesulfonate, hydrogensulfate, borate, bromide, butyrate, chloride, citrate, caphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylsulfonate, phosphate, hydrogenphosphate, dihydr
  • solvates of compounds that can be used in the present invention may exist in the form of solvates with water, for example hydrates, or with organic solvents such as methanol, ethanol or acetonitrile, i.e. as a methanolate, ethanolate or acetonitrilate, respectively.
  • Pharmaceutically acceptable prodrugs of compounds that can be used in the present invention are derivatives which have chemically or metabolically cleavable groups and become, by solvolysis or under physiological conditions, the compounds of the invention which are pharmaceutically active in vivo.
  • Prodrugs of compounds that can be used in the present invention may be formed in a conventional manner with a functional group of the compounds such as with an amino or hydroxy group, e.g.
  • prodrug derivative form often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgaard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985).
  • the pharmaceutical compositions described herein can be administered to the subject at a suitable dose.
  • the dosage regiment will be determined by the attending physician and clinical factors. As is well known in the medical arts, dosages for any one patient depends upon many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently.
  • the regimen as a regular administration of the pharmaceutical composition should be in the range of 0.1 ⁇ g to 15000 mg units per day. If the regimen is a continuous infusion, it may also be in the range of 0.1 ng to 10 ⁇ g units per kilogram of body weight per minute, respectively. Progress can be monitored by periodic assessment.
  • cholesterylamines for the treatment, amelioration and/or prevention of (an) infectious disease(s) is of medical as well as pharmaceutical interest.
  • the present invention also relates to a method of treating a subject in need of such a medical treatment, said method comprising the administration of (a) cholesterylamine(s) as defined herein in an amount sufficient to elucidate a pharmaceutical effect, i.e. to ameliorate or cure the medical conditions said subject is suffering from, in particular to counter-act the infectious diseases.
  • the subject to be treated is a human. Due to the medical importance of the cholesterylamines described in context of the present invention, the invention also provides for a method for the preparation of a pharmaceutical composition which comprises the admixture of the herein defined compound with one or more pharmaceutically acceptable excipients.
  • compositions of the invention comprise, but are not limited to lipid derivatives used for liposome formation.
  • pharmaceutical composition is an emulsion.
  • an emulsion can be made of 67 w-% lipoid S 100 (Lipoid catalog number 790), ethanol (25 w-%) and glycerol (8.33 w-%) by stirring for 60 min at 37°C or until homogeneity.
  • Test compound e.g. 14.1 mg in the case of compound 1i, is dissolved in 185.9 mg formulation by mixing for 90 min at 37°C in Agilent glass tubes (volume 1.7 mL) in a thermomixer (Eppendorf). This lipid emulsion represents a pro-liposomal concentrate of the test compound.
  • lipid emulsion is diluted in 1.04 g of 0.536% NaCI solution, giving an isotonic solution, and vortexed for 20 s.
  • This liposome suspension (11.35 mg/mL test compound) is further diluted in 0.9% NaCI solution to achieve desired concentrations.
  • Synthesis of compound 1a started from dihydroepicholesterol, which was prepared from commercial 3-cholestanone using the L-selectride protocol described by Boonyarattanakalin, J. Am. Chem. Soc. 126 (2004), 16379-16386. Dihydroepicholesterol was then transformed to the corresponding mesylate followed by substitution with azide (Davis, Tetrahedron Lett. 38 (1997), 4305-4308) and subsequent reduction of the azide to amine by treatment with lithium aluminium hydride.
  • Synthesis of compound 1b started from commercial dihydrocholesterol, which was transformed to the corresponding mesylate followed by substitution with azide (Davis, Tetrahedron Lett. 38 (1997), 4305-4308) and subsequent reduction of the azide to amine by treatment with lithium aluminium hydride.
  • Example 6 Preparation of 3 ⁇ -Trimethylammonium-5 ⁇ -cholestane chloride 1e
  • a suspension of 3 ⁇ -Methylamino-5 ⁇ -cholestane 1c (1.0 eq) and sodium hydride (8.0 eq as 60% suspension in mineral oil) in dry dichloromethane was heated to reflux for 30 min.
  • Neat methyl iodide (20 eq) was added and the reaction mixture was heated at 45°C for further two days.
  • the reaction mixture was cooled and diluted with dichloromethane (50 ml_), washed repeatedly with brine and extracted with dichloromethane (3 x 100 ml_).
  • the combined organic layers were dried over sodium sulfate and concentrated in vacuo.
  • Compound 1g was prepared from 2 ⁇ ,3 ⁇ -epoxycholestane, which is available by a known procedure involving dehydration of dihydrocholesterol to 2-cholestene followed by epoxidation (Cruz Silva, Tetrahedron 61 (2005), 3065-3073). As outlined in the following, epoxide opening with benzylamine and debenzylation with hydrogen and palladium on charcoal provided aminoalcohol 1g.
  • Compound 1j was prepared as its hydrochloride salt from commercial 5 ⁇ -cholestane- 3-one via the corresponding O-trimethylsilyl-protected cyanhydrin derivative (Evans, J. Org. Chem. 39 (1974), 914-917) and subsequent treatment with lithium aluminium hydride followed by precipitation with HCI.
  • the cyanhydrin intermediate was not purified, but subjected as crude material to the hydride reduction.
  • Preparation of compound 1j by reduction of cyanhydrin derivative with lithium aluminium hydride was achieved as previously described for compound 1i, and the formation of the corresponding hydrochloride as previously described for compound 1h.
  • Compound 11 was prepared from commercial dihydrocholesterol in a one-pot procedure using the phosphoramidite method employing the commercial reagents methyl ⁇ /,N,/V,/V-tetraisopropylphosphorodiamidite, tetrazole, choline tosylate, N- phenylimidazolium trifluoromethanesulfonate and terf-butylperoxide as described in the general synthetic discussion above. The crude product was then purified by preparative HPLC resulting in isolation of the corresponding trifluoroacetate salt. MS (ESI): 568.4 M + .
  • Compound 2a was prepared from commercial cholestan-3-one via the corresponding oxime in a Beckmann-type rearrangement reaction as described by Doorenbos et al. (Doorenbos, N. J.; J. Org. Chem. 1961, 26, 2548-2549).
  • Compound 2b was prepared from commercial cholest-4,5-en-3-one via the sequence 4,5-bishydroxylation, reduction of 3-keto to 3-hydroxy, oxidative cleavage of the 3,4,5- triol using either lead tetraacetate or perchloric acid in methanol, saponification of the resulting methyl ester, condensation to 4-azacholest-4,5-en-3-one by treatment with ammonia under pressure, hydrogenation of the 5,6-double bond and reduction of the resulting lactam to 2b using lithium aluminium hydride (Bo ⁇ cza-Tomaszewski, Z.; Tetrahedron Lett. 1986, 27, 3767-3770; Doorenbos, NJ. ; J. Org. Chem.
  • the above identified compounds were evaluated for their potential in inhibiting virus replication and/or lowering virus infectivity.
  • influenza was employed.
  • Antiviral effects were evaluated by virus titration, equivalent to a traditional plaque reduction assay.
  • the present assay was carried out on microtiter plates and developed as a cell ELISA. Cells (Madin-Darby canine kidney cells, MDCK) are preincubated for 5 min with serial dilutions of test compound and then infected with serially diluted virus. Potency in the virus reproduction and infectivity assay (characterized by IC 50 and IC 90 values, i.e.
  • the following materials are used for the Focus Reduction Assay: low retention tubes and glass dilution plate (from 70% ethanol, dried under hood); two thermomixers, 1.5 ml_ Eppendorf and 96-well blocks; 96-well glass plates or glass-coated plates (Zinsser or Lab Hut) to prepare test compounds dilutions; Costar 96-well plates (black) or glass-coated Lab Hut plates containing MDCK cells 1-2 days of age; virus aliquots with known titer; IM (infection medium) supplemented with bovine serum albumin (BSA) (commercial from Celliance, catalogue number 82-046-4); 2 mg/mL stock solution of trypsin, stored in aliquots at -8O 0 C; 0.05% solution of glutaraldehyde (25% in water, Sigma catalogue number G 5882, kept at -20 0 C) in PBS (phosphate- buffered saline, dilution 1 :500), which is freshly prepared in an amount
  • test compounds which are stored at -2O 0 C as 1OmM, 5mM or 3mM stock solutions in DMSO, are thawed out at 37°C and sonicated, if necessary, in order to obtain a clear solution.
  • test compound stock solutions are added in the following manner (example calculated for a 1OmM test compound stock solution): for a 100 ⁇ M test compound solution: 1078 ⁇ l_ IM + 22 ⁇ l_ test compound stock solution; for a 50 ⁇ M test compound solution: 1089 ⁇ l_ IM + 11 ⁇ l_ test compound stock solution; for a 25 ⁇ M test compound solution: 1094 ⁇ L IM + 5.5 ⁇ l_ test compound stock solution; for a 10 ⁇ M test compound solution: 1098 ⁇ L IM + 2.2 ⁇ L test compound stock solution.
  • test compound solutions are shaken for 30 to 60 min and transferred into a 96-well glass plate, which was preheated in a thermomixer microplate block at 37 0 C.
  • a thermomixer microplate block For two titration plates one glass plate is used, the left half receives the test media for plate 1 , the right half for plate 2.
  • Each well receives 250 ⁇ L test compound solution or control medium (see template below).
  • the test compound dilutions 100 ⁇ L each) are transferred using a multichannel pipette from the glass dilution plate to the MDCK cell culture plate.
  • virus dilutions e.g. 2 x 10 ⁇ 6 foci forming units, I x IO "6 foci forming units or 5 x 10 ⁇ 7 foci forming units, so that the 2 x 10 "6 foci forming units dilution will generate 50 to 100 foci.
  • virus dilutions were determined by virus titration. All virus dilutions are prepared in IM.
  • the virus is prediluted 1 :64 in IM (i.e. 630 ⁇ L IM + 10 ⁇ L virus solution).
  • IM 1 :2000 1
  • For one 96-well plate 3 mL, 1.5 mL, and 1.5 mL of such solutions are prepared, for two plates 6 mL, 3 mL, and 3 mL, and these solutions are kept at 4°C.
  • a 20 ⁇ g/mL solution of trypsin is prepared and passed through a 0.2 ⁇ m sterile syringe filter, and then diluted to 4 ⁇ g/mL in IM.
  • virus dilutions are added, whereby the pipette tips are changed every time.
  • the well content is pipetted up and down.
  • the plate is incubated at 37 0 C for 16 h. Toxicity/cell morphology/precipitation in mock-infected wells is assessed by microscopy.
  • the infection is terminated by fixing and immersing/filling the whole plate with 250 mL of a 0.05% glutaraldehyde solution in PBS for at least 20 min at room temperature.
  • Step 3 Detection
  • the glutaraldehyde solution is shaken off and the plate is rinsed with PBS, permeabilized with 50 ⁇ L of 0.1 % Triton X-100 in PBS for 30 min and rinsed again with PBS.
  • the wells are blocked on a rocker for 1h at room temperature or overnight at 4 0 C with 200 ⁇ L per well of a mixture of PBS + 10% heat-inactivated fetal calf serum (block), followed by 1 h treatment with 50 ⁇ L per well antibody to viral nucleoprotein (MAb pool 5, US Biological I7650-04A) diluted 1 :1000 in block.
  • the antibody is removed by three times 5 min washes with TBS (tris-buffered saline) + 0.1 % Tween.
  • a 1 h incubation follows with 50 ⁇ L per well of a secondary anti-mouse antibody, conjugated to horseradish peroxidase, which is 1 :2000 diluted in block.
  • the plate is put on a rocker for 1 h at room temperature, washed three times with TBS/0.1% Tween and once with TBS.
  • microtiter wells are filled with 50 ⁇ L substrate solution (SuperSignal West Dura, Pierce 34076) which is prepared just before use by mixing equal volumes of the two components.
  • substrate solution SuperSignal West Dura, Pierce 34076
  • the plates are then placed in the Fresnel lense rack of the CCD camera LAS 3000 (Fuji/Raytest) and exposed at high resolution for 10 min.
  • I [0.25 x i(well b) + 0.5 * i(well c) + i(well d)] / 1.75 wherein i is defined by 10000 times the intensity per area measured for the relevant well b, c or d. This calculation corresponds to the classical plaque assay. The factors represent the weighting of the individual values.
  • Results are expressed as % inhibition defined as follows:
  • % inhibition 100 - % control wherein % control is calculated by multiplying a given I for test compound by 100 and dividing by I for the appropriate solvent control. If I is a control or solvent control, its value is set as 100 %.
  • This evaluation to quantify the assay results is made for a series of different test compound concentrations, e.g. 100 ⁇ M, 50 ⁇ M, 25 ⁇ M, 10 ⁇ M, 2.5 ⁇ M, 0.25 ⁇ M, 0.1 ⁇ M, whereby it is ensured that the highest concentration used in this series is nontoxic, as evaluated in a toxicity assay using MDCK Il cells prior to IC 50 /IC 90 evaluation.
  • cholesterylamines showed strong inhibitory effects in the PR8 (H1 N1) virus replication assay (as a cellular model for influenza infection).
  • PR8 H1 N1 virus replication assay
  • compounds 1a to 11, 2a and 2b yielded good results (Table 1).
  • Table 1 the combination of the cholestane scaffold with an amino function either attached to the steroidal A-ring (cholesterylamines and derivatives thereof) or being part of it (azacholestanes, azahomocholestanes or derivatives thereof) is a structural motif leading to inhibition of viral replication.
  • cholesteryl sulfate provided no inhibition of viral replication when tested at concentrations of 10, 20 and 50 ⁇ M, whereby at 50 ⁇ M and higher concentrations toxicity was observed.
  • cholesteryl- 3 ⁇ -glycolic acid displaying a negatively charged function under assay conditions
  • 3-oximocholestane showing a nitrogen atom attached to the A-ring of the cholesteryl core structure
  • 3-keto-4 ⁇ ,5 ⁇ -cholestanediol IC 50 16.0 ⁇ M
  • 3 ⁇ ,4 ⁇ ,5 ⁇ -cholestanetriol IC 5O 16.1 ⁇ M
  • compounds 1a to 11 and compounds 2a and 2b are preferred compounds for the pharmaceutical intervention in influenza infection.
  • Eight of these compounds i.e. compounds 1a, 1b, 1g, 1h, 1i, 1j, 1k and 2a provided for particularly good results in the influenza virus replication assay. Furthermore, these compounds showed good results in solubility tests and therapeutic indices.
  • the solubility of cholesterylamines in a polar medium increases with increasing substitution of hydrogen atoms attached to the steroidal A-ring by hydroxy functions, so that a slight decrease of potency is counterbalanced by an increased solubility, which may lead to increased bioavailability.
  • compounds 1g and 1i are preferred molecular entities for the treatment of viral infections, in particular influenza infections.
  • Example 16 Antimicrobial Activity Assay The aim of this assay is the identification of compounds having antituberculosis activity, as evaluated using the strain M. tuberculosis H 37 RV as disease model for tuberculosis. Potency in antimicrobial assays (MIC 90 ) was evaluated as described below and compared to toxicity in mammalian Vera cells.
  • Microplate Alamar Blue Assay used as aerobic replication assay
  • LORA Low Oxygen Recovery Assay
  • NRP non-replicating persistence
  • LORA luminescence-based low oxygen-recovery assay
  • tuberculosis H 37 Rv containing a plasmid with an acetamidase promoter driving a bacterial luciferase gene was adapted to low oxygen conditions by extended culture in a fermentor and MIC 90 was determined in microplate cultures maintained under anaerobic conditions for 10 days. Percent inhibition was determined as for MABA.
  • cholesterylamine derivatives to be used in accordance with the present invention also inhibit bacterial growth.
  • compounds 1a, 1f, 1h, 1i, 2a and 2b provided good results (Table 2).
  • the combination of the cholestane scaffold with an amino function attached to the steroidal A-ring is a preferred structural motif in the inhibition of mycobacterial growth, in particular Mycobacterium tuberculosis.
  • cholesteryl sulfate or - ⁇ a ⁇ s-2-aminomethyl-i-cyclohexanol provided no corresponding effect on mycobacteria when tested at concentrations up to 100 ⁇ M. It was also found that incorporation of the amino moiety into the steroidal A-ring provides azacholesteryl derivatives which efficiently inhibit bacterial growth as exemplified by the MABA assay (Table 2).
  • the combination of the cholestane scaffold with a nitrogen which is incorporated into the steroidal A-ring or analogue derivatives with an expanded or constricted A-ring are preferred structural motifs for the inhibition of mycobacterial growth, in particular Mycobacterium tuberculosis, as exemplified by compounds 2a and 2b.
  • Table 2 Inhibition of replication of M. tuberculosis (strain H 37 Rv) by examples provided herein.
  • Compounds 1a, 1f, 1h, 1i, 2a and 2b are preferred compounds for the pharmaceutical intervention of mycobacterial diseases, in particular of tuberculosis.
  • compounds 1f and 1h represent even more preferred compounds to be used in the pharmaceutical compositions for the treatment of mycobacterial diseases, like tuberculosis.
  • compounds 1a and 2a When evaluating the potential of test compounds to target the persistent bacterial subpopulation, it was found that compounds 1a and 2a provided for particularly good results in the LORA model. Thus, compounds 1a and 2a represent particularly preferred compounds to be used in pharmaceutical compositions for treating persistent Mycobacterium tuberculosis phenotypes.

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Abstract

La présente invention concerne l'utilisation de cholestérylamines dans la préparation des compositions pharmaceutiques. Ces compositions pharmaceutiques sont destinées à être utilisées dans l'intervention médicale des maladies infectieuses, en particulier des maladies causées par un virus ou une bactérie.
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US20190169227A1 (en) * 2016-06-22 2019-06-06 University Of Maryland, Baltimore Method for production of novel galeterone analogs and uses thereof
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