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WO2009090063A1 - Dérivés de sapogénine stéroïde, androstane et sapogénine triterpénoïde pour le traitement et la prévention de maladies infectieuses - Google Patents

Dérivés de sapogénine stéroïde, androstane et sapogénine triterpénoïde pour le traitement et la prévention de maladies infectieuses Download PDF

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Publication number
WO2009090063A1
WO2009090063A1 PCT/EP2009/000216 EP2009000216W WO2009090063A1 WO 2009090063 A1 WO2009090063 A1 WO 2009090063A1 EP 2009000216 W EP2009000216 W EP 2009000216W WO 2009090063 A1 WO2009090063 A1 WO 2009090063A1
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hpv
virus
compound according
mycobacterium
compound
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Hans-Joachim KNÖLKER
Sameer Agarwal
Georg Schlechtingen
Tobias Braxmeier
Cornelia Schroeder
Gary Jennings
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Technische Universitaet Dresden
Jado Technologies GmbH
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Technische Universitaet Dresden
Jado Technologies GmbH
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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • 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
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • 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
    • A61P31/04—Antibacterial agents
    • A61P31/08—Antibacterial agents for leprosy
    • 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
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • 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 steroid sapogenin, androstane and triterpenoid sapogenin derived amines or ammonium derivatives in the medical intervention of infectious diseases, in particular diseases caused by a virus or a bacterium, including drug-resistant strains.
  • 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;
  • 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 analyzed) but they can coalesce 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 (Simons, J. Clin. Invest. 110 (2002), 597-603; 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.
  • 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.
  • 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).
  • 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 (Peyron, J. Immunol. 165 (2000), 5186-5191).
  • bacterial cytoplasmic membrane domains are functionally and to an extent structurally analogous to mammalian lipid rafts.
  • WO 01/22957 describes the use of gangliosides for the modulation of sphingolipid/cholesterol microdomains.
  • WO 01/23406, WO 01/23407 and WO 01/49703 disclose the use of certain substituted sapogenins in the treatment of cognitive dysfunction and similar conditions.
  • WO 02/79221 discloses certain steroidal sapogenins and derivatives thereof, and their use in the treatment of cognitive dysfunction, non-cognitive neurodegeneration, non- cognitive neuromuscular degeneration, and receptor loss in the absence of cognitive, neural and neuromuscular impairment.
  • WO 03/082893 describes therapeutic methods and uses of certain steroidal sapogenins, related compounds and derivatives thereof, in the treatment of non-cognitive neurodegeneration, non-cognitive neuromuscular degeneration, motor-sensory neurodegeneration or receptor dysfunction or loss in the absence of cognitive, neural and neuromuscular impairment.
  • WO 02/26762 describes certain triterpenes having antibacterial activity, wherein said triterpenes include betulin, allobetulin and lupeol.
  • WO 03/62260 provides certain quarternary amine derivatives of betulin and other triterpenes having antibacterial, antifungal and surfactant properties.
  • WO 07/101873 describes the use of certain betulonic and betulinic acid derivatives for the treatment of cancer or a viral infection.
  • 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.
  • amino-substituted steroid sapogenin, androstane and triterpenoid sapogenin derivatives are suitable for the medical management of infectious diseases, in particular disorders or diseases caused by viral agents and bacteria.
  • the present invention provides a compound of one of the following formulae 1 , 2 or 3:
  • disorders or diseases may be caused by a virus or bacterium, including drug-resistant bacteria.
  • the general formulae given in the present invention are intended to cover all possible stereoisomers and diastereomers of the indicated compounds. Unless indicated differently, the stereochemical configuration of naturally occurring steroid sapogenin, androstane and triterpenoid sapogenin derivatives as shown in the exemplified compounds is preferred.
  • R 1 , R 2 , R 3 , if R 3 is present, R 4 , if R 4 is present, and R 5 is a linear amine-containing group selected from X(CH 2 ) n NH 2 , X(CH 2 ) H NH(Ci -4 alkyl), X(CH 2 ) O N(Ci -4 alkyl) 2 or X(CH 2 ) n N(Ci-4 alkyl) 3 + , or a cyclic amine-containing group selected from piperidin-1-yl, 1-(Ci -4 alkyl) + -pipehdin-1-yl, morpholin-4-yl or 4-(Ci -4 alkyl) + -morpholin-4-yl.
  • R 1 , R 2 , R 3 , if R 3 is present, R 4 , if R 4 is present, and R 5 is the linear amine-containing group, preferably X(CH 2 ) n NH 2 .
  • R 1 , R 2 , R 3 , if R 3 is present, R 4 , if R 4 is present, and R 5 is the cyclic amine-containing group, preferably piperidin-1-yl or morpholin-4-yl.
  • R 4 is not the amine-containing group and one of R 1 , R 2 , R 3 , if R 3 is present, and R 5 is the amine-containing group. Yet, in most embodiments of the compounds described herein, only R 5 is the amine-containing group.
  • X is a direct bond or a phosphorus-containing group selected from OP(O)(CT)O, OP(O)(OC 1-4 alkyl)O, OP(O)(O " )CH 2 O or OP(O)(OCi -4 alkyl)CH 2 O.
  • P is attached to the A ring via O and to the amine-containing moiety (i.e. to (CH 2 )nNH 2 , (CH 2 )HNH(Ci -4 alkyl), (CH 2 J n N(Ci -4 alkyl) 2 or (CH 2 )nN(Ci- 4 alkyl) 3 + ) via CH 2 O.
  • X is a direct bond. In one embodiment of formula 1 or 3, X is OP(O)(O-)O. In another embodiment of formula 1 or 3, X is OP(O)(OCi -4 alkyl)O. In yet another embodiment of formula 1 or 3, X is OP(O)(O-)CH 2 O. In a further embodiment of formula 1 or 3, X is OP(O)(OC 1 ⁇ alkyl)CH 2 O.
  • X is a direct bond or a phosphorus-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.
  • P is attached to the A ring via O and to the amine- containing moiety (i.e. to (CH 2 ) n NH 2 , (CH 2 ) n NH(d ⁇ alkyl), (CH 2 ) n N(C 1-4 alkyl) 2 or (CH 2 ) P iN(C 1-4 alkyl) 3 + ) via CH 2 O.
  • X is a direct bond.
  • X is OP(O)(OCi -4 alkyl)O. In yet another embodiment of formula 2, X is OP(O)(O-)CH 2 O. In a further embodiment of formula 2, X is OP(O)(OC 1 ⁇ 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 , if R 3 is present, and R 4 , if R 4 is present, are independently H or OH.
  • R 6 is H or, when X is a direct bond and n is 1 or 2, R 6 can also be OH.
  • R 6 is H.
  • R 2 is the amine-containing group
  • R 3 if R 3 is present, 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.
  • R 4 is the amine-containing group
  • R 2 and R 6 are independently H or OH.
  • the compound of formula 1 , 2 or 3 contains one to four hydroxy! groups.
  • the hydroxyl groups increase solubility of the material in an amphiphilic or polar medium which can be advantageous in medical applications.
  • R 7 is a C 6-H aliphatic group, such as C 6 -n alkyl, C 6- n alkylidene or C 6- n alkenyl, provided that R 7 is not the branched C 8 alkyl occurring in natural cholesterol, i.e. 2-methyl-hept-6-yl.
  • R 7 is linear C 5 - 11 alkyl, linear C 6- n alkylidene or linear C 6 -n alkenyl, in which one or more (preferably one) hydrogens are optionally replaced by a methyl group (the total number of carbon atoms after replacement of hydrogen by methyl is to be 6 to 11).
  • R 7 is C 7-I2 alkyl, in which one or two (preferably one) CH 2 is/are replaced by oxygen (the total number of carbon atoms after replacement of the CH 2 by O is to be 6 to 11).
  • R 7 is a C 9-H aliphatic group comprising a linear C 6 alkyl or a linear C 6 alkenyl main chain and three or four side chains independently selected from methyl or ethyl (the total number of carbon atoms is to be 9 to 11 ).
  • R 7 is the branched C 8 alkyl occurring in natural cholesterol, i.e. 2-methyl-hept-6-yl.
  • R 8 , R 9 and R 10 are independently C 1-4 alkyl, C 1-4 alkenyl or H. Preferably, at least one of R 8 , R 9 and R 10 is H.
  • n is 1 or 2. In one embodiment, m is 1 and R 9 and R 10 are preferably H. In another embodiment, m is 2 and R 9 is preferably C 1-4 alkyl, more preferably CH 3 .
  • R 11 is H or 0(C 1-4 alkyl). Preferably, R 11 is H or OCH 3 .
  • m is 2, R 8 and R 9 are both CH 3 , R 10 is H and R 11 is OCH 3 .
  • m is 2, R 8 is H, R 9 and R 10 are both CH 3 and R 11 is OCH 3 .
  • m is 1 , R 8 is prop-2-yl or propen-2-yl, R 9 and R 10 are both H and R 11 is H or OCH 3 .
  • the compound of formula 1 , 2 or 3 contains 0 or 1 hydroxyl groups. In another embodiment, the compound of formula 1 , 2 or 3 does not contain any hydroxyl group.
  • R 5 is the linear amine-containing group
  • R 1 , R 2 , R 3 , if R 3 is present, and R 4 , if R 4 is present, are independently H or OH;
  • R 5 is the linear amine-containing group
  • R 1 , R 2 , R 3 , if R 3 is present, and R 4 , if R 4 is present, are independently H or OH
  • R 6 is H
  • X is the phosphorus-containing group
  • R 7 is linear C 6- - I 1 alkyl, linear C 6-11 alkylidene or linear C 6- - I1 alkenyl, in which one or more hydrogens are optionally replaced by a methyl group (the total number of carbon atoms after replacement of hydrogen by methyl is to be 6 to 11);
  • compounds 2a to 2g are preferred.
  • compound 2h is preferred.
  • the compounds to be used in accordance with the present invention can be prepared by standard methods known in the art.
  • Compounds of the general formula 1 can be prepared starting from commercially available steroid sapogenin derivatives, e.g. diosgenin, sarsasapogenin, smilagenin, and the corresponding stereoisomers thereof.
  • Compounds of the general formula 2 can be prepared starting from commercially available steroid derivatives, e.g. androsterone, pregnolone, stigmasterol, 3- cholestanone, and isomers thereof.
  • Various side chains can be introduced via the 17- or 20-keto derivatives using Wittig- or Wittig-type reactions.
  • O-alkylations can be used to generate various ether-decorated side chain motifs.
  • the corresponding alkyl precursors for Wittig or alkylation reactions are either commercially available or can be easily prepared by standard techniques.
  • Compounds of the general formula 3 can be prepared starting from commercially available triterpenoid sapogenin derivatives, e.g. ursolic acid, oleanolic acid, betulinic acid, betulin or lupeol, and the corresponding stereoisomers thereof.
  • triterpenoid sapogenin derivatives e.g. ursolic acid, oleanolic acid, betulinic acid, betulin or lupeol, and the corresponding stereoisomers thereof.
  • the various A-ring substitution patterns of compounds of the general formula 1 , 2 or 3 can be prepared from the corresponding hydroxy or keto derivatives using methods, protocols and/or synthetic strategies described and/or developed for cholesteryl or cholestane derivatives or similar steroid derivatives.
  • Compounds of the general formula 1 , 2 or 3 wherein X is a direct bond and which have a primary amino function at position 3, can be prepared from the corresponding alcohol via the sequence sulfonate-azide-amine.
  • a ketone e.g. 3- androstanone
  • substrate for reductive aminations with a plethora of (commercially available) amines.
  • standard strategies can be used, such as Mitsunobu reactions or stereoselective reductions of ketones using L-selectride followed by the sequence sulfonate-azide- amine.
  • the corresponding ketone can be used as synthetic precursor, which can be produced similar to cholestane derivatives as described 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-androstanone.
  • allyl amines can be prepared from a suitable 2 ⁇ ,3 ⁇ -epoxy-5 ⁇ - androstane derivative 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 ⁇ -androstane derivatives are, for example, available via meta-chloroperbenzoic acid mediated epoxidation of the corresponding 5 ⁇ -androst-2-ene derivative which itself can be prepared as described in the literature for cholestane derivatives (Cruz Silva, Tetrahedron 61 (2005), 3065-3073).
  • 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.
  • the present invention provides in particular for the use of the compounds as shown in formulae 1a to 1d as well as 2a to 2i and 3a to 3d in a medical setting for the treatment of disorders and diseases which are caused by a viral or bacterial infection.
  • mycobacterial infections such as tuberculosis, and influenza infections.
  • more detailed information on diseases and disorders is given.
  • raft modulators steroid sapogenin, androstane and triterpenoid sapogenin derivatives 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".
  • 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.
  • 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.
  • a tighter than normal packing of lipid rafts/lipid raft components or a direct bacteriocidal effect on the bacterial membrane is considered a "biochemical/biophysical pathological process" in accordance with this invention.
  • bacterial infections such as tuberculosis, shigellosis and infection by Chlamydia and uropathogenic bacteria
  • the organism is taken up into the cell in a raft- dependent internalization process often involving caveolae.
  • caveolae which depend on a cholesterol binding protein, caveolin, exclusion of cholesterol from the raft with steroid sapogenin, androstane or triterpenoid sapogenin derivatives may prevent uptake of the pathogen.
  • Bacterial infections to be treated in accordance with the present invention include in particular infections induced by clinically and medically relevant bacteria and corresponding bacterial strains.
  • Such bacteria or strains comprise, for example, Borrelia spp., Bartonella quintana, Chlamydia trachomatis, Chlamydophila pneumoniae, Chlamydophila felis, Chlamydophila psittaci, Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium leprae, Mycobacterium ulcerans, Mycobacterium kanasasii, Mycobacterium avium, Mycobacterium paratuberculosis, Mycobacterium scrofulaceam, Mycobacterium microti, Mycobacterium africanum, Mycobacterium canettii, Mycobacterium intracellular, Mycobacterium simiae, Mycobacterium szulgai, Mycobacterium xenopi, Mycobacterium fort
  • the compounds of the present invention are in particular of medical relevance in a treatment and medical intervention of mycobacterial disorders/diseases, like tuberculosis and leprosis.
  • a "mycobacteria-induced disease” may comprise a 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, M. marinum, M. microti and M. canettii.
  • the appended examples provide in particular data for the inventive use of the compounds disclosed herein in the treatment and/or prevention of tuberculosis, i.e. an infection caused by M. tuberculosis.
  • the present invention is not limited to the treatment/prevention of a disorder/disease caused by the pathogen agent (e.g. bacterium) per se, but comprises also the medical amelioration of a disorder/disease caused by products produced by the 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.
  • the mycobacteria-induced disease is caused by bacterial strains resistant to standard drugs for the treatment of tuberculosis as described in more detail below.
  • the present invention also provides for the use of the compounds disclosed herein in the treatment and/or amelioration of a Mycobacterium infection, preferably of a Mycobacterium tuberculosis infection.
  • preferred compounds for the medical intervention or prevention of bacterial infections caused by Mycobacteria are compounds 1a, 1c and 1d, 2a to 2c, 2e, 2f, 2h, 2i and 3a to 3d; particularly preferred compounds are 1a, 1c and 1d as well as 2a, 2c, 2h and 3a to 3d.
  • the present invention also provides for the medical use of these compounds in pharmaceutical and medical interventions of other bacterial or viral infections.
  • the cell wall of M. tuberculosis in its full structural and functional integrity, is essential for growth and survival of the bacterial cell in the infected host.
  • some of the most effective antituberculosis agents including isoniazid (INH) act on cell wall targets, for instance by inhibiting the biogenesis of cell wall components (Chatterjee, D.; Curr. Opin. Chem. Biol. 1997, 1, 579-588; and literature cited therein).
  • Rifamycins form another class of drugs used for standard treatment of tuberculosis. They act via inhibition of bacterial RNA synthesis by binding to the beta-subunit of the DNA- dependent polymerase. Remarkably, rifamycins are the only clinically used antibiotics with this mechanism, and rifampin (RMP) is the most prominent example of the rifamycins.
  • Drug resistance may, in the context of this invention, be defined as a decrease in the in vitro susceptibility of infectious agents, e.g. bacteria like M. tuberculosis, of sufficient degree to be reasonably certain that the strain concerned of said infectious agent is different from a corresponding wild strain that has never come into contact with the drug, and it comprises primary drug resistance and acquired drug resistance (see, e.g. "Anti-tuberculosis Drug Resistance in the World.
  • second line drugs such as ethionamide, thiacetazone, para-aminosalicylic acid, cycloserine, streptomycin, kanamycin, capreomycin, or the fluoroquinolones, e.g. ofloxacin, moxifloxacin) used for the treatment of tuberculosis.
  • Multidrug-resistant tuberculosis is a form of tuberculosis (TB) that is resistant to two or more of the primary drugs used for the treatment of tuberculosis.
  • Extensively drug-resistant TB is as form of tuberculosis resistant to at least isoniazid and rifampin among first-line anti-TB drugs and among second-line drugs, is resistant to any fluoroquinolone and at least one of the injectable drugs (Raviglione, M.; N. Engl. J. Med. 2007, 356, 7).
  • M. tuberculosis strains in particular said drug-resistant or multidrug- resistant strains and clinical isolates, to be treated with the compounds described herein are, inter alia, NCTC 8337 (OV 185/10; ATCC® 25584), H 37 Rv (ATCC® 25618), H 37 Rv(mma1), H 37 Ra, HN34, HN35, HN40, HN59, HN88, HN93, HN224, HN386, NHN5, NHN50, Aoyama B (ATCC® 31726), TMC 102 (H 37 Rv; ATCC® 27294), TMC 106 (Summit Park; ATCC® 35800), TMC 107 (Erdman; ATCC® 35801), TMC 108 (Campbell; ATCC® 35802), TMC 109 (NIH-199RB; ATCC® 35803), TMC 110 (Amerzaga; ATCC® 35804), TMC 111 (Kerrigan; ATCC® 3580
  • Bacterial infections to be treated in accordance with the present invention also 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., Corynebactehum diphtheriae and Propionibactehum 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, Burkholderia cepacia, Enterobacter spp., Pseudomonas aeruginosa, Campylobacter jejuni and Legionella pneumophila.
  • Gram-negative cocci are, for example, Neisseria gonorrhoeae and Moraxella catarrhalis.
  • Bacterial toxins are known in the art and comprise, inter alia, toxins as produced by Vibrio cholerae, aerolysin as, inter alia, produced by Aeromonas spp., anthrax as produced by Bacillus anthracis or helicobacter toxin. These toxins may form oligomeric structures in the raft, crucial to their function.
  • the raft is targeted by binding to raft lipids such as ganglioside GM1 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.
  • the person skilled in the art, in particular an attending physician is readily in a position to adopt the treatment regime with the herein defined steroid sapogenin, androstane and triterpenoid sapogenin derived amines or ammonium derivatives in the treatment of a bacterial infection per se and/or in the amelioration of disorders and diseases caused by the corresponding toxins.
  • Diseases/disorders to be treated in accordance with the present invention also include, inter alia, borreliosis, relapsing fever, trench fever, endocarditis, cervicitis, conjunctivitis, diseases of the thyphos group, diseases of the spotted fever group, pinta and syphilis.
  • Viral diseases to be treated in accordance with the present invention include diseases induced by a virus selected from the group consisting of influenza virus (A, B, C), HIV, Hepatitis virus (A, B, C, D, E), Rotavirus, Respiratory syncytial virus, Herpetoviridae (e.g. Herpes simplex virus, Epstein-Barr virus), Echovirus 1 , measles virus, Picornaviridae (e.g. Enterovirus, Coxsackie virus), Filoviridae (e.g. Ebola virus, Marburg virus), Papillomaviridae (e.g.
  • a virus selected from the group consisting of influenza virus (A, B, C), HIV, Hepatitis virus (A, B, C, D, E), Rotavirus, Respiratory syncytial virus, Herpetoviridae (e.g. Herpes simplex virus, Epstein-Barr virus), Echovirus 1 , measles virus, Picornavirida
  • human papilloma viruses HPV-1 , HPV-2, HPV- 3, HPV-4, HPV-5, HPV-6, HPV-7, HPV-10, HPV-11 , HPV-13, HPV-16, HPV-18, HPV- 31 , HPV-32, HPV-33, HPV-35, HPV-39, HPV-42, HPV-43, HPV-44, HPV-45, HPV-51 , HPV-52, HPV-55, HPV-56, HPV-58, HPV-59, HPV-68, HPV-73, HPV-82) and Polyomaviridae.
  • the virus to be treated is influenza virus or HIV.
  • the steroid sapogenin, androstane and triterpenoid sapogenin derived amines or ammonium derivatives 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) or 5) disrupt the envelope of the free virus to render it non-infectious or of reduced infectivity (virucidal effect).
  • the compounds 1a to 1d as well as 2b to 2g have an effect in a virus replication assay.
  • Preferred in this context are the compounds 1a to 1d as well as 2b, 2e and 2g; particularly preferred are compounds 1a, 1 b, 1c, 2e and 2g.
  • the structural feature underlying this effect is thought to be represented by the combination of an amine-substitution at the steroidal A ring and the presence of a steroid-type B, C, D ring system having a hydrocarbon side chain, including hydrocarbon side chains comprising an oxa function, or having an additional E, F ring system displaying a spiroacetal system as provided by the steroid sapogenin scaffold. Additional decoration with hydroxy functions inside the A ring might provide compounds of increased solubility, thus enhancing bioavailability. As demonstrated by the results obtained in the viral replication assay described in the experimental part, these compounds may be useful for pharmaceutical intervention.
  • 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, coxsackie virus, hepatitis C, rotavirus and respiratory syncytial virus. Accordingly, particularly preferred compounds as well as preferred compounds provided herein in the 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 are also evaluated in several toxicity assays.
  • 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.
  • LDH lactate dehydrogenase
  • AK adenylate kinase
  • cytotoxicity of test compounds was evaluated in mammalian Vero cells and in J774A.1 macrophages, which are a widely used assay model particularly useful for the evaluation of toxicity of lipophilic compounds showing limited solubility.
  • these (cyto)-toxicity assays are, as known by the skilled artisan, not limited to these assays.
  • compositions comprising as an active ingredient a compound of formula 1 , 2 or 3, in particular one of the formulae 1a to 1d, 2a to 2i as well as 3a to 3d 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.
  • the compounds described herein may be administered in the context of a monotherapy or in combination with one or more other anti-infective pharmaceutical agents, in particular for the treatment of a primary infection complicated by one or more co- infections.
  • a combination therapy might be of particular use for the treatment or prevention of infections caused by drug resistant or multi-drug resistant bacterial strains.
  • infections caused by viral agents may be employed in co- therapeutical medical interventions in viral infections like the HAART therapy in HIV infections.
  • the pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in Remington's Pharmaceutical Sciences, 20 th Edition.
  • the pharmaceutical 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.
  • Pharmaceutically acceptable salts of compounds that can be used in the present invention can be formed with various organic and inorganic acids and bases.
  • 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 pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium 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.
  • 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. as carbamates esters or glycosides.
  • the 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/patient 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 depend 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.
  • the subject/patient is a mammal; more preferably, the subject/patient is a human.
  • 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) compound of one of the formulae 1 , 2 or 3 as defined herein or a pharmaceutically acceptable salt, derivative, solvate or prodrug thereof 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/disorders.
  • the subject to be treated is a mammal.
  • the subject to be treated is a human.
  • the present invention further relates to the use of a compound of one of the formulae 1 , 2 or 3 as defined herein or a pharmaceutically acceptable salt, derivative, solvate or prodrug thereof for the preparation of a medicament for the treatment, prevention and/or amelioration of an infectious disease/disorder.
  • 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 excipierits.
  • a pharmaceutical composition which comprises the admixture of the herein defined compound with one or more pharmaceutically acceptable excipierits.
  • Corresponding excipients are mentioned herein above and comprise, but are not limited to lipid derivatives used for liposome formation.
  • the pharmaceutical composition of the invention be administered by injection or infusion, it is preferred that the pharmaceutical composition is an emulsion.
  • preferred compounds for the medical intervention in tuberculosis and/or an infection with M. tuberculosis are compounds of formula 1a, 1c, 1d, 2a, 2b, 2c, 2e, 2f, 2h, 2i, 3a, 3b, 3c or 3d. These compounds are also useful in the medical intervention of (drug-) resistant strains of mycobacteria. Again, selective examples are provided in the appended experimental data and results. Similarly, preferred compounds for the medical intervention in influenza infection and/or viral hepatitis are compounds of formula 1a, 1b, 1c, 1d, 2b, 2c, 2d, 2e, 2f or 2g. Also for these selective compounds experimental data and non-limiting examples are provided below.
  • Examples 1 , 2, 3 and 4 Preparation of 3 ⁇ -amino-5 ⁇ ,6-dihydrodiosgenin (1a), 3 ⁇ - amino-5 ⁇ ,6-dihydrodiosgenin (1b), 3 ⁇ -methylamino-5 ⁇ ,6-dihydrodiosgenin (1c), and 3 ⁇ -aminomethyl-5 ⁇ ,6-dihydrodiosgenin (1d)
  • diosgenin was transformed to 5,6-dihydrodiosgenin by hydrogenation with hydrogen and palladium on charcoal.
  • Compound 1c was obtained by reductive amination of the 3-ketone using a solution of methylamine in tetrahydrofuran and sodium trisacetoxy borohydride.
  • Compound 1d was prepared via a two-step process using treatment with tosylmethylisocyanide followed by reduction of the resulting isocyanide with hydrogen and Raney nickel.
  • Examples 5 and 6 Preparation of 3 ⁇ -amino-17 ⁇ -hexyl-5 ⁇ -androstane (2a) and 3 ⁇ -amino-c/s- ⁇ 17(20) -17-hexylidene-5 ⁇ -androstane (2c)
  • Starting from commercial androsterone Wittig reaction with n-hexyl triphenylphosphonium bromide provided 17-hexylidene-3 ⁇ -androstanol, which was transformed to the corresponding 3 ⁇ -azide by mesylation followed by treatment with sodium azide in dimethylsulfoxide. Then, reaction with lithium aluminium hydride afforded amine 2c. Subsequent hydrogenation using palladium on charcoal as catalyst provided saturated amine 2a.
  • Example 7 Preparation of 3 ⁇ -aminomethyl-17 ⁇ -hexyl-5 ⁇ -androstane (2b) Oxidation of the above mentioned 17-hexylidene-3 ⁇ -androstanol to the corresponding 3-keto derivative with pyridinium chlorochromate (PCC) followed by treatment with tosylmethylisocyanide (TosMIC), chromatographic separation of the obtained epimers and subsequent reactions with lithium aluminium hydride and hydrogen in the presence of palladium on charcoal provided compound 2b.
  • PCC pyridinium chlorochromate
  • TosMIC tosylmethylisocyanide
  • stigmasterol was completely saturated by hydrogenation using hydrogen and palladium on charcoal. Subsequent oxidation of the alcohol to the 3- ketone with PCC followed by reductive amination with methylamine and sodium trisacetoxy borohydride provided compound 2e.
  • Example 11 Preparation of 3 ⁇ -aminoethyl-17 ⁇ -(6-oxadodec-2-yl)-5 ⁇ -androstane (2g)
  • Commercial pregnolone was transformed to the corresponding terf-butyldimethylsilyl ether followed by Wittig reaction with commercial (3-benzyloxypropyl)triphenyl- phosphonium bromide.
  • Wittig reaction with commercial (3-benzyloxypropyl)triphenyl- phosphonium bromide.
  • O-alkylation with sodium hydride and n-hexyl iodide established the 17 ⁇ -(6- oxadodec-2-yl) side chain.
  • Example 12 and 13 Preparation of 3 ⁇ -(piperidin-1-yl)-5 ⁇ -cholestane (2h) and 3 ⁇ - (morpholin-4-yl)-5 ⁇ -cholestane (2i)
  • Compounds 2h and 2i were prepared from commercially available 3-cholestanone and piperidine (for 2h) or morpholine (for 2i) using a standard protocol for reductive amination.
  • ursolic acid was transformed to the corresponding methyl ester by treatment with trimethylsilyldiazomethane followed by Dess-Martin oxidation to the 3-keto derivative.
  • Reductive amination with methylamine and sodium cyanoborohydride followed by reduction of the methyl ester using lithium aluminium hydride provided the corresponding alcohol.
  • Boc-protection of the methylamino group, O-methylation with sodium hydride and methyl iodide and subsequent Boc- deprotection by treatment with trifluoroacetic acid afforded compound 3a.
  • Performing the same synthetic sequence starting from commercial oleanolic acid provided compound 3b.
  • betulinic acid was transformed to the corresponding methyl ester by treatment with trimethylsilyldiazomethane followed by Dess-Martin oxidation to the 3-keto derivative.
  • Reductive amination by subsequent treatment with hydroxylamine and lithium aluminium hydride followed by Raney-nickel-mediated reduction of the methyl ester to the corresponding carbinol provided the 3 ⁇ -amino intermediate after chromatographic separation of the 3-epimers.
  • ⁇ /, ⁇ /-Bis-Boc- protection followed by O-methylation with sodium hydride and methyl iodide and final Boc-deprotection by treatment with trifluoroacetic acid provided compound 3c.
  • the aim of this assay is the identification of compounds having antituberculosis activity, as evaluated using the strain M. tuberculosis H 37 Rv (ATCC® 27294; ATCC® stands for American Type Culture Collection®, and various M. tuberculosis strains are commercially available from that source) as disease model for tuberculosis.
  • Potency in antimicrobial assays MIC 90 , i.e. the minimum concentration at which microbial growth or non-replicating persistence, respectively, is inhibited by 90%
  • MIC 90 i.e. the minimum concentration at which microbial growth or non-replicating persistence, respectively, is inhibited by 90%
  • 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 MICgo was determined in microplate cultures maintained under anaerobic conditions for 10 days. Percent inhibition was determined as for MABA.
  • the combination of the steroid sapogeni ⁇ , androstane or triterpenoid sapogenin scaffold with an amino function directly or indirectly attached to the steroidal A-ring are preferred structural motifs for the inhibition of mycobacterial growth, in particular Mycobacterium tuberculosis.
  • frans-2-aminomethyl-1- cyclohexanol does not show any inhibitory effect. This demonstrates that an amino or aminoalcohol moiety attached to a cyclic hydrocarbon motif is not the sole reason for antituberculosis activity.
  • Compounds 1a, 1c and 1d, 2a to 2c, 2e, 2f, 2h, 2i and 3a to 3d are preferred compounds for the pharmaceutical intervention of mycobacterial diseases, in particular of tuberculosis.
  • compounds 1a, 1c, 1d, 2a, 2c, 2h and 3a to 3d represent even more preferred compounds to be used in pharmaceutical compositions for the treatment of mycobacterial diseases, like tuberculosis.
  • compounds 1a and 1d, 2a, 2c and 2h as well as 3a and 3c provided for particularly good results in the LORA model.
  • compounds 1a and 1d, 2a, 2c and 2h as well as 3a and 3c represent particularly preferred compounds to be used in pharmaceutical compositions for treating persistent Mycobacterium tuberculosis phenotypes.
  • MABA described herein was used to assess the potential of various steroid sapogenin and androstane derivatives for inhibiting the replication of isoniazid- resistant M. tuberculosis strain ATCC® 35822.
  • compounds 1a, 1c and 1d as well as 2a, 2h and 2i provided particularly good results for stopping the growth of isoniazid-resistant bacteria (Table 3).
  • the steroid sapogenin and androstane derivatives described herein were also found to be highly potent growth inhibitors of various further drug resistant strains . of M. tuberculosis. Evaluation was performed in the experimental setting of the MABA as described above using the pyrazinamide-resistant (r-pza) strain ATCC® 35828, the ethambutol-resistant (r-emb) strain ATCC® 35837, the kanamycin-resistant (r-km) strain ATCC® 35827, the streptomycin-resistant (r-sm) strain ATCC® 35834 and the moxifloxacin-resistant (r-mox) strain. The moxifloxacin-resistant strain of M.
  • tuberculosis used herein is not commercially available, but was prepared in analogy to literature reports (Matrat, Antimicrob. Agents Chemother. 2006, 50(12), 4170-4173 and literature cited therein).
  • compounds 1a, 1c and 1d as well as 2a, 2h and 2i provided particularly good results (Table 4).
  • compounds 1a, 1c, 1d, 2a, 2h and 2i represent preferred compounds to be used in pharmaceutical compositions for the treatment of mycobacterial diseases, like tuberculosis, caused by bacterial strains which are resistant against standard drugs such as rifampin, isoniazid, pyrazinamide or ethambutol used for first-line treatment of tuberculosis or standard drugs such as kanamycin, streptomycin or moxifloxacin used for second-line treatment of tuberculosis.
  • Two of these compounds, i.e. 1a and 2a inhibited the growth of the majority of drug-resistant strains of M. tuberculosis very effectively when applied in nanomolar concentration and thus represents a most preferred embodiment of the present invention (Tables 2, 3 and 4).
  • Example 21 Virus Reproduction and Infectivity Assay (Focus Reduction Assay)
  • influenza A virus was employed as corresponding viral agent.
  • 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) were 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 -80 0 C; 0.05% solution of glutaraldehyde (25% in water, Sigma catalogue number G 5882, kept at -20 "C) in PBS (phosphate- buffered saline, dilution 1 :500), which is freshly prepared in an amount of 250
  • test compounds which are stored at -20 0 C as 1 OmM, 5mM or 3mM stock solutions in DMSO, are thawed out at 37°C and sonicated, if necessary, in order to obtain a clear solution.
  • the IM is preheated in low retention tubes at 37°C in a thermomixer, and 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, 1 x 10 "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 i.e. 630 ⁇ l_ IM + 10 ⁇ L virus solution
  • 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°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 1 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 1 h at room temperature or overnight at 4°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 (ATCC® HB65) diluted 1 :2000 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.
  • Step 4 Imaging Following removal of the last wash, 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. The plates are then placed in the
  • 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.
  • 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 IC50/IC90 evaluation. Values for each concentration are the mean of three replicate experiments.
  • the obtained dose-response results are processed using the software Sigmaplot 9.0 (Systat Software Inc.) based on a four parameter logistic function to provide IC50 and IC90 values.
  • compounds 1a to 1d and compounds 2b, 2e and 2g are preferred compounds for the pharmaceutical intervention in influenza infection.
  • Five of these compounds, i.e. compounds 1a, 1b, 1c, 2e and 2g provided for particularly good results in the influenza virus replication assay.
  • these compounds showed good results in solubility tests and provided for therapeutic indices making them particularly suitable for pharmaceutical compositions for the treatment of viral infections, in particular influenza infections.

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Abstract

La présente invention porte sur des dérivés amines ou d'ammonium issus de la sapogénine stéroïde, de l'androstane et de la sapogénine triterpénoïde dans l'intervention médicale de maladies infectieuses, en particulier des maladies provoquées par un virus ou une bactérie, comprenant des souches résistantes au médicament.
PCT/EP2009/000216 2008-01-16 2009-01-15 Dérivés de sapogénine stéroïde, androstane et sapogénine triterpénoïde pour le traitement et la prévention de maladies infectieuses Ceased WO2009090063A1 (fr)

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FR2967914A1 (fr) * 2010-11-29 2012-06-01 Centre Nat Rech Scient Composes inhibiteurs d'interactions proteine-proteine ciblant les proteines kinases et leurs applications biologiques
CN104558093A (zh) * 2015-02-04 2015-04-29 江苏耐雀生物工程技术有限公司 C21甾体皂苷苷元衍生物、其制备方法及其在制备抗肿瘤药物中的应用
CN104558094A (zh) * 2015-02-04 2015-04-29 江苏耐雀生物工程技术有限公司 皂苷苷元衍生物、其制备方法及在制备抗肿瘤药物中的应用
CN104610420A (zh) * 2015-02-04 2015-05-13 江苏耐雀生物工程技术有限公司 抗肿瘤化合物、其制备方法及其制备抗肿瘤药物中的应用
CN104774241A (zh) * 2015-03-30 2015-07-15 江苏耐雀生物工程技术有限公司 含吲哚骨架的二氢吡唑磺胺甾体皂苷苷元衍生物、其制备方法及应用
CN104788531A (zh) * 2015-04-29 2015-07-22 江苏耐雀生物工程技术有限公司 含噻吩骨架的二氢吡唑哌嗪c21甾体皂苷苷元衍生物,及其制备方法与应用
CN105037471A (zh) * 2014-05-02 2015-11-11 于跃 一种甾体类抗病毒剂
US9457033B2 (en) 2011-02-15 2016-10-04 Socpra Sciences Et Genie, S.E.C. Steroid alkaloids and uses thereof as antimicrobial agents against electron transport-deficient microbes and as potentiators for antimicrobial agents against pathogenic bacteria
US10201550B2 (en) 2015-07-06 2019-02-12 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
US10227375B2 (en) 2013-03-13 2019-03-12 Sage Therapeutics, Inc. Neuroactive steroids and methods of use thereof
US10259840B2 (en) 2014-06-18 2019-04-16 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
CN109652384A (zh) * 2019-02-21 2019-04-19 昆明理工大学 一种体外培养戊型肝炎病毒的方法
WO2019234189A1 (fr) * 2018-06-06 2019-12-12 Centro Nacional De Investigaciones Cardiovasculares Carlos Iii (F.S.P.) Augmentation de l'immunité entraînée de cellules myéloïdes par inhibition de ship-1
US10696712B2 (en) 2015-07-06 2020-06-30 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
US10752653B2 (en) 2016-05-06 2020-08-25 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
US10759828B2 (en) 2011-09-08 2020-09-01 Sage Therapeutics, Inc. Neuroactive steroids, compositions, and uses thereof
US10781231B2 (en) 2016-07-07 2020-09-22 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
US11111266B2 (en) 2016-10-18 2021-09-07 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
US11117924B2 (en) 2015-07-06 2021-09-14 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
US11149054B2 (en) 2016-10-18 2021-10-19 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
US11149056B2 (en) 2016-09-30 2021-10-19 Sage Therapeutics, Inc. C7 substituted oxysterols and methods of use thereof
US11884697B2 (en) 2016-04-01 2024-01-30 Sage Therapeutics, Inc. Oxysterols and methods of use thereof

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FR2967914A1 (fr) * 2010-11-29 2012-06-01 Centre Nat Rech Scient Composes inhibiteurs d'interactions proteine-proteine ciblant les proteines kinases et leurs applications biologiques
US9457033B2 (en) 2011-02-15 2016-10-04 Socpra Sciences Et Genie, S.E.C. Steroid alkaloids and uses thereof as antimicrobial agents against electron transport-deficient microbes and as potentiators for antimicrobial agents against pathogenic bacteria
US12129275B2 (en) 2011-09-08 2024-10-29 Sage Therapeutics, Inc. Neuroactive steroids, compositions, and uses thereof
US10759828B2 (en) 2011-09-08 2020-09-01 Sage Therapeutics, Inc. Neuroactive steroids, compositions, and uses thereof
US10227375B2 (en) 2013-03-13 2019-03-12 Sage Therapeutics, Inc. Neuroactive steroids and methods of use thereof
US11104701B2 (en) 2013-03-13 2021-08-31 Sage Therapeutics, Inc. Neuroactive steroids and methods of use thereof
US11905309B2 (en) 2013-03-13 2024-02-20 Sage Therapeutics, Inc. Neuroactive steroids and methods of use thereof
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US10723758B2 (en) 2014-06-18 2020-07-28 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
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CN104558094B (zh) * 2015-02-04 2016-06-29 江苏耐雀生物工程技术有限公司 皂苷苷元衍生物、其制备方法及在制备抗肿瘤药物中的应用
CN104610420A (zh) * 2015-02-04 2015-05-13 江苏耐雀生物工程技术有限公司 抗肿瘤化合物、其制备方法及其制备抗肿瘤药物中的应用
CN104558094A (zh) * 2015-02-04 2015-04-29 江苏耐雀生物工程技术有限公司 皂苷苷元衍生物、其制备方法及在制备抗肿瘤药物中的应用
CN104558093A (zh) * 2015-02-04 2015-04-29 江苏耐雀生物工程技术有限公司 C21甾体皂苷苷元衍生物、其制备方法及其在制备抗肿瘤药物中的应用
CN104774241A (zh) * 2015-03-30 2015-07-15 江苏耐雀生物工程技术有限公司 含吲哚骨架的二氢吡唑磺胺甾体皂苷苷元衍生物、其制备方法及应用
CN104788531A (zh) * 2015-04-29 2015-07-22 江苏耐雀生物工程技术有限公司 含噻吩骨架的二氢吡唑哌嗪c21甾体皂苷苷元衍生物,及其制备方法与应用
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US11111266B2 (en) 2016-10-18 2021-09-07 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
WO2019234189A1 (fr) * 2018-06-06 2019-12-12 Centro Nacional De Investigaciones Cardiovasculares Carlos Iii (F.S.P.) Augmentation de l'immunité entraînée de cellules myéloïdes par inhibition de ship-1
CN109652384A (zh) * 2019-02-21 2019-04-19 昆明理工大学 一种体外培养戊型肝炎病毒的方法
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