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WO2012041493A1 - Sels d'aminoquinoline, leurs procédés de production et leur utilisation en tant qu'agents actifs pour des applications biotechnologiques et médicales contre les toxines binaires - Google Patents

Sels d'aminoquinoline, leurs procédés de production et leur utilisation en tant qu'agents actifs pour des applications biotechnologiques et médicales contre les toxines binaires Download PDF

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Publication number
WO2012041493A1
WO2012041493A1 PCT/EP2011/004846 EP2011004846W WO2012041493A1 WO 2012041493 A1 WO2012041493 A1 WO 2012041493A1 EP 2011004846 W EP2011004846 W EP 2011004846W WO 2012041493 A1 WO2012041493 A1 WO 2012041493A1
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Prior art keywords
alkyl
aminoquinolinium
toxin
compound
compounds
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Inventor
Gerhard Bringmann
Melanie LÖDIGE
Angelika Kronhardt
Christoph Beitzinger
Holger Barth
Roland Benz
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Julius Maximilians Universitaet Wuerzburg
Universitaet Ulm
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Julius Maximilians Universitaet Wuerzburg
Universitaet Ulm
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to aminoquinolinium compounds, in particular salts, their uses and to methods of synthesizing such aminoquinolinium compounds. Moreover, the present invention relates to compositions comprising aminoquinolinium compounds in accordance with the present invention.
  • the present invention relates to bioactive compounds from the class of aminoquinolinium compounds, and in particular their inhibitory effects on the binary toxins of an AB-type of a number of bacteria, such as Clostridium perfringens, Clostridium botulinum and, Bacillus anthracis.
  • the invention also relates to the use of these aminoquinolinium compounds as drugs, more particularly as drugs for the treatment of bacterial infections, even more particularly bacterial infections caused by bacteria which produce pore forming toxins of a binary type.
  • the present invention also relates to methods of producing the compounds in accordance with the present invention.
  • pore-forming toxins are the binary toxins, sometimes also referred to as pore forming toxins of a binary type or binary toxins of an AB-type.
  • binary toxins sometimes also referred to as pore forming toxins of a binary type or binary toxins of an AB-type.
  • anthrax toxin from Bacillus anthracis
  • iota toxin from Clostridium perfringens
  • C2-toxin from Clostridium botulinum.
  • One characteristic of these toxins is that they are composed of two different components, one of which is the so-called A-component which is the carrier of enzymatic activity, and the other one of which is the separate B-component which is necessary for a specific binding to the target cell and for the transport of the enzymatic component into the target cell.
  • the pre-pore After proteolytic activation of the B-subunits, their hep- tamerisation to form the so-called pre-pore, and after the binding of the enzymatic component to the heptamer, this complex is incorporated in early endosomes. After acidification of the endosomes, the pre-pore is transformed into a membrane-located channel in the endosome. This membrane-located channel plays an important role for the transport of the A-component into the cytoplasm. Through this transport, the enzymatic component in its entirety or at least its catalytic domain becomes transferred into the cytoplasm and can develop its toxic effects on the target cell. The transport of the enzymatic component into the target cell is the cause of cell death.
  • Anthrax being the consequence of an infection with Bacillus anthracis (anthrax toxin) manifests itself in different forms: pulmonary anthrax may develop after inhalation of spore containing dusts and aerosols. Intestinal anthrax may develop by consumption of infected foodstuff. Cutaneous anthrax may develop after direct contact with the bacteria. The so-called anthrax sepsis is a frequently lethal complication of the above manifestations after the bacteria have been disseminated via blood circulation.
  • Bacillus anthracis, Clostridium perfringens and Clostridium botulinum are also biological weapons, but an anthrax infection is considered to be the largest threat of all.
  • WHO World Health Organization
  • a release of 50 kg of spores of Bacillus anthracis directed against the wind would cause 125,000 infections with 95,000 casualties after 3 days along a 2 km line within a city having 500,000 inhabitants (Report of a WHO group of consultants. Health aspects of chemical and biological weapons. Geneva; World Health Organization, 1970, 97-99).
  • the capability of the spores of Bacillus anthracis to survive for several decades in the environment is particularly problematic.
  • an immunisation is recommended which, after application of three vaccine doses over a time of 4 weeks may end the chemical prophylaxis (A. M. Friedlander, S. L. Welkos, M .L. M. Pitt, J. W. Ezzell, P. L. Worsham, K. J. Rose; Post exposure prophylaxis against experimental inhalation anthrax; J. Infect. Dis. 1993, 167, 1239-1242).
  • Anthrax has an incubation time of more than 24 hours.
  • a further binary bacterial toxin is the C2-toxin from Clostridium botulinum.
  • This toxin is a prototype of the family of binary actin-ADP-ribosylating toxins.
  • the enzymatic subunit causes an ADP-ribosylation of monomeric G-actin, not of polymeric F-actin in the cytosol of mammalian cells. Consequently, the actin cytoskeleton of the cells is destroyed leading to cell death.
  • C2-toxin consists of a binding/translocation component C2II (80.5 kDa) and an enzy- matic component C2I (49.4 kDa).
  • the activated C2IIa (-60 kDa) forms a heptamer (H. Barth, D. Blocker, J. Behlke, W. Bergsma-Schutter, A. Brisson, R. Benz, K. Aktories; Cellular uptake of Clostridium botulinum C2 toxin requires oligomeriza- tion and acidification; J. Biol. Chem. 2000, 275, 18704-18711), just like the protective antigen (PA) of anthrax-toxin.
  • the heptamer first mediates the binding of the C2IIa/C2I-complex to its cellular receptor, a carbohydrate structure (M. Eckhardt, H.
  • Clostridium botulinum C2 toxin Low pH-induced pore formation is required for translocation of the enzyme component C2I into the .cytosol of host cells; J. Biol. Chem. 2003, 278, 37360-37367).
  • the C2I-protein is believed to be unfolded during its membrane translocation and directly transported through the C2IIa-pore the inner diameter of which is, however, very small ( ⁇ 2-4 nm) (G. Haug, C. Wilde, J. Leemhuis, D. K. Meyer, K. Aktories, H.
  • PPIases peptidyl prolyl cis/trans isomerases
  • the incubation time is hours to a few days (F. H. Kayser, K. A. Bienz, J. Eckert, R. M. Zinkernagel, Mediz- inische Mikrobiologie, 10. Auflage, 2001, Thieme Verlag).
  • Clostridium perfringens iota-toxin just like Clostridium botulinum C2-toxin, also belongs to the family of the binary actin-ADP-ribosylating toxins.
  • Iota-toxin also consists of an enzymatic component (ADP-ribosyltransferase, iota a, la) and a separate binding and translocation component (iota b, lb) which mediates the cellular uptake.
  • ADP-ribosyltransferase iota a, la
  • a separate binding and translocation component iota b, lb
  • the heptamerisation of lb and the acid induced pore formation in the membrane of acidic endosomes leads to a translocation of la into the cytoplasm (D. Blocker, J. Behlke, K. Aktories, H. Barth; Cellular uptake of the binary Clostridium perfringens iota toxin; Infect. Immun.
  • the translocation mechanism of la has, however, not yet been characterized.
  • the enzymatically active toxin component iota a (la) transfers the ADP-ribose residue from NAD to arginine-177 of actin, whereby the polymerisation of F-actin is inhibited. This leads to the degradation of the actin cytoskeleton.
  • the toxins differ in their substrate specificity: While C2I only ADP-ribosylates beta/gamma-actin, iota a also modifies alpha- actin-isoforms.
  • surgical therapy is the predominant therapy, additionally, the administration of antibiotics, such as penicillin and cephalosporin as well as insufflation using hyperbaric oxygen.
  • antibiotics such as penicillin and cephalosporin
  • insufflation using hyperbaric oxygen A polyvalent gas gangrene-antitoxin is not available.
  • R 1 , R 3 , R 4 , R 6 , R 7 are independently, at each occurrence, selected from the group comprising:
  • unsubstituted alkyl monosubstituted alkyl, polysubstituted alkyl, the alkyl being linear, cyclic or branched, saturated or unsaturated;
  • O-bound alkyl such as -0-C n H 2n+ i, n being 1 - 30, said alkyl being linear, branched or cyclic; saturated, unsaturated;
  • aryl is unsubstituted, monosubstituted, polysubstituted, mono-or oligo- cyclic, iso- or heterocyclic.
  • S-bound alkyl such as -S-C n H 2n+1 , n being 1 - 30, said alkyl being linear, branched or cyclic, saturated or unsaturated;
  • a nitrogen substitutent such as -NH 2 , -NHR, -NRR', -NC, -CN, -N0 2 , R and R' being independently unsubstituted, monosubstituted, polysubstituted, saturated, unsaturated alkyl, aryl or heteroaryl;
  • halogen such as -F, -CI, -Br, -I; or pseudohalogen such as -CN, -NC;
  • R 2 is selected from -CI, H, -F, -Br, -I, -NC and-CN; wherein R 5 is selected from -NH 2 and -NHR", R" being unsubstituted alkyl, monosubstituted alkyl, polysubstituted alkyl, the alkyl being linear, cyclic or branched, saturated or un- saturated; or aryl, wherein aryl is unsubstituted, monosubstituted, polysubstituted, mono or oligocyclic, iso- or heterocyclic;
  • R is selected from the group comprising:
  • unsubstituted alkyl unsubstituted alkyl, monosubstituted alkyl, polysubstituted alkyl, alkyl substituted with imidyl, e.g. with phthalimidyl, the alkyl being linear, cyclic or branched alkyl, saturated or unsaturated;
  • acyl such as formyl, acetyl, trichloroacetyl, fumaryl, maleyl, succinyl, benzoyl;
  • branched acyl such as tigloyl, isobutyryl, heteroatom substituted acyl, such as piperazin-acyl,
  • aminoquinolinium salt may also form a dimer or oligomer via one or several of the aforementioned Rl - R8, preferably via R8;
  • X being selected from the group comprising halogenide, such as bromide, chloride, fluoride, iodide, in particular bromide, acetate, aconate, ascorbate, benzene sulfonate, benzoate, zinna- mate, citrate, embonate, enantate, formate, fumarate, glutamate, glycolate, hydrochloride, hydrobromide, lactate, maleate, malpnate, mandelate, methane sulfonate, naphthalene-2- sulfonate, nitrate, perchlorate, phosphate, phthalate, salicylate, sorbate, stearate, succinate, sulphate, tartrate, toluene-p-sulphonate, including its stereoisomers and mixtures of stereoisomers,
  • halogenide such as bromide, chloride, fluoride, iodide, in particular bromide,
  • R may only be H if R is a substituted alkyl, in particular an alkyl substituted with imidyl, e.g. phthalimidyl.
  • the objects of the present invention are also solved by the aminoquinolinium salt according to the present invention for use as a medicament.
  • the objects of the present invention are also solved by the aminoquinolinium salt according to the present invention for use in the treatment of a bacterial infection.
  • the bacterial infection is caused by bacteria which produce pore forming toxins of a binary type.
  • the bacteria are selected from the group comprising Bacillus anthracis, Clostridium perfringens, Clostridium botulinum.
  • the bacterial infection is anthrax, intoxication with the C2 toxin from Clostridium botulinum or gas gangrene.
  • said use comprises the administration of said aminoquinolinium salt to a patient in need thereof.
  • compositions comprising an aminoquinolinium salt according to the present invention and a pharmaceutically acceptable carrier.
  • L being a leaving group such as a halogen, e.g. -Br or -I, R - R being as defined above.
  • reaction of said compound of formula 2 with said compound of formula 3 is performed at a temperature in the range of from 120°C to 200°C, preferably 150 °C - 170 °C.
  • substituted as used herein is meant to indicate that a hydrogen atom attached to a member atom within a group is replaced by another group, such as halogen including fluorine, d-do alkyl, d-C 3 haloalkyl, C 3 -C 7 cycloalkyl, oxo, -OH, -OR'", -OC(0)R" ⁇ -CN, -N0 2 , - N(R '" ) 2 , -N(R '" )C(0)R '" , -C(0)R “' , -C(0)0R " , -C(0)N(R '” ) 2 , -S(0)R “ , -S(0) 2 R “ , - S(0) 2 N(R ) 2 , -NC(0)2(R”') 2 , imidyl, e.g.
  • phthalimidyl phenyl, benzyl, heteroaryl,or hetero- cyclyl
  • an example of a substituted alkyl is an alkyl substituted with an imidyl, e.g. with a phthalimidyl.
  • R is independently, at each occurrence, selected from the group consisting of hydrogen, aryl, benzyl, heteroaryl, heterocyclyl, Cj-Q alkyl, or C 3 -C 7 cycloalkyl, imidyl, e.g. phthalimidyl, tert-butylcarbonate (Boc), benzyl (Bn).
  • alkyl refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range. Thus, for example, "C !
  • -C 6 alkyl refers to any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec-, and t-butyl, n- and isopropyl, ethyl and methyl.
  • alkoxy means a group having the formula -O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom.
  • the alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., C 1 -C 20 alkoxy), 1 to 12 carbon atoms (i.e., C ⁇ -Cn alkoxy), or 1 to 6 carbon atoms (i.e., C C 6 alkoxy).
  • alkoxy groups include, but are not limited to, methoxy (-O-CH 3 or OMe), ethoxy (-OCH 2 CH 3 or - OEt), t-butoxy (-0-C(CH 3 ) 3 or -OtBu) and the like.
  • alkenyl refers to a monovalent straight or branched chain aliphatic hydrocarbon radical containing one carbon-carbon double bond and having a number of carbon atoms in the specified range.
  • C 2 -C 6 alkenyl refers to all of the hexenyl and pen- tenyl isomers as well as 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 1-propenyl, 2-propenyl, and ethenyl (or vinyl).
  • alkynyl refers to a monovalent straight, or branched chain aliphatic hydrocarbon radical containing one carbon-carbon triple bond and having a number of carbon atoms in the specified range.
  • C 2 -C 6 alkynyl refers to all of the hexynyl and pentynyl isomers as well as 1-butynyl, 2-butynyl, 3-butynyl, 1-propynyl, 2-propynyl, and ethynyl.
  • alkylene refers to a saturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Typical alkylene radicals include, but are not limited to, methylene (-CH 2 -), 1,1 -ethyl (- CH(CH 3 )-), 1,2-ethyl (-CH 2 CH 2 -), 1,1 -propyl (-CH(CH 2 CH 3 )-), 1,2-propyl (-CH 2 CH(CH 3 )-), 1,3-propyl (-CH 2 CH 2 CH 2 -), 1,4-butyl (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • alkenylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of parent alkene.
  • an al- kenylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • alkynylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of parent alkyne.
  • an alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms or 1 to 6 carbon atoms.
  • Typical alkynylene radicals include, but are not limited to, acetylene (-C ⁇ C-), propargyl (- CH 2 C ⁇ C-), and 4-pentynyl (-CH 2 CH 2 CH 2 C ⁇ CH-).
  • cycloalkyl refers to a group, such as optionally substituted or non-substituted cyclic hydrocarbon, having from three to eight carbon atoms, unless otherwise defined.
  • C 3 -C 8 cycloalkyl refers to cyclo- propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • haloalkyl refers to an alkyl group, as defined herein that is substituted with at least one halogen.
  • straight or branched chained “haloalkyl” groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, H-butyl, and t- butyl substituted independently with one or more halogens.
  • haloalkyl should be interpreted to include such substituents such as -CHF 2 , -CF 3 , -CH 2 -CH 2 -F, -CH 2 -CF 3 , and the like.
  • heteroalkyl refers to an alkyl group where one or more carbon atoms have been replaced with a heteroatom, such as, O, N, or S.
  • a heteroatom such as, O, N, or S
  • the resulting heteroalkyl groups are, respectively, an alkoxy group (e.g., -OCH3, etc.), an amine (e.g., -NHCH 3 , -N(CH 3 ) 2 , etc.), or thioalkyl group (e.g., -SCH 3 , etc.).
  • a non-terminal carbon atom of the alkyl group which is not attached to the parent molecule is replaced with a heteroatom (e.g., O, N, or S) and the resulting heteroalkyl groups are, respectively, an alkyl ether (e.g., -CH 2 CH 2 -0-CH 3 , etc.), alkyl amine (e.g., -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , etc.), or thioalkyl ether (e.g., -CH 2 -S-CH 3 ).
  • an alkyl ether e.g., -CH 2 CH 2 -0-CH 3 , etc.
  • alkyl amine e.g., -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , etc.
  • thioalkyl ether e.g., -CH 2 -S-CH 3
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • aryl refers to (i) optionally substituted phenyl, (ii) optionally substituted 9- or 10 membered bicyclic, fused carbocyclic ring systems in which at least one ring is aromatic, and (iii) optionally substituted 1 1- to 14-membered tricyclic, fused carbocyclic ring systems in which at least one ring is aromatic.
  • Suitable aryls include, for example, phenyl, biphenyl, naphthyl, tetrahydronaphthyl (tetralinyl), indenyl, anthracenyl, and fluorenyl.
  • phenyl as used herein is meant to indicate that optionally substituted or non- substituted phenyl group.
  • benzyl as used herein is meant to indicate that optionally substituted or non- substituted benzyl group.
  • heteroaryl refers to (i) optionally substituted 5- and 6-membered heteroaromatic rings and (ii) optionally substituted 9- and 10-membered bicyclic, fused ring systems in which at least one ring is aromatic, wherein the heteroaromatic ring or the bicyclic, fused ring system contains from 1 to 4 heteroatoms independently selected from N, O, and S, where each N is optionally in the form of an oxide and each S in a ring which is not aromatic is optionally S(O) or S(0) 2 .
  • Suitable 5- and 6-membered heteroaromatic rings include, for example, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.
  • Suitable 9-and 10-membered heterobicyclic, fused ring systems include, for example, benzofuranyl, indolyl, indazolyl, naphthyridinyl, isobenzofuranyl, benzopiperidinyl, benzisoxazolyl, benzoxazolyl, chromenyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolyl, benzodioxolyl, benzofuranyl, imi- dazo[l,2-a]pyridinyl, benzotriazolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, 2,3-dihydr
  • heterocyclyl refers to (i) optionally substituted 4- to 8-membered, saturated and unsaturated but non-aromatic monocyclic rings containing at least one carbon atom and from 1 to 4 heteroatoms, (ii) optionally substituted bicyclic ring systems containing from 1 to 6 heteroatoms, and (iii) optionally substituted tricyclic ring systems, wherein each ring in (ii) or (iii) is independent of fused to, or bridged with the other ring or rings and each ring is saturated or unsaturated but nonaromatic, and wherein each heteroatom in (i), (ii), and (iii) is in- dependency selected from N, O, and S, wherein each N is optionally in the form of an oxide and each S is optionally oxidized to S(O) or S(0) 2 .
  • Suitable 4- to 8-membered saturated het- erocyclyls include, for example, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thia- zolidinyl, isothiazolidinyl, oxazolidinyl, oxazolidonyl, isoxazolidinyl, pyrrolidinyl, imida- zolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimid- inyl, thiazinanyl, thiazepanyl, azepanyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxanyl, and azacyclooctyl.
  • Suitable unsaturated heterocyclic rings include those corresponding to the saturated heterocyclic rings listed in the above sentence in which a single bond is replaced with a double bond. It is understood that the specific rings and ring systems suitable for use in the present invention are not limited to those listed in this and the preceding paragraphs. These rings and ring systems are merely representative.
  • the invention relates all possible stereoisomers and their mixtures. Moreover, the present invention relates to the physiologically acceptable salts and solvates of the aminoquinolinium compounds.
  • the present invention also relates to a method of treatment of bacterial infections which are caused by bacteria which produce pore forming toxins of a binary type, said method comprising the application of a suitable amount of an aminoquinolinium salt of formula 1, as defined above, to a person in need thereof.
  • the bacteria are selected from the group comprising Bacillus anthracis, Clostridium perfringens, Clostridium botulinum.
  • the bacterial infection is selected from anthrax, intoxication with the C2 toxin from Clostridium botulinum or gas gangrene.
  • aminoquinolinium compounds of formula 1 in accordance with the present invention may be produced by a method, wherein a compound of formula 2
  • this reaction is performed at a temperature in the range of from 120°C to 200°C, preferably 150°C to 170°C. In a preferred embodiment, the reaction is performed without any solvent.
  • R 5 -NH 2 and -NHR' ' as defined above, the reactions occur at a good yield because of the increased nucleophilic character of the quinoline nitrogen and because of the electron pushing effect of the non-bonding electron pairs of the amino moiety in R 5 .
  • Typical yields are 30%-50% at a scale of 100-200 mg. If the scale is enlarged, the reaction and subsequent work-up is performed even more easily and the yield is likely to be higher.
  • the compounds in accordance with the present invention have valuable pharmacological qualities. These are determined in accordance with the following procedure:
  • the binding component of the various AB-toxins from Bacillus anthracis (anthrax-toxin), from Clostridium perfringens (iota-toxin) and from Clostridium botulinum. (C2-toxin) are reconstituted in artificial membranes which leads to the formation of channels in these membranes.
  • the compounds in accordance with the present invention appear capable to block the channels formed by the binding components PA, lb and C2II. This applies to both the blocking of the channel binding in vitro as well as to the intoxication of target cells in defined experiments using intact cells.
  • the present inventors succeeded to resolve the kinetics (i. e.
  • the on- and off-rates of the reaction between the aminoquinolinium compounds and the putative binding sites at the various heptamers from the binding proteins.
  • the on-rate of binding of the compounds does not depend on the structure of the molecules under a set of defined conditions, such as a defined pH value and salt concentration.
  • the off-rates appear to be very characteristic and depended on the individual structures.
  • the compounds in accordance with the present invention have high stability constants of binding, in a range of 10 5 -10 6 M "1 and higher (which translates into a half saturation concentration for blocking of ⁇ or less), and for these high stability constants the small off-rates are responsible. These small off-rates are approximately 10 s "1 , whereas with the known compound (not in accor- dance with the present invention) chloroquine, such off-rate is 1000 s " .
  • chloroquine such off-rate is 1000 s " .
  • the channels are oriented completely within the membrane and the binding site of the aminoquinolinium compounds is facing the cis-side where the protein is added.
  • physiologically acceptable salts are addition salts which include, without limitation, the non-toxic inorganic and organic acid addition salts such as the acetate derived from acetic acid, the aconate derived from aconitic acid, the ascorbate derived from ascorbic acid, the benzenesulfonate derived from benzensulfonic acid, the benzoate derived from benzoic acid, the cinnamate derived from cinnamic acid, the citrate derived from citric acid, the em- bonate derived from embonic acid, the enantate derived from enanthic acid, the formate derived from formic acid, the fumarate derived from fumaric acid, the glutamate derived from glutamic acid, the glycolate derived from glycolic acid, the hydrochloride derived from hydrochloric acid, the hydrobromide derived from hydrobromic acid, the lactate derived from lactic acid, the maleate derived from maleic acid, the mal
  • acids such as oxalic acid, which may not be considered physiologically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its physiologically acceptable acid addition salt.
  • halogenides such as bromide, chloride, fluoride and iodide, in particular bromide.
  • Metal salts of a chemical compound of the invention includes alkali metal salts, such as the sodium salt of a chemical compound of the invention containing a carboxy group.
  • the chemical compounds of the invention may be provided in unsolvated or solvated forms together with a pharmaceutically, acceptable solvents such as water, ethanol, and the like.
  • Solvated forms may also include hydrated forms such as the monohydrate, the dihydrate, the hemihydrate, the trihydrate, the tetrahydrate, and the like. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of this invention.
  • aminoquinolinium compounds of the invention useable according to the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
  • Such salts of the amino- quinolinium compounds of the invention may be anhydrous or solvated.
  • the invention provides medicaments comprising a compound useable according to the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers therefor, and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.
  • a medicament of the invention may be those suitable for oral, rectal, bronchial, nasal, topical, buccal, sub-lingual, transdermal, parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for administration by inhalation or insufflation, including powders and liquid aerosol administration, or by sustained release systems.
  • sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the invention, which matrices may be in form of shaped articles, e.g. films or microcapsules.
  • the compounds useable according to the invention may thus be placed into the form of medicament and unit dosages thereof.
  • Such forms include solids, and in particular tablets, filled capsules, powder and pellet forms, and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with the same, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral use.
  • Such medicament and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the compound useable according to the invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compounds useable accord- ing to the invention or a pharmaceutically acceptable salt of a compounds useable according to the invention.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubi- lizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation” is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glyceride or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
  • Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • the aminoquinolinium compound according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methyl- cellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the medicament is applied topically or systemi- cally or via a combination of the two routes.
  • the medicament is prepared in form of an ointment, a gel, a plaster, an emulsion, a lotion, a foam, a cream, a cream of a mixed phase or amphiphilic emulsion system (oil/water- water/oil mixed phase), a liposome, a transfersome, a paste or a powder.
  • an ointment a gel, a plaster, an emulsion, a lotion, a foam, a cream, a cream of a mixed phase or amphiphilic emulsion system (oil/water- water/oil mixed phase), a liposome, a transfersome, a paste or a powder.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
  • the compounds of the present invention may be administered in a formulation containing 0,001% to 10% per weight of the compound, preferably between 0,01% to 10% per weight of the compound, even more preferred between 0,1 % and 5% per weight of the compound.
  • Compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the compositions may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoro- methane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoro- methane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by. provision of a metered valve.
  • the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the powder carrier will form a gel in the nasal cavity
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the compound In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
  • compositions adapted to give sustained release of the active ingredient may be employed.
  • the pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
  • Figure 1 shows a schematic scheme of the cellular uptake of anthrax-toxin
  • Figure 2 shows the structure of diphytanoyl phosphatidyl cholin which was used for the production of artificial membranes
  • Figure 3 shows in-vitro-titration experiments using the compound la
  • Figure 4 shows the experimental set up for lipid bilayer experiments
  • FIG. 5 shows experimental results of experiments performed using intact mammalian cells
  • Figure 6 shows an exemplary synthesis scheme of chloroquine-derivatives
  • Figure 7 shows an exemplary synthesis scheme of 4-amino-7-chloroquinolinium-compounds; compound 11 of this scheme corresponds to compound lc of the compounds according to the claims, compound 12 of this scheme corresponds to compound Id of the compounds according to the claims;
  • Figure 8 shows an exemplary synthesis scheme of 4-amino-7-chloroquinolinium-compounds having a phthalimidyl substituent and of 4-amino-7-chloroquinolinium-compounds as a dimer.
  • compound 15 of this scheme corresponds to compound la of the claims
  • compound 16 of this scheme corresponds to compound If of the claims
  • compound 18 of this scheme corresponds to compound lb of the claims.
  • figure 1 is a schematic drawing illustrating the cellular uptake of anthrax- toxins, wherein PA represents the protective antigen which is the binding component, PA 20 is the cleavage product after proteolytic activation of PA, resulting in the activated PA 63 .
  • ⁇ $3 is the binding component which has been activated by proteolysis.
  • EF is the edema factor which is an enzymatic component.
  • LF is the lethal factor which is a further enzymatic component.
  • ATR is the anthrax toxin receptor, more specifically called CMG2.
  • ATP is adenosine triphosphate.
  • MAPKK is mitogen-activated protein kinase kinase.
  • Figure 2 shows diphytanoylphosphatidylcholine which is a semi-synthetic lecithin having phytanic acid side chains. This lipid was used in the in-vitro experiments of the present application for producing artificial lipid membranes.
  • Figure 3 shows results of an in-vitro titration experiment using the synthetic compound la in accordance with the present invention.
  • compound la is herein, most notably in the experimental schemes, also sometimes referred to as compound 15.
  • FIG 4 shows the experimental setup of lipid-bilayer-experiments.
  • Tefionhunt means teflon chamber.
  • Elektroden means electrodes.
  • ConstantIn kunstliche Membran ein concludedes Toxin means toxin incorporated into artificial membrane.
  • Figure 5 shows experimental results of experiments performed with intact mammalian cells. The rounding of the cells is a measure of the cytopathic effect of the toxin.
  • Figure 6 shows an exemplary synthesis scheme of chloroquine-derivatives with the reagent conditions indicated underneath.
  • the literature reference between compound 3 and compound 4 is J. Am. Chem. Soc. 1946, 68, 1807-1808.
  • Figure 7 shows an exemplary synthesis scheme of 4-amino-7-chloroquinolinium-compounds, with the reaction conditions indicated underneath.
  • the literature reference leading to compound 9 is J. Am. Chem. Soc. 1955, 77, 4816-4819; J. Am. Chem. Soc. 2004, 126, 7788-7789.
  • Figure 8 shows an exemplary synthesis scheme of 4-amino-7-chloroquinolinium-compounds having a phthalimidyl substituent, with the reaction conditions indicated underneath, as well as an exemplary synthesis scheme for dimer compounds in accordance with the present invention, in particular of the dimer 18, which is also sometimes herein referred to as compound lb.
  • NMR spectra were obtained on a Bruker DMX 600 apparatus and are reported in ppm relative to internal solvent signal with coupling constants (J) in Hertz (Hz); in case of D 2 0 Dioxan was added as internal solvent signal. Spectra were usually obtained at 25 °C, compound 10 and 11 were measured at (calibrated) 2 °C. EI mass spectrometry was carried out on a Finnigan MAT 8200; ESI-HRMS was measured on a Bruker Daltonik micrOTOF-focus.
  • teri-Butyl benzyI(4-bromobutyl)carbamate 10
  • a solution of tert-Butyl benzylcarbamate 9 (4.789 g, 0.023 mol) in 20 ml DMF was cooled to 0 °C.
  • NaH 3.055 g, 0.070 mol
  • 1 ,4-Dibromobutane was given to the mixture and stirred for additional 5 h at 0 °C.
  • Lipids are amphiphilic molecules which have a certain similarity with soaps.
  • Phospholipids are an important representative in many biological membranes. These are glycerol derivatives wherein, in the 1 -position and 2-position, fatty acids having 14- 20 carbon atoms are attached via an ester group. The fatty acids are partially saturated and partially unsaturated. In the 3 -position, there is a polar head, such as phosphoryl choline in diphytanoyl phosphatidylcholine (DiphPC, lecithin) (see also figure 2).
  • Artificial lipid membranes are composed of a lipid bilayer having a thickness of approximately 5 nm. Using these lipid bilayers, the matrix of biological membranes can be imitated, which biological membranes are used in various manners for forming compartments within cells.
  • the advantage of such model membranes is that they have a relatively simple composition and thus represent a well-controlled system. This may, of course, at the same time, represent a certain disadvantage, since biological membranes have a complex composition. Nevertheless, model membranes, such as artificial lipid membranes have an enormous technological significance for examining transport processes in membranes.
  • the coloured film At the lower edge of the coloured film, there appear black spots without transition, having a thickness of two fatty acids (approximately 5 nm thick). Those positions appear black, because the rays which are reflected at the front and back of the membrane have a phase difference of ⁇ /2 and therefore extinguish each other. After a certain time, these black positions have spread across the whole membrane, and the membrane consists of a bilayer of lipids. In this form, the artificial lipid membranes have an analogous thickness as the matrix of biological membranes.
  • Figure 3 shows an in-vitro-titration experiment using the synthetic compound la.
  • anthrax-protective antigen anthrax- PA
  • anthrax- PA anthrax-protective antigen
  • This reaction is the biological key for the action of the various synthetic aminoquinolinium-derivatives to the above-mentioned toxins from Bacillus an- thracis, Clostridium botulinum and Clostridium perfringens. If the binding site of the channels formed from the binding component is blocked, the release of the enzymatic component (i.e. the A component) can no longer occur from the early endosome, and the toxin action is blocked.
  • the enzymatic component i.e. the A component
  • G max is the maximum conductivity (prior to addition of compound la) and G(c) is the conductivity at substrate concentration c.
  • Table 1 shows the affinity of different synthetic exemplary compounds (la- If) of the general structure 1 with respect to the anthrax PA-channel in comparison to the already known substances chloroquine and fluphenazine, which had already been previously examined.
  • compounds la and If show a substantially higher affinity than chloroquine and fluphenazine.
  • Chloroquine T. Neumeyer, B. Schiffler, E. Maier, A. E. Lang, K. Aktories, R. Benz; Clostridium botulinum C2 toxin-identification of the binding site for chloroquine and related compounds and influence of the binding site on properties of the C2II channel; J. Biol. Chem.
  • fluphenazine have a relatively high toxic effect on living tissue, if they are to be used in concentrations which are sufficient for prophylaxis, such that chloroquine can only be used in extreme cases, and fluphenazine cannot be used at all for prophylaxis, in an infection by the producers of the different AB-toxins, such as Bacillus anthracis, Clostridium botulinum, Clostridium difficile, and Clostridium perfringens.
  • Table 1 Stability constant K of binding of various synthetic aminoquinolinium-derivatives to the anthrax PA-channel in 150 mM KC1, 6. With the half saturation constant ki /2 , 50 % of the channels are blocked in titration experiments, as described with artificial lipid membranes above. The data correspond to the mean values of at least three titration experiments using membranes of diphytanoyllecithin/n-decane. titration: noise:
  • a basis for the binding of synthetic compounds of the general structure 1 to the pores formed from the binding components of the various AB toxins of Bacillus anthracis, Clostridium botulinum, Clostridium difficile and/or Clostridium perfringens is a chemical reaction, consisting of a forward reaction (kjc) and back reaction (k-i). If a ligand L (e.g. compound la) is bound to the pore (PL), the pore (P) is closed:
  • binding kinetics that is the determination of the forward reaction (k ⁇ c) and the back reaction (k-i). This can only be determined in accordance with general physicochemical principles by disturbation of the equilibrium.
  • An alternative possibility for determining the kinetics is the examination of the so-called microscopic reversibility which can be studied by methods in analogy to correlation spectroscopy.
  • an examination of the current noise of the C2II-channels, of the PA-channels or of the iota b-channels in the presence of ligands, such as chloroquine and/or fluphenazine, but also of the synthetic compounds of the general structure 1, is performed in accordance with known methods (G. Haug, C. Wilde, J. Leem- huis, D. K. Meyer, K. Aktories, H. Barth; Cellular uptake of Clostridium botulinum C2 toxin: membrane translocation of a fusion toxin requires un-folding of its dihydrofolate reductase domain; Biochemistry 2003, 42, 15284-15291.
  • Table 1 shown above not only shows the stability constants for binding of the different synthetic compounds of the general structure 1 to the pores but also the rate constants of the forward-reaction and the back reaction. A comparison of these constants shows that the on-rates (k ⁇ ) are all in about the same range. However, the off-rates (k. ⁇ ) appear far more variable. The off-rates of binding are factually decisive for the large effects (kj) of the binding of the synthetic compounds to the general structure 1 at the pores formed from the binding components. In fact, the synthetic compound la has the highest residence time at the binding site of the PA pore and thus the highest stability constant for the binding.
  • Recombinant protective antigen which has been treated with protease (PA 63 ) of B. anthracis was acquired from List Biological Laboratories Inc., Campbell, CA. 1 mg of the lyophilized protein was dissolved in 1 ml 5-mM HEPES, 50 mM NaCl, pH 7.5 and was mixed with 1.25 % trehalose. Aliquots were stored at -20°C.
  • the formation of the black membrane bilayers was performed as described by Benz et al. (J. Membrane Biol. 1978, 44, 353-376).
  • the experimental setup (see also figure 4) consists of a Teflon chamber having two aqueous compartments which are connected with each other by a small round opening of 0.4 mm 2 .
  • the membranes are formed from a 1 % solution of diphy- tanoyl phosphatidylcholine in n-decane.
  • the aqueous salt solution is buffered with 10 mM MES, pH 6. Control experiments show that the pH- value remained constant during measurements.
  • PA 63 was added from the concentrated stock solution to one side of the membrane, and the toxin was thus allowed to incorporate into the artificial lipid membrane.
  • the apparatus is maintained at constant 20°C during the experiments.
  • For a graphical representation of the experimental setup see figure 4.
  • the measurements are performed on multi channel membranes.
  • the transmembrane current is continuously measured with a continuous voltage applied.
  • the current measurement was done using Ag/AgCl-electrodes (with salt bridges), connected in series with a battery powered voltage source and a highly sensitive current measuring device (Keithley 427).
  • the feedback resistor of the current measurement device is dependent on the number of pores in the mem- brane and lies between 0.01 and 10 ⁇ .
  • the output signal of the current amplifier and the amplified signal are observed using an oscilloscope and are recorded with a recording device, in order to measure the absolute height of the membrane current and in order to determine the stability constants of the ligands binding to PA, as also shown in figure 3.
  • the results of the measurement (figure 3) are analyzed using the above outlined formulae.
  • the stability constants of the binding of the synthetic compounds of the general structure to the pores formed from the binding components can be determined, as well as the binding kinetics (see table 1).
  • an artificial lipid membrane is produced from diphy- tanoyl lecithin/n-decane in a 100 mM or 150 mM KC1 solution.
  • the type and structure of the lipid is relatively insignificant, since the membrane only is the matrix for the examined objects.
  • the actual experiment can be started.
  • the integrity i.e. the high resistance of the membrane, is examined in a control experiment. This resistance should be 100-500 Gigaohm (GQ).
  • GQ Gigaohm
  • the activated binding component of the individual AB-toxins is added to one side of the membrane at a concentration of approximately 20-100 ng/ml and is shortly stirred.
  • the incorporation of the channels starts and reaches a saturation at an average at 30-60 minutes.
  • the resistance of the membrane should then be in a range of approximately 1-10 Megaohm ( ⁇ ). In the experiment shown in figure 3, the resistance of the membrane was approximately 2 ⁇ .
  • the titration experiment may be started, and also the current noise of the system may be examined.
  • the synthetic compounds of the general structure 1 are added at a concentration in the ⁇ -range into the aqueous phase on one or both sides of the membrane. By blocking the current, one can determine the affinity of the synthetic compounds of the general structure 1 to the channels formed from the binding components using Lineweaver-Burke-methodology.
  • the output signal of the current amplifier is filtered by a quadrupole-Butterworth-low-pass-filter (Krohn-Hite model 113340, Brockton, MA) and digitized using an AD-card and stored in a PC.
  • the digitized data are analyzed with a programmed Fourier-transformation. These spectra are averaged 128 times or 256 times on the basis of 400 points.
  • the spectral density S(f) of the current noise is determined for the open PA-pores, C2II-pores or iota-b-pores, as a function of the frequency f. Typically, a de- pendency on the inverse frequency 1/f results therefrom.
  • the so-called cut-off frequency is determined from the course of the spectra, wherein the spectral density So drops to 50 %.
  • the kinetics of the binding of the synthetic compounds of the general structure 1 to the pores formed from the binding components can be determined in accordance with the following equation (G. Haug, C. Wilde, J. Leem- huis, D. K. Meyer, K. Aktories, H.
  • Vero cells are pre-treated for 30 minutes at 37°C using the substance bafilomycin Al (100 nM), a pharmacological inhibitor of the vesicular v-ATPase in the endosomal membrane, in order to prevent an acidification of the endosomal lumen and thus the normal incorporation of toxin pores into the membranes of acidified endosomes.
  • bafilomycin Al also inhibits the physiological uptake of binary toxins via acidic endosomes (H. Barth, D. Blocker, J. Behlke, W. Bergsma-Schutter, A. Brisson, R. Benz, K.
  • Aktories Cellular uptake of Clostridium botulinum C2 toxin requires oligomerization and acidification; J. Biol. Chem. 2000, 275, 18704-18711).
  • the cells are subsequently incubated at 4°C in serum-free medium with C2IIa (200 ng/ml) and C2I (100 ng/ml), in order to enable the toxin binding.
  • the conditions in an acidic endosome on the cell surface are imitated.
  • This method allows the precise characterisation of the individual steps, such as pore formation and toxin translocation on the surface of intact cells, and has been successfully used for earlier examinations on C2-toxins (H. Barth, D. Blocker, J.
  • compound la is applied during the acid pulse and the subsequent incubation period.
  • the number of rounded cells is photographically recorded.
  • FIG. 5 shows that C2-toxin and iota-toxin treated cells round as a consequence of the acid pulse (figures 5A and C). This occurs less significantly so in both cases in the presence of substance la (figures 5A-D). This suggests that in the presence of compound la, less C2I or la was transported into the cytosol.

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Abstract

La présente invention concerne des sels d'aminoquinoline, leurs utilisations et des procédés de synthèse de ces sels d'aminoquinoline. La présente invention concerne par ailleurs des compositions comprenant des sels d'aminoquinoline selon la présente invention. La présente invention concerne des composés bioactifs issus de la catégorie des composés d'aminoquinoline, et en particulier, leurs effets inhibiteurs sur les toxines binaires d'un type AB d'un certain nombre de bactéries, telles que Clostridium perfringens, Clostridium botulinum et Bacillus anthracis. L'invention concerne également l'utilisation de ces composés d'aminoquinoline comme médicaments, plus particulièrement, comme médicaments pour le traitement d'infections bactériennes, encore plus particulièrement, d'infections bactériennes causées par des bactéries qui produisent des toxines porogènes de type binaire. La présente invention concerne également des procédés de production des composés selon la présente invention.
PCT/EP2011/004846 2010-09-28 2011-09-28 Sels d'aminoquinoline, leurs procédés de production et leur utilisation en tant qu'agents actifs pour des applications biotechnologiques et médicales contre les toxines binaires Ceased WO2012041493A1 (fr)

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WO2016065348A1 (fr) * 2014-10-24 2016-04-28 Keck Graduate Institute Of Applied Life Sciences Compositions et procédés d'inhibition de pathogènes bactériens et viraux
WO2018183668A1 (fr) * 2017-03-30 2018-10-04 The Board Of Regents Of The University Of Texas System Inhibiteurs à petites molécules dérivés de quinoléine de la nicotinamide n-méthyltransférase (nnmt) et leurs utilisations
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