EP2297088A2 - Neue verbindungen mit gegen die wirkung von toxinen und viren im intrazellulären aktionsmodus schützender wirkung - Google Patents

Neue verbindungen mit gegen die wirkung von toxinen und viren im intrazellulären aktionsmodus schützender wirkung

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Publication number
EP2297088A2
EP2297088A2 EP09766019A EP09766019A EP2297088A2 EP 2297088 A2 EP2297088 A2 EP 2297088A2 EP 09766019 A EP09766019 A EP 09766019A EP 09766019 A EP09766019 A EP 09766019A EP 2297088 A2 EP2297088 A2 EP 2297088A2
Authority
EP
European Patent Office
Prior art keywords
compound
adamantylamine
radical
methyl
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09766019A
Other languages
English (en)
French (fr)
Inventor
Roman Lopez
Séverine Hebbe
Daniel Gillet
Julien Barbier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Commissariat a lEnergie Atomique et aux Energies Alternatives CEA
Original Assignee
Commissariat a lEnergie Atomique CEA
Commissariat a lEnergie Atomique et aux Energies Alternatives CEA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Commissariat a lEnergie Atomique CEA, Commissariat a lEnergie Atomique et aux Energies Alternatives CEA filed Critical Commissariat a lEnergie Atomique CEA
Priority to EP09766019A priority Critical patent/EP2297088A2/de
Priority to EP17172035.2A priority patent/EP3239131A1/de
Publication of EP2297088A2 publication Critical patent/EP2297088A2/de
Withdrawn legal-status Critical Current

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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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    • C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
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    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/16—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring not being further substituted
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    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
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Definitions

  • the present invention relates to novel families of compounds derived from benzodiazepine, aminoadamantane, imine and aromatic amine, medicaments comprising them and their use as inhibitors of the toxic effects of toxins with intracellular activity, such as for example ricin, and viruses using the internalisation pathway to infect cells.
  • Intracellular mode of action toxins or AB toxins, are organized enzymes in several domains: a catalytic domain A which carries the toxic activity and one or more B domains providing cellular recognition and allowing transmembrane translocation of fragment A in the cytoplasm (Faines, PO, Sandvig, K. Leather, Opin, Biol., 2000, 12, 407).
  • diphtheria toxin and cholera toxin have an A-domain which carries ADP-ribosyltransferase-type enzymatic activity; large clostridial toxins have glucosyltransferase activity; botulinum toxin, tetanus toxin and lethal anthrax toxin are metalloproteases; Shiga toxins and ricin have N-glucosidase activity.
  • ricin is a toxalbumin produced by a shrub of the euphorbiaceae family, ricinus (Ricinus communis). It is present at a concentration varying from 1 to 10% in the castor seed.
  • the A chain (RTA, 267 amino acids) provides the catalytic function of ricin (N-glucosidase), whereas the B chain (RTB, lectin of 262 residues) acts as a transporter allowing the entry of ricin into the cell.
  • the B chain has two galactose binding sites and allows the binding of the toxin to glycoreceptors present on the cell surface. Ricin can then enter these cells through multiple pathways of endocytosis, reaching the Frans-Golgian network where it is transported to the endoplasmic reticulum (ER) by retrograde transport.
  • ER endoplasmic reticulum
  • the toxin is then partially unfolded and the A chain is translocated into the cytosol by the Sec61p translocon, which normally translocates neoformed proteins into the ER or transports the misfolded proteins out of the ER and to the cytoplasm for degradation.
  • Ricin is able to escape this proteolysis which allows it to bind to the ribosome with high efficiency and to cleave adenine at position 4324 (hereinafter A4324) 1 I of 28S RNA subunit of the ribosome 6OS. It can inactivate up to 2000 ribosomes per minute.
  • Ricin is a cytotoxin that can be easily extracted in large quantities. Its toxicity differs according to the routes of introduction: digestive, because it is poorly absorbed or inactivated by digestive enzymes, it is about 1000 times less toxic than pulmonary (inhalation) or parenteral. The symptoms of intoxication are numerous and depend on the route of introduction, they appear in a few hours and can lead to death in 2 to 3 days. There is no antidote for intoxication, the treatment being essentially symptomatic. Since ricin is also very soluble in water and can disperse in aerosol form, this toxin is considered a major bioterrorism agent (Category B agent on the US Center for Outbreak Control List (CDC, Atlanta). )).
  • Targeted adenosine is stabilized at the active site by formation of H bonds between the purine ring of adenosine and certain residues of RTA: valine at position 81 (V81), glutamic acid at position 177 (E177) and arginine in position 180 (R180).
  • R180 will then allow partial protonation of the adenine base, weakening the bond between base and ribose.
  • the adenine is then released and the formed oxonium ion, stabilized by E177, is trapped by R180-activated water, thus forming ribose.
  • small molecules these are molecules that will for example bind to ricin at its catalytic site and prevent the depuration of ribosomes.
  • Molecular modeling studies have allowed Robertus' group to discover the first inhibitor of enzymatic activity of ricin: pteroic acid and a derivative shown below.
  • pteroic acid as well as its derivative, are poor inhibitors of N-glycosylase activity with an inhibition constant of the order of 0.6 mM. (Miller, D., Ravikumar, K., Shen, H., Sun, J, Kerwin, S., Robertus, JDJ Med Chem 2002, 45, 90. Yan, X. et al., J. Mol. Biol 1997, 266, 1043).
  • I ⁇ RN28S the SRL loop (Sarcin-Ricin Loop), inhibitors were designed based on this nucleotide sequence. They are analogues of the transition state of the natural substrate of ricin which have non-cleavable groups at the level of the target adenine. Schramm's studies (Schramm, V.L. et al., Biochemistry 2001, 40 (23), 6845;
  • RNA ligands or aptamers, specific for the RTA catalytic chain. These aptamers do not resemble the native substrate of RTA (SRL loop) and are not not depurined by ricin.
  • SRL loop native substrate of RTA
  • nM (Hesselberth, JR, Miller, D., Robertus, JD, Ellington, ADJ Biol Chem 2000, 275, 4937).
  • Haslam et al. (Saenz, JB, Doggett, TA, Haslam, D 1 B. Identification and Characterization of Small Molecules That Inhibit Intracellular Toxin
  • the inventors have identified by high throughput screening of molecules capable of protecting cells in culture placed in contact with ricin.
  • the mode of action of these compounds remains unknown even though they appear to act at the cellular level - and not directly on the toxin - probably by modifying one or more steps of the intracellular routing of ricin.
  • the chemical optimization of these compounds has made it possible to progress towards compounds having a higher cell protection capacity.
  • the identified compounds act at the cellular level by modifying the intracellular routing of ricin, these compounds may also be able to block the internalization of other AB toxins and viruses.
  • the AB toxins and the viruses exploit cell trafficking pathways partly common with those used by the ricin.
  • cellular protection was obtained from diphtheria toxin and verotoxin-2 (Shiga-like toxin) in the presence of some of the compounds identified by screening.
  • the subject of the present invention is thus compounds having the property of protecting eukaryotic cells from the effects of toxins with intracellular activity, such as ricin, botulinum toxins, diphtheria toxins, anthrax toxins, toxin cholera, pertussis toxin, Shiga toxin (verotoxin-2), thermolabile Escherichia coli toxins, large clostridial toxins, dermonecrotic and virus factors using the intemalisation pathway to infect cells, for example, RNA virus 1 Flaviviridae (such as dengue fever, yellow fever), Orthomyxoviridae (such as influenza) or Rhabdoviridae (such as rabies). This property is particularly advantageous since during ricin intoxication by respiratory (inhalation) or absorption (ingestion), these cells are the first in contact with the toxin.
  • toxins with intracellular activity such as ricin, botulinum toxins, diphtheria toxins, anthrax toxins, toxin
  • Cy represents a group chosen from: or
  • W is chosen from a hydrogen atom or a halogen atom
  • Y is chosen from a hydrogen atom or a hydroxyl function
  • Z is a carbon atom or a bond (Cy is then a noradamantyl ring)
  • Cy when Cy is an adamantyl ring, the chain is attached to it in position 1 or 2, p represents 0 or 1;
  • X represents either: a bond; an optionally unsaturated C 1 -C 6 alkyl chain, optionally branched, optionally substituted by a phenyl radical, an acid function and / or a C 1 -C 3 alkyl ester radical; said chain being optionally interrupted by an oxygen atom;
  • R 1 represents a radical of 1 to 21 carbon atoms optionally branched and / or cyclic, saturated or unsaturated, one or more of the carbon atoms may be replaced by a nitrogen atom, oxygen and / or sulfur; said radical optionally being mono- or disubstituted with a halogen atom, a -COOH function, -OH, - NO 2, alkyl radical Ci-C 3 alkoxy radical, Ci-C 3 or an acyloxy radical Ci-C 3 ;
  • R 2 represents either a bond or is chosen from a hydrogen atom, a C 1 -C 3 alkyl radical, optionally unsaturated, optionally branched, an acyl radical,
  • the invention also relates to the pharmaceutically acceptable salts of these compounds such as hydrochlorides, hydrobromides, sulphates or bisulfates, phosphates or hydrogen phosphates, acetates, oxalates, benzoates, succinates, fumarates, maleates, lactates, citrates, tartrates, gluconates, methanesulphonates, benzene - sulphonates and paratoluene-sulphonates.
  • Halogen atom means the chemical elements of group VII of the Periodic Table of Elements, in particular fluorine, chlorine, bromine and iodine.
  • Preferred halogen atoms for carrying out the present invention are bromine (Br) and fluorine (F).
  • C 1 -C 3 alkyl chain or radical denotes, respectively, a linear or branched chain or a hydrogenocarbon radical; mention may be made, for example, of methyl, ethyl, propyl or isopropyl.
  • C 1 -C 3 alkoxy radical means a radical -OC n H 2n + 1 , n being an integer between 1 and 3; mention may be made, for example, of the methoxy, ethoxy, propyloxy and isopropyloxy radicals.
  • n is 1.
  • acyloxy radical C 1 -C 3 is meant a radical -O (CO) C n H 2n + I or - (CO) OC n H 2n + I, n being an integer between 1 and 3; for example, the acetyl radical may be mentioned.
  • n is 1.
  • C 1 -C 3 acyl radical is meant a radical - (CO) C n H 2n + I , n being an integer between 1 and 3.
  • the radical R 1 of 1 to 21 carbon atoms, optionally branched and / or cyclic, saturated or unsaturated, of which one or more of the carbon atoms may be replaced by a nitrogen atom , oxygen and / or sulfur is selected from: an alkyl radical of 1 to 8 carbon atoms linear or branched, saturated or not, a cyclic radical with 5 or 6 carbon atoms, saturated or not, a bicyclic radical at 9 or 10 carbon atoms, saturated or unsaturated, a tricyclic radical with 14 carbon atoms, saturated or unsaturated, a heterocyclic radical with 5 atoms, saturated or unsaturated, a heterocycle with 6 atoms, saturated or unsaturated, a biheterocyclic radical with 9 or 10 atoms, saturated or not.
  • linear or branched, saturated or unsaturated, alkyl radical of 1 to 8 carbon atoms is chosen from: a tert-butyl radical, 2,4,4-trimethylpentanyl, 3-hydroxy-2-methylpropanoate, hydroxymethylpropane radical -1,3-diol.
  • cyclic radicals listed above are preferably chosen from the following radicals: cyclopentylmethanol, cyclomethanoate, phenyl, cyclohexyl, pyridine, furan, thiophene, imidazole, quinoline, indole, benzofuran, adamantyl, naphthalene, anthracene,
  • the compounds of general formula (I) are such that R 1 is an optionally substituted phenyl radical and / or X is -CH 2 - and / or R 2 is a hydrogen atom and / or W represents an atom from Br.
  • R 1 is the radical:
  • R 3 is chosen from a cyclic radical with 5 or 6 carbon atoms, saturated or unsaturated; a bicyclic radical with 9 or 10 carbon atoms, saturated or not; a tricyclic radical with 14 carbon atoms, saturated or unsaturated; a heterocyclic radical with 5 atoms, saturated or unsaturated; a heterocycle radical with 6 atoms, saturated or not; a biheterocyclic radical with 9 or 10 atoms, saturated or not; said radicals being optionally substituted with at least one halogen atom, -NO 2 , -OH or a C 1 -C 3 alkyl radical; the radicals are preferably chosen from the radicals: phenyl, furan, indole and thiophene; and
  • the compounds of general formula (I) are defined by the general formula (I '):
  • W, p, R 3 and R 4 are as previously defined and X is either a bond or -CO-.
  • the present invention also relates to compounds of general formula (I) as defined above and their pharmaceutically acceptable salts as such excluding compounds 1, 6, 8, 11, 18, 29, 30, 34 , 74, 78, 98, 100, 113, 114, 116, 121, 122, 124, 128, 135, 145 and 161.
  • the invention relates to the process for preparing the compounds of general formula (Ia):
  • Cy is the adamantyl ring with the nitrogen atom at position 1 or 2,
  • X represents a C 1 -C 3 alkyl chain, optionally unsaturated, branched, optionally interrupted by an oxygen atom;
  • R 1 is a radical of 1 to 21 carbon atoms optionally branched or cyclic, saturated or unsaturated, one or more of the carbon atoms may be replaced by a nitrogen atom, oxygen and / or sulfur and optionally mono or bi-substituted with a halogen atom, a -OH, -NO 2 function , a C 1 -C 3 alkoxy radical or a C 1 acyloxy radical;
  • R 2 is chosen from -H or a C 1 -C 3 alkyl radical, characterized in that it comprises the following steps:
  • the compounds of general formula (la) in Tables A1 and A2 according to Example 1 are prepared in methanol by treatment of 1-adamantylamine (for compounds of Table A1) or 2-adamantylamine (for the compounds of Table A2) in the presence of an aromatic aldehyde (1 equiv.) depending on the compound to be prepared.
  • the supported cyanoborohydride is used (BH 3 CN on resin, 1.5 equiv) as a reducing agent in the presence of acetic acid (3 equiv.). The whole is stirred for 2 days at room temperature, filtered, washed with methanol, evaporated and then purified according to the methods known to those skilled in the art.
  • X represents a C 1 -C 3 alkyl chain, optionally unsaturated, branched, optionally
  • R 2 is chosen from nothing, -H, -CH 3 or ; it being understood that when R 2 is nothing then the nitrogen atom and X are linked by a double bond.
  • the invention therefore also relates to the process for the preparation of compounds of general formula (Ib), characterized in that it comprises the following stages: addition of a suspension in methanol of 3-bromobenzylamine while stirring to a chosen aromatic aldehyde depending on the compound of general formula (Ib) to be prepared in the presence of BH 3 CN on resin and acetic acid; stirring the mixture for 2 days at room temperature.
  • the compounds (Ib) in Table A3 and in Table A4 are prepared by adding with stirring a suspension of an amine
  • Cy is with Z is a carbon atom or nothing (noradamantyl ring), with the nitrogen atom in position 1 or 2 when Cy in the adamantyl ring,
  • R 1 is chosen from a phenyl radical, a heterocyclic radical such as the pyridine, furan, thiophene, quinoline and indole radicals, preferably the indole radical, said radical optionally being mono or bi-substituted by a halogen atom, an -OH function, - NO 2, alkoxy radical dC 3 or an acyloxy radical C 1 -C 3, an alkyl radical in C 1 -C 3 alkyl, preferably a methyl radical; are prepared as follows: a stirred suspension in methanol of 1-, 2- or noradamantylamine (1 equiv.) is added to an aldehyde (1 equiv.) selected according to the compound to be prepared (see Tables C1, C2 and C3 of Example 1).
  • a stirred suspension in methanol of 1-, 2- or noradamantylamine (1 equiv.) is added to an aldehyde (1 equiv.) selected according to
  • the invention relates to the process for the preparation of 1-aminoadamantane, 2-aminoadamantane or noradamantylamine derivatives of general formula (Ic), characterized in that it comprises the following steps:
  • the preparation of the imines is carried out by adding a solution of the amine in MeOH to the aldehyde, the amine and the aldehyde being chosen according to the imine to be prepared, and the mixture is stirred for 2 days. After evaporation and purification the imines are obtained.
  • the imines are reduced as follows: To a solution of imine in MeOH is added BH 3 CN on resin (3 equiv.) And AcOH. After 3 days at room temperature, the mixture is filtered, washed with methanol and then concentrated in vacuo. The crude compound thus obtained is purified according to conventional methods.
  • the invention also relates to a process for the preparation of imines of general formula (I), characterized in that it comprises the following stages:
  • the invention also relates to a process for the preparation of reduced imine of general formula (I), characterized in that it comprises the following steps:
  • the compounds ⁇ / -1-adamantylbenzamide and ⁇ / -2-adamantylbenzamide are prepared from the corresponding amines (1- or 2-adamantylamine (1 equiv.)) Via base treatment such as NaH (1.1 equiv. ) in DMF and then adding benzoyl chloride (1.2 equiv) to 0 ° C. The mixture is stirred for 24 hours at room temperature, evaporated and then washed with cyclohexane.
  • the invention finally relates to a process for the preparation of the compounds N-1-adamantylbenzamide and ⁇ / -2-adamantylbenzamide comprising the following steps:
  • the invention also relates to a process for the preparation of a urea derivative of general formula (I), characterized in that it comprises the following steps: a suspension of the amine derived from 1-adamantyl (1 equiv.) in THF is added at 0 ° C., the isocyanate, amine and isocyanate corresponding to said desired urea derivative (1, 1) equiv.)
  • the alcohols are initially treated with iodine (2.5 equiv) and a base such as potassium carbonate in tert-butanol and are heated for 24 hours at 70 ° C.
  • the nucleophile (amine, alcohol) is then added (1.5 equiv). After conventional treatment and purification, the alkylated compounds are obtained.
  • the invention also relates to a process for the preparation of triazole derivatives of general formula (I), characterized in that it comprises the following steps: reaction of an azide with an acetylenic (1 , 1 equiv), these two reactants being chosen according to said triazole compound of general formula (I) to be synthesized, in the presence of copper on carbon (catalytic) and triethylamine (1, 0 equiv) in dioxane for 24 hours at room temperature;
  • the invention also relates to 2-amino-N-phenylbenzamide as synthesis intermediate of the amines of general formula (I).
  • the present invention also relates to the use of compounds derived from benzodiazepine of general formula (II):
  • R 3 is selected from hydrogen or halogen; an alkyl radical in C 1 -C 6 -alkoxy or C 1 -C 6 acyloxy C 1 -C 6 alkyl, these radicals being optionally substituted with a C 1 -C 6 alkoxy radical; an aryloxy radical or a heteroaryloxy radical;
  • R 4 represents either a bond or is selected from a hydrogen atom, an acyloxy radical of C 1 -C 3 alkoxy C 1 -C 3 alkyl or phenyl
  • R 5 represents either a bond or is selected from a hydrogen atom; a C 1 -C 3 alkyl radical; a C 1 -C 3 alkoxy radical; an acyloxy C 1 -C 3 alkyl or a phenyl radical optionally substituted by an -OH function and / or a halogen atom, an alkyl radical in C 1 -C 3 alkoxy C 1 -C 3 C 1 -C 3 acyloxy radical, a
  • R 4 and R 5 can not simultaneously represent a bond and that when one of the two is a bond then A and B are linked by a double bond; and that when B is a carbon atom, R 5 can also form with the hydrogen atom carried by the carbon adjacent to B a ring of 5 or 6 atoms optionally substituted with a phenyl radical, optionally interrupted by a hydrogen atom.
  • nitrogen, sulfur or oxygen preferably, it is a 5-atom ring interrupted by an oxygen atom; for the preparation of a pharmaceutical composition for the prevention and / or treatment of poisoning to at least one intracellular mode of action toxin or at least one virus using the internalisation route for infecting eukaryotic mammalian cells.
  • the invention also relates to the pharmaceutically acceptable salts of these compounds
  • the C 1 -C 6 alkyl radical denotes a linear or branched hydrocarbon radical of 1 to 6 carbon atoms, for example methyl, ethyl, propyl or isopropyl.
  • alkoxy radical C 1 -C 6 is meant a radical -OC m H 2m + i, rn being an integer between 1 and 6.
  • C 1 -C 6 acyloxy radical is meant a radical -O (CO) C m H 2m + 1 or - (CO) OC m H 2m + 1 , m being an integer between 1 and 6.
  • radical aryloxy means an aryl group connected by an oxygen atom to the rest of the compound.
  • heteroaryloxy radical is meant a heteroaryl group connected by an oxygen atom to the rest of the compound.
  • the compounds of general formula (II) are such that R 3 is a bond and / or R 4 represents a hydrogen atom and / or R 5 represents a radical phenyl and / or when A is a carbon atom then R 4 is a phenyl radical and / or when B is a carbon atom then R 5 is a phenyl radical.
  • the present invention also relates to the compounds of general formula (II) and their pharmaceutically acceptable salts as such excluding compounds 162, 163, 164, 165, 166, 167, 169, 170, 171 and 193.
  • the synthesis of the compounds of general formula (II) according to the invention is described in Example 1.
  • benzo [e] [1, 4] diazepine derivatives and the benzo [ ⁇ ] [1, 4] diazepine derivatives of general formula (II) are prepared as follows: - addition to a suspension of diamine, chosen according to compound to be prepared, for example from benzene-1, 2-diamine, 4-bromobenzene-1,2-diamine (1 equiv) in toluene (2 ml) with a ⁇ -ketoester (1 equiv);
  • the invention also relates to compounds which are useful as synthesis intermediates for the compounds of general formula (II) chosen from: te / ⁇ -Butyl
  • the compounds according to the invention are pharmacologically active substances and find their interest thanks to their inhibitory effect on toxins with an intracellular mode of action, in particular, ricin.
  • the invention relates to the compounds of general formula (I) and (II) and their pharmaceutically acceptable salts, excluding the compounds of compounds 1, 6, 8, 11, 18, 29, 30 , 34, 74, 78, 98, 100, 113, 114, 116, 121,
  • the invention also relates to pharmaceutical or medicinal compositions comprising one or more compounds of general formula (I) or (II) and their pharmaceutically acceptable salts, excluding the compounds of compounds 1, 6, 8,
  • a pharmaceutically acceptable vehicle compatible with administration to a subject, preferably a mammal, by any route of administration.
  • the drug may be administered orally, parenterally, pulmonary, ocular, nasal ....
  • the preferred modes of administration of compounds (I) and (II) are those using the airway (inhalation), oral (ingestion), parenteral or local (topical).
  • the amount of compound of formula (I) or (II) to be administered to the mammal depends on the specific activity of this compound, which activity can be measured by means which are set forth in the examples. This amount also depends on the severity of the pathology to be treated, including the amount of ricin absorbed and the route by which it was, it finally depends on the age and weight of the individual to be treated.
  • the use of the compounds of general formula (I) or (II) is particularly advantageous for preventing and / or treating disorders caused by intracellular mode of action AB toxins and viruses using the intemalisation pathway for infecting cells. .
  • AB toxins or toxins with an intracellular mode of action include: ricin, botulinum toxins, diphtheria toxins, anthrax toxins, cholera toxin, pertussis toxin, Shiga toxin (verotoxin-2) , the thermolabile toxins of Escherichia coli, the large clostridial toxins, the dermonecrotic factors, examples of these toxins are listed in the Table below:
  • viruses using the intemalisation pathway to infect cells are, for example, RNA viruses, Flaviviridae (such as dengue fever, yellow fever), Orthomyxoviridae (such as influenza), or still Rhabdoviridae (like rabies). This use proves effective that the subject touches, ingests or inhales the toxin or the virus, or that the toxin or the virus is injected.
  • these compounds may be used for the preparation of a pharmaceutical composition for treating the effects of AB toxins or toxins with an intracellular mode of action and viruses using the intemalisation pathway for infecting cells.
  • a toxin like ricine when inhaled, leads to signs of ocular irritation (burning sensation, tearing, conjunctivitis more or less severe) and pharyngeal as well as a more or less marked respiratory irritation: cough, dyspnea, pulmonary edema that may lead to acute respiratory distress syndrome (ARDS).
  • ARDS acute respiratory distress syndrome
  • the invention relates to the use of a compound of general formula (I) or (II) for the preparation of a pharmaceutical composition intended to protect against the effects of ricin, other AB toxins and of viruses using the internalization pathway for infecting cells of eukaryotic, in particular epithelial, ocular, pharyngeal, tracheal, bronchial, cutaneous and muscular cells, in particular pulmonary and digestive epithelial cells, preferably intestinal cells, mammal cells, preference of the man.
  • eukaryotic in particular epithelial, ocular, pharyngeal, tracheal, bronchial, cutaneous and muscular cells, in particular pulmonary and digestive epithelial cells, preferably intestinal cells, mammal cells, preference of the man.
  • the invention relates more specifically to the use of the compounds of general formula (I) and (II) and their pharmaceutically acceptable salts for the preparation of a pharmaceutical composition for preventing and / or treating ricin toxin intoxication. ; preferably, the compounds of general formula (I) and (II) and their pharmaceutically acceptable salts are chosen from compounds 1, 3, 5, 9, 15, 19, 24, 28,
  • the invention relates to the use of compounds of general formula (I) defined by general formula (1.1) in which
  • Cy represents a group chosen from
  • Z is a carbon atom or a bond (Cy is then a noradamantyl ring) with the proviso that when Cy is an adamantyl ring, the nitrogen atom is attached to it in position 1 or 2,
  • R 1 represents: a phenyl ring, optionally substituted with a radical -OCH 3 in para to the carbon atom bonded to the chain -CH 2 -NH-Cy; said cycle being alternatively optionally substituted by a halogen atom in the meta position of the carbon atom bonded to the chain - CH 2 -NH-Cy and in this case, said ring optionally carries a second substitution in the para position of said atom of halogen, said second substitution being selected from -NO 2 and -OCH 3 ; an indole, imidazole or furan ring substituted by a methyl radical, a benzo- (1,3) -dioxolo ring, a naphthalenyl ring or a phenanthrenyl ring; and pharmaceutically acceptable salts thereof for the preparation of a pharmaceutical composition for preventing and / or treating ricin toxin intoxication.
  • the compounds of general formula (1.1) are chosen from compounds 1, 3, 5, 9, 15, 19, 24, 28, 34, 36, 39, 59, 65, 86, 109, 110, 111, 112, 138, 139, 140, 142, 143 and 148.
  • the invention relates to the use of compounds of general formula (I) defined by general formula (1.2):
  • X represents - (CH 2 J 2 -O-CH 2 -, - (CH 2 ) 3 -, -CO-, -SO 2 - and their pharmaceutically acceptable salts for the preparation of a pharmaceutical composition for preventing and / or treat ricin toxin poisoning.
  • the compounds of general formula (1.2) are chosen from compounds 68, 69, 122 and 128.
  • the invention relates to the use of compounds of general formula (I) defined by general formula (1.3):
  • W represents a halogen atom and pharmaceutically acceptable salts thereof for the preparation of a pharmaceutical composition for preventing and / or treating ricin toxin intoxication.
  • the compounds of general formula (1.3) are chosen from compounds 117 and 118.
  • Y is O or S and their pharmaceutically acceptable salts for the preparation of a pharmaceutical composition for preventing and / or treating ricin toxin intoxication.
  • the compounds of general formula (1.4) are chosen from compounds 154 and 161.
  • the present invention also relates to the use of the compounds of general formula (I) and (II) and their pharmaceutically acceptable salts for the preparation of a pharmaceutical composition for preventing and / or treating diphtheria toxin poisoning.
  • Cy represents a grouping: to which the nitrogen atom is attached at position 1 or 2, W and W are, independently of one another, chosen from a hydrohene atom, a halogen atom and a C 1 -C 3 alkoxy radical and their pharmaceutically acceptable salts.
  • the compounds of general formula (1.5) are chosen from compounds 5, 9, 39, 110, 111, 112, 139 and 140.
  • FIG. 1 is a schematic representation of the high-throughput cellular test.
  • Figure 2 shows the results of the screening.
  • the yellow dots represent the positive controls (cells with ricin + lactose)
  • the green dots represent the negative controls (cells treated with ricin alone) and, in red, the compounds according to the invention tested in the presence of ricin.
  • Injection volume 1 ⁇ L with Waters 2767 autosampler Method: 95% solution A (99.99% water, 0.01% formic acid), 5% B (100% acetonitrile) up to 0% A, 100% B on a gradient of 8 minutes and then 5 minutes.
  • the 1-aminoadamantane and 2-aminoadamantane derivatives of general formula (Ia) as described above and appearing respectively in Tables A1 and A2 are prepared as follows: a suspension in methanol of 1-adamantylamine or of 2-adamantylamine (0.5 mmol, 75 mg, 1 equiv) is added with stirring to an aromatic aldehyde (1 equiv) depending on the compound in the presence of BH 3 CN on resin (0.75 mmol; Equiv) and acetic acid (1.5 mmol, 84 ⁇ L, 3 equiv). The whole is stirred for 2 days at ambient temperature, filtered, washed with methanol, evaporated and then purified.
  • Tables A1 and A2 show the number of the compound, the aldehyde used, the name of the compound obtained, the characteristics of the compound as well as the code of the purification method used, the appearance of the compound obtained and its yield.
  • Table A1 1-aminoadamantane derivative compounds prepared by Method A from 1-adamantylamine
  • the derivatives and the alkylamines of general formula (Ib) as described above and appearing in Table A3 and in Table A4 are prepared by adding with stirring a suspension of an amine (1 equiv.) Chosen according to the compound to be prepared (see Tables A3 and A4) in methanol to 3-bromobenzaldehyde or 3-fluorobenzaldehyde (1 equiv) for compounds of Table A3 or 3-bromobenzylamine or 3-fluorobenzylamine (1 equiv. ) to obtain the compounds of Table A4, in the presence of BH 3 CN on resin (0.75 mmol, 1.5 equiv) and acetic acid (1.5 mmol, 84 ⁇ l, 3 equiv). The whole is stirred for 2 days at room temperature, filtered, washed with methanol, evaporated and then purified according to the methods known to those skilled in the art.
  • Tables A3 and A4 show the number of the compound, the reagents used, the name of the compound obtained, the characteristics of the compound as well as the code of the purification method used, the appearance of the compound obtained and its yield.
  • Table A3 Amino Alkyl Compounds of General Formula (I) Prepared by Method A from 3-Halogenobenzaldehydes
  • the compounds of Table A5 are made according to Method A by adding a microwave heating step Table A5
  • Process B Formation of acid salts To a solution in the CH 2 Cl 2 of the amine (corresponding to the desired hydrochloride salt) is added a solution of HCl in I 1 and 2 O (2N). The salt is obtained after filtration and vacuum drying of the precipitate.
  • Table B1 salts derived from 1 or 2-aminoadamantane
  • the derivatives of 1-aminoadamantane, 2-aminoadamantane or noradamantylamine of general formula (Ic) as described above and appearing respectively in Tables C1, C2 and C3 are prepared as follows: a stirred suspension in methanol of 1-, 2- aminoadamantane or noradamantylamine (1 equiv) is added to an aldehyde (1 equiv) selected according to the compound to be prepared (see Tables C1, C2 and C3). The mixture is mixed for two days at room temperature and then evaporated.
  • the compounds ⁇ / -1-adamantylbenzamide and ⁇ / -2-adamantylbenzamide are prepared as follows: to a suspension of NaH (1.1 equiv) in DMF is added 1- or 2-adamantylamine (1 equiv) and benzoyl chloride (1, 2 equiv.) at 0 ° C. The mixture is stirred for 24 hours at room temperature, evaporated and then washed with cyclohexane.
  • Table D1 1-aminoadamantane derivatives prepared by Method E prepared from 1-adamantylamine
  • the sulphonylation is carried out according to the following method:
  • Lane 1 4-Bromoaniline (1 eq, 0.05 mol, 8.6 g) is dissolved in benzoyl chloride (2.7 eq, 0.135 mol, 15.7 mL). The reaction mixture is heated to 180 ° C and then zinc chloride (1.25 eq, 0.063 mol, 8.5 g) is added. After heating for two hours at 205 ° C., the mixture is cooled to 120 ° C. and then 60 ml of 3N hydrochloric acid are added. After refluxing and decanting the hot acid layer, the residue The insoluble solution in water is dissolved in 80 ml of 70% sulfuric acid, refluxed for 8 hours and then poured into a large quantity of ice water.
  • aminobenzophenone (2.85 eq, 5 mmol, 1.0 g) was dissolved in 15 mL of pyridine containing 4A molecular sieve.
  • the ethyl glycinate hydrochloride (1 eq, 1.75 mmol, 244 mg) is then added and the mixture is refluxed for 3 hours.
  • About 5 mL of pyridine is removed from the Dean-Stark and replaced with 5 mL of fresh pyridine.
  • 2-benzoyl-4-bromoaniline (2 eq, 0.47 mmol, 130 mg) is dissolved in 5 mL of pyridine.
  • the methyl glycinate hydrochloride (1 eq, 1, 24 mmol, 30 mg) is then added and the mixture is refluxed for 3 hours.
  • About 2 mL of pyridine is removed from Dean-Stark and replaced with 2 mL of fresh pyridine.
  • the pyridine is evaporated, adding 5 ml of toluene, and then the residue is dissolved in 20 ml of dichloromethane and 20 ml of 2.5% Na 2 CO 3 .
  • 1,2-diamino-benzene (1 eq, 2 mmol, 216 mg) and ethyl 3-oxo-3-phenylpropanoate (1 eq, 2 mmol, 384 mg) are mixed.
  • the reaction mixture is then heated at 150 ° C for two hours.
  • the residue is then diluted in ethyl acetate and hydrochloric acid (pH ⁇ 5), then the organic phase is washed with water and then with a saturated solution of sodium chloride. Finally, the solution is dried with Na 2 SO 4 and then evaporated.
  • the following second method also allows the synthesis of compound 166: in a pillbox, 1,2-diamino-benzene (1 eq, 10 mmol, 1, 08 g) is mixed with cinnamic acid (1 eq, 10 mmol, 1.48 g). The reaction mixture is then heated at 150 ° C without solvent for two hours. The residue is diluted in dichloromethane and a solution of Na 2 CO 3 at 5%. The organic phase is extracted several times with the Na 2 CO 3 solution and then with a saturated solution of sodium chloride. Finally, the solution is dried with Na 2 SO 4 and then evaporated. Purification on a column of silica gel (cyclohexane / ethyl acetate in a gradient of 80: 20 to 1: 1) makes it possible to isolate 166 with a yield of 12% (286 mg).
  • the compound 166 (1 eq, 0.218 mmol, 52 mg) is dissolved with ethyl chloroformate (1.2 eq, 0.262 mmol, 25 ⁇ l) in a solution composed of dichloromethane and triethylamine in proportions of 10: 1. two days at room temperature, the contents of the pillbox is evaporated. Purification on a column of silica gel (cyclohexane / ethyl acetate in a 90: 10 to 1: 1 gradient) makes it possible to isolate 15 mg of 168, ie a yield of 21%.
  • the mixture is stirred at reflux (120 ° C.) for 3 h.
  • the mixture is diluted with EtOAc, acidified
  • a cell test was developed to demonstrate the cytotoxic activity of ricin while being adapted to the constraints of high throughput screening (see Figure 1 the schematic representation of this test).
  • the use of such a test has several advantages: (i) selection of molecules that can act on the various stages of cellular intoxication (receptor binding, intemalisation, intracellular routing, enzymatic activity, etc.);
  • the assay used directly measures the ability of cells to synthesize proteins, making it an excellent screening assay because this biosynthetic pathway is stopped by ricin.
  • Yellow-stained wells are positive controls (A549 treated with ricin (10 -10 M) in the presence of 20 mM lactose which is a ricin binding inhibitor to cells), whereas green wells: negative controls ( cells treated with ricin alone) Red wells: cells in contact with the compounds of the banks in the presence of ricin
  • the compounds were tested on A549 cells at the concentration of 30 ⁇ M by incubation with different concentrations of ricin (10 9 to 10-12 M) with the protocol described above for the high-throughput screening, the measured radioactivity is then proportional to the rate
  • I 1 EC 50 the effective concentration for which one observes 50% of assimilation of leucine radioactive which corresponds to 50% of viable cells.
  • the EC 50 value is high, the higher the cellular protection, because a higher concentration of ricin is needed to generate the same cytotoxicity.
  • the compounds were also tested on Vero cells (ATCC No. CCL-81) at a concentration of 30 ⁇ M by incubation with different concentrations of diphtheria toxin (10 -9 to 10-12 M) (Sigma) with the protocol described in 2.1.

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EP09766019A 2008-06-17 2009-06-17 Neue verbindungen mit gegen die wirkung von toxinen und viren im intrazellulären aktionsmodus schützender wirkung Withdrawn EP2297088A2 (de)

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PCT/FR2009/000727 WO2009153457A2 (fr) 2008-06-17 2009-06-17 Nouveaux composés ayant une activité protectrice vis-à-vis de l'action de toxines et de virus au mode d'action intracellulaire
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EP3239131A1 (de) 2017-11-01
US20170233386A1 (en) 2017-08-17
US20120283249A1 (en) 2012-11-08
WO2009153457A2 (fr) 2009-12-23
EP2296757A2 (de) 2011-03-23
EP2145873A1 (de) 2010-01-20
WO2009153457A3 (fr) 2010-07-29
WO2009153665A3 (en) 2010-04-08
US20160083355A1 (en) 2016-03-24
US20110201601A1 (en) 2011-08-18
US9034868B2 (en) 2015-05-19
US8609732B2 (en) 2013-12-17
US20140073633A1 (en) 2014-03-13

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