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US20120283249A1 - Novel compounds which have a protective activity with respect to the action of toxins and of viruses with an intracellular mode of action - Google Patents

Novel compounds which have a protective activity with respect to the action of toxins and of viruses with an intracellular mode of action Download PDF

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Publication number
US20120283249A1
US20120283249A1 US12/999,576 US99957609A US2012283249A1 US 20120283249 A1 US20120283249 A1 US 20120283249A1 US 99957609 A US99957609 A US 99957609A US 2012283249 A1 US2012283249 A1 US 2012283249A1
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Prior art keywords
compound
adamantylamine
radical
methyl
phenyl
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US12/999,576
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Inventor
Roman Lopez
Séverine Hebbe
Daniel Gillet
Julien Barbier
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Commissariat a lEnergie Atomique et aux Energies Alternatives CEA
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Individual
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Assigned to COMMISSARIAT A L'ENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES reassignment COMMISSARIAT A L'ENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HEBBE, SEVERINE, LOPEZ, ROMAN, BARBIER, JULIEN, GILLET, DANIEL
Publication of US20120283249A1 publication Critical patent/US20120283249A1/en
Priority to US14/810,342 priority Critical patent/US20160083355A1/en
Priority to US15/494,798 priority patent/US20170233386A1/en
Abandoned legal-status Critical Current

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    • 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
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Definitions

  • the subject of the present invention is novel families of compounds which are aromatic amine, imine, aminoadamantane and benzodiazepine derivatives, medicaments comprising same and the use thereof as inhibitors of the toxic effects of toxins with intracellular activity, such as, for example, ricin, and of viruses that use the internalization pathway for infecting cells.
  • Toxins with an intracellular mode of action are enzymes that are organized into several domains: a catalytic domain A which carries the toxic activity and one or more B domains which provide cell recognition and enable transmembrane translocation of the A fragment into the cytoplasm (Falnes, P. O.; Sandvig, K. Curr. Opin. Cell. Biol. 2000, 12, 407).
  • diphtheria toxin and cholera toxin have an A domain which carries an ADP-ribosyltransferase enzyme activity; the major clostridial toxins have a glucosyltransferase activity; botulinum toxin, tetanus toxin and anthrax lethal toxin are metalloproteases; Shiga toxins and ricin have an N-glucosidase activity.
  • ricin is a toxalbumin produced by a shrub of the family Euphorbiaceae, the castor oil plant ( Ricinus communis ). It is present at a concentration ranging from 1% to 10% in the castor oil plant seed.
  • the A chain (RTA, 267 amino acids) performs the catalytic function of ricin (N-glucosidase), while the B chain (RTB, lectin of 262 residues) plays the role of transporter allowing ricin to enter the cell.
  • the ribosomal-RNA depurination enzymatic activity located on the A chain, causes the arrest of protein synthesis in poisoned cells and results in cell death.
  • the B chain has two galactose-binding sites and enables binding of the toxin to glycoreceptors present at the cell surface.
  • the ricin can then penetrate into these cells via multiple endocytosis pathways, so as to reach the trans-Golgi network, where it is conveyed 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 is normally used to translocate newly formed proteins into the ER or to transport incorrectly folded proteins out of the ER and to the cytoplasm so as to be degraded therein.
  • Ricin is capable of escaping this proteolysis, thereby allowing it to bind to the ribosome with great efficiency and to cleave the adenine at position 4324 (hereinafter A4324) of the 28S RNA of the 60S ribosomal subunit. It can thus inactive up to 2000 ribosomes per minute.
  • Ricin is a cytotoxin which can be easily extracted in large amounts. Its toxicity differs according to the routes of introduction: via the digestive route, because it is absorbed little or inactivated by the digestive enzymes, it is approximately 1000 times less toxic than via the pulmonary route (inhalation) or the parenteral route. There are many symptoms of poisoning, which depend on the route of introduction, and they appear in a few hours and can result in death in 2 to 3 days. There is no antidote in the event of poisoning, treatment being essentially symptomatic. Since ricin is also very soluble in water and can disperse in aerosol form, this toxin is considered to be a major bioterrorist agent (category B agent on the list of the US centers for disease control (CDC, Atlanta)).
  • the enzymatic activity inhibitors were described following the elucidation of the mechanism of action of ricin studied firstly by Robertus et al. (Lord, J. M.; Robertus, L. M.; Robertus, J. D. FASEB J. 1994, 8, 201). This author described the depurination mechanism of ricin, the N-glycosylase attacking the 28S RNA of the ribosome. After cleavage of an adenine base (A4324), the rRNA obtained will no longer be able to bind the elongation factors necessary for the movement of the ribosome along the mRNA, which stops protein synthesis and causes death of the cell.
  • the adenosine targeted is stabilized at the active site by formation of H bonds between the purine ring of the adenosine and certain residues of RTA: valine at position 81 (V81), glutamic acid at position 177 (E177) and arginine at position 180 (R180).
  • R180 will subsequently allow partial protonation of the adenine base, weakening the link between the base and the ribose.
  • the adenine is then released and the oxonium ion formed, stabilized by E177, is trapped by the water activated by R180, thus forming the ribose.
  • ricin recognizes a very precise sequence in the 28S RNA, the SRL loop (Sarcin-Ricin Loop), inhibitors were designed on the basis of this nucleotide sequence. They are transition state analogs of the natural substrate for ricin which have noncleavable groups at the level of the target adenine.
  • the studies by Schramm (Schramm, V. L. et al. Biochemistry 2001, 40 (23), 6845; Roday, S. et al. Biochemistry 2004, 43, 4923) thus made it possible to identify various inhibitors, one of the best compounds of which (P14) is represented below.
  • This modified RNA is capable of inhibiting the enzymatic activity in vitro, with a K i of 0.18 ⁇ M.
  • RNA ligands or aptamers, specific for the RTA catalytic chain. These aptamers bear no resemblance to the natural RTA substrate (SRL loop) and are not depurinated by ricin.
  • SRL loop natural RTA substrate
  • 31RA 31 nucleotides
  • immunotherapy has several disadvantages: (i) its efficacy is linked to it being rapidly administered since the antibodies cannot rescue the poisoned cells, they act only on extracellular ricin, and (ii) it appears to be relatively ineffective in the event of aerial or digestive poisoning, since the antibodies are unable to reach the affected pulmonary or digestive epithelium.
  • IC 50 Inhibitors 1 0.74 Lactose 2 1.39 Galactose 3 3rd-generation dendrimer.
  • Haslam et al. (Saenz, J. B.; Doggett, T. A.; Haslam, D. B. Identification and Characterization of Small Molecules That Inhibit Intracellular Toxin Transport ”, Infect. Immun. 2007, 75, 4552-4561) have described a high-throughput screening on a cell assay (Vero monkey kidney cells) for searching for ricin inhibitors, and have presented the following compounds:
  • these compounds may also be capable of blocking the internalization of other AB toxins and of viruses. This is because AB toxins and viruses (Sieczkarski, S. B., Whittaker, G. R. Dissecting virus entry via endocytosis, J. Gen. Virol. 2002, 83, 1535) exploit cellular trafficking pathways which are partly in common with those used by ricin. Thus, cell protection has been obtained with respect to diphtheria toxin and verotoxin-2 (Shiga-like toxin) in the presence of some of the compounds identified by screening.
  • AB toxins and viruses Zeczkarski, S. B., Whittaker, G. R. Dissecting virus entry via endocytosis, J. Gen. Virol. 2002, 83, 1535
  • diphtheria toxin and verotoxin-2 Shiga-like toxin
  • the subject of the present invention is thus compounds having the property of protecting eukaryotic cells against the effects of toxins with intracellular activity, such as ricin, botulinum toxins, diphtheria toxins, anthrax toxins, cholera toxin, pertussis toxin, Shiga toxin (verotoxin-2) Escherichia coli thermolabile toxins, the major clostridial toxins, dermonecrotic factors and viruses which use the internalization pathway for infecting cells, for example RNA viruses, Flaviviridae (such as dengue or yellow fever), Orthomyxoviridae (such as the flu) or else Rhabdoviridae (such as rabies). This property is particularly advantageous since, during ricin poisoning via the respiratory route (inhalation) or by absorption (ingestion), these cells are the first that come into contact with the toxin.
  • toxins with intracellular activity such as ricin, botulinum toxins, diphtheria toxins, anthrax
  • the invention relates to the use of compounds of general formula (I)
  • Cy represents a group chosen from:
  • 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 nucleus), it being understood that, when Cy is an adamantyl nucleus, the chain
  • R 1 represents a radical containing 1 to 21 carbon atoms, which is optionally branched and/or cyclic, and saturated or unsaturated, in which one or more of the carbon atoms can be replaced with a nitrogen, oxygen and/or sulfur atom; said radical being optionally monosubstituted or disubstituted with a halogen atom, a —COOH, —OH or —NO 2 function, a C 1 -C 3 alkyl radical, a C 1 -C 3 alkoxy radical or a C 1 -C 3 acyloxy radical; R 2 either represents a bond or is chosen from a hydrogen atom, an optionally unsaturated, optionally branched, C 1 -C 3 alkyl radical, a C 2 -C 4 acyl radical or the radical
  • the invention also relates to the pharmaceutically acceptable salts of these compounds, such as hydrochlorides, hydrobromides, sulfurtes or bisulfurtes, phosphates or hydrogen phosphates, acetates, oxalates, benzoates, succinates, fumarates, maleates, lactates, citrates, tartrates, gluconates, methanesulfonates, benzenesulfonates and para-toluenesulfonates.
  • these compounds such as hydrochlorides, hydrobromides, sulfurtes or bisulfurtes, phosphates or hydrogen phosphates, acetates, oxalates, benzoates, succinates, fumarates, maleates, lactates, citrates, tartrates, gluconates, methanesulfonates, benzenesulfonates and para-toluenesulfonates.
  • halogen atom is intended to mean the chemical elements of group VII of the Periodic Table of Elements, in particular fluorine, chlorine, bromine and iodine.
  • the halogen atoms that are preferred for implementing the present invention are bromine (Br) and fluorine (F).
  • C 1 -C 3 alkyl chain or radical denotes, respectively, a linear or branched hydrocarbon-based chain or radical; mention may be made, for example, of methyl, ethyl, propyl or isopropyl.
  • C 1 -C 3 alkoxy radical is intended to mean an —OC n H 2n+1 radical, n being an integer between 1 and 3; mention may be made, for example, of the methoxy, ethoxy, propyloxy or isopropyloxy radical.
  • n being an integer between 1 and 3; mention may be made, for example, of the methoxy, ethoxy, propyloxy or isopropyloxy radical.
  • C 1 -C 3 acyloxy radical is intended to mean an —O(CO)C n H 2n+1 or —(CO)OC n H 2n+1 radical, n being an integer between 1 and 3; mention may be made, for example, of the acetyl radical. Preferably, n is 1.
  • C 1 -C 3 acyl radical is intended to mean a —(CO)C n H 2n+1 radical, n being an integer between 1 and 3.
  • the R 1 radical containing 1 to 21 carbon atoms which is optionally branched and/or cyclic, and saturated or unsaturated, in which one or more of the carbon atoms can be replaced with a nitrogen, oxygen and/or sulfur atom
  • linear or branched, saturated or unsaturated alkyl radical containing from 1 to 8 carbon atoms is chosen from: a tert-butyl, 2,4,4-trimethylpentanyl, 3-hydroxy-2-methylpropanoate and hydroxymethylpropane-1,3-diol radical.
  • cyclic radicals listed above are preferably chosen from the radicals: cyclopentylmethanol, cyclomethanoate, phenyl, cyclohexyl, pyridine, furan, thiophene, imidazole, quinoline, indole, benzofuran, adamantyl, naphthalene, anthracene, and the following cyclic radicals:
  • W′ being —H or —COOC n H2 n+1 , with n being between 1 and 3,
  • 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 a Br atom.
  • the compounds of general formula (I) are such that R 1 is the radical:
  • W, p, R 3 and R 4 are as defined above and X is either a bond or —CO—.
  • the present invention also relates to the compounds of general formula (I) as defined above and the pharmaceutically acceptable salts thereof as such, except for 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):
  • the compounds of general formula (Ia) which appear in tables A1 and A2 according to example 1 are prepared in methanol by treatment of 1-adamantylamine (for the compounds of table A1) or of 2-adamantylamine (for the compounds of table A2) in the presence of an aromatic aldehyde (1 equiv.) according to the compound to be prepared.
  • Supported cyanoborohydride is used (BH 3 CN on resin, 1.5 equiv.) as reducing agent in the presence of acetic acid (3 equiv.). The whole is stirred for 2 days at ambient temperature, filtered, washed with methanol, evaporated, and then purified according to methods known to those skilled in the art.
  • the invention therefore also relates to a process for preparing the compounds of general formula (Ib), characterized in that it comprises the following steps:
  • the compounds (Ib) that appear 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 according to example 1) in methanol to an aldehyde (1 equiv.) for the compounds of table A3 or of 3-bromobenzylamine (1 equiv.) and an aldehyde in order to obtain the compounds of table A4, in the presence of 1.5 equiv. of BH 3 CN on resin and of acetic acid (3 equiv.). The whole is stirred for 2 days at ambient temperature, filtered, washed with methanol, evaporated, and then purified according to methods known to those skilled in the art.
  • the formation of the salts is carried out by treatment of the amine compound (corresponding to the desired salt) in CH 2 Cl 2 with a solution of the corresponding acid in a solvent (for example, HCl in ether).
  • a solvent for example, HCl in ether
  • Z being a carbon atom or nothing (noradamantyl nucleus), with the nitrogen atom in position 1 or 2 when Cy is the adamantyl nucleus;
  • the invention relates to the process for preparing the 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 stirring the mixture for 2 days. After evaporation and purification, the imines are obtained.
  • the imines are reduced as follows: BH 3 CN on resin (3 equiv.) and AcOH are added to a solution of the imine in MeOH. After 3 days at ambient temperature, the mixture is filtered, washed with methanol, and then concentrated under vacuum. The resulting crude compound is purified according to conventional methods.
  • the invention also relates to a process for preparing the imines of general formula (I), characterized in that it comprises the following steps:
  • the invention also relates to a process for preparing a reduced imine of general formula (I), characterized in that it comprises the following steps:
  • N-1-adamantylbenzamide and N-2-adamantylbenzamide compounds are prepared from the corresponding amines (1- or 2-adamantylamine (1 equiv.)) via treatment with a base such as NaH (1.1 equiv.) in DMF then addition of benzoyl chloride (1.2 equiv.) at 0° C. The mixture is stirred for 24 hours at ambient temperature, evaporated, and then washed with cyclohexane.
  • the invention relates to a process for preparing the N-1-adamantylbenzamide and N-2-adamantylbenzamide compounds comprising the following steps:
  • the invention also relates to a process for preparing a urea derivative of general formula (I), characterized in that it comprises the following steps:
  • the alcohols are firstly treated with iodine (2.5 equiv.) and a base such as potassium carbonate in tert-butanol and are heated for 24 h 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 preparing triazole derivatives of general formula (I), characterized in that it comprises the following steps:
  • the invention also relates to 2-amino-N-phenylbenzamide as synthesis intermediate for the amines of general formula (I).
  • the present invention also relates to the use of compounds which are benzodiazepine derivatives of general formula (II):
  • R 3 is chosen from a hydrogen or halogen atom; a C 1 -C 6 alkyl radical, a C 1 -C 6 alkoxy radical or a C 1 -C 6 acyloxy radical, these radicals being optionally substituted with a C 1 -C 6 alkoxy radical; an aryloxy radical or a heteroaryloxy radical;
  • R 4 either represents a bond or is chosen from a hydrogen atom, a C 1 -C 2 acyloxy radical, a C 1 -C 2 alkoxy radical or a phenyl;
  • R 5 either represents a bond or is chosen from a hydrogen atom; a C 1 -C 2 alkyl radical; a C 1 -C 2 alkoxy radical; a C 1 -C 2 acyloxy radical or a pheny
  • R 4 and R 5 cannot 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 borne by the carbon adjacent to B, a ring of 5 or 6 atoms, optionally substituted with a phenyl radical, optionally interrupted with a nitrogen, sulfur or oxygen atom; preferably, it is a ring containing 5 atoms, interrupted with an oxygen atom; for the preparation of a pharmaceutical composition intended for the prevention and/or treatment of poisonings with at least one toxin with an intracellular mode of action or with at least one virus that uses the internalization pathway for infecting mammalian eukaryotic cells.
  • the invention also relates to the pharmaceutically acceptable salts of these compounds.
  • C 1 -C 6 alkyl radical denotes a linear or branched hydrocarbon-based radical containing from 1 to 6 carbon atoms; mention may be made, for example, of methyl, ethyl, propyl, or isopropyl.
  • C 1 -C 6 alkoxy radical is intended to mean an —OC m H 2m+1 radical, m being an integer between 1 and 6.
  • C 1 -C 6 acyloxy radical is intended to mean an —O(CO)C m H 2m+1 or —(CO)OC m H 2m+1 radical, m being an integer between 1 and 6.
  • aryloxy radical is intended to mean an aryl group linked to the rest of the compound by an oxygen atom.
  • heteroaryloxy radical is intended to mean a heteroaryl group linked to the rest of the compound by an oxygen atom.
  • 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 phenyl radical 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 the pharmaceutically acceptable salts thereof as such, except for compounds 162, 163, 164, 165, 166, 167, 169, 170, 171 and 193.
  • benzo[e][1,4]diazepine derivatives and the benzo[b][1,4]diazepine derivatives of general formula (II) are prepared as follows:
  • the invention also relates to the compounds which are of use as synthesis intermediates for the compounds of general formula (II), chosen from: tert-butyl N-[(phenylcarbamoyl)methyl-]carbamate, tert-butyl (4-methoxyphenylcarbamoyl)methylcarbamate, 2-amino-N-phenylacetamide, 2-amino-N-(4-methoxyphenyl)acetamide and 2-benzoyl-4-bromoaniline.
  • the compounds according to the invention are pharmacologically active substances and are of value by virtue of their inhibitory effect on toxins with an intracellular mode of action, in particular on ricin.
  • the invention relates to the compounds of general formulae (I) and (II) and the pharmaceutically acceptable salts thereof except for compounds 1, 6, 8, 11, 18, 29, 30, 34, 74, 78, 98, 100, 113, 114, 116, 121, 122, 124, 128, 135, 145, 161, 162, 163, 164, 165, 166, 167, 169, 170, 171 and 193 , for use as a medicament, in particular as an active ingredient.
  • the invention also relates to pharmaceutical compositions or medicaments comprising one or more compounds of general formula (I) or (II) and the pharmaceutically acceptable salts thereof except for compounds 1, 6, 8, 11, 18, 29, 30, 34, 74, 78, 98, 100, 113, 114, 116, 121, 122, 124, 128, 135, 145, 161, 162, 163, 164, 165, 166, 167, 169, 170, 171 and 193, in a pharmaceutically acceptable vehicle.
  • pharmaceutically acceptable is intended to mean compatible with administration to an individual, preferably a mammal, by any route of administration.
  • the medicament may be administered by the oral, parenteral, pulmonary, ocular, nasal, etc., route.
  • the modes of administration of the compounds (I) and (II) that are preferred are those which use the aerial (inhalation), oral (ingestion), parenteral or local (topical) routes.
  • the amount of compound of formula (I) or (II) to be administered to the mammal depends on the actual activity of this compound, it being possible for said activity to be measured by means which are disclosed in the examples. This amounts also depends on the seriousness of the pathological condition to be treated, in particular on the amount of ricin absorbed and on the route via which it was absorbed; finally, it depends on the age and the 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 AB toxins with an intracellular mode of action and viruses that use the internalization pathway for infecting cells.
  • the AB toxins or toxins with an intracellular mode of action are in particular: ricin, botulinum toxins, diphtheria toxins, anthranx toxins, cholera toxin, pertussis toxin, Shiga toxin (verotoxin-2), Escherichia coli thermolabile toxins, the major clostridial toxins, and dermonecrotic factors; examples of these toxins are listed in the table below:
  • sordellii (+) Glucosyltransferase Ras/Rho High- Hemorragic toxin (HT) proteins molecular- Toxin A (Tox A) C. difficile (+) weight toxins Toxin B (Tox B) ⁇ -toxin ( ⁇ -Tox) C. novyi (+) Dermonecrotic toxin (DNT) B. pertussis ( ⁇ ) Deamidase Rho Dermonecrotic Cytotoxic necrotizing E. coli ( ⁇ ) proteins toxins factor type 1 and 2 (CNF1/2) Ab Cholera toxin (CT) V. cholerae ( ⁇ ) ADP- Gs ⁇ [illegible] Thermolabile toxins (LT) E.
  • viruses that use the internalization pathway for infecting cells, hereinafter also denoted viruses, are, for example, RNA viruses, Flaviviridae (such as dengue or yellow fever), Orthomyxoviridae (such as the flu) or else Rhabdoviridae (such as rabies).
  • Flaviviridae such as dengue or yellow fever
  • Orthomyxoviridae such as the flu
  • Rhabdoviridae such as rabies
  • these compounds may be used for the preparation of a pharmaceutical composition intended for treating the effects of AB toxins or toxins with an intracellular mode of action and of viruses that use the internalization pathway for infecting cells.
  • a toxin such as ricin
  • a toxin when it is inhaled, produces signs of ocular irritation (burning sensation, watering of the eyes, more or less severe conjunctivitis) and pharyngeal irritation and also a more or less marked respiratory irritation: cough, dyspnea, pulmonary edema which can result in 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 for protection against the effects of ricin, of other AB toxins and of viruses that use the internationalization pathway for infecting eukaryotic cells, especially epithelial, ocular, pharyngeal, tracheal, bronchial, skin or muscle cells, in particular pulmonary and digestive, preferably intestinal, epithelial cells, of mammals, preferably of humans.
  • eukaryotic cells especially epithelial, ocular, pharyngeal, tracheal, bronchial, skin or muscle cells, in particular pulmonary and digestive, preferably intestinal, epithelial cells, of mammals, preferably of humans.
  • the invention relates more specifically to the use of the compounds of general formulae (I) and (II) and the pharmaceutically acceptable salts thereof, for the preparation of a pharmaceutical composition for preventing and/or treating poisoning with ricin toxin; preferably, the compounds of general formulae (I) and (II) and the pharmaceutically acceptable salts thereof are chosen from compounds 1, 3, 5, 9, 15, 19, 24, 28, 34, 36, 39, 59, 65, 67, 68, 69, 75, 86, 89, 105, 106, 109, 110, 111, 112, 117, 118, 122, 128, 131, 138, 139, 140, 142, 143, 148, 154, 161 and 193.
  • the invention relates to the use of compounds of general formula (I) which are defined by general formula (I.1):
  • Cy represents a group chosen from:
  • Z is a carbon atom or a bond (Cy is then a noradamantyl nucleus), it being understood that, when Cy is an adamantyl nucleus, the nitrogen atom is attached thereto in position 1 or 2, R 1 represents:
  • the compounds of general formula (I.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) which are defined by general formula (I.2):
  • X represents —(CH 2 ) 2 —O—CH 2 —, —(CH 2 ) 3 —, —CO— or —SO 2 —, and the pharmaceutically acceptable salts thereof, for the preparation of a pharmaceutical composition for preventing and/or treating poisoning with ricin toxin.
  • the compounds of general formula (I.2) are chosen from compounds 68, 69, 122 and 128.
  • the invention relates to the use of compounds of general formula (I) which are defined by general formula (I.3):
  • W represents a halogen atom, and the pharmaceutically acceptable salts thereof, for the preparation of a pharmaceutical composition for preventing and/or treating poisoning with ricin toxin.
  • the compounds of general formula (I.3) are chosen from compounds 117 and 118.
  • Y is O or S, and the pharmaceutically acceptable salts thereof, for the preparation of a pharmaceutical composition for preventing and/or treating poisoning with ricin toxin.
  • the compounds of general formula (I.4) are chosen from compounds 154 and 161.
  • the present invention also relates to the use of the compounds of general formulae (I) and (II) and the pharmaceutically acceptable salts thereof, for the preparation of a pharmaceutical composition for preventing and/or treating poisoning with diphtheria toxin.
  • the compounds suitable for the prevention and/or treatment of poisoning with diphtheria toxin are in particular those of general formula (I.5):
  • W and W′ are, independently of one another, chosen from a hydrogen atom, a halogen atom and a C 1 -C 3 alkoxy radical, and the pharmaceutically acceptable salts thereof.
  • the compounds of general formula (I.5) are chosen from compounds 5, 9, 39, 110, 111, 112, 139 and 140.
  • FIG. 1 is a diagrammatic representation of the high-throughput cell assay.
  • FIG. 2 represents the results of the screening.
  • the yellow dots horizontal cloud of dots on the upper part of the graph
  • the green dots horizontal cloud of dots on the lower part of the graph
  • the negative controls cells treated with ricin alone
  • the compounds according to the invention tested in the presence of ricin are the compounds according to the invention tested in the presence of ricin.
  • the commercial reactants were purchased from Sigma-Aldrich and were used without prior purification. All the reactions were carried out under nitrogen with freshly distilled dry solvents and oven-dried glassware.
  • the 1 H NMR was carried out with a Brucker Advance 400 MHz instrument with a BBO probe. The solvents are specified for each experiment. The chemical shifts are given in parts per million (ppm), relative to the internal reference (TMS). The data are listed in the following order: ⁇ , chemical shift; multiplicity (with singlet, d doublet, t triplet, q quadruplet, m, multiplet), integration, coupling constants (J in Hertz, Hz).
  • LC/MS analyses were carried out by HPLC (High Pressure Liquid Chromatography) coupled with a Waters® Autopurif mass spectrometer.
  • the ionization is obtained either by electron impact or by electrochemical ionization.
  • Injection volume 1 ⁇ l with the Waters 2767 autosampler.
  • the 1-aminoadamantane and 2-aminoadamantane derivatives of general formula (Ia) as described above and which appear, respectively, in tables A1 and A2 are prepared as follows: a suspension, in methanol, of 1-adamantylamine or 2-adamantylamine (0.5 mmol; 75 mg; 1 equiv.) is added, with stirring, to an aromatic aldehyde (1 equiv.) according to the compound to be prepared, in the presence of BH 3 CN on resin (0.75 mmol; 1.5 equiv.) and of 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 give the number of the compound, the aldehyde used, the name of the compound obtained, the characteristics of the compound and also the code of the purification method used, the appearance of the compound obtained and its yield.
  • the derivatives and the alkylamines of general formula (Ib) as described above and which appear 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 the compounds of table A3, or 3-bromobenzylamine or 3-fluorobenzylamine (1 equiv.) for obtaining the compounds of table A4, in the presence of BH 3 CN on resin (0.75 mmol; 1.5 equiv.) and of 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 according to methods known to those skilled in the art.
  • Tables A3 and A4 give the number of the compound, the reactants used, the name of the compound obtained, the characteristics of the compound and also the code of the purification method used, the appearance of the compound obtained and its yield.
  • the compounds of table A5 are prepared according to process A, adding a microwave heating step.
  • the 1-aminoadamantane, 2-aminoadamantane or noradamantylamine derivatives of general formula (Ic) as described above and which appear, respectively, in tables C1, C2 and C3 are prepared as follows: a stirred suspension of 1-aminoadamantane, 2-aminoadamantane or noradamantylamine (1 equiv.) in methanol is added to an aldehyde (1 equiv.) chosen according to the compound to be prepared (see tables C1, C2 and C3). The whole is mixed for two days at ambient temperature and then evaporated.
  • N-1-adamantylbenzamide and N-2-adamantylbenzamide compounds are prepared as follows: 1-adamantylamine or 2-adamantylamine (1 equiv.) and benzoyl chloride (1.2 equiv.) are added, at 0° C., to a suspension of NaH (1.1 equiv.) in DMF. The mixture is stirred for 24 hours at ambient temperature, evaporated, and then washed with cyclohexane.
  • the sulfonylation is carried out according to the following process:
  • Phenylisocyanate or phenylthioisocyanate (0.75 mmol; 1.5 equiv.) is added, at 0° C., to a stirred suspension of 1-adamantylamine (0.5 mmol; 1 equiv.) in THF (3 ml). The mixture is stirred for 24 hours at ambient temperature and then evaporated;
  • phenylisocyanate or phenylthioisocyanate (0.75 mmol; 1.5 equiv.) and triethylamine (1.05 equiv.) are added, at 0° C., to a stirred suspension of 2-adamantylamine hydrochloride (0.5 mmol; 1 equiv.) in DMF (3 ml). The mixture is stirred for 24 hours at ambient temperature, then evaporated, placed in solution in Et 2 O, and filtered, and then the filtrate is evaporated.
  • Phenylisocyanate or phenylthioisocyanate (0.75 mmol; 1.5 equiv.) and triethylamine (1.05 equiv.) are added, at 0° C., to a stirred suspension of 2-adamantylamine hydrochloride (0.5 mmol; 1 equiv.) in DMF (3 ml). The mixture is stirred for 24 h at ambient temperature, evaporated, placed in solution in Et 2 O and filtered, and then the filtrate is evaporated.
  • phenyl chloroformate (0.6 mmol; 1.2 equiv.) and triethylamine (2.5 mmol; 5 equiv.) are added, at ambient temperature, to a stirred suspension of 1-adamantylamine hydrochloride or 2-adamantylamine hydrochloride (0.5 mmol; 1 equiv.) in CH 2 Cl 2 (4 ml).
  • the mixture is stirred for 24 h at ambient temperature, washed with water, placed in a saturated solution of NH 4 Cl, dried over Na 2 SO 4 , filtered, evaporated and short-pad-purified.
  • Benzoyl chloride (0.47 mmol; 55 ⁇ l; 3 equiv.) and triethylamine (109 ⁇ l; 5 equiv.) are added, at ambient temperature, to a stirred suspension of 1-adamantylamine (0.156 mmol; 50 mg; 1 equiv.) in CH 2 Cl 2 (3 ml).
  • the mixture is stirred for 24 h at ambient temperature, washed with water, placed in a saturated solution of NH 4 Cl, dried over Na 2 SO 4 , filtered, evaporated and short-pad-purified.
  • Phenylisocyanate (19 ⁇ l; 1.1 equiv.) is added, at 0° C., to a stirred suspension of 1-adamantylamine (0.156 mmol; 50 mg; 1 equiv.) in THF (3 ml). The mixture is stirred for 24 h at ambient temperature, evaporated and short-pad-purified.
  • Benzoyl chloride (0.47 mmol; 55 ⁇ l; 3 equiv.) and triethylamine (109 ⁇ l; 5 equiv.) are added, at ambient temperature, to a stirred suspension of 2-adamantylamine (0.156 mmol; 50 mg; 1 equiv.) in CH 2 Cl 2 (2 ml).
  • the mixture is stirred for 24 h at ambient temperature, washed with water, placed in a saturated solution of NH 4 Cl, dried over Na 2 SO 4 , filtered, evaporated and short-pad-purified.
  • the 2-amino-N-phenylbenzamide (1 eq., 42 mg, 0.2 mmol) is dissolved in 2 ml of methanol with 3-bromobenzaldehyde (1 eq., 23 ⁇ l, 0.2 mmol). After an overnight period, the reaction mixture is evaporated (disappearance of the 2-amino-N-phenylbenzamide is observed by NMR) and the imine 149 is formed quantitatively.
  • the 2-amino-N-phenylbenzamide (1 eq., 21 mg, 0.1 mmol) is dissolved in 1 ml of methanol with 3-fluorobenzaldehyde (1 eq., 10 ⁇ l, 0.1 mmol). After an overnight period, the reaction mixture is evaporated (disappearance of the 2-amino-N-phenylbenzamide is observed by NMR) and the imine 151 is formed quantiatively.
  • N-boc-glycine (1 eq., 5.71 mmol, 1.0 g) is dissolved in 10 ml of dichloromethane at 0° C.
  • DCC 1.1 eq., 6.28 mmol, 1.3 g
  • aniline 1.4 eq., 8.0 mmol, 0.73 ml
  • the content of the round-bottom flask is filtered and then evaporated.
  • N-boc-glycine (1 eq., 7.2 mmol, 1.26 g) is dissolved in 10 ml of dichloromethane at 0° C.
  • DCC 1.1 eq., 8.0 mmol, 1.65 g
  • para-anisidine 1.4 eq., 10 mmol, 1.23 g
  • Silica gel column purification (98:2 mixture of acetone/dichloromethane) makes it possible to obtain 1.154 g of purified tert-butyl (4-methoxyphenylcarbamoyl)methylcarbamate compound (57%).
  • the tert-butyl N-[(phenylcarbamoyl)methyl]carbamate compound (1 eq., 3 mmol, 450 mg) is dissolved in a 2:1 mixture of dichloromethane/trifluoroacetic acid. After one hour, the 2-amino-N-phenylacetamide product is quantitatively obtained after evaporation and used directly in Pictet-Spengler reaction tests.
  • tert-butyl (4-methoxyphenylcarbamoyl)methyl-carbamate compound (1 eq., 3 mmol, 540 mg) is dissolved in a 2:1 mixture of dichloromethane/trifluoroacetic acid. After one hour, 2-amino-N-(4-methoxyphenyl)acetamide is quantitatively obtained after evaporation and used directly in Pictet-Spengler reaction tests.
  • Pathway 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 separation of the hot acid layer by settling out, the water-insoluble residue is dissolved in 80 ml of 70% sulfuric acid, brought to reflux for 8 hours, and then poured into a large amount of ice-cold water. After the addition of ethyl acetate (3 ⁇ 50 ml), the organic phases are combined and then evaporated. After purification by HPLC, the yield is less than 1% (the mass obtained was approximately 200 mg).
  • Pathway 2 2-aminobenzophenone (1 eq., 5 mmol, 0.986 g) is dissolved in dichloromethane at 0° C. N-bromosuccinimide (1 eq., 5 mmol, 0.890 g) is then added in small portions. The temperature of the reaction mixture is allowed to return to ambient temperature over approximately two hours. The reaction mixture is then evaporated and 2-benzoyl-4-bromoaniline is quantitatively obtained.
  • 2-amino-N-(4-methoxyphenyl)acetamide (1 eq., 0.5 mmol, 140 mg) is dissolved in 2 ml of acetonitrile.
  • Benzaldehyde (1.5 eq., 0.75 mmol, 76 ⁇ l) is added to the reaction medium, followed by 1 ml of trifluoroacetic acid. After refluxing for 3 hours, the mixture is evaporated and then purified by silica gel chromatography (mixture of cyclohexane/ethyl acetate in a gradient of 80:20 to 50:50), which makes it possible to obtain 16 mg of compound 167, i.e. a yield of 12%.
  • aminobenzophenone (2.85 eq., 5 mmol, 1.0 g) is dissolved in 15 ml of pyridine containing 4 ⁇ molecular sieve.
  • Ethyl glycinate hydrochloride (1 eq., 1.75 mmol, 244 mg) is then added, and the mixture is then brought to reflux for 3 hours.
  • Approximately 5 ml of pyridine are withdrawn from the Dean-Stark apparatus 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.
  • Methyl glycinate hydrochloride (1 eq., 1.24 mmol, 30 mg) is then added and the mixture is then brought to reflux for 3 hours.
  • Approximately 2 ml of pyridine are withdrawn from the Dean-Stark apparatus and replaced with 2 ml of fresh pyridine.
  • the product obtained is purified by silica gel chromatography (cyclohexane/ethyl acetate in a gradient of from 80:20 to 1:2), and the desired product 164 is obtained with a yield of 52%.
  • 1,2-Diaminobenzene (1 eq., 2 mmol, 216 mg) and ethyl 3-oxo-3-phenylpropanoate (1 eq., 2 mmol, 384 mg) are mixed together in a pill bottle flask.
  • the reaction mixture is then heated at 150° C. for 2 hours.
  • the residue is then diluted in ethyl acetate and hydrochloric acid (pH ⁇ 5), and 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.
  • Purification on a silica gel column 70:30 cyclohexane/ethyl acetate
  • a ⁇ -keto ester (0.5 mmol; 1 equiv.) is added to a stirred suspension of diamine (0.5 mmol; 54 mg; 1 equiv.) in toluene (2 ml). The mixture is stirred at reflux (120° C.) for 3 h. The mixture is diluted in EtOAc, acidified (ph 5), extracted with EtOAc, filtered, evaporated and washed with Et 2 O to give the desired compound.
  • a ⁇ -keto ester (0.5 mmol; 1 equiv.) is added to a stirred suspension of diamine (0.5 mmol; 94 mg; 1 equiv.) in toluene (2 ml).
  • the mixture is stirred at reflux (120° C.) for 3 h.
  • the mixture is diluted with EtOAc, acidified (pH 5), extracted with EtOAc, filtered, evaporated and washed with Et 2 O.
  • a cell assay was developed in order to demonstrate the cytotoxic activity of ricin while at the same time being suitable for the constraints of high-throughput screening (see FIG. 1 , diagrammatic representation of this assay).
  • the use of such an assay has several advantages:
  • the assay used directly measures the ability of the cells to synthesize proteins, which makes it an excellent screening assay since this biosynthetic pathway is stopped by ricin.
  • the yellow-colored wells are positive controls (A549 treated with ricin (10 ⁇ 10 M) in the presence of 20 mM of lactose, which is an inhibitor of ricin binding to cells), whereas the green wells are negative controls (cells treated with ricin alone).
  • the red wells are cells in contact with the compounds of the libraries in the presence of ricin (80 different compounds per plate, 50 ⁇ M final concentration).
  • the results of the screening carried out are represented in the graph of FIG. 2 .
  • the compounds were tested on A549 cells at the concentration of 30 ⁇ M by incubation with various ricin concentrations (10 ⁇ 9 to 10 ⁇ 12 M), with the protocol described previously for the high-throughput screening. The radioactivity measured is then proportional to the cell survival rate. Analysis of the data by nonlinear regression makes it possible to estimate the EC 50 , i.e. the effective concentration for which 50% radioactive leucine assimilation is observed, which corresponds to 50% of viable cells. The higher the EC H value, the greater the cell protection, since a higher concentration of ricin is then necessary in order to generate the same cytotoxicity.
  • These compounds are the first inhibitors that are active on human pulmonary and digestive epithelial cells with respect to the toxic activity of ricin.
  • the compounds were also tested on Vero cells (ATCC No. CCL-81) at the concentration of 30 ⁇ M by incubation with various concentrations of diphtheria toxin (10 ⁇ 9 to 10 ⁇ 12 M) (Sigma), with the protocol described in point 2.1.

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US9884832B2 (en) * 2011-12-06 2018-02-06 The Trustees Of The University Of Pennsylvania Inhibitors targeting drug-resistant influenza A
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CN104844532A (zh) * 2014-02-19 2015-08-19 周敬业 抗病毒化合物、其制备方法和用途
CN106029635A (zh) * 2014-02-28 2016-10-12 海蔻有限公司 用于维达列汀的新的经济的方法
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CN107663159A (zh) * 2016-07-29 2018-02-06 上海迪诺医药科技有限公司 多环化合物、其药物组合物及应用
US20200281873A1 (en) * 2017-10-31 2020-09-10 Commissariat A L'energie Atomique Et Aux Energies Alternatives Adamantane or Bicyclic Monoterpenoid Derivatives for Use in the Treatment of Leishmaniasis

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