Compounds Which Have a Protective Activity with Respect to the Action of Toxins and of Viruses with an Intracellular Mode of Action

The subject matter 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.

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Description

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, or AB toxins, 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). There are many bacterial toxins with intracellular activity: for example, and nonexhaustively, 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.

More particularly, 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.

It is more specifically a 66 kDa glycoprotein composed of two chains linked by a disulfide bridge. 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.

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)).

In view of the potential for the use of ricin, of other intracellular toxins or of viruses as a biological weapon, it is therefore essential to have medical countermeasures which inhibit the action of a toxin or of a virus.

In order to counter the threat posed by ricin, several types of antitoxins have been developed: neutralizing antibodies, enzymatic activity inhibitors (small molecules and substrate analogs, soluble receptor mimics).

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.

Thus, there are among the enzyme activity inhibitors:

    • the small molecules: these are molecules which will, for example, bind to ricin at its catalytic site and prevent ribosome depurination. Molecular modeling studies have allowed the group of Robertus to discover the first inhibitor of the enzymatic activity of ricin: pteroic acid and also a derivative represented below.

However, pteroic acid, and also its derivative, are mediocre inhibitors of the N-glycosylase activity, with an inhibition constant of about 0.6 mM (Miller, D.; Ravikumar, K.; Shen, H.; Suh, J.; Kerwin, S.; Robertus, J. D. J. Med. Chem. 2002, 45, 90. Yan, X. et al. J. Mol. Biol. 1997, 266, 1043).

Since 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 Ki of 0.18 μM.

In addition, the development of circular oligonucleotides derived from the sequence of the SRL loop is materialized through the obtaining of molecules which inhibit RTA at micromolar and nanomolar concentrations (Sturm, M. B.; Roday S.; Schramm, V. L. J. Am. Chem. Soc., 2007, 129, 5544-5550).

In vitro selection methods were also used to generate 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. This study made it possible to identify an aptamer of 31 nucleotides (31RA) capable of interacting with RTA (high-affinity complex, Kd=7.3 nM) and of competitively inhibiting ribosome depurination (IC50=100 nM) (Hesselberth, J. R.; Miller, D.; Robertus, J. D.; Ellington, A. D. J. Biol. Chem. 2000, 275, 4937).

The therapeutic potential of all these enzymatic inhibitors nevertheless appears to be weak. This is because they are compounds that are active only on enzymatic tests; no cell protection or protection on animals has been reported for these molecules. Furthermore, these molecules exhibit deficiencies such as a weak efficacy as regards pteroic acid and its derivatives, or instability in biological media and poor effectiveness in penetrating cells, as regards the RNA derivatives.

Neutralizing monoclonal antibodies have also been developed. Thus, antibodies directed against the RTB chain are capable of protecting mice poisoned with 10 LD50 (Lemley, P. V.; Amanatides, P.; Wright, D. C. Hybridoma 1994, 13, 417. Guo, J. W.; Shen, B. F.; Feng, J. N.; Sun, Y. X.; Yu, M.; Hu, M. R. Hybridoma 2005, 24, 263. Furukawa-Stoffer, T. L.; Mah, D. C.; Cherwonogrodzky, J. W.; Weselake, R. J. Hybridoma 1999, 18, 505).

Several studies are in the process of being carried out in order to develop neutralizing “humanized” antibodies that can be used in the event of ricin poisoning. However, 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.

Studies based on the use of soluble receptor mimics for trapping ricin have also been carried out. This involves sugar derivatives (including dendrimers) that do not have an inhibitory effect greater than that of lactose alone (Rivera-Sagredo, A.; Solis, D.; Diaz-Mauriro, T.; Jimenez-Barbero, J.; Martin-Lomes, M. Eur. J. Biochem. 1991, 197, 217. and Dawson, R. M.; Alderton, M. R.; Wells, D.; Hartley, P. G. J. Appl. Toxicol. 2006, 26, 247).

Sugar derivatives as weak ricin inhibitors IC50 Inhibitors (mM) 1 0.74 2 1.39 3 3rd-generation dendrimer. Terminal 1.16 sugars: galactoses 4 Dispersed linear polymer. Terminal 0.42-0.85 sugars: galactoses 5 —

Other sugars carrying a water-insoluble lipid chain in the anomeric position have also been synthesized. They form a self-assembled lyotropic gel which is capable of sequestering ricin by means of the galactose-based surfactants.

A certain number of vaccines have been described in particular in patents by the US ARMY. They claim protection with respect to ricin via the administration of an immunogenic amount of RTA or RTB derivatives (U.S. Pat. No. 6,869,787).

However, a vaccine approach for countering the effects of ricin does not appear, at the current time, to be an effective response against this threat.

This is because only a few categories of individuals, identified as potentially exposed to ricin, could be preventively vaccinated. As things stand, it is not envisioned to vaccinate the population against this bioagent.

More recently, 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:

The mode of action of these compounds is not specified, but these molecules appear to block the transport of the toxin inside the cells (endosomes and Golgi apparatus). However, these compounds, in particular compound A, which is a benzodiazepine derivative, have been tested and it has been noted that they do not protect A549 human pulmonary epithelial cells, unlike the compounds which are subjects of the present invention.

Thus, to date, these strategies have not made it possible to identify compounds capable of effectively protecting cells or animals exposed to ricin. The antibodies which are effective in the case of ricin injection are not affected in the case of inhalation or ingestion.

In conclusion, no specific treatment is yet available in humans for combating ricin poisoning.

In this perspective, the inventors have identified, by high-throughput screening, molecules capable of protecting cells in culture brought into 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 trafficking of ricin. Chemical optimization of these compounds has made it possible to progress to compounds having a greater cell protection capacity.

It should be emphasized that these compounds are the first inhibitors active on human pulmonary and digestive epithelial cells with respect to the toxic activity of ricin that have been identified to date.

Given that the compounds identified act at the cellular level by modifying the intracellular trafficking of ricin, 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.

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.

Firstly, the invention relates to the use of compounds of general formula (I)

in which:
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 and 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

is attached thereto in position 1 or 2,
p represents 0 or 1;
X represents either:

    • a bond;
    • an optionally unsaturated, optionally branched, C1-C6 alkyl chain which is optionally substituted with a phenyl radical, an acid function and/or a C1-C3 alkyl ester radical; said chain being optionally interrupted with an oxygen atom;
    • —CO—, —O—CO—, —CO—NH— or

R1 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 —NO2 function, a C1-C3 alkyl radical, a C1-C3 alkoxy radical or a C1-C3 acyloxy radical;
R2 either represents a bond or is chosen from a hydrogen atom, an optionally unsaturated, optionally branched, C1-C3 alkyl radical, a C2-C4 acyl radical or the radical

it being understood that, when R2 is a bond, then the nitrogen atom bearing R2 and X or the adjacent carbon atom (when p=1) are linked by a double bond,
it being understood that X, R1 and R2 can form, with the adjacent nitrogen atom, an imidazole, oxazole, triazole or benzimidazole ring, which is optionally partially saturated, such as in particular dihydroimidazole, optionally substituted with a phenyl or pyridine radical;
and the pharmaceutically acceptable salts thereof,
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, 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.

The term “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).

The term “C1-C3 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.

The term “C1-C3 alkoxy radical” is intended to mean an —OCnH2n+1 radical, n being an integer between 1 and 3; mention may be made, for example, of the methoxy, ethoxy, propyloxy or isopropyloxy radical. Preferably, n is 1.

The term “C1-C3 acyloxy radical” is intended to mean an —O(CO)CnH2n+1 or —(CO) OCnH2n+1 radical, n being an integer between 1 and 3; mention may be made, for example, of the acetyl radical. Preferably, n is 1.

The term “C1-C3 acyl radical” is intended to mean a —(CO)CnH2n+1 radical, n being an integer between 1 and 3.

According to one particular embodiment of the invention, the R1 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, is chosen from: a linear or branched, saturated or unsaturated alkyl radical containing from 1 to 8 carbon atoms, a saturated or unsaturated cyclic radical containing 5 or 6 carbon atoms, a saturated or unsaturated bicyclic radical containing 9 or 10 carbon atoms, a saturated or unsaturated tricyclic radical containing 14 carbon atoms, a saturated or unsaturated heterocyclic radical containing 5 atoms, a saturated or unsaturated heterocycle containing 6 atoms, and a saturated or unsaturated biheterocyclic radical containing 9 or 10 atoms.

More specifically, the 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.

The 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:

with W′ being —H or —COOCnH2n+1, with n being between 1 and 3,

Preferably, the compounds of general formula (I) are such that R1 is an optionally substituted phenyl radical and/or X is —CH2— and/or R2 is a hydrogen atom and/or W represents a Br atom.

According to one particular variant of the invention, the compounds of general formula (I) are such that R1 is the radical:

in which:

    • R3 is chosen from a saturated or unsaturated cyclic radical containing 5 or 6 carbon atoms; a saturated or unsaturated bicyclic radical containing 9 or 10 carbon atoms; a saturated or unsaturated tricyclic radical containing 14 carbon atoms; a saturated or unsaturated heterocyclic radical containing 5 atoms; a saturated or unsaturated heterocyclic radical containing 6 atoms; a saturated or unsaturated biheterocyclic radical containing 9 or 10 atoms; said radicals being optionally substituted with at least one halogen, —NO2, —OH or one C1-C3 alkyl radical; the radicals are preferably chosen from the radicals: phenyl, furan, indole and thiophene; and
    • R4 is chosen from —CO—O—, —N═CH— or —NH—CH2—.

According to another variant of the invention, the compounds of general formula (I) are defined by general formula (I′):

where W, p, R3 and R4 are as defined above and X is either a bond or —CO—.

More particularly, the compounds of general formula (I) are chosen from:

TABLE 1 1 N-benzyladamantylamine 2 N-(2-bromobenzyl)adamantylamine 3 N-(3-bromobenzyl)adamantylamine 4 N-(4-bromobenzyl)adamantylamine 5 N-(3-fluorobenzyl)adamantylamine 6 N-(3-hydroxybenzyl)adamantylamine 7 N-(2-methoxybenzyl)adamantylamine 8 N-(3-methoxybenzyl)adamantylamine 9 N-(4-methoxybenzyl)adamantylamine 10 N-(2-nitrobenzyl)adamantylamine 11 N-(4-nitrobenzyl)adamantylamine 12 N-(4-carbethoxybenzyl)adamantylamine 13 4-bromo-2-((1- adamantylino)methyl)phenol 14 N-(2-bromo-5- methoxybenzyl)adamantylamine 15 N-[(2-methoxy-5- bromo)benzyl]adamantylamine 16 N-((pyridin-2-yl)methyl)adamantylamine 17 N-((pyridin-3-yl)methyl)adamantylamine 18 N-((pyridin-4-yl)methyl)adamantylamine 19 N-((5-methylfuran-2- yl)methyl)adamantylamine 20 N-((5-methylthiophen-2- yl)methyl)cyclohexanamine 21 N-[(3-furyl)methyl]adamantylamine 22 N-((1-methyl-1H-imidazol-5- yl)methyl)adamantylamine 23 N-[(5-N- methylimidazolyl)methyl]adamantylamine 24 Benzo[d][1,3]dioxol-4- yl)methyl)adamantylamine 25 N-((5-nitrobenzo[d][1,3]dioxol-6- yl)methyl)adamantylamine 26 N-((quinolin-3-yl)methyl)adamantylamine 27 N-((quinolin-4-yl)methyl)adamantylamine 28 N-((1-methyl-1H-indol-2- yl)methyl)adamantylamine 29 N-phenethyladamantylamine 30 N-(3-phenylpropyl)adamantylamine 31 N-(2-(benzyloxy)ethyl)adamantylamine 32 N-cinnamyladamantylamine 33 N-methyl(3-bromobenzyl)adamantylamine 34 N-benzyl-2-adamantylamine 35 N-(2-bromobenzyl)-2-adamantylamine 36 N-(3-bromobenzyl)-2-adamantylamine 37 N-(4-bromobenzyl)adamantylamine 38 N-(2-fluorobenzyl)-2-adamantylamine 39 N-(3-fluorobenzyl)-2-adamantylamine 40 N-(4-fluorobenzyl)-2-adamantylamine 41 N-(3-hydroxybenzyl)-2-adamantylamine 42 N-(2-methoxybenzyl)-2-adamantylamine 43 N-(3-methoxybenzyl)-2-adamantylamine 44 N-(4-methoxybenzyl)-2-adamantylamine 45 N-(2-nitrobenzyl)-2-adamantylamine 46 N-(4-nitrobenzyl)-2-adamantylamine 47 N-(4-carbethoxybenzyl)-2- adamantylamine 48 4-bromo-2-((2- adamantylamino)methyl)phenol 49 N-(2-bromo-5-nitrobenzyl)-2- adamantylamine 50 N-(5-bromo-2-methoxybenzyl)-2- adamantylamine 51 N-(5-fluoro-2-nitrobenzyl)-2- adamantylamine 52 N-(2,5-difluorobenzyl)-2-adamantylamine 53 N-((pyridin-2-yl)methyl)-2- adamantylamine 54 N-((pyridin-3-yl)methyl)-2- adamantylamine 55 N-((pyridin-4-yl)methyl)-2- adamantylamine 56 N-((5-methylfuran-2-yl)methyl)-2- adamantylamine 57 N-((5-methylthiophen-2-yl)methyl)-2- adamantylamine 58 N-((furan-3-yl)methyl)-2-adamantylamine 59 N-((1-methyl-1H-imidazol-5-yl)methyl)-2- adamantylamine 60 N-[(5-N-methylimidazolyl)methyl]-2- adamantylamine 61 Benzo[d][1,3]dioxol-4-yl)methyl)-2- adamantylamine 62 N-((5-nitrobenzo[d][1,3]dioxol-6- yl)methyl)-2-adamantylamine 63 N-((quinolin-3-yl)methyl)-2- adamantylamine 64 N-((quinolin-4-yl)methyl)-2- adamantylamine 65 N-((1-methyl-1H-indol-2-yl)methyl)-2- adamantylamine 66 N-(1-(3-bromophenyl)ethyl)-2- adamantylamine 67 N-benzhydryl-2-adamantylamine 68 N-(2-(benzyloxy)ethyl)-2-adamantylamine 69 N-(phenylpropyl)-2-adamantylamine 70 N-(1-phenylethyl)-2-adamantylamine 71 N-(1-(pyridin-2-yl)ethyl)-2- adamantylamine 72 N-(2-adamantylmethyl)-1- (adamantyl)ethanamine 73 N-methyl(3-bromobenzyl)-2- adamantylamine 74 N-(3-bromobenzyl)-2-methylpropan-2- amine 75 N-(3-bromobenzyl)-2,4,4-trimethylpentan- 2-amine 76 2-(3-bromobenzylamino)-3-hydroxy-2- methylpropanoic acid 77 2-(3-bromobenzylamino)-2- (hydroxymethyl)propane-1,3-diol 78 N-(3-bromobenzyl)cyclohexanamine 79 4-(3-bromobenzylamino)cyclohexanol 80 N-(3-fluorobenzyl)cyclohexylamine 81 4-(3-fluorobenzylamino)cyclohexanol 82 (1-(3- bromobenzylamino)cyclopentyl)methanol 83 1-(3- bromobenzylamino)cyclopentanecarboxylic acid 84 N-(3-bromobenzyl)bicyclo[2.2.1]heptan-2- amine 85 2-(3- bromobenzylamino)bicyclo[2.2.1]heptane- 2-carboxylic acid 86 N-(3-bromobenzyl)noradamantylamine 87 N-(3-bromobenzyl)-1-hydroxy-2- adamantylamine 88 N-(3-bromobenzyl)-N- ((benzo[d][1,3]dioxol-6-yl)methyl)(3- bromophenyl)methanamine 89 2-(3-bromobenzylamino)-2-(4- hydroxybenzyl)propanoic acid 90 2-(3,4-dihydroxybenzyl)-2-(3- bromobenzylamino)propanoic acid 91 2-(3-bromobenzylamino)-2- phenylbutanoic acid 92 2-(3-bromobenzylamino)-2,2- diphenylacetic acid 93 methyl 2-(3-bromobenzylamino)-2-methyl- 3-phenylpropanoate 94 methyl 3-(3-bromobenzylamino)-8- azabicyclo[3.2.1]octane-8-carboxylate 95 N-(3-bromobenzyl)-9-methyl-9- azabicyclo[3.3.1]nonan-3-amine 96 N-(3-bromobenzyl)benzo[d][1,3]dioxol-5- amine 97 2-(3-bromobenzylideneamino)-2-(3,4- dihydroxyphenyl)propanoic acid 98 N-benzyl(3-bromophenyl)methanamine 99 bis(3-bromobenzyl)amine 100 N-(3-fluorobenzyl)(3- bromophenyl)methanamine 101 N-(3-bromobenzyl)(1-methyl-1H-indol-2- yl)methanamine 102 N-(3-bromobenzyl)-1-phenylethanamine 103 N-(3-bromobenzyl)-1-(3- bromophenyl)ethanamine 104 N-(3-bromobenzyl)-1-(pyridin-2- yl)ethanamine 105 N-(3-bromobenzyl)quinuclidin-3-amine 106 (1R*,5S*)-N-(3- bromobenzyl)bicyclo[3.3.1]nonan-9-amine 107 N-(3-bromobenzyl)-8-methyl-8-aza- bicyclo[3.2.1]octan-3-amine 108 N-(1-(3- bromophenyl)ethyl)adamantylamine 109 N-(3-fluorobenzyl)noradamantylamine 110 N-(3-bromobenzyl)adamantylamine hydrochloride salt 111 N-(5-bromo-2- methoxybenzyl)adamantylamine hydrochloride salt 112 N-(2-bromobenzyl)-2-adamantylamine hydrochloride salt 113 (E)-N-(3- bromobenzylidene)adamantylamine 114 (E)-N-(3- fluorobenzylidene)adamantylamine 115 (E)-N-((1-methyl-1H-indol-2- yl)methylene)adamantylamine 116 (E)-N-benzylideneadamantylamine 117 (E)-N-(3- bromobenzylidene)adamantylamine 118 (E)-N-(3- fluorobenzylidene)adamantylamine 119 (E)-N-(3- bromobenzylidene)noradamantylamine 120 (E)-N-((1-methyl-1H-indol-2- yl)methylene)noradamantylamine 121 N-1-adamantylbenzamide 122 N-2-adamantylbenzamide 123 phenyl N-adamantylcarbamate 124 N-adamantyl benzenesulfonamide 125 N-adamantyl-N-(3- bromobenzyl)acetamide 126 phenyl N-2-adamantylcarbamate 127 N-adamantyl-N-(3- bromobenzyl)benzamide 128 N-2-adamantyl benzenesulfonamide 129 1-(adamantyl)-3-phenylurea 131 1-(adamantyl)-1-(3-bromobenzyl)-3- phenylurea 132 1-(2-adamantyl)-3-phenylurea 134 1-(adamantyl)-2,5-dihydro-1H-imidazole 135 1-(adamantyl)-2,5-dihydrooxazole 136 1-(adamantyl)-1-phenyl-4,5-dihydro-1H- imidazole 137 1-(adamantyl)-3a,4,5,6,7,7a-hexahydro- 1H-benzo[d]imidazole 138 N-(3-chlorobenzyl)adamantylamine 139 N-(3-chlorobenzyl)-2-adamantylamine 140 N-(3-iodobenzyl)-2-adamantylamine 141 N-(2,2-diphenylethyl)-2-adamantylamine 142 N-(naphthalen-1-ylmethyl)-2- adamantylamine 143 N-(phenanthren-9-ylmethyl)-2- adamantylamine 144 4-((adamantylamino)methyl)benzoic acid 145 adamantylamino-4-phenyl-1H-1,2,3- triazole 146 adamantylamino-4-phenyl-1H-1,2,3- triazole 147 2-(adamantylamino-1H-1,2,3-triazol-4- yl)pyridine 148 N-(2-bromo-5- nitrobenzyl)adamantylamine 149 2-(3-bromobenzylideneamino)-N- phenylbenzamide 150 2-(3-bromobenzylamino)-N- phenylbenzamide 151 2-(3-fluorobenzylideneamino)-N- phenylbenzamide 152 (E)-2-((furan-2-yl)methyleneamino)-N- phenylbenzamide 153 (E)-2-((furan-3-yl)methyleneamino)-N- phenylbenzamide 154 (E)-2-((5-methylfuran-2- yl)methyleneamino)-N-phenylbenzamide 155 (E)-2-(5-fluoro-2-nitrobenzylideneamino)- N-phenylbenzamide 156 (E)-2-(4-fluorobenzylideneamino)-N- phenylbenzamide 157 (E)-2-(2-fluorobenzylideneamino)-N- phenylbenzamide 158 (E)-2-((1-methyl-1H-indol-2- yl)methyleneamino)-N-phenylbenzamide 159 (E)-2-(5-bromo-2- hydroxybenzylideneamino)-N- phenylbenzamide 160 2-(2-fluorobenzylamino)-N- phenylbenzamide 161 (E)-2-(2-(5-methylthiophen-2-yl)vinyl)-N- phenylbenzamide 191 N-cinnamyl-2-adamantylamine 192 N-(3-nitrobenzyl)-2-adamantylamine

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 compounds which are aminoadamantane derivatives were prepared by reductive amination according to the reaction which follows:

Specifically, the invention relates to the process for preparing the compounds of general formula (Ia):

in which:

    • Cy is the adamantyl nucleus with the nitrogen atom in position 1 or 2;
    • X represents a branched, optionally unsaturated, C1-C3 alkyl chain which is optionally interrupted with an oxygen atom;
    • R1 is a radical containing from 1 to 21 carbon atoms which is optionally branched 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, and which is optionally monosubstituted or disubstituted with a halogen atom, an —OH or —NO2 function, a C1-C3 alkoxy radical or a C1-C3 acyloxy radical;
    • R2 is chosen from —H or a C1-C3 alkyl radical, characterized in that it comprises the following steps:
    • adding a suspension of 1-adamantylamine or 2-adamantylamine in methanol, with stirring, to an aromatic aldehyde chosen according to the compound of general formula (Ia) to be prepared, in the presence of BH3CN on resin and of acetic acid;
    • stirring the mixture for 2 days at ambient temperature.

In a more detailed manner, 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 (BH3CN 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.

This same process makes it possible to prepare the derivatives of general formula (Ib):

in which:

    • Cy is

    • X represents a branched, optionally unsaturated, C1-C3 alkyl chain which is optionally interrupted with an oxygen atom, —CO—, —CO—NH—, —CS—NH— or

    • R2 is chosen from nothing, —H, —CH3 or

it being understood that, when R2 is nothing, then the nitrogen atom and X are linked by a double bond.

The invention therefore also relates to a process for preparing the compounds of general formula (Ib), characterized in that it comprises the following steps:

    • adding a suspension of 3-bromobenzylamine in methanol, with stirring, to an aromatic aldehyde chosen according to the compound of general formula (Ib) to be prepared, in the presence of BH3CN on resin and of acetic acid;
    • stirring the mixture for 2 days at ambient temperature.

In a more detailed manner, 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 BH3CN 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 CH2Cl2 with a solution of the corresponding acid in a solvent (for example, HCl in ether).

The precipitate is filtered off and dried under vacuum so as to give the salt of the acid (for example, hydrochloride in the case of HCl). They appear in table B of example 1.

The 1-aminoadamantane, 2-aminoadamantane or noradamantylamine derivatives of general formula (Ic)

in which:

    • Cy is

with Z being a carbon atom or nothing (noradamantyl nucleus), with the nitrogen atom in position 1 or 2 when Cy is the adamantyl nucleus;

    • R1 is chosen from a phenyl radical, a heterocyclic radical such as the pyridine, furan, thiophene, quinoline or indole radicals, preferably the indole radical, said radical being optionally monosubstituted or disubstituted with a halogen atom, an —OH or —NO2 function, a C1-C3 alkoxy radical or a C1-C3 acyloxy radical, a C1-C3 alkyl radical, 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.) chosen according to the compound to be prepared (see tables C1, C2 and C3 of example 1). The whole is mixed for two days at ambient temperature and then evaporated.

Thus, 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:

    • stirring a suspension, in methanol, of 1-, 2- or noradamantylamine (1 equiv.);
    • adding to an aldehyde (1 equiv.) chosen according to the compound to be prepared;
    • mixing the whole for two days at ambient temperature and then evaporating.

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: BH3CN 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:

    • adding a solution of amine in MeOH to an aldehyde, said amine and said aldehyde being chosen according to the compound of general formula (I) to be prepared;
    • stirring the mixture for 2 days;
    • evaporating and purifying.

The invention also relates to a process for preparing a reduced imine of general formula (I), characterized in that it comprises the following steps:

    • adding BH3CN on resin (3 equiv.) and AcOH to a solution of the imine obtained according to the above process, in MeOH;
    • treating for 3 days at ambient temperature;
    • filtering the mixture;
    • washing with methanol;
    • concentrating under vacuum.

The 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.

Finally, the invention relates to a process for preparing the N-1-adamantylbenzamide and N-2-adamantylbenzamide compounds comprising the following steps:

    • adding 1- or 2-adamantylamine and benzoyl chloride, at 0° C., to a suspension of NaH in DMF;
    • stirring the mixture for 24 hours at ambient temperature.

Formation of Ureas

The invention also relates to a process for preparing a urea derivative of general formula (I), characterized in that it comprises the following steps:

    • adding, at 0° C., the isocyanate, the amine and the isocyanate corresponding to said desired urea derivative (1.1 equiv.) to a suspension of the amine which is a 1-adamantyl derivative (1 equiv.) in THF,
    • stirring the mixture for 24 hours at ambient temperature,
    • evaporating and purifying on a small silica cartridge.

Alkylation of Alcohols (for Example, Adamantane-Methanol)

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.

Formation of the Triazole Derivatives by Click Chemistry

The invention also relates to a process for preparing triazole derivatives of general formula (I), characterized in that it comprises the following steps:

    • reacting an azide with an acetylenic compound (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 h at ambient temperature;
    • filtering the mixture through celite and evaporating;
    • purifying.

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):

where
A and B represent a carbon atom or a nitrogen atom with the proviso that, if A=N then B=C, and if A=C then B=N;
R3 is chosen from a hydrogen or halogen atom; a C1-C6 alkyl radical, a C1-C6 alkoxy radical or a C1-C6 acyloxy radical, these radicals being optionally substituted with a C1-C6 alkoxy radical; an aryloxy radical or a heteroaryloxy radical;
R4 either represents a bond or is chosen from a hydrogen atom, a C1-C3 acyloxy radical, a C1-C3 alkoxy radical or a phenyl;
R5 either represents a bond or is chosen from a hydrogen atom; a C1-C3 alkyl radical; a C1-C3 alkoxy radical; a C1-C3 acyloxy radical or a phenyl radical which is optionally substituted with an —OH function and/or a halogen atom, a C1-C3 alkyl radical, a C1-C3 alkoxy radical, a C1-C3 acyloxy radical, an —NO2 or —CF3 function, or a radical

it being understood that R4 and R5 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, R5 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.

The term “C1-C6 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.

The term “C1-C6 alkoxy radical” is intended to mean an —OCmH2m+1 radical, m being an integer between 1 and 6.

The term “C1-C6 acyloxy radical” is intended to mean an —O(CO) CmH2m+1 or —(CO) OCmH2m+1 radical, m being an integer between 1 and 6.

The term “aryloxy radical” is intended to mean an aryl group linked to the rest of the compound by an oxygen atom.

The term “heteroaryloxy radical” is intended to mean a heteroaryl group linked to the rest of the compound by an oxygen atom.

Preferably, the compounds of general formula (II) are such that R3 is a bond and/or R4 represents a hydrogen atom and/or R5 represents a phenyl radical and/or, when A is a carbon atom, then R4 is a phenyl radical, and/or, when B is a carbon atom, then R5 is a phenyl radical.

More particularly, the compounds of general formula (II) are chosen from:

TABLE 2 162 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin- 2-one 163 7-bromo-5-phenyl-2,3-dihydro-1H-1,4- benzodiazepin-2-one 164 7-bromo-5-phenyl-2,3,4,5-tetrahydro-1H- 1,4-benzodiazepin-2-one 165 4-phenyl-2,3-dihydro-1H-1,5-benzodiazepin- 2-one 166 4-phenyl-2,3,4,5-tetrahydro-1H-1,5- benzodiazepin-2-one 167 4,5-dihydro-7-methoxy-5-phenyl-1H- benzo[e][1,4]diazepin-2(3H)-one 168 Ethyl 4-oxo-2-phenyl-2,3,4,5-tetrahydro-1H- 1,5-benzodiazepine-1-carboxylate 169 5-phenyl-2,3,4,5-tetrahydro-1H-1,4- benzodiazepin-2-one 170 7-chloro-5-phenyl-2,3-dihydro-1H-1,4- benzodiazepin-2-one 171 7-chloro-5-phenyl-2,3,4,5-tetrahydro-1H-1,4- benzodiazepin-2-one 172 4-(2-hydroxyphenyl)-1H- benzo[b][1,4]diazepin-2(3H)-one 173 4-(5-bromo-2-hydroxyphenyl)-1H- benzo[b][1,4]diazepin-2(3H)-one 174 4-(5-fluoro-2-hydroxyphenyl)-1H- benzo[b][1,4]diazepin-2(3H)-one 175 8-bromo-3-phenyl-3,3a,5,10- tetrahydrobenzo[b]pyrrolo[2,3- e][1,4]diazepin-4(2H)-one 176 4-m-tolyl-1H-benzo[b][1,4]diazepin- 2(3H)-one 177 4-(3-methoxyphenyl)-1H- benzo[b][1,4]diazepin-2(3H)-one 178 4-(3-nitrophenyl)-1H-benzo[b][1,4]diazepin- 2(3H)-one 179 4-(3-chlorophenyl)-1H-benzo[b][1,4]diazepin- 2(3H)-one 180 4-(3-bromophenyl)-1H-benzo[b][1,4]diazepin- 2(3H)-one 181 4-(3-(trifluoromethyl)phenyl)-1H- benzo[b][1,4]diazepin-2(3H)-one 182 7-bromo-4-m-tolyl-1H-benzo[b][1,4]diazepin- 2(3H)-one 183 7-bromo-4-(3-methoxyphenyl)-1H- benzo[b][1,4]diazepin-2(3H)-one 184 7-bromo-4-(3-nitrophenyl)-1H- benzo[b][1,4]diazepin-2(3H)-one 185 7-bromo-4-(3-chlorophenyl)-1H- benzo[b][1,4]diazepin-2(3H)-one 186 7-bromo-4-(3-bromophenyl)-1H- benzo[b][1,4]diazepin-2(3H)-one 187 7-bromo-4-(3-(trifluoromethyl)phenyl)-1H- benzo[b][1,4]diazepin-2(3H)-one 193 7-bromo-5-phenyl-4-propionyl-4,5-dihydro- 1H-benzo[e][1,4]diazepin-2(3H)-one

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.

The synthesis of the compounds of general formula (II) according to the invention is described in example 1.

More particularly, the benzo[e][1,4]diazepine derivatives and the benzo[b][1,4]diazepine derivatives of general formula (II) are prepared as follows:

    • addition to a suspension of diamine, chosen according to the compound to be prepared, for example from benzene-1,2-diamine or 4-bromobenzene-1,2-diamine (1 equiv.) in toluene (2 ml) with a β-keto ester (1 equiv.);
    • stirring of the mixture at reflux (120° C.) for 3 hours;
    • dilution of the mixture in EtOAc, acidification (pH 5) and extraction with EtOAc;
    • filtration, evaporation, and washing with Et2O.

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.

According to another of its subjects, 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.

The term “pharmaceutically acceptable” is intended to mean compatible with administration to an individual, preferably a mammal, by any route of administration.

Those skilled in the art will be capable of adapting the formulation of the compounds of general formulae (I) and (II) according to their physicochemical properties and their 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.

More specifically, 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:

Molecular Toxin Origin* Enzymatic activity target Class A/B toxins Diphtheria toxin (DT) C. diphtheriae (+) ADP- Elongation Exotoxin A (ETA) P. aeruginosa (−) ribosyltransferase factor 2 Botulinum toxins (NTBo C. Botulinum (+) Zinc-endopeptidase SNARE Neurotoxins A/G) proteins Tetanus toxin (NTTe) C. tetani (+) Lethal toxin (LT) C. sordellii (+) Glucosyltransferase Ras/Rho High- Hemorragic toxin (HT) proteins molecular- Toxin A (Tox A) C. difficile (+) weight toxins Toxin B (Tox B) α-toxin (α-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 [illegible] Cholera toxin (CT) V. cholerae (−) ADP- Gsα toxins Thermolabile toxins (LT) E. coli (−) ribosyltransferase protein Pertussis toxin (PTX) B. pertussis (−) Gsα protein Shiga toxins S. dysenteriae (−) Ribonuclease 28S rRNA Shiga family Shiga-like toxins E. coli (−) toxins A Edema toxin B. anthracis (+) Adenylate cyclase Calmodulin Anthrax [illegible] (edema factor EF + toxins protective antigen PA) Lethal toxin Zinc-endopeptidase MAP (lethal factor LF + kinases protective antigen PA) C2 toxin (C2I + C2II) C. botulinum (+) ADP- Actin Actin ADP- Iota toxin (Ia + Ib) C. perfringens (+) ribosyltransferase ribosylating Spiroform toxin (Sa + Sb) C. spiroforme (+) toxins CDT toxin (CDTa + CDTb) C. difficile (+) VIP toxin (VIP1 + VIP2) B. cereus (−) *Between parentheses, Gram staining Various activities, molecular targets and structures of the main bacterial toxins with an intracellular action

The 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).

This use proves to be effective whether the individual touches, ingests or inhales the toxin or the virus, or else whether the toxin or the virus is injected into said individual.

Thus, 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.

Concretely, a toxin such as ricin, 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). It should be noted that there is a risk of anaphylactic reaction. The lethal dose is 1 mg/kg (Ministry of Health, France).

Thus, 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.

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.

According to one preferred variant, the invention relates to the use of compounds of general formula (I) which are defined by general formula (I.1):

in which:
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,
R1 represents:

    • a phenyl ring, optionally substituted with an —OCH3 radical in the para-position with respect to the carbon atom bonded to the —CH2—NH-Cy chain; said ring being alternatively optionally substituted with a halogen atom in the meta-position with respect to the carbon atom bonded to the —CH2—NH-Cy chain, and in this case, said ring optionally bears a second substitution in the para-position with respect to said halogen atom, said second substitution being chosen from —NO2 and —OCH3;
    • an indole, imidazole or furan ring substituted with a methyl radical;
    • a benzo(1,3)dioxolo ring, a naphthalenyl ring or a phenanthrenyl ring;
      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 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.

According to another preferred variant, the invention relates to the use of compounds of general formula (I) which are defined by general formula (I.2):

in which X represents —(CH2)2—O—CH2—, —(CH2)3—, —CO— or —SO2—,
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 formula (I.2) are chosen from compounds 68, 69, 122 and 128.

According to yet another preferred variant, the invention relates to the use of compounds of general formula (I) which are defined by general formula (I.3):

in which 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.

Preferably, the compounds of general formula (I.3) are chosen from compounds 117 and 118.

Another preferred variant of the invention relates to the use of the compounds of general formula (I.4):

in which 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.

Preferably, 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):

in which:
Cy represents a group:

to which the nitrogen atom is attached in position 1 or 2,
W and W′ are, independently of one another, chosen from a hydrogen atom, a halogen atom and a C1-C3 alkoxy radical,
and the pharmaceutically acceptable salts thereof.

Preferably, the compounds of general formula (I.5) are chosen from compounds 5, 9, 39, 110, 111, 112, 139 and 140.

In addition to the above arrangements, the invention also comprises other arrangements which will emerge from the description that follows, which refer to examples of implementation of the present invention, and also to the appended figures in which:

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) represent the positive controls (cells with ricin+lactose), the green dots (horizontal cloud of dots on the lower part of the graph) represent the negative controls (cells treated with ricin alone) and, in red, are the compounds according to the invention tested in the presence of ricin.

 EXAMPLE 1—EXAMPLES OF SYNTHESIS OF COMPOUNDS According to the Invention

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 purification methods used for preparing the compounds are specified in the “Purification method” column of the tables and coded as follows:

1: Filtration

2: Short pad (small column with silica already packaged)
3: Silica gel chromatography column

4: HPLC 5: Crystallization

6: Aqueous treatment then separation.

The 1H 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: δ, chemical shift; multiplicity (with s singlet, d doublet, t triplet, q quadruplet, m, multiplet), integration, coupling constants (J in Hertz, Hz).

The 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.

The data are obtained in m/z form.

Column: Xbridge C18 3-5 μM, 4.6 mm×100 mm
Flow rate: 1 ml/min

Detectors:

    • Waters 2996 photodiode array detector: UV (200-400 nm),
    • PL-ELS 1000,
    • MS ZQ 2000.
      Injection volume: 1 μl with the Waters 2767 autos ampler.
      Method: 95% solution A (99.99% water, 0.01% formic acid), 5% B (100% acetonitrile) to 0% A, 100% B on a gradient of 8 minutes, then 5-minute stage.

The column chromatographies were carried out with a Merck silica gel (particle size: 230-400 mesh). All the reactions were monitored by thin-layer chromatography with plates precoated with 0.2 mm-thick silica gel 60G-264 (Merck). Developing was carried out with a UV lamp or with diode.

Process A

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 BH3CN on resin (0.75 mmol; 1.5 equiv.) and of acetic acid (1.5 mmol; 84 μl; 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.

TABLE A1 Compounds which are 1-aminoadamantane derivatives, prepared by process A starting from 1- adamantylamine Purification method/ Compound appearance/ Compound Aldehyde Compound name characteristics yield 1 Benzaldehyde N-benzyladamantylamine 1H NMR (CDCl3, 1 400 MHz): δ 7.39 (m, 2H), white solid 7.32 (m, 3H), 3.86 (s, 2H), 100% 3.66 (bs, 1H), 2.12 (s, 3H), 1.84-1.63 (m, 12H). ESI+MS: calcd for C17H23N: 241.18; found: 242.2 (MH+) 2 2-bromobenzaldehyde N-(2- 1 bromobenzyl)- yellow solid adamantylamine 24% 3 3-bromobenzaldehyde N-(3- 1H NMR (CDCl3, 1 bromobenzyl)- 400 MHz): δ 7.56 (s, 1H), white solid adamantylamine 7.39 (d, 1H, J = 6.7 Hz), 35% 7.33 (d, 1H, J = 7.6 Hz), 7.18 (t, 1H, J = 8 Hz), 6.09 (bs, 1H), 3.81 (s, 2H), 2.12 (s, 3H), 1.79-1.63 (m, 12H). 13C NMR (CDCl3, 100 MHz): δ 139.7, 132.2, 130.7, 130.0, 127.8, 122.4, 53.7, 43.7, 40.9, 36.2, 29.3. 4 4-bromobenzaldehyde N-(4- ESI+MS: calcd for 1 bromobenzyl)- C17H22BrN: 319.09; found: green solid adamantylamine 320.1 (MH+) 70% 5 3-fluorobenzaldehyde N-(3- 1H NMR (CDCl3, 1 fluorobenzyl)- 400 MHz): δ 7.26 (m, 1H), white solid adamantylamine 7.15 (m, 2H), 6.95 (m, 100% 1H), 4.10 (bs, 1H), 3.85 (s, 2H), 2.12 (s, 3H), 1.79-1.62 (m, 12H). ESI+MS: calcd for C17H22FN: 259.17; found: 260.2 (MH+) 6 3-hydroxybenzaldehyde N-(3- 1H NMR (CDCl3, 1 hydroxybenzyl)- 400 MHz): δ 7.06 (t, 1H, J = 7.6 Hz), pale adamantylamine 6.83 (s, 1H), yellow solid 6.75 (d, 1H, J = 7.6 Hz), 98% 6.63 (d, 1H, J = 8 Hz), 3.83 (s, 2H), 3.49 (bs, 1H), 2.18 (s, 3H), 1.93-1.67 (m, 12H). 13C NMR (DMSO-d6, 100 MHz): δ 156.3, 137.2, 127.7, 117.9, 114.6, 113.2, 52.0, 42.3, 38.8, 34.6, 27.6. ESI+MS: calcd for C17H23NO: 257.18; found: 258.1 (MH+) 7 2- N-(2- ESI+MS: calcd for 1 methoxybenzaldehyde methoxybenzyl)- C18H25NO: 271.19; found: pale adamantylamine 272.2 (MH+) yellow solid 32% 8 3- N-(3- ESI+MS: calcd for 1 methoxybenzaldehyde methoxybenzyl)adamantyl- C18H25NO: 271.19; found: green oil amine 272.2 (MH+) 40% 9 4- N-(4- 1H NMR (CDCl3, 1 methoxybenzaldehyde methoxybenzyl)- 400 MHz): δ 7.19 (d, 2H, J = 8.4 Hz), green solid adamantyl-amine 6.77 (d, 2H, J = 8.4 Hz), 42% 3.70 (s, 3H), 3.64 (s, 2H), 2.01 (s, 3H), 1.65-1.54 (m, 12H). 13C NMR (CDCl3, 100 MHz): δ 158.5, 129.6, 113.8, 55.2, 51.4, 44.3, 42.4, 36.6, 29.6. ESI+MS: calcd for C18H25NO: 271.19; found: 272.2 (MH+) 10 2-nitrobenzaidehyde N-(2- 1H NMR (CDCl3, 1 nitrobenzyl)- 400 MHz): δ 7.85 (d, 1H, J = 8.0 Hz), orange solid adamantylamine 6.68 (d, 1H, J = 7.6 Hz), 44% 7.52 (t, 1H, J = 7.2 Hz), 7.34 (t, 1H, J = 7.6 Hz), 3.96 (s, 2H), 2.04 (s, 3H), 1.69-1.56 (m, 12H). 13C NMR (CDCl3, 100 MHz): δ 149.3, 133.1, 131.8, 127.7, 124.5, 51.2, 42.7, 42.2, 36.7, 29.6. ESI+MS: calcd for C17H22N2O2: 286.17; found: 287.2 (MH+) 11 4-nitrobenzaldehyde N-(4- ESI+MS: calcd for 1 nitrobenzyl)- C17H22N2O2: 286.17; orange solid adamantylamine found: 287.2 (MH+) 58% 12 4-methyl 4- N-(4- 1H NMR (CDCl3, 1 formylbenzoate carbethoxybenzyl)- 400 MHz): δ 7.99 (d, 2H, J = 8.4 Hz), white solid adamantylamine 7.46 (d, 2H, J = 8.4 Hz), 100% 6.37 (bd, 1H), 3.90 (s, 5H), 2.12 (s, 3H), 1.81-1.62 (m, 12H). 13C NMR (CDCl3, 100 MHz): δ 176.1, 166.4, 139.4, 129.7, 129.3, 55.5, 51.9, 43.1, 39.2, 35.6, 28.9. ESI+MS: calcd for C19H25NO2: 299.19; found: 300.1 (MH+) 13 5-bromo-2- 4-bromo-2-((1- 1H NMR (CDCl3, 2 hydroxybenzaldehyde adamantylino)methyl)- 400 MHz): δ 7.28 (dd, 1H, white solid phenol J = 2.4 and 8.8 Hz), 15% 7.14 (dd, 1H, J = 2.4 and 25.6 Hz), 6.73 (dd, 1H, J = 8.4 and 34 Hz), 5.17 (bs, 2H), 3.95 (s, 2H), 2.12 (s, 3H), 1.84-1.61 (m, 12H). ESI+MS: calcd for C17H22BrNO: 335.09; found: 336.2 (MH+) 14 2-bromo-5- N-(2-bromo-5- 1H NMR (CDCl3, 1 methoxybenzaldehyde methoxybenzyl)adamantyl- 400 MHz): δ 7.46 (d, 1H, J = 2.4 Hz), white solide amine 7.31 (dd, 1H, J = 2.4 55% and 8.8 Hz), 6.71 (d, 1H, J = 8.8 Hz), 3.82 (s, 3H), 3.76 (s, 2H), 3.19 (bs, 1H), 2.10 (s, 3H), 1.74-1.62 (m, 12H). 13C NMR (CDCl3, 100 MHz): δ 156.5, 132.6, 130.7, 111.8, 55.5, 51.8, 42.1, 39.6, 36.6, 29.5. ESI+MS: calcd for C18H24BrNO: 349.10; found: 350.1 (MH+) 15 2-methoxy-5- N-[(2-methoxy-5- 1 bromobenzaldehyde bromo)benzyl]- white solid adamantylamine 100% 16 picolinaldehyde N-((pyridin-2- 1H NMR (CDCl3, 1 yl)methyl)adamantylamine 400 MHz): δ 8.52 (d, 1H, J = 4.8 Hz), brown solid 7.67 (dt, 1H, J = 1.6 55% and 7.6 Hz), 7.38 (d, 1H, J = 7.6 Hz), 7.21 (dd, 1H, J = 4.8 and 6.8 Hz), 4.17 (s, 3H), 3.76 (s, 2H), 2.14 (s, 3H), 1.92-1.64 (m, 12H). 13C NMR (CDCl3, 100 MHz): δ 148.7, 137.1, 122.8, 114.0, 54.5, 43.9, 40.4, 36.0, 29.2. ESI+MS: calcd for C15H22N2: 242.18; found: 243.2 (MH+) 17 nicotinaldehyde N-((pyridin-3- 1H NMR (CDCl3, 1 yl)methyl)adamantylamine 400 MHz): δ 8.59 (s, 1H), white solid 8.52 (d, 1H, J = 6.6 Hz), 93% 7.92 (d, 1H, J = 8.0 Hz), 7.31 (m, 1H), 4.00 (s, 2H), 2.16 (s, 3H), 1.90-1.63 (m, 12H). 13C NMR (CDCl3, 100 MHz): δ 150.1, 149.1, 138.3, 129.6, 123.7, 56.4, 40.9, 39.2, 35.7, 29.1. ESI+MS: calcd for C15H22N2: 242.18; found: 243.2 (MH+) 18 isonicotinaldehyde N-((pyridin-4- 1H NMR (CDCl3, 1 yl)methyl)adamantylamine 400 MHz): δ 8.53 (d, 1H, J = 4.4 Hz), pale yellow 7.38 (d, 1H, J = 5.2 Hz), solid 3.91 (s, 2H), 61% 2.13 (s, 3H), 1.80-1.61 (m, 12H). ESI+MS: calcd for C16H22N2: 242.18; found: 243.2 (MH+) 19 5-methylfuran-2- N-((5-methylfuran-2- 1H NMR (CDCl3, 1 carbaldehyde yl)methyl)adamantylamine 400 MHz): δ 6.22 (d, 1H, J = 2.8 Hz), yellow solid 5.83 (d, 1H, J = 2.0 Hz), 84% 5.80 (s, 1H), 3.89 (s, 2H), 2.19 (s, 3H), 2.07 (s, 3H), 1.79 (m, 6H), 1.60 (m, 6H). 13C NMR (CDCl3, 100 MHz): δ 152.6, 145.4, 111.3, 106.6, 55.5, 39.0, 36.1, 35.6, 28.9, 13.2. ESI+MS: calcd for C16H23NO: 245.18; found: 246.2 (MH+) 20 5-methylthiophene-2- N-((5-methylthiophen-2- 1H NMR (CDCl3, 1 carbaldehyde yl)methyl)- 400 MHz): δ 6.80 (d, 1H, J = 3.2 Hz), yellow solid cyclohexanamine 6.57 (d, 1H, J = 3.2 Hz), 89% 5.33 (bs, 1H), 3.98 (s, 2H), 2.43 (s, 3H), 2.11 (s, 3H), 1.78 (m, 6H), 1.66 (m, 6H). 13C NMR (CDCl3, 100 MHz): δ 139.7, 138.3, 126.5, 124.9, 53.3, 41.1, 39.0, 36.3, 29.4, 15.3. ESI+MS: calcd for C16H23NS: 261.16; found: 262.2 (MH+) 21 Furan-3-carbaldehyde N-[(3- 1H NMR (CDCl3, 1 furyl)methyl]- 400 MHz): δ 7.51 (s, 1H), yellow solid adamantylamine 7.36 (s, 1H), 6.52 (s, 1H), 70% 3.84 (s, 2H), 2.15 (s, 3H), 1.89-1.64 (m, 12H). ESI+MS: calcd for C15H21NO: 231.16; found: 232.2 (MH+) 22 1-methyl-1H-imidazole- N-((1-methyl-1H-imidazol- 1H NMR (CDCl3, 1 5-carbaldehyde 5- 400 MHz): δ 7.53 (s, 1H), white solid yl)methyl)adamantylamine 6.97 (s, 1H), 6.71 (bs, 100% 1H), 3.81 (s, 2H), 3.70 (s, 3H), 2.12 (s, 3H), 1.76-1.62 (m, 12H). 23 1-methyl-1H-imidazole- N-[(5-N- 1H NMR (CDCl3, 1 2-carbaldehyde methylimidazolyl)methyl]- 400 MHz): δ 7.75 (bs, 1H), white solid adamantylamine 6.96 (s, 1H), 6.837 (s, 100% 1H), 4.15 (s, 2H), 3.72 (s, 3H), 2.14 (s, 3H), 1.83-1.64 (m, 12H). 13C NMR (CDCl3, 100 MHz): δ 131.8, 126.2, 121.8, 54.3, 40.1, 36.1, 29.3. ESI+MS: calcd for C15H23N3: 245.18; found: 246.2 (MH+) 24 Benzo[d][1,3]dioxole-4- Benzo[d][1,3]dioxol-4- 1H NMR (CDCl3, 1 carbaldehyde yl)methyl)adamantylamine 400 MHz): δ 6.87 (d, 1H, J = 8.4 Hz), white solid 6.79 (t, 1H, J = 7.6 Hz), 100% 6.73 (dd, 1H, J = 1.2 and 7.6 Hz), 5.97 (s, 2H), 3.82 (s, 2H), 3.22 (bs, 1H), 2.11 (s, 3H), 1.78-1.62 (m, 12H). ESI+MS: calcd for C18H23NO2: 285.17; found: 286.2 (MH+) 25 6-nitro[d][1,3]dioxole-5- N-((5- 1H NMR (CDCl3, 400 MHz): δ 1 carbaldehyde nitrobenzo[d][1,3]dioxol-6- 7.56 (s, 1H), 7.25 (s, 1H), brown solid yl)methyl)adamantylamine 6.36 (bs, 1H), 6.13 (s, 2H), 54% 4.18 (s, 2H), 2.19 (s, 3H), 1.99-1.67 (m, 12H). ESI+MS: calcd for C18H22N2O4: 330.16; found: 331.2 (MH+) 26 Quinoline-3- N-((quinolin-3- 1H NMR (CDCl3, 1 carbaldehyde yl)methyl)adamantylamine 400 MHz): δ 8.91 (s, 1H), yellow solid 8.22 (s, 1H), 8.08 (d, 1H, J = 8.4 Hz), 100% 7.81 (d, 1H, J = 8.4 Hz), 7.68 (t, 1H, J = 7.2 Hz), 7.53 (t, 1H, J = 7.6 Hz), 4.02 (s, 2H), 3.31 (bs, 1H), 2.11 (s, 3H), 1.88-1.62 (m, 12H). ESI+MS: calcd for C20H24N2: 292.19; found: 293.3 (MH+) 27 Quinoline-4- N-((quinolin-4- ESI+MS: calcd for 1 carbaldehyde yl)methyl)adamantylamine C20H24N2: 292.19; found: orange solid 293.2 (MH+) 100% 28 1-methyl-1H-indole-2- N-((1-methyl-1H-indol-2- 1H NMR (CDCl3, 1 carbaldehyde yl)methyl)adamantylamine 400 MHz): δ 7.54 (d, 1H, J = 7.6 Hz), yellow solid 7.28 (d, 1H, J = 8.0 Hz), 100% 7.17 (t, 1H, J = 7.2 Hz), 7.06 (t, 1H, J = 7.6 Hz), 6.38 (s, 1H), 3.92 (s, 2H), 3.79 (s, 3H), 2.11 (s, 3H), 1.75-1.63 (m, 12H). ESI+MS: calcd for C20H26N2: 294.21; found: 295.2 (MH+) 29 2-phenylacetaldehyde N- ESI+MS: calcd for 2 phenethyladamantylamine C18H25N2: 255.20; found: colorless oil 256.3 (MH+) 5% 30 3-phenylpropanal N-(3- 1H NMR (CDCl3, 1 phenylpropyl)- 400 MHz): δ 8.02 (bs, 1H), white solid adamantylamine 7.26 (m, 2H), 7.16 (m, 100% 3H), 2.78 (t, 2H, J = 7.6 Hz), 2.62 (t, 2H, J = 8.4 Hz), 2.06 (s, 2H), 1.85 (s, 6H), 1.62 (m, 6H), 13C NMR (CDCl3, 100 MHz): δ 128.5, 128.4, 128.3, 126.0, 55.2, 38.9, 38.8, 35.8, 33.2, 28.9, 28.3. ESI+MS: calcd for C19H27N: 269.22; found: 270.3 (MH+) 31 2- N-(2- 1H NMR (CDCl3, 1 (benzyloxy)- (benzyloxy)ethyl)- 400 MHz): δ 7.33 (m, 5H), orange solid acetaldehyde adamantylamine 4.53 (s, 2H), 3.69 (t, 2H, J = 5.2 Hz), 100% 2.96 (t, 2H, J = 5.2 Hz), 2.12 (s, 3H), 1.78 (m, 5H), 1.66 (m, 7H). ESI+MS: calcd for C19H27NO: 285.21; found: 286.3 (MH+) 32 cinnamaldehyde N- 1H NMR (CDCl3, 1 cinnamyladamantylamine 400 MHz): δ 8.81 (bs, 1H), yellow solid 7.36-7.11 (m, 5H), 6.59 (d, 100% 1H, J = 16 Hz), 6.35 (dt, 1H, J = 6.8 and 15.6 Hz), 3.54 (d, 2H, J = 6.4 Hz), 2.00 (s, 3H), 1.84-1.55 (m, 12H). ESI+MS: calcd for C19H25N: 267.20; found: 268.3 (MH+) 33 paraformaldehyde N-methyl(3- 1H NMR (CDCl3, 2 bromobenzyl)- 400 MHz): δ 7.51 (s, 1H), colorless oil adamantylamine 7.34 (d, 1H, J = 7.6 Hz), 23% 7.25 (d, 1H, J = 6.8 Hz), 7.17 (t, 1H, J = 7.6 Hz), 3.53 (s, 2H), 2.13 (s, 6H), 1.77 (s, 6H), 1.66 (m, 6H). ESI+MS: calcd for C18H24BrN: 333.11; found: 334.0 (MH+)

TABLE A2 Compounds which are 2-aminoadamantane derivatives, prepared by process A starting from 2- adamantylamine Purification method/ Compound appearance/ Compound Aldehyde Compound name characteristics yield 34 Benzaldehyde N-benzyl-2- 1H NMR (CDCl3, 1 adamantylamine 400 MHz): δ 7.55 (m, 2H), white oil 7.37 (m, 3H), 6.33 (bs, 100% 1H), 3.05 (s, 1H), 2.28-1.59 (m, 14H). 13C NMR (CDCl3, 100 MHz): δ 131.5, 130.1, 128.9, 60.2, 48.4, 37.1, 36.8, 30.4, 29.2, 26.9, 26.6, 22.8. ESI+MS: calcd for C17H23N: 241.18; found: 242.2 (MH+) 35 2-bromobenzaldehyde N-(2-bromobenzyl)-2- LC-MS (ES+) m/z 1 adamantylamine 320.1 (M + H)+ colorless oil 1H NMR (CDCl3, 62% 400 MHz): δ 7.70 (d, 1H, J = 7.6 Hz), 7.56 (d, 1H, J = 7.6 Hz), 7.33 (t, 1H, J = 7.2 Hz), 7.18 (m, 1H), 5.42 (bs, 1H), 4.11 (s, 2H), 3.02 (s, 1H), 2.20-1.59 (m, 14H). ESI+MS: calcd for C17H22BrN: 319.09; found: 320.1 (MH+) 36 3-bromobenzaldehyde N-(3-bromobenzyl)-2- 1H NMR (CDCl3, 1 adamantylamine 400 MHz): δ 7.66 (s, 1H), white solid 7.53 (d, 1H, J = 6.8 Hz), 60% 7.46 (d, 1H, J = 8.4 Hz), 7.26 (m, 1H), 4.02 (s, 2H), 2.98 (s, 1H), 2.22-1.61 (m, 14H). 13C NMR (CDCl3, 100 MHz): δ 132.7, 131.8, 128.5, 122.8, 60.8, 48.3, 37.3, 36.9, 30.7, 29.8, 27.1, 26.9. ESI+MS: calcd for C17H22BrN: 319.09; found: 320.1 (MH+) 37 4-bromobenzaldehyde N-(4-bromobenzyl)-2- 1H NMR (CDCl3, 400 MHz): δ 1 adamantylamine 7.50 (d, 1H, J = 8.4 Hz), white solid 7.43 (d, 1H, J = 8.0 Hz), 5.65 (bs, 27% 1H), 4.00 (s, 2H), 2.97 (s, 1H), 2.22-1.60 (m, 14H). ESI+MS: calcd for C17H22BrN: 319.09; found: 320.1 (MH+) 38 2-fluorobenzaldehyde N-(2-fluorobenzyl)-2- 1H NMR (CDCl3, 400 MHz): δ 2 adamantylamine 7.42 (td, 1H, J = 1.2 and 7.2 Hz), yellow solid 7.22 (m, 1H), 7.33 (td, 9.6% 1H, J = 0.8 and 7.2 Hz), 7.03 (t, 1H, J = 9.6 Hz), 3.87 (s, 2H), 2.81 (s, 1H), 2.33 (bs, 1H), 2.04 (d, 2H, J = 12.4 Hz), 1.87 (s, 2H), 1.84 (m, 4H), 1.70 (m, 4H), 1.52 (d, 2H, J = 12 Hz). ESI+MS: calcd for C17H22FN: 259.17; found: 260.2 (MH+) 39 3-fluorobenzaldehyde N-(3-fluorobenzyl)-2- 1H NMR (CDCl3, 1 adamantylamine 400 MHz): δ 7.34 (m, 3H), white solid 7.03 (m, 1H), 4.08 (s, 2H), 100% 3.01 (s, 1H), 2.22-1.61 (m, 14H). ESI+MS: calcd for C17H22FN: 259.17; found: 260.2 (MH+) 40 4-fluorobenzaldehyde N-(4-fluorobenzyl)-2- 1H NMR (CDCl3, Short pad adamantylamine 400 MHz): δ 7.33 (dd, 2H, yellow solid J = 5.6 and 8.4 Hz), 5.2% 7.00 (t, 2H, J = 8.8 Hz), 3.77 (s, 2H), 2.79 (s, 1H), 2.04 (d, 2H, J = 12.4 Hz), 1.85 (m, 6H), 1.70 (m, 4H), 1.52 (d, 2H, J = 12.4 Hz). ESI+MS: calcd for C17H22FN: 259.17; found: 260.2 (MH+) 41 3-hydroxybenzaldehyde N-(3-hydroxybenzyl)-2- 1H NMR (CDCl3, 400 MHz): δ 1 adamantylamine 7.25 (s, 1H), 7.18 (t, 1H, J = 7.6 Hz), white 6.87 (dd, 1H, J = 2.0 foam and 8.4 Hz), 6.80 (d, 1H, J = 7.2 Hz), 88% 4.04 (s, 2H), 3.12 (s, 2H), 2.24-1.62 (m, 14H). 13C NMR (CDCl3, 100 MHz): δ 157.7, 131.7, 129.9, 121.1, 116.9, 116.9, 116.9, 60.6, 48.4, 36.9, 36.7, 30.3, 29.1, 26.7, 26.5. ESI+MS: calcd for C17H23NO: 257.18; found: 258.1 (MH+) 42 2- N-(2-methoxybenzyl)-2- 1H NMR (CDCl3, 400 MHz): δ 1 methoxybenzaldehyde adamantylamine 7.42 (dd, 1H, J = 1.2 and 7.6 Hz), white solid 7.33 (m, 1H), 6.96 (t, 54% 1H, J = 8 Hz), 5.66 (bs, 1H), 4.09 (s, 2H), 3.88 (s, 3H), 3.10 (s, 1H), 2.19-1.63 (m, 14H). ESI+MS: calcd for C18H25NO: 271.19; found: 272.2 (MH+) 43 3- N-(3-methoxybenzyl)-2- 1H NMR (CDCl3, 1 methoxybenzaldehyde adamantylamine 400 MHz): δ 7.32-6.83 (m, white solid 4H), 3.97 (s, 2H), 3.83 (s, 48% 3H), 2.94 (s, 1H), 2.18-1.58 (m, 14H). ESI+MS: calcd for C18H25NO: 271.19; found: 272.2 (MH+) 44 4- N-(4-methoxybenzyl)-2- 1H NMR (CDCl3, 1 methoxybenzaldehyde adamantylamine 400 MHz): δ 7.39 (d, 2H, J = 8.8 Hz), white solid 6.89 (d, 2H, J = 8.4 Hz), 45% 5.62 (bs, 1H), 3.96 (s, 2H), 3.79 (s, 3H), 2.97 (s, 1H), 2.15-1.59 (m, 14H). ESI+MS: calcd for C18H25NO: 271.19; found: 272.2 (MH+) 45 2-nitrobenzaldehyde N-(2-nitrobenzyl)-2- ESI+MS: calcd for 1 adamantylamine C17H22N2O2: 286.17; yellow oil found: 287.2 (MH+) 59% 46 4-nitrobenzaldehyde N-(4-nitrobenzyl)-2- 1H NMR (CDCl3, 1 adamantylamine 400 MHz): δ 8.20 (d, 2H, J = 8.4 Hz), yellow oil 7.63 (d, 2H, J = 8.4 Hz), 56% 3.99 (s, 2H), 2.82 (s, 1H), 2.20-1.54 (m, 14H). ESI+MS: calcd for C17H22N2O2: 286.17; found: 287.2 (MH+) 47 4-methyl-4- N-(4-carbethoxybenzyl)-2- 1H NMR (CDCl3, 1 formylbenzoate adamantylamine 400 MHz): δ 8.86 (bs, 1H), white solid 7.97 (d, 2H, J = 8.4 Hz), 100% 7.57 (d, 2H, J = 8.4 Hz), 4.11 (s, 2H), 3.85 (s, 3H), 3.02 (s, 1H), 2.17-1.54 (m, 14H). 13C NMR (CDCl3, 100 MHz): δ 166.3, 136.6, 130.5, 130.0, 129.9, 60.8, 52.1, 48.1, 37.0, 36.7, 30.3, 29.2, 26.7, 26.5. ESI+MS: calcd for C19H25NO2: 299.19; found: 300.1 (MH+) 48 5-bromo-2- 4-bromo-2-((2- ESI+MS: calcd for 2 hydroxybenzaldehyde adamantylamino)methyl)- C17H22BrNO: 335.09; pale yellow phenol found: 336.1 (MH+) solid 18% 50 5-bromo-2- N-(5-bromo-2- ESI+MS: calcd for 1 methoxybenzaldehyde methoxybenzyl)-2- C18H24BrNO2: 349.10; white solid adamantylamine found: 350.1 (MH+) 56% 51 5-fluoro-2- N-(5-fluoro-2-nitrobenzyl)- ESI+MS: calcd for 4 nitrobenzaldehyde 2-adamantylamine C17H21FN2O2: 304.16; colorless oil found: 305.2 (MH+) 2.3% 52 2,5- N-(2,5- 1H NMR (CDCl3, 6, 2 difluorobenzaldehyde difluorobenzaldehyde)-2- 400 MHz): δ 7.67-7.62 (m, yellow solid adamantylamine 1H), 7.19-7.15 (m, 1H), 28% 7.11-6.93 (m, 1H), 4.24 (s, 2H), 3.11 (s, 1H), 2.24 (bs, 2H), 1.95-1.89 (m, 6H), 1.75 (m, 4H), 1.67 (m, 2H). ESI+MS: calcd for C17H21F2N: 277.16; found: 278.2 (MH+) 53 picolinaldehyde N-((pyridin-2-yl)methyl)-2- ESI+MS: calcd for 1 adamantylamine C16H22N2: 242.18; found: yellow oil 243.2 (MH+) 71% 54 nicotinaldehyde N-((pyridin-3-yl)methyl)-2- 1H NMR (CDCl3, 1 adamantylamine 400 MHz): δ 8.62 (s, 1H), yellow solid 8.55 (d, 1H, J = 4.4 Hz), 79% 8.00 (s, 1H), 7.32 (m, 1H), 3.99 (s, 2H), 2.91 (s, 1H), 2.17-1.57 (m, 14H). 13C NMR (CDCl3, 100 MHz): δ 150.0, 149.1, 137.8, 130.7, 123.8, 60.9, 46.5, 37.3, 37.0, 30.6, 30.1, 27.1, 26.9, 22.0. ESI+MS: calcd for C15H22N2: 242.18; found: 243.2 (MH+) 55 isonicotinaldehyde N-((pyridin-4-yl)methyl)-2- 1H NMR (CDCl3, 1 adamantylamine 400 MHz): δ 8.58 (m, 2H), yellow solid 7.44 (d, 1H, J = 4.0 Hz), 46% 7.31 (d, 1H, J = 5.6 Hz), 3.95 (s, 2H), 2.86 (s, 1H), 2.17-1.56 (m, 14H). 13C NMR (CDCl3, 100 MHz): δ 150.0, 149.1, 137.8, 130.7, 123.8, 60.9, 46.5, 37.3, 37.0, 30.6, 30.1, 27.1, 26.9, 22.0. ESI+MS: calcd for C16H22N2: 242.18; found: 243.2 (MH+) 56 5-methylfuran-2- N-((5-methylfuran-2- 1H NMR (CDCl3, 1 carbaldehyde yl)methyl)-2- 400 MHz): δ 6.33 (d, 1H, J = 2.8 Hz), yellow oil adamantylamine 5.93 (d, 1H, J = 2.0 Hz), 59% 4.80 (bs, 1H), 4.01 (s, 2H), 3.00 (s, 1H), 2.28 (s, 3H), 2.16-1.59 (m, 14H). 13C NMR (CDCl3, 100 MHz): δ 152.8, 146.3, 111.7, 106.7, 60.7, 41.4, 37.4, 37.1, 30.7, 29.9, 27.2, 26.9, 13.6. ESI+MS: calcd for C16H23NO: 245.18; found: 246.2 (MH+) 57 5-methylthiophene-2- N-((5-methylthiophen-2- 1H NMR (CDCl3, 1 carbaldehyde yl)methyl)-2- 400 MHz): δ 6.88 (d, 1H, J = 3.2 Hz), yellow oil adamantylamine 6.62 (d, 1H, J = 2.4 Hz), 55% 5.39 (bs, 1H), 4.10 (s, 2H), 3.00 (s, 1H), 2.46 (s, 3H), 2.14-1.57 (m, 14H). ESI+MS: calcd for C16H23NS: 261.16; found: 262.1 (MH+) 58 furan-3-carbaldehyde N-((furan-3-yl)methyl)-2- 1H NMR (CDCl3, 1 adamantylamine 400 MHz): δ 7.58 (d, 1H, J = 6.8 Hz), orange solid 7.42 (s, 1H), 61% 6.74 (d, 1H, J = 13.6 Hz), 4.01 (s, 2H), 3.07 (s, 1H), 2.28-1.42 (m, 14H). ESI+MS: calcd for C15H21NO: 231.16; found: 232.1 (MH+) 59 1-methyl-1H-imidazole- N-((1-methyl-1H-imidazol- 1H NMR (CDCl3, 1 5-carbaldehyde 5-yl)methyl)-2- 400 MHz): δ 7.62 (s, 1H), white solid adamantylamine 7.01 (s, 1H), 5.75 (bs, 100% 1H), 3.95 (s, 2H), 3.80 (s, 3H), 2.99 (s, 1H), 2.14-1.58 (m, 14H). 13C NMR (CDCl3, 100 MHz): δ 138.9, 129.0, 124.8, 61.2, 37.6, 37.2, 36.9, 32.1, 30.6, 30.0, 29.9, 27.0, 26.8. ESI+MS: calcd for C15H23N3: 245.19; found: 246.1 (MH+) 60 1-methyl-1H-imidazole- N-[(5-N- 1H NMR (CDCl3, 1 2-carbaldehyde methylimidazolyl)methyl]- 400 MHz): δ 7.08 (bs, 1H), white solid 2-adamantylamine 7.02 (d, 1H, J = 1.2 Hz), 100% 6.88 (d, 1H, J = 1.2 Hz), 4.12 (s, 2H), 3.80 (s, 3H). 3.14 (s, 1H), 2.13-1.58 (m, 14H). 13C NMR (CDCl3, 100 MHz): δ 141.0, 126.2, 122.4, 62.3, 39.7, 37.2, 36.9, 33.6, 30.5, 29.8, 27.0, 26.8. ESI+MS: calcd for C15H23N3: 245.19; found: 246.2 (MH+) 61 Benzo[d][1,3]dioxole-4- Benzo[d][1,3]dioxol-4- 1H NMR (CDCl3, 2 carbaldehyde yl)methyl)-2- 400 MHz): δ 6.84 (d, 1H, J = 7.6 Hz), white solid adamantylamine 6.80 (t, 1H, J = 7.6 Hz), 9% 6.74 (dd, 1H, J = 1.2 and 7.6 Hz), 5.96 (s, 2H), 3.79 (s, 2H), 2.78 (s, 1H), 2.11 (s, 1H), 2.05-1.49 (m, 14H). ESI+MS: calcd for C18H23NO2: 285.17; found: 286.2 (MH+) 62 6-nitro[d][1,3]dioxole-5- N-((5- ESI+MS: calcd for 1 carbaldehyde nitrobenzo[d][1,3]dioxol-6- C18H22N3O4: 330.16; brown solid yl)methyl)-2- found: 331.2 (MH+) 62% adamanlylamine 63 Quinoline-3- N-((quinolin-3-yl)methyl)- 1H NMR (CDCl3, 2 carbaldehyde 2-adamantylamine 400 MHz): δ 8.87 (d, 1H, J = 4.4 Hz), yellow solid 8.15 (m, 2H), 100% 7.41 (m, 1H), 7.56 (m, 2H), 6.99 (bs, 1H), 4.30 (s, 2H), 2.92 (s, 1H), 2.21-1.54 (m, 14H). ESI+MS: calcd for C20H24N2: 292.19; found: 293.2 (MH+) 64 Quinoline-4- N-((quinolin-4-yl)methyl)- 1H NMR (CDCl3, 1 carbaldehyde 2-adamantylamine 400 MHz): δ 8.87 (d, 1H, J = 4.4 Hz), yellow solid 8.15 (m, 2H), 100% 7.41 (m, 1H), 7.56 (m, 2H), 6.99 (bs, 1H), 4.30 (s, 2H), 2.92 (s, 1H), 2.21-1.54 (m, 14H), ESI+MS: calcd for C20H24N2: 292.19; found: 293.2 (MH+) 65 1-methyl-1H-indole-2- N-((1-methyl-1H-indol-2- 1H NMR (CDCl3, 1 carbaldehyde yl)methyl)-2- 400 MHz): δ 7.56 (d, 1H, J = 8.0 Hz), yellow solid adamantylamine 7.31 (d, 1H, J = 8 Hz), 100% 7.22 (t, 1H, J = 7.6 Hz), 7.08 (t, 1H, J = 7.6 Hz), 6.59 (bs, 1H), 4.14 (s, 2H), 3.83 (s, 3H), 3.07 (s, 1H), 2.26-1.58 (m, 14H). ESI+MS: calcd for C20H26N2: 294.21; found: 295.2 (MH+) 66 1-(3- N-(1-(3- 1H NMR (CDCl3, 4 bromophenyl)ethanone bromophenyl)ethyl)-2- 400 MHz): δ 7.54 (m, 1H), colorless oil adamantylamine 7.41 (m, 2H), 7.26 (m, 18% 2H), 4.88 (q, 1H, J = 6.4 Hz), 2.74 (bs, 1H), 2.08-1.53 (m, 14H), 1.49 (d, 3H, J = 6.4 Hz). 13C NMR (CDCl3, 100 MHz): δ 147.6, 130.1, 130.0, 129.9, 125.4, 122.5, 59.2, 54.7, 32.5, 31.3, 31.1, 30.6, 27.6, 27.4, 24.2. ESI+MS: calcd for C18H24BrN: 333.11; found: 334.2 (MH+) 67 benzophenone N-benzhydryl-2- 1H NMR (CDCl3, 4 adamantylamine 400 MHz): δ 7.73 (bs, 1H), white solid 7.29 (m, 10H), 4.57 (t, 1H, 3% J = 7.6 Hz), 3.48 (dd, 1H, J = 1.2 and 7.6 Hz), 3.06 (s, 1H), 2.08 (s, 4H), 1.83 (m, 4H), 1.71-1.64 (m, 6H). 13C NMR (CDCl3, 100 MHz): δ 140.7, 129.0, 127.9, 127.3, 61.8, 49.5, 48.1, 37.0, 36.9, 30.5, 29.4, 26.9, 26.5. ESI+MS: calcd for C24H29N: 331.23; found: 331.9 (MH+) 68 2- N-(2-(benzyloxy)ethyl)-2- 1H NMR (CDCl3, 1 (benzyloxy)- adamantylamine 400 MHz): δ 7.34 (m, 5H), white solid acetaldehyde 4.58 (s, 2H), 3.85 (m, 2H), 79% 3.15 (m, 3H), 2.20-1.64 (m, 14H). ESI+MS: calcd for C19H27NO: 285.21; found: 286.3 (MH+) 69 3-phenylpropanal N-(phenylpropyl)-2- 13C NMR (CDCl3, 1 adamantylamine 100 MHz): δ 140.8, 128.4, white solid 128.3, 126.0, 62.5, 45.7, 100% 37.3, 37.1, 33.3, 30.5, 29.9, 28.5, 27.2, 26.8. ESI+MS: calcd for C19H27N: 269.22; found: 270.2 (MH+) 70 acetophenone N-(1-phenylethyl)-2- 1H NMR (CDCl3, 2 adamantylamine 400 MHz): δ 7.57 (d, 2H, J = 11.2 Hz), colorless oil 7.38 (m, 3H), 18% 4.91 (q, 1H, J = 6.4 Hz), 2.87 (s, 1H), 2.14-1.54 (m, 14H), 1.51 (d, 3H, J = 5.1 Hz). ESI+MS: calcd for C18H25N: 255.20; found: 256.3 (MH+) 71 1-(pyridin-2-yl)ethanone N-(1-(pyridin-2-yl)ethyl)-2- 1H NMR (CDCl3, 1 adamantylamine 400 MHz): δ 8.58 (d, 1H, J = 4.4 Hz), colorless oil 7.73 (m, 1H), 100% 7.48 (m, 1H), 7.26 (m, 1H), 6.51 (bs, 1H), 4.28 (m, 1H), 3.00 (bs, 1H), 2.18-1.51 (m, 14H), 1.62 (d, 3H, J = 6.4 Hz). ESI+MS: calcd for C17H24N: 256.19; found: 257.2 (MH+) 72 1-adamantyl methyl N-(2-adamantylmethyl)-1- 1H NMR (CDCl3, 4 ketone (adamantyl)ethanamine 400 MHz): δ 3.25 (s, 1H), white solid 2.50 (q, 1H, J = 5.1 Hz), 4.7% 2.36 (s, 1H), 2.06-1.65 (m, 28H), 1.27 (d, 3H, J = 6.8 Hz). ESI+MS: calcd for C22H35N: 313.28; found: 314.2 (MH+) 73 paraformaldehyde N-methyl(3-bromobenzyl)- 1H NMR (CDCl3, 400 MHz): δ 2 2-adamantylamine 7.50 (s, 1H), 7.35 (d, 1H, J = 8 Hz), white oil 7.27 (d, 1H, J = 9.2 Hz), 35% 7.17 (t, 1H, J = 7.6 Hz), 3.48 (s, 2H), 2.22-2.14 (m, 5H), 1.86 (m, 4H), 1.72 (m, 4H), 1.47 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ 143.6, 131.5, 129.7, 129.5, 127.2, 122.3, 67.6, 57.5, 38.7, 37.8, 37.3, 31.6, 29.9, 27.6, 27.3. ESI+MS: calcd for C18H24BrN: 333.11; found: 334.0 (MH+) 191 cinnamaldehyde N-cinnamyl-2- 1H NMR (CDCl3, white solid adamantylamine 400 MHz): δ 7.42-7.27 (m, 100% 5H), 6.63 (d, 1H, J = 15.6 Hz), 6.42 (dt, 1H, J = 6.8 and 16 Hz), 3.70 (d, 2H, J = 6.8 Hz), 3.18 (s, 1H), 2.20-1.43 (m, 14H). ESI+MS: calcd for C19H25N: 267.20; found: 268.3 (MH+)

Similarly, 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 BH3CN on resin (0.75 mmol; 1.5 equiv.) and of acetic acid (1.5 mmol; 84 μl; 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.

TABLE A3 Alkylamine compounds of general formula (I) prepared by process A starting from 3-halobenzaldehydes Purification method/ Compound appearance/ Compound Reactant 1 Reactant 2 Compound name structure yield 74 3- tert-Butylamine N-(3-bromobenzyl)- 1H NMR (CDCl3, 1 bromobenzaldehyde 2-methylpropan-2- 400 MHz): δ 7.59 (s, yellow solid amine 1H), 7.40 (d, 1H, J = 8 Hz), 83% 7.36 (d, 1H, J = 7.6 Hz), 7.19 (t, 1H, J = 7.6 Hz), 4.78 (bs, 1H), 3.82 (s, 2H), 1.26 (s, 9H). ESI+MS: calcd for C11H16BrN: 241.05; found: 242.1 (MH+) 75 3- 2,4,4- N-(3-bromobenzyl)- 1H NMR (CDCl3, 2 bromobenzaldehyde trimethylpentan- 2,4,4- 400 MHz): δ 7.54 (s, yellow solid 2-amine trimethylpentan-2- 1H), 7.39 (d, 1H, J = 8 Hz), 26% amine 7.33 (d, 1H, J = 7.6 Hz), 7.18 (t, 1H, J = 8 Hz), 3.81 (s, 2H), 1.60 (s, 2H). 1.31 (s, 6H), 1.04 (s, 9H). 13C NMR (CDCl3, 100 MHz): δ 140.0, 132.0, 130.6, 130.0, 127.6, 122.4, 57.2, 51.8, 45.3, 31.7, 27.5. ESI+MS: calcd for C15H24BrN; 297.11; found: 298.1 (MH+) 76 3- 2-amino-3- 2-(3- ESI+MS: calcd for 2 bromobenzaldehyde hydroxy-2- bromobenzylamino)- C11H14BrNO3: 287.02; white solid methyl- 3-hydroxy-2- found: 288.1 (MH+) 18% propanoic acid methylpropanoic acid 77 3- 2-amino-2- 2-(3- 1H NMR (CDCl3, 2 bromobenzaldehyde (hydroxymethyl)- bromobenzylamino)- 400 MHz): δ 7.54 (s, colorless propane-1,3-diol 2- 1H), 7.41 (d, 1H, J = 8 Hz), oil (hydroxymethyl)- 7.30 (d, 1H, J = 8 Hz), 10% propane-1,3-diol 7.21 (t, 1H, J = 7.6 Hz), 3.77 (s, 2H), 3.66 (s, 6H), 1.98 (bs, 4H). ESI+MS: calcd for C11H16BrNO3: 289.03; found: 290.1 (MH+) 78 3- cyclohexyl- N-(3- 1H NMR (CDCl3, 1 bromobenzaldehyde amine bromobenzyl) 400 MHz): δ 7.52 (s, pale yellow cyclo-hexanamine 1H), 7.40 (d, 1H, J = 7.6 Hz), solid 7.29 (d, 1H, J = 7.6 Hz), 100% 7.20 (t, 1H, J = 8 Hz), 3.86 (s, 2H), 2.56 (s, 1H), 2.02 (m, 2H), 1.95 (m, 2H), 1.75 (m, 2H), 1.64 (m, 2H), 1.20 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ 138.9, 132.0, 130.8, 130.1, 127.6, 122.6, 55.8, 48.5, 31.3, 25.6, 24.8. ESI+MS: calcd for C13H18BrN: 267-06: found: 268.0 (MH+) 79 3- 4- 4-(3- 1H NMR (CDCl3, 1 bromobenzaldehyde aminocyclo- bromobenzylamino)- 400 MHz): δ 7.54 (s, white solid hexanol cyclohexanol 1H), 7.43 (d, 1H, J = 7.6 Hz), 100% 7.32 (d, 1H, J = 7.6 Hz), 7.22 (t, 1H, J = 7.6 Hz), 5.28 (bs, 2H), 3.88 (s, 2H), 3.64 (m, 1H), 2.64 (m, 1H), 2.02 (m, 4H), 1.43-1.23 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ 137.6, 132.2, 131.3, 130.2, 127.7, 125.3, 69.6, 54.9, 48.8, 33.4, 28.7. ESI+MS: calcd for C13H18BrNO: 283.06; found: 284.0 (MH+) 80 3-fluorobenzaldehyde cyclohexyl- N-(3- ESI+MS: calcd for 1 amine fluorobenzyl)- C13H18FN: 207.14; white solid cyclo-hexylamine found: 208.12 (MH+) 100% 81 3-fluorobenzaldehyde 4- 4-(3- ESI+MS: calcd for 1 aminocyclo- fluorobenzylamino)- C13H18FNO: 223.14; white solid hexanol cyclohexanol found: 224.10 (MH+) 100% 82 3- (1- (1-(3- 1H NMR (CDCl3, 1 bromobenzaldehyde aminocyclo- bromobenzylamino)- 400 MHz): δ 7.55 (s, pale yellow pentyl)methanol cyclopentyl)- 1H), 7.40 (d, 1H, J = 8 Hz), solid methanol 7.31 (d, 1H, J = 7.6 Hz), 100% 7.18 (t, 1H, J = 7.6 Hz), 6.14 (bs, 2H), 3.77 (s, 2H), 3.47 (s, 2H), 1.72 (m, 4H), 1.57 (m, 4H). ESI+MS; calcd for C13H18BrNO: 283.06; found: 284.1 (MH+) 83 3- (1- 1-(3- ESI+MS: calcd for 4 bromobenzaldehyde aminocyclo- bromobenzylamino)- C13H18BrNO2: 297.04; colorless pentyl)methanol cyclopentane- found: 298.1 (MH+) oil carboxylic acid 6.6% 84 3- bicyclo[2.2.1]- N-(3-bromobenzyl)- ESI+MS: calcd for 2 bromobenzaldehyde heptan-2- bicyclo[2.2.1]heptan- C14H18BrN: 279.06; yellow oil amine 2-amine found: 280.2 (MH+) 23% 85 3- 2-aminobicyclo- 2-(3- ESI+MS: calcd for 1 bromobenzaldehyde [2.2.1]heptane- bromobenzylamino)- C15H18BrNO2: 323.05; white solid 2-carboxylic bicyclo[2.2.1]- found: 324.1 (MH+) 8% acid heptane-2-carboxylic acid 86 3- noradamantyl- N-(3-bromobenzyl)- 1H NMR (CDCl3, 2 bromobenzaldehyde amine noradamantylamine 400 MHz): δ white solid 10.01 (bs, 1H), 7.48 (m, 88% 2H), 7.31 (m, 3H), 3.93 (s, 2H), 2.27 (s, 2H), 2.11 (t, 1H, J = 6.4 Hz), 2.05 (d, 2H, J = 10 Hz), 1.78 (m, 4H), 1.57 (d, 1H, J = 12.8 Hz), 1.46-1.37 (m, 3H). 13C NMR (CDCl3, 100 MHz): δ 132.1, 130.2, 128.7, 128.6, 69.9, 47.6, 45.4, 42.8, 42.0, 37.1, 34.2. ESI+MS: calcd/for C16H20BrN: 305.08; found: 306.1 (MH+) 87 3- 3-Amino-1- N-(3-bromobenzyl)- 1H NMR (CDCl3, 2 bromobenzaldehyde adamantanol 1-hydroxy-2- 400 MHz): δ 7.53 (s, yellow oil adamantylamine 1H), 7.37 (d, 1H, J = 8 Hz), 17% 7.26 (m, 1H), 7.18 (t, 1H, J = 7.6 Hz), 3.75 (s, 2H), 2.56 (s, 1H), 2.29 (s, 2H), 1.77-1.54 (m, 12H). 13C NMR (CDCl3, 100 MHz): δ 138.9, 132.0, 130.8, 130.1, 127.6, 122.6, 55.8, 48.5, 31.3, 25.6, 24.8. ESI+MS: calcd for C17H22BrNO: 335.09; found: 336.1 (MH+) 88 3- benzo[d][1,3]- N-(3-bromobenzyl)- 2 bromobenzaldehyde dioxol-5-amine N-((benzo[d][1,3]- 5% dioxol-6-yl)methyl)- (3-bromophenyl)- methanamine 89 3- 2-(4- 2-(3- ESI+MS: calcd for 2 bromobenzaldehyde hydroxybenzyl)- bromobenzylamino)- C17H18BrNO3: 363.05; white solid 2-amino- 2-(4- found: 364.0 (MH+) 2% propanoic acid hydroxybenzyl)- propanoic acid 90 3- 2-(3,4- 2-(3,4- ESI+MS: calcd for 4 bromobenzaldehyde dihydroxy- dihydroxybenzyl)-2- C17H18BrNO4: 379.04; yellow oil benzyl)-2- (3- found: 380.1 (MH+) 20% amino- bromobenzylamino)- propanoic acid propanoic acid 91 3- 2-amino-2- 2-(3- ESI+MS: calcd for 2 bromobenzaldehyde phenylbutanoic bromobenzylamino)- C17H18BrNO2: 347.05; white solid acid 2-phenylbutanoic found: 348.1 (MH+) 9% acid 92 3- 2-amino-2,2- 2-(3- ESI+MS: calcd for 2 bromobenzaldehyde diphenylacetic bromobenzylamino)- C21H18BrNO2: 395.05; white solid acid 2,2-diphenylacetic found: 396.1 (MH+) 1.4% acid 93 3- methyl 2- methyl 2-(3- ESI+MS: calcd for 2 bromobenzaldehyde amino-2- bromobenzylamino)- C18H20BrNO2: 361.07; colorless benzyl- 2-methyl-3- found: 362.1 (MH+) oil propanoate phenylpropanoate 15.5% 94 3- methyl 3-(3- 6 bromobenzaldehyde bromobenzylamino)- 8-azabicydo[3.2.1]octane- 8-carboxylate 95 3- 8-methyl-8- N-(3- 1H NMR (CDCl3, 4 bromobenzaldehyde aza- bromobenzyl)-9- 400 MHz): δ 8.57 (bs, colorless bicyclo[3.2.1]- methyl-9- 1H), 7.49 (s, 1H), oil octan-3-one azablcycio[3.3.1]- 7.39 (d, 1H, J = 7.6 Hz), 25% nonan-3-amine 7.25 (d, 1H, J = 7.6 Hz), 7.20 (t, 1H, J = 7.6 Hz), 3.78 (s, 2H), 3.44 (m, 3H), 2.75 (s, 3H), 2.64 (m, 2H), 2.10 (m, 2H), 1.61-1.44 (m, 6H). 13C NMR (CDCl3, 100 MHz): δ 141.1, 131.4, 130.5, 130.1, 127.0, 122.6, 52.0, 50.6, 46.2, 38.3, 31.5, 24.2, 12.8. 96 3- benzo[d][1,3]- N-(3- ESI+MS: calcd for 2 bromobenzaldehyde dioxol-5-amine bromobenzyl)benzo- C15H14BrNO2: 319.02; colorless [d][1,3]dioxol-5- found: 320.1 (MH+) oil amine 39% 97 3- 2-(3,4- 2-(3- 4 bromobenzaldehyde dihydroxybenzyl)- bromobenzylidene- 10% 2-amino- amino)-2-(3,4- propanoic acid dihydroxyphenyl)- propanoic acid

TABLE A4 Alkylamine compounds of general formula (I) prepared by process A starting from 3-halobenzylamines Purification method/ Compound appearance/ Compound Reactant 1 Reactant 2 Compound name structure yield 98 3- benzaldehyde N-benzyl(3- 1H NMR (CDCl3, 400 MHz): 1 bromobenzylamine bromophenyl)- δ 7.52 (s, 1H), white solid methanamine 7.46-7.23 (m, 9H), 78% 5.62 (bs, 1H), 3.93 (s, 2H), 3.34 (s, 2H). ESI+MS: calcd for C14H14BrN: 275.03; found: 276.0 (MH+) 99 3- 3- bis(3- ESI+MS: calcd for 1 bromobenzylamine bromobenzaldehyde bromobenzyl)- C14H13Br2N: 352.94; white solid amine found: 353.8 (MH+) 75% 100 3- 3- N-(3- 1H NMR (CDCl3, 400 MHz): 1 bromobenzylamine fluorobenzaldehyde fluorobenzyl)(3- δ 7.53 (s, 1H), white solid bromophenyl)- 7.45 (d, 1H, J = 8 Hz), 86% methanamine 7.33 (m, 3H), 7.13 (dd, 2H, J = 7.6 and 16 Hz), 7.02 (td, 1H, J = 2 and 8 Hz), 3.89 (s, 2H), 3.86 (s, 2H), 3.50 (bs, 1H). ESI+MS: calcd for C14H13BrFN: 293.02; found: 293.9 (MH+) 101 3- 1-methyl-1H- N-(3- ESI+MS: calcd for 1 bromobenzylamine indole-2- bromobenzyl)(1- C17H17BrN2: 328.06; yellow solid carbaldehyde methyl-1H-indol-2- found: 328.9 (MH+) 27% yl)methanamine 102 3- acetophenone N-(3-bromobenzyl)- 1H NMR (CDCl3, 400 MHz): 1 bromobenzylamine 1- δ 7.47-7.18 (m, white solid phenylethanamine 9H), 3.94 (q, 1H, J = 6.4 Hz), 34% 3.75 (d, 1H, J = 13.2 Hz), 3.61 (d, 1H, J = 13.6 Hz), 1.55 (d, 3H, J = 6.4 Hz). 103 3- 1-(3- N-(3-bromobenzyl)- 1H NMR (CDCl3, 400 MHz); 1 bromobenzylamine bromophenyl)- 1-(3- δ 7.54-7.19 (m, white solid ethanone bromophenyl)- 8H), 3.87 (q, 1H, J = 6.8 Hz), 43% ethanamine 3.73 (d, 1H, J = 13.6 Hz), 3.60 (d, 1H, J = 13.6 Hz), 1.50 (d, 3H, J = 6.8 Hz). ESI+MS: calcd for C15H15Br2N: 366.96; found: 367.8 (MH+) 104 3- 1-(pyridin-2- N-(3-bromobenzyl)- 1H NMR (CDCl3, 400 MHz): 1 bromobenzylamine yl)ethanone 1-(pyridin-2- δ 8.63 (d, 1H, J = 4.4 Hz), colorless yl)ethanamine 7.75 (t, 2H, oil J = 2 and 8 Hz), 100% 7.47-7.18 (m, 5H), 4.21 (q, 1H, J = 6.8 Hz), 3.86 (d, 1H J = 13.2 Hz), 3.76 (d, 1H, J = 13.2 Hz), 1.58 (d, 3H, J = 6.8 Hz). ESI+MS: calcd for C14H15BrN2: 290.04; found: 291.0 (MH+) 105 3- quinuclidin-3- N-(3- 13C NMR (CDCl3, 1 bromobenzylamine amine bromobenzyl)- 100 MHz): δ 141.5, colorless quinuclidin-3-amine 131.0, 130.4, 130.1, oil 126.7, 122.6, 63.8, 63% 55.7, 53.4, 51.6, 50.6, 46.4, 46.2, 45.5, 45.3, 26.5, 24.2, 22.2, 17.4, 16.6. ESI+MS: calcd for C14H19BrN2: 294.07; found: 295.0 (MH+) 106 3- 9-Methyl-9- (1R*,5S*)-N-(3- 1H NMR (CDCl3, 1 bromobenzylamine azabicyclo[3.3.1]- bromobenzyl)bicyclo- 400 MHz): δ 7.66 (s, white solid nonan-3-one [3.3.1]nonan-9- 8 Hz), 7.47 (d, 1H, J = 8 Hz), 100% amine 7.26 (m, 1H,), 4.02 (s, 2H), 2.80 (s, 1H), 2.08 (m, 2H), 1.88-1.47 (m, 12H). 13C NMR (CDCl3, 100 MHz): δ 134.3, 133.0, 132.0, 130.4, 128.7, 122.7, 59.1, 47.7, 31.9, 29.2, 24.0, 21.3, 20.4. ESI+MS: calcd for C16H22BrN: 307.09; found: 308.0 (MH+) 107 3- 8-methyl-8-aza- N-(3-bromobenzyl)- 13C NMR (CDCl3, 1 bromobenzylamine bicyclo[3.2.1]- 8-methyl-8-aza- 100 MHz): δ 142.1, colorless octan-3-amine bicyclo[3.2.1]octan- 130.9, 130.2, 130.1, oil 3-amine 126.6, 122.6, 62.0, 100% 51.8, 49.0, 47.9, 46.3, 43.2, 24.9. ESI+MS: calcd for C15H21BrN2: 308.09; found: 309.0 (MH+) 108 3- 1-adamantyl N-(1-(3- 13C NMR (CDCl3, 1 bromobenzylamine methyl ketone bromophenyl)ethyl)- 100 MHz): δ 137.4, white solid adamantylamine 132.3, 131.4, 130.4, 84% 127.9, 122.7, 60.9, 49.4, 38.0, 37.7, 37.2, 36.7, 35.5, 28.3, 28.1. ESI+MS: calcd for C19H26BrN: 347.12; found: 348.0 (MH+) 109 3- noradamantyl- N-(3-fluorobenzyl)- ESI+MS: calcd for 1 fluorobenzylamine amine noradamantylamine C16H20FN: 245.16; 100% found: 246.09 (MH+)

The compounds of table A5 are prepared according to process A, adding a microwave heating step.

TABLE A5 Purification method/ appearance/ Compound Compound name Compound characteristics yield 138 N-(3-chlorobenzyl)adamantylamine 1H NMR (CDCl3, 400 MHz): δ 7.38 (s, 1H), 1 7.26 (m, 3H), 6.86 (bs, 1H), 3.82 (s, 2H), white solid 2.13 (s, 3H), 1.79-1.63 (m, 12H). 88% 13C NMR (CDCl3, 100 MHz): δ 139.2, 134.2, 129.7, 129.3, 127.8, 127.4, 53.9, 43.6, 40.7, 40.6, 36.2, 29.3. ESI+MS: calcd for C17H22CIN: 275.14; found: 276.1 (MH+) 139 N-(3-chlorobenzyl)-2-adamantylamine 1H NMR (CDCl3, 400 MHz): δ 7.47 (s, 1H), 1 7.41-7.28 (m, 3H), 3.99 (s, 2H), 2.97 (s, 1H), 2.13 (m, 4H), 1.87 (m, 4H), white solid 1.73-1.59 (m, 6H). 88% 13C NMR (CDCl3, 100 MHz): δ 135.3, 134.6, 130.1, 129.8, 128.8, 127.9, 60.8, 48.3, 37.3, 37.0, 30.6, 29.8, 27.1, 26.8. ESI+MS: calcd for C17H22ClN: 275.14; found: 276.2 (MH+) 140 N-(3-iodobenzyl)-2-adamantylamine 1H NMR (CDCl3, 400 MHz): δ 7.80 (s, 1H), 1 7.65 (d, 1H, J = 8 Hz), 7.49 (d, 1H, J = 7.2 Hz), white solid 7.11 (t, 1H, J = 7.6 Hz), 3.93 (s, 2H), 100% 2.94 (s, 1H), 2.15 (m, 4H), 1.89 (m, 4H), 1.73-1.59 (m, 6H). 13C NMR (CDCl3, 100 MHz): δ 138.6, 137.7, 135.7, 130.5, 129.0, 94.4, 60.9, 48.2, 37.3, 37.0, 30.6, 29.8, 27.1, 26.8. ESI+MS: calcd for C17H22IN: 367.08; found: 367.6 (MH+) 141 N-(2,2-diphenylethyl)-2- 1H NMR (CDCl3, 400 MHz): δ 7.73 (bs, 1 adamantylamine 1H), 7.29 (m, 10H), 4.57 (t, 1H, J = 7.6 Hz), white solid 3.48 (dd, 1H, J = 1.2 and 7.6 Hz), 100% 3.06 (s, 1H), 2.08 (s, 4H), 1.83 (m, 4H), 1.71-1.64 (m, 6H). 13C NMR (CDCl3, 100 MHz): δ 140.7, 129.0, 127.9, 127.3, 61.8, 49.5, 48.1, 37.0, 36.9, 30.5, 29.4, 26.9, 26.5. ESI+MS: calcd for C24H29N: 331.23; found: 331.9 (MH+) 142 N-(naphthalen-1-ylmethyl)-2- 1H NMR (CDCl3, 400 MHz): δ 8.14 (d, 1H, 1 adamantylamine J = 8.4 Hz), 7.88 (d, 1H, J = 8 Hz), white solid 7.84 (d, 1H, J = 8.4 Hz), 7.76 (bs, 1H), 7.68 (d, 100% 1H, J = 7.2 Hz), 7.59 (t, 1H, J = 7.2 Hz), 7.49 (m, 2H), 4.51 (s, 2H), 3.13 (s, 1H), 2.14 (m, 4H), 1.86 (m, 4H), 1.72-1.60 (m, 6H). 13C NMR (CDCl3, 100 MHz): δ 133.7, 131.7, 129.5, 129.2, 128.9, 128.8, 126.9, 126.0, 125.4, 122.9, 61.6, 46.1, 37.2, 37.0, 30.6, 30.1, 27.0, 26.8. ESI+MS: calcd for C21H25N: 291.2; found: 291.8 (MH+) 143 N-(phenanthren-9-ylmethyl)-2- 1H NMR (CDCl3, 400 MHz): δ 8.74 (m, 1H), 1 adamantylamine 8.65 (d, 1H, J = 8 Hz), 8.20 (bs, 1H), white solid 7.91 (m, 2H), 7.70-7.57 (m, 4H), 4.48 (s, 2H), 100% 3.14 (s, 1H), 2.14 (m, 2H), 2.05 (m, 2H), 1.87 (m, 4H), 1.74-1.60 (m, 6H). 13C NMR (CDCl3, 100 MHz): δ 131.0, 130.7, 130.5, 130.2, 129.8, 128.9, 127.9, 127.3, 127.2, 127.0, 126.9, 126.8, 123.7, 123.4, 122.4, 61.9, 46.8, 37.3, 37.1, 30.7, 30.2, 30.2, 27.1, 26.9. ESI+MS: calcd for C25H27N: 341.21; found: 341.8 (MH+) 144 4-((adamantylamino)methyl)benzoic 1H NMR (CDCl3, 400 MHz): δ 7.83 (d, 2H, 1 acid J = 8.4 Hz), 7.49 (d, 2H, J = 8 Hz), white solid 4.16 (s, 2H), 3.27 (s, 1H), 2.32-1.67 (m, 14H). 100% 13C NMR (CDCl3, 100 MHz): δ 170.4, 134.5, 133.5, 130.2, 129.8, 61.2, 48.2, 36.9, 36.7, 30.1, 29.0, 26.7, 26.5. ESI+MS: calcd for C18H23NO2: 285.17; found: 286.1 (MH+)

Process B: Formation of Acid Salts

A solution of HCl in Et2O (2N) is added to a solution of the amine (corresponding to the desired hydrochloride salt) in CH2Cl2. The salt is obtained after filtration and drying of the precipitate under vacuum.

TABLE B1 Salts derived from 1- or 2-aminoadamantane Purification method/ appearance/ Compound Compound name Compound characteristics yield 110 N-(3- 1H NMR (CDCl3, 400 MHz): δ 9.55 (bs, 1H), 1 bromobenzyl)adamantylamine 7.81 (s, 1H), 7.66 (d, 1H, J = 7.6 Hz), 7.39 (d, 1H, J = 8 Hz), white solid hydrochloride salt 7.23 (t, 1H, J = 8 Hz), 3.86 (t, 2H, J = 6 Hz), 2.12 (s, 3H), 1.95 (s, 5H), 1.65 (s, 4H), 1.55 (s, 3H). 111 N-(5-bromo-2- 1H NMR (CDCl3, 400 MHz): δ 8.94 (bs, 1H), 1 methoxybenzyl)adamantylamine 7.66 (d, 1H, J = 2.4 Hz), 7.38 (dd, 1H, J = 2.4 and 8.8 Hz), white solid hydrochloride salt 6.75 (d, 1H, J = 8.4 Hz), 3.91 (s, 5H), 2.13 (s, 3H), 1.89, 1.67 and 1.53 (3s, 12H). 13C NMR (DMSO-d6, 100 MHz): δ 155.7, 133.2, 131.8, 121.2, 111.2, 110.5, 56.1, 54.4, 36.6, 36.0, 34.1, 27.5. 112 N-(2-bromobenzyl)-2- 1H NMR (CDCl3, 400 MHz): δ 9.84 (bs, 1H), 1 adamantylamine hydrochloride 7.78 (s, 1H), 7.51 (dd, 1H, J = 2.4 and 10.8 Hz), white solid salt 7.30 (m, 2H), 4.18 (s, 2H), 3.05 (s, 1H), 2.48-1.55 (s, 14H). 13C NMR (CDCl3, 100 MHz): δ 1133.3, 132.5, 132.4, 130.7, 129.1, 122.8, 60.2, 47.4, 37.1, 36.7, 30.4, 29.0, 26.8, 26.6.

Process C

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.

TABLE C1 Compounds which are 1-aminoadamantane derivatives, prepared by process C starting from 1- adamantylamine Purification method/ Compound appearance/ Compound Aldehyde Compound name characteristics yield 113 3- (E)—N-(3- 1H NMR (DMSO, white solid bromobenzaldehyde bromobenzylidene)- 400 MHz): δ 8.30 (s, adamantylamine 1H), 7.94 (s, 1H), 7.74 (d, 1H, J = 7.6 Hz), 7.62 (d, 1H, J = 7.6 Hz), 7.40 (t, 1H, J = 7.6 Hz), 2.12 (s, 3H), 1.74-1.64 (m, 12H). 114 3-fluorobenzaldehyde (E)—N-(3- 1H NMR (DMSO, yellow solid fluorobenzylidene)- 400 MHz): δ 8.32 (s, 90% adamantylamine 1H), 7.59 (d, 1H, J = 8 Hz), 7.55-7.45 (m, 2H), 7.27 (m, 1H), 2.12 (s, 3H), 1.75-1.64 (m, 12H). 115 1-methyl-1H-indole-2- (E)—N-((1-methyl-1H-indol-2- 1H NMR (DMSO, brown solid carbaldehyde yl)methylene)adamantylamine 400 MHz): δ 8.41 (s, 55% 1H), 7.58 (d, 1H, J = 7.6 Hz), 7.46 (dd, 1H, J = 2.4 and 8.4 Hz), 7.23 (t, 1H, J = 7.6 Hz), 7.05 (t, 1H, J = 7.6 Hz), 6.86 (s, 1H), 4.09 (s, 3H), 2.12 (s, 3H), 1.77-1.64 (m, 12H). 13C NMR (CDCl3, 100 MHz): δ 147.8, 139.8, 136.4, 127.0, 126.9, 123.3, 121.3, 119.7, 109.6, 108.2, 57.8, 43.1, 36.6, 29.6. ESI+MS: calcd for C20H24N2: 292.19; found: 293.2 (MH+) 116 benzaldehyde (E)—N- 1H NMR (DMSO, brown solid benzylideneadamantylamine 400 MHz): δ 8.31 (s, 99% 1H), 7.75 (m, 2H), 7.42 (m, 3H), 2.12 (s, 3H), 1.75-1.64 (m, 12H).

TABLE C2 Compounds which are 2-aminoadamantane derivatives, prepared by process C starting from 2- adamantylamine Purification method/ Compound appearance/ Compound Aldehyde Compound name characteristics yield 117 3- (E)-N-(3- 1H NMR (CDCl3, white solid bromobenzaldehyde bromobenzylidene)- 400 MHz): δ 8.52 (bs, 60% adamantylamine 1H), 7.62 (s, 1H), 7.46 (d, 1H, J = 8 Hz), 7.38 (d, 1H, J = 8 Hz), 7.23 (d, 1H, J = 7.6 Hz), 3.52 (s, 1H), 2.23 (s, 5H), 1.96-1.66 (m, 9H). 118 3-fluorobenzaldehyde (E)-N-(3- 1H NMR (CDCl3, white solid fluorobenzylidene)- 400 MHz): δ 8.52 (bs, 74% adamantylamine 1H), 7.34 (m, 1H), 7.23 (d, 1H, J = 7.6 Hz), 7.18 (d, 1H, J = 9.6 Hz), 7.02 (dt, 1H, J = 2 and 8 Hz), 3.51 (s, 1H), 2.23 (s, 3H), 1.96-1.66 (m, 11H).

TABLE C3 Compounds prepared by process C starting from noradamantylamine Compound Compound Reactant 2 Compound name characteristics Yield 119 3- (E)—N-(3- 98% bromobenzaldehyde bromobenzylidene)- noradamantylamine 120 1-methyl-1H-indole-2- (E)—N-((1-methyl-1H-indol-2- 100% carbaldehyde yl)methylene)- noradamantylamine

Process E: Benzoylation

The 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.

TABLE D1 Compounds which are 1-aminoadamantane derivatives prepared by process E starting from 1- adamantylamine Purification method/ Compound Compound appearance/ number Reactant 2 Compound name characteristics yield 121 benzoyl chloride N-1-adamantylbenzamide 1H NMR (CDCl3, 400 MHz): δ 6 7.72 (dd, 2H, J = 1.2 and 7.2 Hz), white solid 7.46 (m, 3H), 5.79 (bs, 74% 1H), 2.13 (s, 9H), 1.73 (m, 6H). 13C NMR (CDCl3, 100 MHz): δ 166.6, 136.0, 131.0, 128.4, 126.7, 52.3, 41.7, 36.4, 29.5. 122 benzoyl chloride N-2-adamantylbenzamide 1H NMR (CDCl3, 400 MHz): δ 6 7.78 (dd, 2H, J = 1.6 and 6.8 Hz), white solid 7.49 (m, 3H), 6.42 (bs, 100% 1H), 4.27 (m, 1H), 2.06-1.55 (m, 14H). ESI+MS: calcd for C17H21NO: 255.16; found: 256.2 (MH+)

The sulfonylation is carried out according to the following process:

Et3N (138 μl; 1 mmol; 5 equiv.) and benzenesulfonyl chloride (76 μl; 0.6 mmol; 3 equiv.) are added to a solution of 1-adamantylamine hydrochloride or 2-adamantylamine hydrochloride (0.2 mmol; 1 equiv.) in CH2Cl2 (1 ml). The mixture is stirred at ambient temperature for 24 h, and hydrolyzed with NH4Cl. The organic phase is washed three times with water, dried over MgSO4, filtered and evaporated to give the expected product.

Preparation of N-1-adamantylsulfonamide (Compound 124)

Starting from 1-adamantylamine, the product obtained is a brown solid (86%).

1H NMR (CDCl3, 400 MHz): δ 7.91 (dd, 2H, J=1.6 and 7.2 Hz), 7.53 (m, 3H), 2.01 (s, 3H), 1.79 (m, 6H), 1.58 (m, 6H).

13C NMR (CDCl3, 100 MHz): δ 143.9, 132.0, 128.8, 126.8, 55.2, 43.0, 35.0, 29.4.

Preparation of N-2-adamantylsulfonamide (Compound 128)

Starting from 2-adamantylamine, the product obtained is a yellow solid (860).

1H NMR (CDCl3, 400 MHz): δ 7.89 (dd, 2H, J=1.9 and 7.2 Hz), 7.55 (m, 3H), 3.43 (s, 1H), 1.79-1.53 (m, 14H).

13C NMR (CDCl3, 100 MHz): δ 141.2, 132.3, 129.0, 126.8, 57.9, 37.3, 37.1, 32.7, 31.1, 26.8, 26.7.

Nucleophilic Addition

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;

or
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 Et2O, and filtered, and then the filtrate is evaporated.

This process makes it possible to prepare the following compounds:

Preparation of 1-adamantan-1-yl-3-phenylurea (Compound 129)

Starting from 1-adamantylamine and phenylisocyanate, a white solid is obtained (95%).

1H NMR (CDCl3, 400 MHz); δ 7.35 (m, 3H), 7.11 (m, 2H), 2.18 (s, 3H), 2.00 (s, 6H), 1.68 (s, 6H).

13C NMR (CDCl3, 100 MHz): δ 160.5, 138.7, 129.2, 123.7, 121.0, 51.5, 42.2, 36.3, 29.5. ESI+MS: calcd for C17H22N2O: 270.17. found: 271.1 (MH+).

Preparation of 1-adamantan-2-yl-3-phenylurea (Compound 132)

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 Et2O and filtered, and then the filtrate is evaporated.

A white solid is obtained (69%).

1H NMR (CDCl3, 400 MHz): δ 7.34 (m, 4H), 7.11 (t, 1H, J=6.8 Hz), 3.96 (s, 1H), 1.96 (s, 2H), 1.84-1.61 (m, 12H).

ESI+MS: calcd for C17H22N2O: 270.17. found: 271.1 (MH+).

The process which follows makes it possible to prepare the compounds below: 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 CH2Cl2 (4 ml). The mixture is stirred for 24 h at ambient temperature, washed with water, placed in a saturated solution of NH4Cl, dried over Na2SO4, filtered, evaporated and short-pad-purified.

Preparation of adamantan-1-ylcarbamic acid phenyl ester (Compound 123)

Starting from 1-adamantylamine and phenyl chloroformate, a white solid is obtained (13%).

1H NMR (CDCl3, 400 MHz): δ 7.35 (t, 2H, J=8 Hz), 7.18 (t, 1H, J=7.2 Hz), 7.12 (d, 2H, J=7.6 Hz), 4.88 (bs, 1H), 2.11 (s, 3H), 2.01 (s, 6H), 1.69 (s, 6H).

13C NMR (CDCl3, 100 MHz): δ 150.9, 129.1, 125.0, 121.7, 51.2, 41.7, 36.3, 29.4.

ESI+MS: calcd for C17H21NO2: 271.16. found: 272.1 (MH+).

Preparation of adamantan-2-ylcarbamic acid phenyl ester (Compound 126)

Starting from 2-adamantylamine hydrochloride and phenyl chloroformate, a white solid is obtained (17%).

1H NMR (CDCl3, 400 MHz): δ 7.36 (t, 2H, J=7.6 Hz), 7.20 (t, 1H, J=7.6 Hz), 7.14 (d, J=8 Hz), 5.36 (bs, 1H), 3.88 (s, 1H), 2.03 (s, 2H), 1.87-1.67 (m, 12H).

13C NMR (CDCl3, 100 MHz): δ 129.2, 125.1, 121.5, 114.9, 55.1, 37.4, 37.0, 32.0, 31.7, 27.1, 27.0.

ESI+MS: calcd for C17H21NO2: 271.16. found: 272.1 (MH+).

Preparation of N-adamantan-1-yl-N-(3-bromobenzyl)benzamide (Compound 125)

Benzoyl chloride (0.47 mmol; 55 μl; 3 equiv.) and triethylamine (109 μl; 5 equiv.) are added, at ambient temperature, to a stirred suspension of 1-adamantylamine (0.156 mmol; 50 mg; 1 equiv.) in CH2Cl2 (3 ml). The mixture is stirred for 24 h at ambient temperature, washed with water, placed in a saturated solution of NH4Cl, dried over Na2SO4, filtered, evaporated and short-pad-purified.

Starting from acetyl chloride, a colorless oil is obtained (26%).

1H NMR (CDCl3, 400 MHz): δ 7.39 (dd, 1H, J=1.2 and 10.8 Hz), 7.25 (t, 1H, J=7.6 Hz), 7.17 (d, 1H, J=7.6 Hz), 4.58 (s, 2H), 2.20 (s, 6H), 2.07 (s, 6H), 1.63 (m, 6H).

13C NMR (CDCl3, 100 MHz): δ 172.2, 142.2, 130.3, 130.1, 128.7, 124.2, 123.0, 59.3, 48.0, 39.9, 36.3, 30.1, 25.7.

ESI+MS: calcd for C19H24BrNO: 361.10. found: 362.0 (MH+).

Preparation of 1-adamantan-1-yl-1-(3-bromobenzyl)-3-phenylurea (Compound 131)

Phenylisocyanate (19 μl; 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.

Starting from phenylisocyanate, a colorless oil is obtained (51%).

1H NMR (CDCl3, 400 MHz): δ 7.52-6.98 (m, 9H), 6.13 (bs, 1H), 4.64 (s, 2H), 2.25 (s, 6H), 2.11 (s, 3H), 1.68 (m, 6H).

13C NMR (CDCl3, 100 MHz): δ 156.5, 141.1, 138.9, 130.8, 130.6, 128.9, 128.7 124.2, 123.4, 122.9, 120.0, 58.2, 47.2, 40.4, 36.3, 30.1.

ESI+MS: calcd for C24H27BrN2O: 438.13. found: 439.0 (MH+).

Preparation of N=adamantan-2-yl-N-(3-bromobenzyl)benzamide (Compound 127)

Benzoyl chloride (0.47 mmol; 55 μl; 3 equiv.) and triethylamine (109 μl; 5 equiv.) are added, at ambient temperature, to a stirred suspension of 2-adamantylamine (0.156 mmol; 50 mg; 1 equiv.) in CH2Cl2 (2 ml). The mixture is stirred for 24 h at ambient temperature, washed with water, placed in a saturated solution of NH4Cl, dried over Na2SO4, filtered, evaporated and short-pad-purified.

Starting from benzoyl chloride, a white oil is obtained (17%).

1H NMR (CDCl3, 400 MHz): δ 7.43 (m, 2H), 7.35 (m, 4H), 7.19 (s, 1H), 7.16 (t, 1H, J=8 Hz), 7.05 (d, 1H, J=7.6 Hz), 4.78 (s, 2H), 4.17 (s, 1H), 2.32 (s, 2H), 2.02-1.66 (m, 12H).

13C NMR (CDCl3, 100 MHz): δ 175.4, 142.1, 137.8, 130.2, 130.0, 129.7, 128.8, 128.4, 127.1, 124.2, 122.8, 60.2, 49.5, 38.0, 37.4, 32.8, 30.0, 27.3, 26.9.

ESI+MS: calcd for C24H26BrNO: 423.12. found: 424.8 (MH+).

Synthesis by Click Chemistry

Et3N (0.83 mmol: 1.1 equiv.), phenylacetylene (0.83 mmol; 1.1 equiv.) or ethynylpyridine (0.83 mmol; 1.1 equiv.), and the 1-adamantylamine-derived azide (0.75 mmol; 1 equiv.) are added to a suspension of Cu/C (50 mg) in 1,4-dioxane (1.5 ml). The mixture is stirred at 60° C. for 2 days, filtered through a short pad, washed with EtOAc and then evaporated. This process makes it possible to prepare the following compounds:

Preparation of 1-adamantan-1-yl-4-phenyl-1H[1,2,3]triazole (Compound 145)

Starting from 1-azidoadamantane and phenylacetylene, a brown oil is obtained (96%).

1H NMR (CDCl3, 400 MHz): δ 7.84 (dd, 3H, J=1.2 and 8.4 Hz), 7.42 (t, 2H, J=8 Hz), 7.32 (t, 1H, J=7.2 Hz), 2.30 (s, 9H), 1.82 (s, 6H), 1.43 (m, 4H).

13C NMR (CDCl3, 100 MHz): δ 146.5, 140.0, 128.6, 127.6, 125.4, 116.0, 59.4, 42.8, 35.7, 29.3.

ESI+MS: calcd for C18H21N3: 279.17. found: 280.2 (MH+).

Preparation of 1-adamantan-1-ylmethyl-4-phenyl-1H[1,2,3]triazole (Compound 146)

Starting from 1-azidomethyladamantane and phenylacetylene, a brown oil is obtained (68%).

1H NMR (CDCl3, 400 MHz): δ 7.86 (dd, 2H, J=1.2 and 8.4 Hz), 7.68 (s, 1H), 7.44 (t, 2H, J=7.2 Hz), 7.34 (t, 1H, J=7.6 Hz), 4.08 (s, 2H), 2.02 (s, 3H), 1.58 (m, 12H).

13C NMR (CDCl3, 100 MHz): δ 147.0, 130.7, 128.7, 127.9, 125.6, 120.9, 62.2, 40.2, 36.4, 34.1, 28.0.

ESI+MS: calcd for C19H23N3: 293.19. found: 294.2 (MH+).

2-(1-adamantan-1-yl-1H[1,2,3]triazol-4-yl)pyridine (Compound 147)

Starting from 1-azidoadamantane and 2-ethynylpyridine, a brown oil is obtained (39%).

1H NMR (CDCl3, 400 MHz): δ 8.58 (d, 1H, J=4.4 Hz), 8.22 (m, 2H), 7.79 (t, 1H, J=7.6 Hz), 7.23 (t, 1H, J=6 Hz), 230 (s, 8H), 1.81 (m, 7H).

13C NMR (CDCl3, 100 MHz): δ 150.7, 149.2, 147.3, 136.9, 122.6, 120.1, 118.6, 59.8, 42.9, 35.9, 29.4.

ESI+MS: calcd for C17H20N4: 280.17. found: 281.2 (MH+).

Imidazolines and Oxazoline

Potassium carbonate (415 mg; 3 mmol; 3 equiv.) and iodine (635 mg; 2.5 mmol; 2.5 equiv.) are added to a solution of 1-adamantanemethanol (166 mg; 1 mmol) in tert-butanol (8 ml). The mixture is stirred at 70° C. for 16 h and the amine (1.5 equiv.) diluted in tert-butanol is added. The mixture is refluxed at 70° C. for 2 h, diluted with a saturated solution of Na2SO3 (5 ml), and extracted with chloroform (20 ml). The organic phases are washed with 2N NaOH (20 ml) and brine (20 ml), dried over Na2SO4, filtered and evaporated.

Preparation of 2-adamantan-1-yl-4,5-dihydro-1H-imidazole (Compound 134)

Starting from 1-adamantanemethanol and ethylenediamine, a colorless oil is obtained (66%).

1H NMR (CDCl3, 400 MHz): δ 3.59 (s, 4H), 2.04 (s, 3H), 1.89 (s, 6H), 1.73 (m, 6H).

Preparation of 2-adamantan-1-yl-4,5-dihydrooxazole (Compound 135)

Starting from 1-adamantanemethanol and 2-aminoethanol, a colorless oil is obtained (2.4%).

1H NMR (CDCl3, 400 MHz): δ 4.23 (t, 2H, J=9.6 Hz), 3.83 (t, 2H, J=9.6 Hz), 2.02 (s, 3H), 1.91 (s, 6H), 1.73 (m, 6H).

Preparation of 2-adamantan-1-yl-1-phenyl-4,5-dihydro-1H-imidazole (Compound 136)

Starting from 1-adamantanemethanol and N-phenylethylenediamine, a yellow oil is obtained (15%).

1H NMR (CDCl3, 400 MHz): δ 7.40-7.18 (m, 5H), 3.82 (t, 2H, J=9.1 Hz), 3.68 (t, 2H, J=9.6 Hz), 1.85 (s, 3H), 1.81 (s, 6H), 1.54 (m, 6H).

13C NMR (CDCl3, 7100 MHz): δ 172.0, 145.0, 129.2, 127.1, 58.2, 52.1, 40.5, 37.5, 36.4, 28.2.

ESI+MS: calcd for C19H24N2: 280.19. found: 281.2 (MH+).

Preparation of 2-adamantan-1-yl-4,5-dicyclohexyl-4,5-dihydro-1H-imidazole (Compound 137)

Starting from 1-adamantanemethanol and (1R,2R)-1,2-cyclohexanediamine, a yellow oil is obtained (10%).

1H NMR (CDCl3, 400 MHz): δ 4.67 (bs, 1H), 2.84 (bs, 2H), 2.03 (s, 3H), 1.87 (s, 6H), 1.72 (m, 6H).

ESI+MS: calcd for C17H26N2: 258.21. found: 259.2 (MH+).

The synthesis of the amine compounds requires the prior preparation of the following synthesis intermediate:

  • 2-amino-N-phenylbenzamide

2-nitro-N-phenylbenzamide (1 eq., 5 mmol, expected m=1.06 g) is dissolved in 12 ml of methanol. A few drops of acetic acid are added to the reaction medium. Decaborane (0.3 eq., 1.5 mmol, 183 mg) is then added, with palladium on carbon (100 mg, 10% of the mass of the 2-nitro-N-phenylbenzamide). After 3 hours at reflux, the mixture is filtered and then purified by silica chromatography (cyclohexane/ethyl acetate in 70:30 proportions), which gives the compound 2-amino-N-phenylbenzamide with a yield of 88% (933 mg).

1H NMR (400 MHz, DMSO d5)

δ: 9.95 (s, 1H, NH), 7.70-7.68 (d, J=7.6 Hz, 2H, HAr 2′), 7.62-7.59 (d, J=8 Hz, 1H, HAr 3), 7.33-7.29 (t, J=7.6 Hz, 2H, HAr 3′), 7.20-7.16 (t, J=8.4 Hz, 1H, HAr 4), 7.08-7.04 (t, J=7.2 Hz, 1H, HAr 4′), 6.75-6.73 (d, J=8.4 Hz, 11-4, HAr 6), 6.60-6.56 (t, J=8 Hz, 1H, HAr 5), 6.29 (2H, NH2).

MS (ES) m/z 213 (M+H+), 120.

Preparation of 2-(3-bromobenzylideneamino)-N-phenylbenzamide (Compound 149)

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 μl, 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.

1H NMR (400 MHz, DMSO d6) δ: 8.40 (s, 1H, CH), 7.70-6.60 (m, 13H, HAr),

Preparation of 2-(3-fluorobenzylideneamino)-N-phenylbenzamide (Compound 151)

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 μl, 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.

1H NMR (400 MHz, DMSO d6) δ: 9.43 (s, 1H, CH), 7.62-6.72 (m, 13H, HAr).

Amination

DCC (10.9 g; 52.7 mmol; 1.1 equiv.), DMAP (1.17 g, 9.6 mmol, 0.2 equiv.) and aniline (6.1 ml; 67.1 mmol; 1.4 equiv.) are added, at ambient temperature, to a solution of nitro acid (8 g; 47.9 mmol; 1 equiv.) in CH2Cl2 (100 ml). The mixture is stirred for 4 days and evaporated. The solid is then solubilized in acetone and then filtered.

The brown filtrate is evaporated, to give a brown solid which is washed with Et2O to give 2-nitro-N-phenylbenzamide in the form of an orange solid (11.6 g; 71%).

Furthermore, palladium on carbon (550 mg) and decaborane (757 mg, 6.2 mmol; 0.3 equiv.) are added, at ambient temperature, to a solution of 2-nitro-N-phenylbenzamide (5 g; 20.7 mmol; 1 equiv.) in MeOH (65 ml). The mixture is heated at 60° C. for 6 h, filtered through celite, washed with EtOAc and evaporated to give 2-amino-N-phenylbenzamide (brown solid, 4.2 g; 96%), which is used without purification.

An aldehyde (0.2 mmol; 1 equiv.) is added to a solution of 2-amino-N-phenylbenzamide (42 mg; 0.2 mmol; 1 equiv.) in MeOH (2 ml), and the mixture is stirred for 2 days at ambient temperature, evaporated, and purified by a suitable method if necessary.

This process makes it possible to prepare the following compounds:

Preparation of (E)-2-((furan-2-yl)methyleneamino)-N-phenylbenzamide (Compound 152)

Starting from furan-2-carbaldehyde, a yellow solid is obtained (99%).

1H NMR (CDCl3, 400 MHz): δ 8.02 (dd, 1H, J=1.2 and 8 Hz), 7.40-7.24 (m, 7H), 6.91 (t, 1H, J=8 Hz), 6.70 (d, 1H, J=8 Hz), 6.33 (d, 1H, J=3.2 Hz), 6.25 (dd, 1H, J=2 and 3.2 Hz), 6.06 (d, 1H, J=2 Hz), 4.94 (bs, 1H).

13C NMR (CDCl3, 100 MHz): δ 162.6, 152.2, 145.1, 142.6, 140.6, 133.7, 128.9, 128.8, 126.7, 126.1, 119.7, 117.1, 115.1, 110.3, 109.0, 68.4.

ESI+MS: calcd for C18H14N2O2: 290.11. found: 291.1 (MH+).

Preparation of (E)-2-((5-methylfuran-2-yl)methyleneamino)-N-phenylbenzamide (Compound 154)

Starting from 5-methylfuran-2-carbaldehyde, a yellow solid is obtained (1000).

ESI+MS: calcd for C19H16N2O2: 304.12. found: 305.0 (MH+).

Preparation of (E)-2-((furan-3-yl)methyleneamino)-N-phenylbenzamide (Compound 153)

Starting from furan-3-carbaldehyde, a yellow solid is obtained (970).

1H NMR (CDCl3, 400 MHz): δ 8.02 (d, 1H, J=7.6 Hz), 7.39-7.23 (m, 7H), 6.93 (t, 1H, J=7.6 Hz), 6.70 (d, 1H, J=8 Hz), 6.28 (s, 1H), 6.04 (s, 1H), 4.70 (bs, 1H).

13C NMR (CDCl3, 100 MHz): δ 162.7, 145.5, 143.6, 140.8, 140.4, 133.8, 129.0, 128.9, 126.9, 126.7, 125.5, 119.7, 117.1, 115.2, 108.7, 67.7.

ESI+MS: calcd for C18H14N2O2: 290.11. found: 291.1 (MH+).

Preparation of (E)-2-(2-fluorobenzylideneamino)-N-phenylbenzamide (Compound 157)

Starting from 2-fluorobenzaldehyde, a yellow solid is obtained (53%).

ESI+MS: calcd for C20H15FN2O: 318.12. found: 319.1 (MH+).

Preparation of (E)-2-(3-bromobenzylideneamino)-N-phenylbenzamide (Compound 151)

Starting from 3-fluorobenzaldehyde, a yield of 100% is obtained.

ESI+MS: calcd for C20H15FN2O: 318.12. found: 319.1 (MH+).

Preparation of (E)-2-(3-fluorobenzylideneamino)-N-phenylbenzamide (Compound 149)

Starting from 3-bromobenzaldehyde, a yield of 100% is obtained.

1H NMR (DMSO-d6, 400 MHz): δ 8.40 (s, 1H), 7.70-6.60 (m, 13H, H).

Preparation of (E)-2-(4-fluorobenzylideneamino)-N-phenylbenzamide (Compound 156)

Starting from 4-fluorobenzaldehyde, a yellow oil is obtained (8%).

Purification Mode: Short Pad

1H NMR (DMSO d6, 400 MHz): δ 9.43 (s, 1H), 7.62-632 (m, 13H) ESI+MS: calcd for C20H15BrN2O: 318.12. found: 319.2 (MH+).

Preparation of (E)-2-(5-fluoro-2-nitrobenzylideneamino)-N-phenylbenzamide (Compound 155)

Starting from 5-fluoro-2-nitrobenzaldehyde, a yellow oil is obtained (2.9%).

Purification Mode: Short Pad

ESI+MS: calcd for C20H14FN3O3: 363.34. found: 364.1 (MW).

Preparation of (E)-2-(5-bromo-2-hydroxybenzylideneamino)-N-phenylbenzamide (Compound 159)

Starting from 5-bromo-2-hydroxybenzaldehyde, a yellow oil is obtained (92%).

ESI+MS: calcd for C20H15BrN2O2: 394.03. found: 395.0 (MH+).

Preparation of (E)-2-((1-methyl-1H-indol-2-yl)methyleneamino)-N-phenylbenzamide (Compound 158)

Starting from 1-methyl-1H-indole-2-carbaldehyde, a yellow oil is obtained (12%).

Purification Mode: Short Pad

ESI+MS: calcd for C23H19N3O: 353.15. found: 354.2 (MH+).

Reductive Amination

Preparation of 2-(3-bromobenzylamino)-N-phenylbenzamide (Compound 150)

Starting from (E)-2-(3-fluorobenzylideneamino)-N-phenylbenzamide.

Yield=100%.

Preparation of 2-(2-fluorobenzylamino)-N-phenylbenzamide (Compound 160)

Starting from (E)-2-(2-fluorobenzylideneamino)-N-phenylbenzamide, a colorless oil is obtained (1%).

Purification Mode: Short Pad

ESI+MS: calcd for C20H17FN2O: 320.13. found: 321.0 (MH+).

Benzodiazepines

The synthesis of the compounds of general formula (II) requires the prior preparation of the following synthesis intermediates:

  • tert-butyl N-[(phenylcarbamoyl)methyl]carbamate

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) is then added in small portions. Finally, aniline (1.4 eq., 8.0 mmol, 0.73 ml) is added at ambient temperature. After two days at ambient temperature, the content of the round-bottom flask is filtered and then evaporated. Silica gel column purification (mixture of ethyl acetate/N-hexane in a gradient of 50:50 to 80:20) makes it possible to obtain 740 mg of purified tert-butyl N-[(phenylcarbamoyl)-methyl]carbamate (51%).

1H NMR (400 MHz, CDCl3)

δ: 9.89 (s, 1H, NH), 7.57-7.55 (d, J=7.6 Hz, 2H, HAr), 7.30-7.26 (t, J=7.6 Hz, 2H, HAr), 7.02-7.00 (d, J=7.2 Hz, 1H, HAr), 5.19 (s, 1H, NH), 3.70-3.69 (d, J=6 Hz, 2H, CH2), 1.38 (s, 9H, (CH3)3)

MS (ES) m/z 251 (M+H+), 195, 151, 94.

  • tert-butyl (4-methoxyphenylcarbamoyl)methylcarbamate

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) is then added in small portions. Finally, para-anisidine (1.4 eq., 10 mmol, 1.23 g) is added at ambient temperature. After two days at ambient temperature, the content of the round-bottom flask is filtered and then evaporated. 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%).

1H NMR (400 MHz, CDCl3)

δ: 9.74 (s, 1H, NH), 7.48-7.45 (d, J=9.2 Hz, 2H, HAr), 7.00 (s, 1H, NH), 6.87-6.84 (d, J=8.8 Hz, 2H, HAr), 3.70 (s, 3H, OCH3), 3.67-3.66 (d, J=6 Hz, 2H, CH2), 1.38 (s, 9H, (CH3)3).

MS (ES) m/z 281 (M+H+), 225, 181, 124.

  • 2-amino-N-phenylacetamide

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.

MS (ES) m/z 151 (M+H+), 94.

  • 2-amino-N-(4-methoxyphenyl)acetamide

The tert-butyl (4-methoxyphenylcarbamoyl)methylcarbamate compound (1 eq., 3 mmol, 540 mg) is dissolved in a 2:1 mixture of dichloromethane/trifluoroacetic acid. After one hour, methoxyphenyl)acetamide is quantatively obtained after evaporation and used directly in Pictet-Spengler reaction tests.

MS (ES) m/z 181 (M+H+), 124.

  • 2-benzoyl-4-bromoaniline

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.

1H NMR (400 MHz, CDCl3)

δ: 7.64-7.63 (d, J=7.2 Hz, 2H, 2′), 7.56 (s, 1H, 6), 7.55-7.54 (d, J=2.4 Hz, 1H, 4′), 7.50-7.47 (t, J=7.6 Hz, 2H, 3′), 7.38-7.35 (q, J=8.8-2.4 Hz, 1H, 4), 6.66-6.64 (d, J=8.4 Hz, 1H, 3), 6.09 (s, 2H, NH2).

MS (ES) m/z 276 (M+H+), 198, 105.

Preparation of 4,5-dihydro-7-methoxy-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (Compound 167)

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 μl) 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%.

1H NMR (400 MHz, CDCl3)

δ: 7.50-6.60 (m, 8H, HN), 6.44 (s, 1H, NH), 5.30 (s, 1H, CH), 3.82-3.72 (dd, J=10 et 15.6 Hz, 2H, CH2), 3.73 (s, 3H, OCH3), 3.49 (s, 1H, NH).

MS (ES) m/z 269 (M+Hf), 222, 204, 145, 106.

Preparation of 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (Compound 162)

In a round-bottomed flask fitted with a Dean-Stark apparatus and a condenser, aminobenzophenone (2.85 eq., 5 mmol, 1.0 g) is dissolved in 15 ml of pyridine containing 4Δ 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. After an overnight period at 110° C., the pyridine is evaporated off, while adding 10 ml of toluene, and the residue is then dissolved in 30 ml of dichloromethane and 30 ml of 2.5% Na2CO3. The combined organic phases are washed with a saturated solution of sodium chloride and then dried with anhydrous Na2SO4 and, finally, evaporated to give the crude product. Purification on a silica gel column (mixture of dichloromethane/acetone in a concentration gradient of from 95:5 to 80:20) makes it possible to obtain 217 mg of purified product 161, i.e. a yield of 52.5%.

1H NMR (400 MHz, CDCl3)

δ: 8.45 (s, 1H, NH), 7.64-7.26 (m, 9H, HAr), 4.34 (s, 2H, CH2).

MS (ES) m/z 237 (M+H+).

Preparation of 7-chloro-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (Compound 170)

In a round-bottomed flask fitted with a Dean-Stark apparatus and a condenser, 4-chloro-2-aminobenzophenone (2.85 eq., 5 mmol, 1.16 g) is dissolved in 15 ml of pyridine containing 4 Å molecular sieve. Methyl glycinate hydrochloride (1 eq., 1.75 mmol, 220 mg) is then added, and the mixture is then brought to reflux for 3 hours. After an overnight period at 110° C., the pyridine is evaporated off, while adding 10 ml of toluene, and the residue is then dissolved in 30 ml of dichloromethane and 30 ml of 2.5% Na2CO3. The combined organic phases are washed with a saturated solution of sodium chloride, then dried with anhydrous Na2SO4 and, finally, evaporated to give the crude product. Purification on a silica gel column (mixture of cyclohexane/ethyl acetate in a gradient of from 90:10 to 50:50) makes it possible to obtain 80 mg of product 170 (17%).

1H NMR (400 MHz, CDCl3)

δ: 9.42 (s, 1H, NH), 7.78-7.16 (m, 8H, HAr), 4.33 (s, 2H, CH2).

MS (ES) m/z 271 (M+H+).

Preparation of 7-bromo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (Compound 163)

In a round-bottomed flask fitted with a Dean-Stark apparatus and a condenser, 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. After an overnight period at 110° C., the pyridine is evaporated off, while adding 5 ml of toluene, and the residue is then dissolved in 20 ml of dichloromethane and 20 ml of 2.5% Na2CO3. The combined organic phases are washed with a saturated solution of sodium chloride, then dried over anhydrous Na2SO4 and, finally, evaporated to give the crude product. Purification on a silica gel column (mixture of cyclohexane/ethyl acetate in a concentration gradient of from 90:10 to 50:50) makes it possible to obtain 100 mg of product 163, i.e. 26%.

1H NMR (400 MHz, CDCl3)

δ: 9.26 (s, 1H, NH), 7.90-7.32 (m, 8H, HAr), 4.37 (s, 2H, CH2).

MS (ES) m/z 315 (M+H+).

Preparation of 5-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one (Compound 169)

Compound 162 (1 eq., 0.42 mmol, 100 mg) is dissolved in 2 ml of methanol. The reducing agent on polymer beads (3 eq., 1.27 mmol, loading: 4.4 mmol/g, 290 mg) is added, as are a few drops of acetic acid (50 μl). The reaction takes place at ambient temperature for 3 days. After filtration and then evaporation, 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 169 is obtained with a yield of 60%.

1H NMR (400 MHz, CDCl3)

δ: 9.12 (s, 1H, NH), 7.35-6.67 (m, 9H, HAr), 5.21 (s, 1H, CH), 3.35-3.25 (q, J=10−14.8 Hz, 2H, CH2), 3.21 (s, 1H, NH).

MS (ES) m/z 239 (M+H+), 182, 132, 91.

Preparation of 7-chloro-5-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one (Compound 171)

Compound 170 (1 eq., 0.22 mmol, 60 mg) is dissolved in 2 ml of methanol. The reducing agent on polymer beads (3 eq., 0.66 mmol, loading: 4.4 mmol/g, 150 mg) is added, as are a few drops of acetic acid (50 μl). The reaction takes place at ambient temperature for 5 days. After filtration and then evaporation, 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 171 is obtained with a yield of 55%.

1H NMR (400 MHz, CDCl3)

δ: 9.15 (s, 1H, NH), 7.40-6.86 (m, 8H, HAr), 5.20 (s, 1H, CH), 3.45-3.36 (q, J=10-13.6 Hz, 2H, CH2), 3.10 (s, 1H, NH).

MS (ES) m/z 273 (M+H+), 221, 91.

Preparation of 7-bromo-5-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one (Compound 164)

Compound 163 (1 eq., 0.25 mmol, 80 mg) is dissolved in 2 ml of methanol. The reducing agent on polymer beads (3 eq., 0.75 mmol, loading: 4.4 mmol/g, 170 mg) is added, as are a few drops of acetic acid (50 μl). The reaction takes place at ambient temperature for 3 days. After filtration and then evaporation, 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%.

1H NMR (400 MHz, CDCl3)

δ: 8.48 (s, 1H, NH), 7.52-6.86 (m, 8H, HAr), 5.18 (s, 1H, CH), 3.45-3.35 (q, J=10-14.8 Hz, 2H, CH2), 2.86 (s, 1H, NH).

MS (ES) m/z 317 (M+H+), 91.

Preparation of 4-phenyl-2,3-dihydro-1H-1,5-benzodiazepin-2-one (Compound 165)

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 Na2SO4 and then evaporated. Purification on a silica gel column (70:30 cyclohexane/ethyl acetate) makes it possible to obtain 325 mg of 165, i.e. a yield of 69%.

1H NMR (400 MHz, CDCl3)

δ: 12.88 (s, 1H, NH), 8.17-6.64 (m, 9H, HAr), 5.50 (s, 2H, CH2).

MS (ES) m/z 237 (M+H+), 195.

Preparation of 4-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one (Compound 166)

Compound 165 (1 eq., 0.42 mmol, 100 mg) is dissolved in 2 ml of methanol. The reducing agent on polymer beads (3 eq., 1.27 mmol, loading: 4.4 mmol/g, 290 mg) is added, as are a few drops of acetic acid (50 μl). The reaction takes place at ambient temperature for 3 days. After filtration then evaporation, 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 166 is obtained with a yield of 77%.

The second process that follows also allows the synthesis of compound 166: 1,2-diaminobenzene (1 eq., 10 mmol, 1.08 g) is mixed with cinnamic acid (1 eq., 10 mmol, 1.48 g) in a pill bottle flask. The reaction mixture is then heated at 150° C. without solvent for two hours. The residue is diluted in dichloromethane and a 5% Na2CO3 solution. The organic phase is extracted several times with the Na2CO3 solution, and then with a saturated solution of sodium chloride. Finally, the solution is dried with Na2SO4 and then evaporated.

Purification on a silica gel column (cyclohexane/ethyl acetate in a gradient of from 80:20 to 1:1) makes it possible to isolate 166 with a yield of 12% (286 mg).

1H NMR (400 MHz, CDCl3)

δ: 9.15 (s, 1H, NH), 7.40-6.72 (m, 9H, HAr), 5.76 (s, 1H, NH), 4.91-4.89 (m, 1H, CH), 2.54-2.52 (d, J=6 Hz, 2H, CH2).

MS (ES) m/z 239 (M+H+), 197, 131.

Preparation of ethyl 4-oxo-2-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-carboxylate (Compound 168)

Compound 166 (1 eq., 0.218 mmol, 52 mg) is dissolved with ethyl chloroformate (1.2 eq., 0.262 mmol, 25 μl) in a solution composed of dichloromethane and triethylamine in 10:1 proportions. After two hours at ambient temperature, the content of the pill bottle flask is evaporated. Purification on a silica gel column (cyclohexane/ethyl acetate in a gradient of from 90:10 to 1:1) makes it possible to isolate 15 mg of 168, i.e. a yield of 21%.

1H NMR (400 MHz, CDCl3)

δ: 9.10 (s, 1H, NH), 7.62-6.72 (m, 9H, HAr), 5.10 (s, 1H, CH), 4.24 (m, 2H, CH2), 2.62-2.61 (d, J=6 Hz, 2H, CH2), 1.46 (t, J=8 Hz, 3H, CH3).

MS (ES) m/z 311 (M+H+), 269, 207, 135.

Synthesis of benzo[b][1,4]diazepines

A β-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 Et2O to give the desired compound.

Starting from benzene-1,2-diamine:

Preparation of (E)-4-m-tolyl-1H-benzo[b][1,4]diazepin-2(3H)-one (Compound 176)

Starting from ethyl 3-oxo-3-m-tolylpropanoate, a brown solid is obtained (31%).

1H NMR (CDCl3, 400 MHz): δ 7.94 (s, 1H), 7.91 (d, 1H, J=8 Hz), 7.69 (bs, 1H), 7.54 (d, 1H, J=8.8 Hz), 7.38 (t, 1H, J=7.6 Hz), 7.31 (m, 2H), 7.05 (dd, 1H, J=1.6 and 7.6 Hz), 3.59 (s, 2H), 2.45 (s, 3H).

ESI+MS: calcd for C16H14N2O: 250.11. found: 250.1 (MH+).

Preparation of (E)-4-(3-methoxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (Compound 177)

Starting from ethyl 3-(3-methoxyphenyl)-3-oxopropanoate, a brown solid is obtained (20%).

1H NMR (CDCl3, 400 MHz): δ 7.68 (m, 3H), 7.55 (dd, 1H, J=2 and 8 Hz), 7.40 (t, 1H, J=8.4 Hz), 7.28 (m, 1H), 7.06 (dt, 2H, J=2.8 and 8 Hz), 3.91 (s, 3H), 3.58 (s, 2H).

13C NMR (CDCl3, 100 MHz): δ 167.3, 159.9, 158.8, 139.8, 138.9, 129.7, 128.9, 128.3, 126.5, 125.2, 121.6, 120.4, 117.7, 112.2, 55.5, 39.9.

ESI+MS: calcd for C16H14N2O2: 266.11. found: 267.0 (MH+).

Preparation of (E)-4-(3-nitrophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (Compound 178)

Starting from ethyl 3-(3-nitrophenyl)-3-oxopropanoate, a brown solid is obtained (23%).

1H NMR (CDCl3, 400 MHz): δ 9.00 (t, 1H, J=2 Hz), 8.40 (d, 1H, J=8 Hz), 8.35 (dd, 1H, J=1.6 and 8 Hz), 7.73 (bs, 1H), 7.68 (t, 1H, J=8.4 Hz), 7.55 (m, 1H), 7.32 (m, 2H), 7.09 (m, 1H), 3.62 (s, 2H).

ESI+MS: calcd for C15H11N3O3: 281.08. found: 282.0 (MH+).

Preparation of (E)-4-(3-chlorophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (Compound 179)

Starting from ethyl 3-(3-chlorophenyl)-3-oxopropanoate, a brown solid is obtained (15%).

1H NMR (CDCl3, 400 MHz): δ 8.14 (t, 1H, J=1.6 Hz), 7.96 (d, 1H, J=7.6 Hz), 7.76 (bs, 1H), 7.53-7.41 (m, 3H), 7.29 (m, 2H), 7.07 (dd, 1H, J=1.2 and 6.8 Hz), 3.56 (s, 2H).

13C NMR (CDCl3, 100 MHz): δ 167.1, 157.3, 139.7, 139.3, 135.0, 131.0, 129.9, 128.9, 128.4, 127.8, 126.9, 125.8, 125.3, 121.7, 39.7.

Preparation of (E)-4-(3-bromophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (Compound 180)

Starting from ethyl 3-(3-bromophenyl)-3-oxopropanoate, a brown solid is obtained (7%).

1H NMR (CDCl3, 400 MHz): δ 8.30 (t, 1H, J=1.6 Hz), 8.00 (d, 1H, J=8 Hz), 7.77 (bs, 1H), 7.63 (dd, 1H, J=0.8 and 8 Hz), 7.52 (dd, 1H, J=2 and 7.6 Hz), 7.36 (t, 1H, J=8 Hz), 7.27 (m, 1H), 7.07 (dd, 1H, J=1.6 and 7.2 Hz), 3.55 (s, 2H).

13C NMR (CDCl3, 100 MHz): δ 166.9, 157.3, 139.7, 139.3, 133.9, 130.7, 130.2, 128.8, 128.4, 126.9, 126.3, 125.3, 123.1, 121.7, 39.7.

Preparation of (E)-4-(3-(trifluoromethyl)phenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (Compound 181)

Starting from ethyl 3-(3-(trifluoromethyl)phenyl)-3-oxopropanoate, a brown solid is obtained (34%).

1H NMR (CDCl3, 400 MHz): δ 8.42 (s, 1H), 8.26 (d, 1H, J=7.6 Hz), 7.78 (bs, 1H), 7.76 (d, 1H, J=8.4 Hz), 7.63 (t, 1H, J=7.6 Hz), 7.54 (dd, 1H, J=2.4 and 8 Hz), 7.33-7.29 (m, 2H), 7.08 (dd, 1H, J=2.4 and 7.2 Hz), 3.60 (s, 2H).

Starting from 4-bromobenzene-1,2-diamine

A β-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 Et2O.

Preparation of (E)-7-bromo-4-m-tolyl-1H-benzo[b][1,4]diazepin-2(3H)-one (Compound 182)

Starting from ethyl 3-oxo-3-m-tolylpropanoate, a brown solid is obtained (28%).

1H NMR (CDCl3, 400 MHz): δ 7.89 (m, 3H), 7.40-7.32 (m, 4H), 3.58 (s, 2H), 2.44 (s, 3H).

ESI+MS: calcd for C16H13BrN2O: 328.02. found: 328.9 (MH+).

Preparation of (E)-7-bromo-4-(3-methoxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (Compound 183)

Starting from ethyl 3-(3-methoxyphenyl)-3-oxopropanoate, a brown solid is obtained (10%).

ESI+MS: calcd for C16H13BrN2O2: 344.02. found: 344.9 (MH+).

Preparation of (E)-7-bromo-4-(3-nitrophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (Compound 184)

Starting from 3-(3-nitrophenyl)-3-oxopropanoate, a brown solid is obtained (6.5%).

ESI+MS: calcd for C15H10BrN3O3: 358.99. found: 359.8 (MH+).

Preparation of (E)-7-bromo-4-(3-chlorophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (Compound 185)

Starting from ethyl 3-(3-chlorophenyl)-3-oxopropanoate, a brown solid is obtained (23%).

ESI+MS: calcd for C15H10BrClN2O: 347.97. found: 348.8 (MH+).

Preparation of (E)-7-bromo-4-(3-bromophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (Compound 186)

Starting from ethyl 3-(3-bromophenyl)-3-oxopropanoate, a brown solid is obtained (10%).

ESI+MS: calcd for C15H10Br2N2O: 391.92. found: 392.8 (MH+).

Preparation of (E)-7-bromo-4-(3-(trifluoromethyl)phenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (Compound 186)

Starting from ethyl 3-(3-(trifluoromethyl)phenyl)-3-oxopropanoate, a brown solid is obtained (29%).

ESI+MS: calcd for C16H10BrF3N2O: 381.99. found: 382.8 (MH+).

EXAMPLE 2—DEMONSTRATION OF THE ACTIVITY OF THE COMPOUNDS ACCORDING TO THE INVENTION

1) Principle of the High-Throughput Screening:

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:

(i) selection of molecules which can act on the various stages of cell poisoning (receptor binding, internalization, intracellular trafficking, enzymatic activity, etc.);
(ii) selection of molecules which penetrate the cell;
(iii) elimination of cytotoxic compounds.

In addition, 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 principle of the cell assay is the following: the compounds of combinatorial libraries are preincubated with ricin and the whole is added to the culture medium of human lung epithelial cells (A549 cells, 60 000 cells/well, [ricin]=10−10 M) cultured on plates having a solid scintillant bottom (Scintiplates, GE). After incubation, the medium is removed and replaced with a leucine-free culture medium containing the radioactive tracer, which is [14C]-leucine (0.05 μCi/well). The incorporation of [14C]-leucine is then measured after a second incubation. The presence of the tracer in the cells reflects the presence of an inhibitor (C=50 μM) in the well (FIG. 1).

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 μM final concentration).

The results of the screening carried out are represented in the graph of FIG. 2.

2) Implementation of the High-Throughput Screening:

2.1. Protective Activity Against Ricin Toxin of the Compounds According to the Invention

The compounds were tested on A549 cells at the concentration of 30 μM by incubation with various ricin concentrations (10−9 to 10−12M), 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 EC50, i.e. the effective concentration for which 50% radioactive leucine assimilation is observed, which corresponds to 50% of viable cells. The higher the EC50 value, the greater the cell protection, since a higher concentration of ricin is then necessary in order to generate the same cytotoxicity.

The results, presented in the table below, are indicated in the form of a protective index (PI=EC50 compound/EC50 ricin ratio): the higher it is, the greater the protection of the cells against the action of ricin (the effect is protective if the ratio is greater than 1).

No Structures Bio 19 1.31 3 2.65 7 1.07 9 1.88 148 2.82 21 1.01 1 1.58 123 1.02 113 1.09 121 1.225 110 3.13 32 1.16 15 4.64 111 3.07 5 2.13 124 1.08 26 1.06 27 1.23 28 2.52 24 1.49 56 1.09 36 2.28/3.57 50 1.22 53 1.17 54 1.17 55 1.21 59 1.30 132 1.03 133 1.10 51 1.063 117 2.199 118 1.48 112 3.54 192 1.2 69 1.84 69 1.52 34 1.93 39 3.77 72 1.27 40 1.16 193 4.1 122 1.49 128 1.30 64 1.16 65 1.61 94 1.18 89 1.41 109 1.32 78 1.09 79 1.02 80 1.05 81 1.03 75 1.62 86 2.24 77 1.15 84 1.25 83 1.05 1.07 120 1.09 102 1.34 99 1.09 105 1.38 106 3.64 108 1.20 107 2.33 165   1 (a) 166 1.14 (a) 166 1.11 (a) 179 1.04 149 1.02 151 1.04 154 1.37 157 1.27 138 1.55 131 1.43 139 2.97 140 2.62 141 1.10 142 1.41 143 1.64 161 2.98

It is clearly observed that these compounds inhibit the cytotoxic action of ricin. Furthermore, they are the only inhibitors known at this time to protect A549 cells (human pulmonary epithelium) against ricin.

These compounds are the first inhibitors that are active on human pulmonary and digestive epithelial cells with respect to the toxic activity of ricin.

2.2. Protective Activity Against Diphtheria Toxin of the Compounds According to the Invention

The compounds were also tested on Vero cells (ATCC No. CCL-81) at the concentration of 30 μM by incubation with various concentrations of diphtheria toxin (10−9 to 10−12 M) (Sigma), with the protocol described in point 2.1.

The results, presented in the table below, also represent a protective index (PI=EC50 compound/EC50 ricin ratio): the higher it is, the greater the protection of the cells against the action of diphtheria toxin.

Compound Structure Activity  5 2.2  9 1.7  39 1.5 110 2.6 111 1.8 112 3.6 139 1.7 140 3.0

Claims

1. A method 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 comprising administering to a subject in need thereof a compound of general formula (I): is attached thereto in position 1 or 2,

in which:
Cy represents:
Y is chosen from a hydrogen atom or a hydroxyl function and Z is a carbon atom or a bond,
wherein the chain
p represents 0 or 1; X represents either: a bond; an optionally unsaturated, optionally branched, C1-C6 alkyl chain which is optionally substituted with a phenyl radical, an acid function and/or a C1-C3 alkyl ester radical; said chain being optionally interrupted with an oxygen atom; —CO—, —O—CO—, —CO—NH— or
R1 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 —NO2 function, a C1-C3 alkyl radical, a C1-C3 alkoxy radical or a C1-C3 acyloxy radical;
R2 either represents a bond or is chosen from a hydrogen atom, an optionally unsaturated, optionally branched, C1-C3 alkyl radical, a C2-C4 acyl radical or the radical
wherein, when R2 is a bond, then the nitrogen atom bearing R2 and X or the adjacent carbon atom (when p=1) are linked by a double bond,
wherein X, R1 and R2 can form, with the adjacent nitrogen atom, an imidazole, oxazole, triazole or benzimidazole ring, which is optionally partially saturated, such as in particular dihydroimidazole, optionally substituted with a phenyl or pyridine radical;
and the pharmaceutically acceptable salts thereof.

2. The method as claimed in claim 1, characterized in that said compound of and/or R2 is a hydrogen atom.

3. The method as claimed in claim 1, characterized in that said compound of general formula (I) is such that R1 is the radical:

in which:
R3 is chosen from a saturated or unsaturated cyclic radical containing 5 or 6 carbon atoms; a saturated or unsaturated bicyclic radical containing 9 or 10 carbon atoms; a saturated or unsaturated tricyclic radical containing 14 carbon atoms; a saturated or unsaturated heterocyclic radical containing 5 atoms; a saturated or unsaturated heterocyclic radical containing 6 atoms; a saturated or unsaturated biheterocyclic radical containing 9 or 10 atoms; said radicals being optionally substituted with at least one halogen atom, —NO2, —OH or one C1-C3 alkyl radical; and
R4 is chosen from —CO—O—, —N═CH— or —NH—CH2—.

4. (canceled)

5. The method as claimed in claim 1, characterized in that said compound of general formula (I) is selected from the group consisting of

Compound 1: N-benzyladamantylamine;
Compound 2: N-(2-bromobenzyl)adamantylamine;
Compound 3: N-(3-bromobenzyl)adamantylamine;
Compound 4: N-(4-bromobenzyl)adamantylamine;
Compound 5: N-(3-fluorobenzyl)adamantylamine;
Compound 6: N-(3-hydroxybenzyl)adamantylamine;
Compound 7: N-(2-methoxybenzyl)adamantylamine;
Compound 8: N-(3-methoxybenzyl)adamantylamine;
Compound 9: N-(4-methoxybenzyl)adamantylamine;
Compound 10: N-(2-nitrobenzyl)adamantylamine;
Compound 11: N-(4-nitrobenzyl)adamantylamine;
Compound 12: N-(4-carbethoxybenzyl)adamantylamine;
Compound 13: 4-bromo-2-((1-adamantylino)methyl)phenol;
Compound 14: N-(2-bromo-5-nitrobenzyl)adamantylamine;
Compound 15: N-[(2-methoxy-5-bromo)benzyl]adamantylamine;
Compound 16: N-((pyridin-2-yl)methyl)adamantylamine;
Compound 17: N-((pyridin-3-yl)methyl)adamantylamine;
Compound 18: N-((pyridin-4-yl)methyl)adamantylamine;
Compound 19: N-((5-methylfuran-2-yl)methy)adamantylamine;
Compound 20: N-((5-methylthiophen-2-yl)methyl)cyclohexanamine;
Compound 21: N-[(3-furyl)methyl]adamantylamine;
Compound 22: N-((1-methyl-1H-imidazol-5-yl)methy)adamantylamine;
Compound 23: N-[(5-N-methylimidazolyl)methyl]adamantylamine;
Compound 24: Benzo[d][1,3]dioxol-4-yl)methyl)adamantylamine;
Compound 25: N-((5-nitrobenzo[d][1,3]dioxol-6-yl)methyl)adamantylamine;
Compound 26: N-((quinolin-3-yl)methyl)adamantylamine;
Compound 27: N-((quinolin-4-yl)methyl)adamantylamine;
Compound 28: N-((1-methyl-1H-indol-2-yl)methyl)adamantylamine;
Compound 29: N-phenethyladamantylamine;
Compound 30: N-(3-phenylpropyl)adamantylamine;
Compound 31: N-(2-(benzyloxy)ethyl)adamantylamine;
Compound 32: N-cinnamyladamantylamine;
Compound 33: N-methyl(3-bromobenzyl)adamantylamine;
Compound 34: N-benzyl-2-adamantylamine;
Compound 35: N-(2-bromobenzyl)-2-adamantylamine;
Compound 36: N-(3-bromobenzyl)-2-adamantylamine;
Compound 37: N-(4-bromobenzyl)adamantylannine;
Compound 38: N-(2-fluorobenzyl)-2-adamantylamine;
Compound 39: N-(3-fluorobenzyl)-2-adamantylamine;
Compound 40: N-(4-fluorobenzyl)-2-adamantylamine;
Compound 41: N-(3-hydroxybenzyl)-2-adamantylamine;
Compound 42: N-(2-methoxybenzyl)-2-adamantylamine;
Compound 43: N-(3-methoxybenzyl)-2-adamantylamine;
Compound 44: N-(4-methoxybenzyl)-2-adamantylamine;
Compound 45: N-(2-nitrobenzyl)-2-adamantylamine;
Compound 46: N-(4-nitrobenzyl)-2-adamantylamine;
Compound 47: N-(4-carbethoxybenzyl)-2-adamantylamine;
Compound 48: 4-bromo-2-((2-adamantylamino)methyl)phenol;
Compound 49: N-(2-bromo-5-nitrobenzyl)-2-adamantylamine;
Compound 50: N-(5-bromo-2-methoxybenzyl)-2-adamantylamine;
Compound 51: N-(5-fluoro-2-nitrobenzyl)-2-adamantylamine;
Compound 52: N-(2,5-difluorobenzyl)-2-adamantylamine;
Compound 53: N-((pyridin-2-yl)methyl)-2-adamantylamine;
Compound 54: N-((pyridin-3-yl)methyl)-2-adamantylamine;
Compound 55: N-((pyridin-4-yl)methyl)-2-adamantylamine;
Compound 56: N-((5-methylfuran-2-yl)methyl)-2-adamantylamine;
Compound 57: N-((5-methylthiophen-2-yl)methyl)-2-adamantylamine;
Compound 58: N-((furan-3-yl)methyl)-2-adamantylamine;
Compound 59: N-((1-methyl-1H-imidazol-5-yl)methyl)-2-adamantylamine;
Compound 60: N-[(5-N-methylimidazolyl)methyl]-2-adamantylamine;
Compound 61: Benzo[d][1,3]dioxol-4-yl)methyl)-2-adamantylamine;
Compound 62: N-((5-nitrobenzo[d][1,3]dioxol-6-yl)methyl)-2-adamantylamine;
Compound 63: N-((quinolin-3-yl)methyl)-2-adamantylamine;
Compound 64: N-((quinolin-4-yl)methyl)-2-adamantylamine;
Compound 65: N-((1-methyl-1H-indol-2-yl)methyl)-2-adamantylamine;
Compound 66: N-(1-(3-bromophenyl)ethyl)-2-adamantylamine;
Compound 67: N-benzhydryl-2-adamantylamine;
Compound 68: N-(2-(benzyloxy)ethyl)-2-adamantylamine;
Compound 69: N-(phenylpropyl)-2-adamantylamine;
Compound 70: N-(1-phenylethyl)-2-adamantylamine;
Compound 71: N-(1-(pyridin-2-yl)ethyl)-2-adamantylamine;
Compound 72: N-(2-adamantylmethyl)-1-(adamantyl)ethanamine;
Compound 73: N-methyl(3-bromobenzyl)-2-adamantylamine;
Compound 86: N-(3-bromobenzyl)noradamantylamine;
Compound 87: N-(3-bromobenzyl)-1-hydroxy-2-adamantylamine;
Compound 109: N-(3-fluorobenzyl)noradamantylamine;
Compound 110: N-(3-bromobenzyl)adamantylamine hydrochloride salt;
Compound 111: N-(5-bromo-2-methoxybenzyl)adamantylamine hydrochloride salt;
Compound 112: N-(2-bromobenzyl)-2-adamantylamine hydrochloride salt;
Compound 113: (E)-N-(3-bromobenzylidene)adamantylamine;
Compound 114: (E)-N-(3-fluorobenzylidene)adamantylamine;
Compound 115: (E)-N-((1-methyl-1H-indol-2-yl)methylene)adamantylamine;
Compound 116: (E)-N-benzylideneadamantylamine;
Compound 117: (E)-N-(3-bromobenzylidene)adamantylamine;
Compound 118: (E)-N-(3-fluorobenzylidene)adamantylamine;
Compound 119: (E)-N-(3-bromobenzylidene)noradamantylamine;
Compound 120: (E)-N-((1-methyl-1H-indol-2-yl)methylene)noradamantylamine;
Compound 121: N-1-adamantylbenzamide;
Compound 122: N-2-adamantylbenzamide;
Compound 123: phenyl N-adamantylcarbamate;
Compound 124: N-adamantyl benzenesulfonamide;
Compound 125: N-adamantyl-N-(3-bromobenzyl)acetamide;
Compound 126: phenyl N-2-adamantylcarbamate;
Compound 127: N-adamantyl-N-(3-bromobenzyl)benzamide;
Compound 128: N-2-adamantyl benzenesulfonamide;
Compound 129: 1-(adamantyl)-3-phenylurea;
Compound 131: 1-(adamantyl)-1-(3-bromobenzyl)-3-phenylurea;
Compound 132: 1-(2-adamantyl)-3-phenylurea;
Compound 134: 1-(adamantyl)-2,5-dihydro-1H-imidazole;
Compound 135: 1-(adamantyl)-2,5-dihydrooxazole;
Compound 136: 1-(adamantyl)-1-phenyl-4,5-dihydro-1H-imidazole;
Compound 137: 1-(adamantyl)-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazole;
Compound 138: N-(3-chlorobenzyl)adamantylamine;
Compound 139: N-(3-chlorobenzyl)-2-adamantylamine;
Compound 140: N-(3-iodobenzyl)-2-adamantylamine;
Compound 141: N-(2,2-diphenylethyl)-2-adamantylamine;
Compound 142: N-(naphthalen-1-ylmethyl)-2-adamantylamine;
Compound 143: N-(phenanthren-9-ylmethyl)-2-adamantylamine;
Compound 144: 4-((adamantylamino)methyl)benzoic acid;
Compound 145: adamantylamino-4-phenyl-1H-1,2,3-triazole;
Compound 146: adamantylamino-4-phenyl-1H-1,2,3-triazole;
Compound 147: 2-(adamantylamino-1H-1,2,3-triazol-4-yl)pyridine;
Compound 148: N-(2-bromo-5-nitrobenzyl)adamantylamine;
Compound 191: N-cinnamyl-2-adamantylamine; and
Compound 192: N-(3-nitrobenzyl)-2-adamantylamine.

6. A compound of general formula (I): is attached thereto in position 1 or 2,

in which:
Cy represents:
Y is chosen from a hydrogen atom or a hydroxyl function and Z is a carbon atom or a bond,
wherein the chain
p represents 0 or 1; X represents either: a bond; an optionally unsaturated, optionally branched, C1-C6 alkyl chain which is optionally substituted with a phenyl radical, an acid function and/or a C1-C3 alkyl ester radical; said chain being optionally interrupted with an oxygen atom;
—CO—, —O—CO—, —CO—NH— or
R1 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 —NO2 function, a C1-C3 alkyl radical, a C1-C3 alkoxy radical or a C1-C3 acyloxy radical;
R2 either represents a bond or is chosen from a hydrogen atom, an optionally unsaturated, optionally branched, C1-C3 alkyl radical, a C2-C4 acyl radical or the radical
wherein, when R2 is a bond, then the nitrogen atom bearing R2 and X or the adjacent carbon atom (when p=1) are linked by a double bond,
wherein X, R1 and R2 can form, with the adjacent nitrogen atom, an imidazole, oxazole, triazole or benzimidazole ring, which is optionally partially saturated, such as in particular dihydroimidazole, optionally substituted with a phenyl or pyridine radical;
and the pharmaceutically acceptable salts thereof,
with the proviso that the compound of general formula (I) excludes the following compounds:
Compound 1: N-benzyladamantylamine;
Compound 6: N-(3-hydroxybenzyl)adamantylamine;
Compound 8: N-(3-methoxybenzyl)adamantylamine;
Compound 11: N-(4-nitrobenzyl)adamantylamine;
Compound 18: N-((pyridin-4-yl)methyl)adamantylamine;
Compound 29: N-phenethyladamantylamine;
Compound 30: N-(3-phenylpropyl)adamantylamine;
Compound 34: N-benzyl-2-adamantylamine;
Compound 113: (E)-N-(3-bromobenzylidene)adamantyiamine;
Compound 114: (E)-N-(3-fluorobenzylidene)adamantylamine;
Compound 116: (E)-N-benzylideneadamantylamine;
Compound 121: N-1-adamantylbenzamide;
Compound 122: N-2-adamantylbenzamide;
Compound 124: N-adamantyl benzenesulfonamide;
Compound 128: N-2-adamantyl benzenesulfonamide;
Compound 135:1-(adamantyl)-2,5-dihydrooxazole; and
Compound 145: adamantylamino-4-phenyl-1H-1,2,3-triazole.

7-10. (canceled)

11. A pharmaceutical composition comprising the compound as claimed in claim 6.

12. The pharmaceutical composition as claimed in claim 11, further comprising at least one pharmaceutically acceptable vehicle.

13. The pharmaceutical composition as claimed in claim 11, wherein the composition is formulated to be administered orally, aerially, parenterally or locally.

14. The method as claimed in claim 1, wherein the poisoning is ricin poisoning.

15. The method as claimed in claim 14, wherein said compound is selected from the group consisting of:

Compound 1: N-benzyladamantylamine;
Compound 3: N-(3-bromobenzyl)adamantylamine;
Compound 5: N-(3-fluorobenzyl)adamantylamine;
Compound 9: N-(4-methoxybenzyl)adamantylamine;
Compound 15: N-[(2-methoxy-5-bromo)benzyl]adamantylamine;
Compound 19: N-((5-methylfuran-2-yl)methy)adamantylamine;
Compound 24: Benzo[d][1,3]dioxol-4-yl)methyl)adamantylamine;
Compound 28: N-((1-methyl-1H-indol-2-yl)methyl)adamantylamine;
Compound 34: N-benzyl-2-adamantylamine;
Compound 36: N-(3-bromobenzyl)-2-adamantylamine;
Compound 39: N-(3-fluorobenzyl)-2-adamantylamine;
Compound 59: N-((1-methyl-1H-imidazol-5-yl)methyl)-2-adamantylamine;
Compound 65: N-((1-methyl-1H-indol-2-yl)methyl)-2-adamantylamine;
Compound 67: N-benzhydryl-2-adamantylamine;
Compound 68: N-(2-(benzyloxy)ethyl)-2-adamantylamine;
Compound 69: N-(phenylpropyl)-2-adamantylamine;
Compound 75: N-(3-bromobenzyl)-2,4,4-trimethylpentan-2-amine;
Compound 86: N-(3-bromobenzyl)noradamantylamine;
Compound 109: N-(3-fluorobenzyl)noradamantylamine;
Compound 110: N-(3-bromobenzyl)adamantylamine hydrochloride salt;
Compound 111: N-(5-bromo-2-methoxybenzyl)adamantylamine hydrochloride salt;
Compound 112: N-(2-bromobenzyl)-2-adamantylamine hydrochloride salt;
Compound 117: (E)-N-(3-bromobenzylidene)adamantylamine;
Compound 118: (E)-N-(3-fluorobenzylidene)adamantylamine;
Compound 122: N-2-adamantylbenzamide;
Compound 128: N-2-adamantyl benzenesulfonamide;
Compound 131: 1-(adamantyl)-1-(3-bromobenzyl)-3-phenylurea;
Compound 138: N-(3-chlorobenzyl)adamantylamine;
Compound 139: N-(3-chlorobenzyl)-2-adamantylamine;
Compound 140: N-(3-iodobenzyl)-2-adamantylamine;
Compound 142: N-(naphthalen-1-ylmethyl)-2-adamantylamine;
Compound 143: N-(phenanthren-9-ylmethyl)-2-adamantylamine; and
Compound 148: N-(2-bromo-5-nitrobenzyl)adamantylamine.

16. The method as claimed in claim 14, wherein the compound of general formula (I) is defined by general formula (I.1):

in which:
Cy represents:
Z is a carbon atom or a bond, wherein the nitrogen atom in formula I.1 is attached thereto in position 1 or 2,
R1 represents: a phenyl ring, optionally substituted with an —OCH3 radical in the para-position with respect to the carbon atom bonded to the —CH2—NH-Cy chain; said ring being alternatively optionally substituted with a halogen atom in the meta-position with respect to the carbon atom bonded to the —CH2—NH-Cy chain, and in this case, said ring optionally bears a second substitution in the para-position with respect to said halogen atom, said second substitution being chosen from —NO2 and —OCH3; an indole, imidazole or furan ring substituted with a methyl radical; a benzo(1,3)dioxolo ring, a naphthalenyl ring or a phenanthrenyl ring;
and the pharmaceutically acceptable salts thereof.

17. The method as claimed in claim 16, wherein said compound of general formula (I.1) is selected from the group consisting of:

Compound 1: N-benzyladamantylamine;
Compound 3: N-(3-bromobenzyl)adamantylamine;
Compound 5: N-(3-fluorobenzyl)adamantylamine;
Compound 9: N-(4-methoxybenzyl)adamantylamine;
Compound 15: N-[(2-methoxy-5-bromo)benzyl]adamantylamine;
Compound 19: N-((5-methylfuran-2-yl)methy)adamantylamine;
Compound 24: Benzo[d][1,3]dioxol-4-yl)methyl)adamantylamine;
Compound 28: N-((1-methyl-1H-indol-2-yl)methyl)adamantylamine;
Compound 34: N-benzyl-2-adamantylamine;
Compound 36: N-(3-bromobenzyl)-2-adamantylamine;
Compound 39: N-(3-fluorobenzyl)-2-adamantylamine;
Compound 59: N-((1-methyl-1H-imidazol-5-yl)methyl)-2-adamantylamine;
Compound 65: N-((1-methyl-1H-indol-2-yl)methyl)-2-adamantylamine;
Compound 86: N-(3-bromobenzyl)noradamantylamine;
Compound 109: N-(3-fluorobenzyl)noradamantylamine;
Compound 110: N-(3-bromobenzyl)adamantylamine hydrochloride salt;
Compound 111: N-(5-bromo-2-methoxybenzyl)adamantylamine hydrochloride salt;
Compound 112: N-(2-bromobenzyl)-2-adamantylamine hydrochloride salt;
Compound 138: N-(3-chlorobenzyl)adamantylamine;
Compound 139: N-(3-chlorobenzyl)-2-adamantylamine;
Compound 140: N-(3-iodobenzyl)-2-adamantylamine;
Compound 142: N-(naphthalen-1-ylmethyl)-2-adamantylamine;
Compound 143: N-(phenanthren-9-ylmethyl)-2-adamantylamine; and
Compound 148: N-(2-bromo-5-nitrobenzyl)adamantylamine.

18. The method as claimed in claim 14, wherein the compound of general formula (I) is defined by general formula (I.2):

in which X represents —(CH2)2—O—CH2—, —(CH2)3—, —CO— or —SO2—,
and the pharmaceutically acceptable salts thereof.

19. The method as claimed in claim 18, wherein said compound of general formula (I.2) is selected from the group consisting of:

Compound 68: N-(2-(benzyloxy)ethyl)-2-adamantylamine;
Compound 69: N-(phenylpropyl)-2-adamantylamine;
Compound 122: N-2-adamantylbenzamide; and
Compound 128: N-2-adamantyl benzenesulfonamide.

20. The method as claimed in claim 14, wherein the compound of general formula (I) is defined by general formula (I.3):

in which W represents a halogen atom,
and the pharmaceutically acceptable salts thereof.

21. The method as claimed in claim 20, wherein said compound of general formula (I.3) is

Compound 117: (E)-N-(3-bromobenzylidene)adamantylamine; or
Compound 118: (E)-N-(3-fluorobenzylidene)adamantylamine.

22-23. (canceled)

24. The method as claimed in claim 1, wherein the poisoning is from diphtheria toxin.

25. The method as claimed in claim 24, characterized in that the compound of general formula (I) is defined by general formula (I.5): to which the nitrogen atom of formula I.5 is attached in position 1 or 2,

in which:
Cy represents
W and W′ are, independently of one another, chosen from a hydrogen atom, a halogen atom and a C1-C3 alkoxy radical,
and the pharmaceutically acceptable salts thereof.

26. The method as claimed in claim 25, characterized in that said compound of general formula (I) is selected from the group consisting of the compounds:

Compound 5: N-(3-fluorobenzyl)adamantylamine;
Compound 9: N-(4-methoxybenzyl)adamantylamine;
Compound 39: N-(3-fluorobenzyl)-2-adamantylamine;
Compound 110: N-(3-bromobenzyl)adamantylamine hydrochloride salt;
Compound 111: N-(5-bromo-2-methoxybenzyl)adamantylamine hydrochloride salt;
Compound 112: N-(2-bromobenzyl)-2-adamantylamine hydrochloride salt;
Compound 139: N-(3-chlorobenzyl)-2-adamantylamine; and
Compound 140: N-(3-iodobenzyl)-2-adamantylamine.

27. A compound of general formula (I.1)

and the pharmaceutically acceptable salts thereof,
in which:
Cy represents:
Z is a carbon atom or a bond,
wherein the nitrogen atom of formula I.1 is attached thereto in position 1 or 2,
R1 represents a phenyl ring, optionally substituted with an —OCH3 radical in the para-position with respect to the carbon atom bonded to the —CH2—NH-Cy chain; said ring being alternatively optionally substituted with a halogen atom in the meta-position with respect to the carbon atom bonded to the —CH2—NH-Cy chain, and in this case, said ring optionally bears a second substitution in the para-position with respect to said halogen atom, said second substitution being chosen from —NO2 and —OCH3; an indole, imidazole or furan ring substituted with a methyl radical; a benzo(1,3)dioxolo ring, a naphthalenyl ring or a phenanthrenyl ring.
Patent History
Publication number: 20170233386
Type: Application
Filed: Apr 24, 2017
Publication Date: Aug 17, 2017
Applicant: Commissariat a l'Energie Atomique et aux Energies Alternatives (Paris)
Inventors: Roman Lopez (Issy-les-moulineaux), Séverine Hebbe (Paris), Daniel Gillet (Paris), Julien Barbier (Gif Sur Yvette)
Application Number: 15/494,798
Classifications
International Classification: C07D 453/02 (20060101); C07C 211/38 (20060101); C07C 217/58 (20060101); C07C 233/58 (20060101); C07C 317/14 (20060101); C07D 215/12 (20060101); C07D 209/14 (20060101); C07D 451/02 (20060101); C07C 229/14 (20060101); C07C 271/56 (20060101); C07C 251/24 (20060101); C07D 317/46 (20060101); C07D 213/38 (20060101); C07D 233/64 (20060101); C07C 275/28 (20060101); C07C 335/02 (20060101); C07D 243/12 (20060101); C07D 243/24 (20060101); C07D 333/20 (20060101); C07D 307/52 (20060101);