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

Abstract

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.

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): ##STR00351## in which: Cy represents: ##STR00352## Y is chosen from a hydrogen atom or a hydroxyl function and Z is a carbon atom or a bond, wherein the chain ##STR00353## is attached thereto in position 1 or 2, p represents 0 or 1; X represents either: a bond; an optionally unsaturated, optionally branched, C.sub.1-C.sub.6 alkyl chain which is optionally substituted with a phenyl radical, an acid function and/or a C.sub.1-C.sub.3 alkyl ester radical; said chain being optionally interrupted with an oxygen atom; —CO—, —O—CO—, —CO—NH— or ##STR00354## R.sup.1 represents a radical containing 1 to 21 carbon atoms, which is optionally branched and/or cyclic, and saturated or unsaturated, in which one or more of the carbon atoms can be replaced with a nitrogen, oxygen and/or sulfur atom; said radical being optionally monosubstituted or disubstituted with a halogen atom, a —COOH, —OH or —NO.sub.2 function, a C.sub.1-C.sub.3 alkyl radical, a C.sub.1-C.sub.3 alkoxy radical or a C.sub.1-C.sub.3 acyloxy radical; R.sup.2 either represents a bond or is chosen from a hydrogen atom, an optionally unsaturated, optionally branched, C.sub.1-C.sub.3 alkyl radical, a C.sub.2-C.sub.4 acyl radical or the radical ##STR00355## wherein, when R.sup.2 is a bond, then the nitrogen atom bearing R.sup.2 and X or the adjacent carbon atom (when p=1) are linked by a double bond, wherein X, R.sup.1 and R.sup.2 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 R.sup.2 is a hydrogen atom.

3. The method as claimed in claim 1, characterized in that said compound of general formula (I) is such that R.sup.1 is the radical: in which: ##STR00356## R.sup.3 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, —NO.sub.2, —OH or one C.sub.1-C.sub.3 alkyl radical; and R.sup.4 is chosen from —CO—O—, —N═CH— or —NH—CH.sub.2—.

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): ##STR00357## in which: Cy represents: ##STR00358## Y is chosen from a hydrogen atom or a hydroxyl function and Z is a carbon atom or a bond, wherein the chain ##STR00359## is attached thereto in position 1 or 2, p represents 0 or 1; X represents either: a bond; an optionally unsaturated, optionally branched, C.sub.1-C.sub.6 alkyl chain which is optionally substituted with a phenyl radical, an acid function and/or a C.sub.1-C.sub.3 alkyl ester radical; said chain being optionally interrupted with an oxygen atom; ##STR00360## —CO—, —O—CO—, —CO—NH— or R.sup.1 represents a radical containing 1 to 21 carbon atoms, which is optionally branched and/or cyclic, and saturated or unsaturated, in which one or more of the carbon atoms can be replaced with a nitrogen, oxygen and/or sulfur atom; said radical being optionally monosubstituted or disubstituted with a halogen atom, a —COOH, —OH or —NO.sub.2 function, a C.sub.1-C.sub.3 alkyl radical, a C.sub.1-C.sub.3 alkoxy radical or a C.sub.1-C.sub.3 acyloxy radical; R.sup.2 either represents a bond or is chosen from a hydrogen atom, an optionally unsaturated, optionally branched, C.sub.1-C.sub.3 alkyl radical, a C.sub.2-C.sub.4 acyl radical or the radical ##STR00361## wherein, when R.sup.2 is a bond, then the nitrogen atom bearing R.sup.2 and X or the adjacent carbon atom (when p=1) are linked by a double bond, wherein X, R.sup.1 and R.sup.2 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): ##STR00362## in which: Cy represents: ##STR00363## Z is a carbon atom or a bond, wherein the nitrogen atom in formula I.1 is attached thereto in position 1 or 2, R.sup.1 represents: a phenyl ring, optionally substituted with an —OCH.sub.3 radical in the para-position with respect to the carbon atom bonded to the —CH.sub.2—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 —CH.sub.2—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 —NO.sub.2 and —OCH.sub.3; 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): ##STR00364## in which X represents —(CH.sub.2).sub.2—O—CH.sub.2—, —(CH.sub.2).sub.3—, —CO— or —SO.sub.2—, 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): ##STR00365## 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): ##STR00366## in which: Cy represents ##STR00367## to which the nitrogen atom of formula I.5 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 C.sub.1-C.sub.3 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) ##STR00368## and the pharmaceutically acceptable salts thereof, in which: Cy represents: ##STR00369## Z is a carbon atom or a bond, wherein the nitrogen atom of formula I.1 is attached thereto in position 1 or 2, R.sup.1 represents a phenyl ring, optionally substituted with an —OCH.sub.3 radical in the para-position with respect to the carbon atom bonded to the —CH.sub.2—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 —CH.sub.2—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 —NO.sub.2 and —OCH.sub.3; an indole, imidazole or furan ring substituted with a methyl radical; a benzo(1,3)dioxolo ring, a naphthalenyl ring or a phenanthrenyl ring.

Description

[0157] 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:

[0158] FIG. 1 is a diagrammatic representation of the high-throughput cell assay.

[0159] 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

[0160] 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.

[0161] The purification methods used for preparing the compounds are specified in the “Purification method” column of the tables and coded as follows:

1: Filtration

[0162] 2: Short pad (small column with silica already packaged)
3: Silica gel chromatography column

4: HPLC

5: Crystallization

[0163] 6: Aqueous treatment then separation.

[0164] The .sup.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).

[0165] The LC/MS analyses were carried out by HPLC (High Pressure Liquid Chromatography) coupled with a Waters® Autopurif mass spectrometer.

[0166] The ionization is obtained either by electron impact or by electrochemical ionization.

[0167] 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:

[0168] Waters 2996 photodiode array detector: UV (200-400 nm), [0169] PL-ELS 1000, [0170] 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.

[0171] 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.

[0172] Process A

[0173] The 1-aminoadamantane and 2-aminoadamantane derivatives of general formula (Ia) as described above and which appear, respectively, in tables A1 and A2 are prepared as follows: a suspension, in methanol, of 1-adamantylamine or 2-adamantylamine (0.5 mmol; 75 mg; 1 equiv.) is added, with stirring, to an aromatic aldehyde (1 equiv.) according to the compound to be prepared, in the presence of BH.sub.3CN 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.

[0174] 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-US-00005 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 .sup.1H NMR (CDCl.sub.3, 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 C.sub.17H.sub.23N: 241.18; found: 242.2 (MH.sup.+) 2 2-bromobenzaldehyde N-(2- 1 bromobenzyl)- yellow solid adamantylamine 24% 3 3-bromobenzaldehyde N-(3- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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)- C.sub.17H.sub.22BrN: 319.09; found: green solid adamantylamine 320.1 (MH.sup.+) 70% 5 3-fluorobenzaldehyde N-(3- .sup.1H NMR (CDCl.sub.3, 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 C.sub.17H.sub.22FN: 259.17; found: 260.2 (MH.sup.+) 6 3-hydroxybenzaldehyde N-(3- .sup.1H NMR (CDCl.sub.3, 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). .sup.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 C.sub.17H.sub.23NO: 257.18; found: 258.1 (MH.sup.+) 7 2- N-(2- ESI+MS: calcd for 1 methoxybenzaldehyde methoxybenzyl)- C.sub.18H.sub.25NO: 271.19; found: pale adamantylamine 272.2 (MH.sup.+) yellow solid 32% 8 3- N-(3- ESI+MS: calcd for 1 methoxybenzaldehyde methoxybenzyl)adamantyl- C.sub.18H.sub.25NO: 271.19; found: green oil amine 272.2 (MH.sup.+) 40% 9 4- N-(4- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.18H.sub.25NO: 271.19; found: 272.2 (MH.sup.+) 10 2-nitrobenzaidehyde N-(2- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.17H.sub.22N.sub.2O.sub.2: 286.17; found: 287.2 (MH.sup.+) 11 4-nitrobenzaldehyde N-(4- ESI+MS: calcd for 1 nitrobenzyl)- C.sub.17H.sub.22N.sub.2O.sub.2: 286.17; orange solid adamantylamine found: 287.2 (MH.sup.+) 58% 12 4-methyl 4- N-(4- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.19H.sub.25NO.sub.2: 299.19; found: 300.1 (MH.sup.+) 13 5-bromo-2- 4-bromo-2-((1- .sup.1H NMR (CDCl.sub.3, 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 C.sub.17H.sub.22BrNO: 335.09; found: 336.2 (MH.sup.+) 14 2-bromo-5- N-(2-bromo-5- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.18H.sub.24BrNO: 349.10; found: 350.1 (MH.sup.+) 15 2-methoxy-5- N-[(2-methoxy-5- 1 bromobenzaldehyde bromo)benzyl]- white solid adamantylamine 100% 16 picolinaldehyde N-((pyridin-2- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.15H.sub.22N.sub.2: 242.18; found: 243.2 (MH.sup.+) 17 nicotinaldehyde N-((pyridin-3- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.15H.sub.22N.sub.2: 242.18; found: 243.2 (MH.sup.+) 18 isonicotinaldehyde N-((pyridin-4- .sup.1H NMR (CDCl.sub.3, 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 C.sub.16H.sub.22N.sub.2: 242.18; found: 243.2 (MH.sup.+) 19 5-methylfuran-2- N-((5-methylfuran-2- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.16H.sub.23NO: 245.18; found: 246.2 (MH.sup.+) 20 5-methylthiophene-2- N-((5-methylthiophen-2- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.16H.sub.23NS: 261.16; found: 262.2 (MH.sup.+) 21 Furan-3-carbaldehyde N-[(3- .sup.1H NMR (CDCl.sub.3, 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 C.sub.15H.sub.21NO: 231.16; found: 232.2 (MH.sup.+) 22 1-methyl-1H-imidazole- N-((1-methyl-1H-imidazol- .sup.1H NMR (CDCl.sub.3, 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- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 100 MHz): δ 131.8, 126.2, 121.8, 54.3, 40.1, 36.1, 29.3. ESI+MS: calcd for C.sub.15H.sub.23N.sub.3: 245.18; found: 246.2 (MH.sup.+) 24 Benzo[d][1,3]dioxole-4- Benzo[d][1,3]dioxol-4- .sup.1H NMR (CDCl.sub.3, 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 C.sub.18H.sub.23NO.sub.2: 285.17; found: 286.2 (MH.sup.+) 25 6-nitro[d][1,3]dioxole-5- N-((5- .sup.1H NMR (CDCl.sub.3, 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 C.sub.18H.sub.22N.sub.2O.sub.4: 330.16; found: 331.2 (MH.sup.+) 26 Quinoline-3- N-((quinolin-3- .sup.1H NMR (CDCl.sub.3, 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 C.sub.20H.sub.24N.sub.2: 292.19; found: 293.3 (MH.sup.+) 27 Quinoline-4- N-((quinolin-4- ESI+MS: calcd for 1 carbaldehyde yl)methyl)adamantylamine C.sub.20H.sub.24N.sub.2: 292.19; found: orange solid 293.2 (MH.sup.+) 100% 28 1-methyl-1H-indole-2- N-((1-methyl-1H-indol-2- .sup.1H NMR (CDCl.sub.3, 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 C.sub.20H.sub.26N.sub.2: 294.21; found: 295.2 (MH.sup.+) 29 2-phenylacetaldehyde N- ESI+MS: calcd for 2 phenethyladamantylamine C.sub.18H.sub.25N.sub.2: 255.20; found: colorless oil 256.3 (MH.sup.+) 5% 30 3-phenylpropanal N-(3- .sup.1H NMR (CDCl.sub.3, 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), .sup.13C NMR (CDCl.sub.3, 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 C.sub.19H.sub.27N: 269.22; found: 270.3 (MH.sup.+) 31 2- N-(2- .sup.1H NMR (CDCl.sub.3, 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 C.sub.19H.sub.27NO: 285.21; found: 286.3 (MH.sup.+) 32 cinnamaldehyde N- .sup.1H NMR (CDCl.sub.3, 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 C.sub.19H.sub.25N: 267.20; found: 268.3 (MH.sup.+) 33 paraformaldehyde N-methyl(3- .sup.1H NMR (CDCl.sub.3, 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 C.sub.18H.sub.24BrN: 333.11; found: 334.0 (MH.sup.+)

TABLE-US-00006 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- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.17H.sub.23N: 241.18; found: 242.2 (MH.sup.+) 35 2-bromobenzaldehyde N-(2-bromobenzyl)-2- LC-MS (ES.sup.+) m/z 1 adamantylamine 320.1 (M + H).sup.+ colorless oil .sup.1H NMR (CDCl.sub.3, 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 C.sub.17H.sub.22BrN: 319.09; found: 320.1 (MH.sup.+) 36 3-bromobenzaldehyde N-(3-bromobenzyl)-2- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.17H.sub.22BrN: 319.09; found: 320.1 (MH.sup.+) 37 4-bromobenzaldehyde N-(4-bromobenzyl)-2- .sup.1H NMR (CDCl.sub.3, 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 C.sub.17H.sub.22BrN: 319.09; found: 320.1 (MH.sup.+) 38 2-fluorobenzaldehyde N-(2-fluorobenzyl)-2- .sup.1H NMR (CDCl.sub.3, 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 C.sub.17H.sub.22FN: 259.17; found: 260.2 (MH.sup.+) 39 3-fluorobenzaldehyde N-(3-fluorobenzyl)-2- .sup.1H NMR (CDCl.sub.3, 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 C.sub.17H.sub.22FN: 259.17; found: 260.2 (MH.sup.+) 40 4-fluorobenzaldehyde N-(4-fluorobenzyl)-2- .sup.1H NMR (CDCl.sub.3, 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 C.sub.17H.sub.22FN: 259.17; found: 260.2 (MH.sup.+) 41 3-hydroxybenzaldehyde N-(3-hydroxybenzyl)-2- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.17H.sub.23NO: 257.18; found: 258.1 (MH.sup.+) 42 2- N-(2-methoxybenzyl)-2- .sup.1H NMR (CDCl.sub.3, 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 C.sub.18H.sub.25NO: 271.19; found: 272.2 (MH.sup.+) 43 3- N-(3-methoxybenzyl)-2- .sup.1H NMR (CDCl.sub.3, 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 C.sub.18H.sub.25NO: 271.19; found: 272.2 (MH.sup.+) 44 4- N-(4-methoxybenzyl)-2- .sup.1H NMR (CDCl.sub.3, 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 C.sub.18H.sub.25NO: 271.19; found: 272.2 (MH.sup.+) 45 2-nitrobenzaldehyde N-(2-nitrobenzyl)-2- ESI+MS: calcd for 1 adamantylamine C.sub.17H.sub.22N.sub.2O.sub.2: 286.17; yellow oil found: 287.2 (MH.sup.+) 59% 46 4-nitrobenzaldehyde N-(4-nitrobenzyl)-2- .sup.1H NMR (CDCl.sub.3, 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 C.sub.17H.sub.22N.sub.2O.sub.2: 286.17; found: 287.2 (MH.sup.+) 47 4-methyl-4- N-(4-carbethoxybenzyl)-2- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.19H.sub.25NO.sub.2: 299.19; found: 300.1 (MH.sup.+) 48 5-bromo-2- 4-bromo-2-((2- ESI+MS: calcd for 2 hydroxybenzaldehyde adamantylamino)methyl)- C.sub.17H.sub.22BrNO: 335.09; pale yellow phenol found: 336.1 (MH.sup.+) solid 18% 50 5-bromo-2- N-(5-bromo-2- ESI+MS: calcd for 1 methoxybenzaldehyde methoxybenzyl)-2- C.sub.18H.sub.24BrNO.sub.2: 349.10; white solid adamantylamine found: 350.1 (MH.sup.+) 56% 51 5-fluoro-2- N-(5-fluoro-2-nitrobenzyl)- ESI+MS: calcd for 4 nitrobenzaldehyde 2-adamantylamine C.sub.17H.sub.21FN.sub.2O.sub.2: 304.16; colorless oil found: 305.2 (MH.sup.+) 2.3% 52 2,5- N-(2,5- .sup.1H NMR (CDCl.sub.3, 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 C.sub.17H.sub.21F.sub.2N: 277.16; found: 278.2 (MH.sup.+) 53 picolinaldehyde N-((pyridin-2-yl)methyl)-2- ESI+MS: calcd for 1 adamantylamine C.sub.16H.sub.22N.sub.2: 242.18; found: yellow oil 243.2 (MH.sup.+) 71% 54 nicotinaldehyde N-((pyridin-3-yl)methyl)-2- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.15H.sub.22N.sub.2: 242.18; found: 243.2 (MH.sup.+) 55 isonicotinaldehyde N-((pyridin-4-yl)methyl)-2- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.16H.sub.22N.sub.2: 242.18; found: 243.2 (MH.sup.+) 56 5-methylfuran-2- N-((5-methylfuran-2- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.16H.sub.23NO: 245.18; found: 246.2 (MH.sup.+) 57 5-methylthiophene-2- N-((5-methylthiophen-2- .sup.1H NMR (CDCl.sub.3, 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 C.sub.16H.sub.23NS: 261.16; found: 262.1 (MH.sup.+) 58 furan-3-carbaldehyde N-((furan-3-yl)methyl)-2- .sup.1H NMR (CDCl.sub.3, 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 C.sub.15H.sub.21NO: 231.16; found: 232.1 (MH.sup.+) 59 1-methyl-1H-imidazole- N-((1-methyl-1H-imidazol- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.15H.sub.23N.sub.3: 245.19; found: 246.1 (MH.sup.+) 60 1-methyl-1H-imidazole- N-[(5-N- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.15H.sub.23N.sub.3: 245.19; found: 246.2 (MH.sup.+) 61 Benzo[d][1,3]dioxole-4- Benzo[d][1,3]dioxol-4- .sup.1H NMR (CDCl.sub.3, 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 C.sub.18H.sub.23NO.sub.2: 285.17; found: 286.2 (MH.sup.+) 62 6-nitro[d][1,3]dioxole-5- N-((5- ESI+MS: calcd for 1 carbaldehyde nitrobenzo[d][1,3]dioxol-6- C.sub.18H.sub.22N.sub.3O.sub.4: 330.16; brown solid yl)methyl)-2- found: 331.2 (MH.sup.+) 62% adamanlylamine 63 Quinoline-3- N-((quinolin-3-yl)methyl)- .sup.1H NMR (CDCl.sub.3, 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 C.sub.20H.sub.24N.sub.2: 292.19; found: 293.2 (MH.sup.+) 64 Quinoline-4- N-((quinolin-4-yl)methyl)- .sup.1H NMR (CDCl.sub.3, 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 C.sub.20H.sub.24N.sub.2: 292.19; found: 293.2 (MH.sup.+) 65 1-methyl-1H-indole-2- N-((1-methyl-1H-indol-2- .sup.1H NMR (CDCl.sub.3, 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 C.sub.20H.sub.26N.sub.2: 294.21; found: 295.2 (MH.sup.+) 66 1-(3- N-(1-(3- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.18H.sub.24BrN: 333.11; found: 334.2 (MH.sup.+) 67 benzophenone N-benzhydryl-2- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.24H.sub.29N: 331.23; found: 331.9 (MH.sup.+) 68 2- N-(2-(benzyloxy)ethyl)-2- .sup.1H NMR (CDCl.sub.3, 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 C.sub.19H.sub.27NO: 285.21; found: 286.3 (MH.sup.+) 69 3-phenylpropanal N-(phenylpropyl)-2- .sup.13C NMR (CDCl.sub.3, 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 C.sub.19H.sub.27N: 269.22; found: 270.2 (MH.sup.+) 70 acetophenone N-(1-phenylethyl)-2- .sup.1H NMR (CDCl.sub.3, 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 C.sub.18H.sub.25N: 255.20; found: 256.3 (MH.sup.+) 71 1-(pyridin-2-yl)ethanone N-(1-(pyridin-2-yl)ethyl)-2- .sup.1H NMR (CDCl.sub.3, 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 C.sub.17H.sub.24N: 256.19; found: 257.2 (MH.sup.+) 72 1-adamantyl methyl N-(2-adamantylmethyl)-1- .sup.1H NMR (CDCl.sub.3, 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 C.sub.22H.sub.35N: 313.28; found: 314.2 (MH.sup.+) 73 paraformaldehyde N-methyl(3-bromobenzyl)- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.18H.sub.24BrN: 333.11; found: 334.0 (MH.sup.+) 191 cinnamaldehyde N-cinnamyl-2- .sup.1H NMR (CDCl.sub.3, 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 C.sub.19H.sub.25N: 267.20; found: 268.3 (MH.sup.+)

[0175] 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 BH.sub.3CN 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.

[0176] 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-US-00007 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)- .sup.1H NMR (CDCl.sub.3, 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 C.sub.11H.sub.16BrN: 241.05; found: 242.1 (MH.sup.+) 75 3- 2,4,4- N-(3-bromobenzyl)- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.15H.sub.24BrN; 297.11; found: 298.1 (MH.sup.+) 76 3- 2-amino-3- 2-(3- ESI+MS: calcd for 2 bromobenzaldehyde hydroxy-2- bromobenzylamino)- C.sub.11H.sub.14BrNO.sub.3: 287.02; white solid methyl- 3-hydroxy-2- found: 288.1 (MH.sup.+) 18% propanoic acid methylpropanoic acid 77 3- 2-amino-2- 2-(3- .sup.1H NMR (CDCl.sub.3, 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 C.sub.11H.sub.16BrNO.sub.3: 289.03; found: 290.1 (MH.sup.+) 78 3- cyclohexyl- N-(3- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.13H.sub.18BrN: 267-06: found: 268.0 (MH.sup.+) 79 3- 4- 4-(3- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.13H.sub.18BrNO: 283.06; found: 284.0 (MH.sup.+) 80 3-fluorobenzaldehyde cyclohexyl- N-(3- ESI+MS: calcd for 1 amine fluorobenzyl)- C.sub.13H.sub.18FN: 207.14; white solid cyclo-hexylamine found: 208.12 (MH.sup.+) 100% 81 3-fluorobenzaldehyde 4- 4-(3- ESI+MS: calcd for 1 aminocyclo- fluorobenzylamino)- C.sub.13H.sub.18FNO: 223.14; white solid hexanol cyclohexanol found: 224.10 (MH.sup.+) 100% 82 3- (1- (1-(3- .sup.1H NMR (CDCl.sub.3, 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 C.sub.13H.sub.18BrNO: 283.06; found: 284.1 (MH.sup.+) 83 3- (1- 1-(3- ESI+MS: calcd for 4 bromobenzaldehyde aminocyclo- bromobenzylamino)- C.sub.13H.sub.18BrNO.sub.2: 297.04; colorless pentyl)methanol cyclopentane- found: 298.1 (MH.sup.+) 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- C.sub.14H.sub.18BrN: 279.06; yellow oil amine 2-amine found: 280.2 (MH.sup.+) 23% 85 3- 2-aminobicyclo- 2-(3- ESI+MS: calcd for 1 bromobenzaldehyde [2.2.1]heptane- bromobenzylamino)- C.sub.15H.sub.18BrNO.sub.2: 323.05; white solid 2-carboxylic bicyclo[2.2.1]- found: 324.1 (MH.sup.+) 8% acid heptane-2-carboxylic acid 86 3- noradamantyl- N-(3-bromobenzyl)- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.16H.sub.20BrN: 305.08; found: 306.1 (MH.sup.+) 87 3- 3-Amino-1- N-(3-bromobenzyl)- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.17H.sub.22BrNO: 335.09; found: 336.1 (MH.sup.+) 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)- C.sub.17H.sub.18BrNO.sub.3: 363.05; white solid 2-amino- 2-(4- found: 364.0 (MH.sup.+) 2% propanoic acid hydroxybenzyl)- propanoic acid 90 3- 2-(3,4- 2-(3,4- ESI+MS: calcd for 4 bromobenzaldehyde dihydroxy- dihydroxybenzyl)-2- C.sub.17H.sub.18BrNO.sub.4: 379.04; yellow oil benzyl)-2- (3- found: 380.1 (MH.sup.+) 20% amino- bromobenzylamino)- propanoic acid propanoic acid 91 3- 2-amino-2- 2-(3- ESI+MS: calcd for 2 bromobenzaldehyde phenylbutanoic bromobenzylamino)- C.sub.17H.sub.18BrNO.sub.2: 347.05; white solid acid 2-phenylbutanoic found: 348.1 (MH.sup.+) 9% acid 92 3- 2-amino-2,2- 2-(3- ESI+MS: calcd for 2 bromobenzaldehyde diphenylacetic bromobenzylamino)- C.sub.21H.sub.18BrNO.sub.2: 395.05; white solid acid 2,2-diphenylacetic found: 396.1 (MH.sup.+) 1.4% acid 93 3- methyl 2- methyl 2-(3- ESI+MS: calcd for 2 bromobenzaldehyde amino-2- bromobenzylamino)- C.sub.18H.sub.20BrNO.sub.2: 361.07; colorless benzyl- 2-methyl-3- found: 362.1 (MH.sup.+) 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- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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- C.sub.15H.sub.14BrNO.sub.2: 319.02; colorless [d][1,3]dioxol-5- found: 320.1 (MH.sup.+) 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-US-00008 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- .sup.1H NMR (CDCl.sub.3, 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 C.sub.14H.sub.14BrN: 275.03; found: 276.0 (MH.sup.+) 99 3- 3- bis(3- ESI+MS: calcd for 1 bromobenzylamine bromobenzaldehyde bromobenzyl)- C.sub.14H.sub.13Br.sub.2N: 352.94; white solid amine found: 353.8 (MH.sup.+) 75% 100 3- 3- N-(3- .sup.1H NMR (CDCl.sub.3, 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 C.sub.14H.sub.13BrFN: 293.02; found: 293.9 (MH.sup.+) 101 3- 1-methyl-1H- N-(3- ESI+MS: calcd for 1 bromobenzylamine indole-2- bromobenzyl)(1- C.sub.17H.sub.17BrN.sub.2: 328.06; yellow solid carbaldehyde methyl-1H-indol-2- found: 328.9 (MH.sup.+) 27% yl)methanamine 102 3- acetophenone N-(3-bromobenzyl)- .sup.1H NMR (CDCl.sub.3, 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)- .sup.1H NMR (CDCl.sub.3, 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 C.sub.15H.sub.15Br.sub.2N: 366.96; found: 367.8 (MH.sup.+) 104 3- 1-(pyridin-2- N-(3-bromobenzyl)- .sup.1H NMR (CDCl.sub.3, 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 C.sub.14H.sub.15BrN.sub.2: 290.04; found: 291.0 (MH.sup.+) 105 3- quinuclidin-3- N-(3- .sup.13C NMR (CDCl.sub.3, 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 C.sub.14H.sub.19BrN.sub.2: 294.07; found: 295.0 (MH.sup.+) 106 3- 9-Methyl-9- (1R*,5S*)-N-(3- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.16H.sub.22BrN: 307.09; found: 308.0 (MH.sup.+) 107 3- 8-methyl-8-aza- N-(3-bromobenzyl)- .sup.13C NMR (CDCl.sub.3, 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 C.sub.15H.sub.21BrN.sub.2: 308.09; found: 309.0 (MH.sup.+) 108 3- 1-adamantyl N-(1-(3- .sup.13C NMR (CDCl.sub.3, 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 C.sub.19H.sub.26BrN: 347.12; found: 348.0 (MH.sup.+) 109 3- noradamantyl- N-(3-fluorobenzyl)- ESI+MS: calcd for 1 fluorobenzylamine amine noradamantylamine C.sub.16H.sub.20FN: 245.16; 100% found: 246.09 (MH.sup.+)

[0177] The compounds of table A5 are prepared according to process A, adding a microwave heating step.

TABLE-US-00009 TABLE A5 Purification method/ appearance/ Compound Compound name Compound characteristics yield 138 N-(3-chlorobenzyl)adamantylamine .sup.1H NMR (CDCl.sub.3, 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% .sup.13C NMR (CDCl.sub.3, 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 C.sub.17H.sub.22CIN: 275.14; found: 276.1 (MH.sup.+) 139 N-(3-chlorobenzyl)-2-adamantylamine .sup.1H NMR (CDCl.sub.3, 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% .sup.13C NMR (CDCl.sub.3, 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 C.sub.17H.sub.22ClN: 275.14; found: 276.2 (MH.sup.+) 140 N-(3-iodobenzyl)-2-adamantylamine .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.17H.sub.22IN: 367.08; found: 367.6 (MH.sup.+) 141 N-(2,2-diphenylethyl)-2- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.24H.sub.29N: 331.23; found: 331.9 (MH.sup.+) 142 N-(naphthalen-1-ylmethyl)-2- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.21H.sub.25N: 291.2; found: 291.8 (MH.sup.+) 143 N-(phenanthren-9-ylmethyl)-2- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.25H.sub.27N: 341.21; found: 341.8 (MH.sup.+) 144 4-((adamantylamino)methyl)benzoic .sup.1H NMR (CDCl.sub.3, 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% .sup.13C NMR (CDCl.sub.3, 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 C.sub.18H.sub.23NO.sub.2: 285.17; found: 286.1 (MH.sup.+)

[0178] Process B: Formation of Acid Salts

[0179] A solution of HCl in Et.sub.2O (2N) is added to a solution of the amine (corresponding to the desired hydrochloride salt) in CH.sub.2Cl.sub.2. The salt is obtained after filtration and drying of the precipitate under vacuum.

TABLE-US-00010 TABLE B1 Salts derived from 1- or 2-aminoadamantane Purification method/ appearance/ Compound Compound name Compound characteristics yield 110 N-(3- .sup.1H NMR (CDCl.sub.3, 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- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (DMSO-d.sup.6, 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- .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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.

[0180] Process C

[0181] 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-US-00011 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- .sup.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- .sup.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- .sup.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). .sup.13C NMR (CDCl.sub.3, 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 C.sub.20H.sub.24N.sub.2: 292.19; found: 293.2 (MH.sup.+) 116 benzaldehyde (E)—N- .sup.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-US-00012 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- .sup.1H NMR (CDCl.sub.3, 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- .sup.1H NMR (CDCl.sub.3, 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-US-00013 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

[0182] Process E: Benzoylation

##STR00224##

[0183] 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-US-00014 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 .sup.1H NMR (CDCl.sub.3, 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). .sup.13C NMR (CDCl.sub.3, 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 .sup.1H NMR (CDCl.sub.3, 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 C.sub.17H.sub.21NO: 255.16; found: 256.2 (MH.sup.+)

[0184] The sulfonylation is carried out according to the following process:

##STR00225##

Et.sub.3N (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 CH.sub.2Cl.sub.2 (1 ml). The mixture is stirred at ambient temperature for 24 h, and hydrolyzed with NH.sub.4Cl. The organic phase is washed three times with water, dried over MgSO.sub.4, filtered and evaporated to give the expected product.

Preparation of N-1-adamantylsulfonamide (Compound 124)

[0185] ##STR00226##

[0186] Starting from 1-adamantylamine, the product obtained is a brown solid (86%).

[0187] .sup.1H NMR (CDCl.sub.3, 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).

[0188] .sup.13C NMR (CDCl.sub.3, 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)

[0189] ##STR00227##

[0190] Starting from 2-adamantylamine, the product obtained is a yellow solid (860).

[0191] .sup.1H NMR (CDCl.sub.3, 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).

[0192] .sup.13C NMR (CDCl.sub.3, 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.

[0193] Nucleophilic Addition

##STR00228##

[0194] 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 Et.sub.2O, and filtered, and then the filtrate is evaporated.

[0195] This process makes it possible to prepare the following compounds:

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

[0196] ##STR00229##

[0197] Starting from 1-adamantylamine and phenylisocyanate, a white solid is obtained (95%).

[0198] .sup.1H NMR (CDCl.sub.3, 400 MHz); δ 7.35 (m, 3H), 7.11 (m, 2H), 2.18 (s, 3H), 2.00 (s, 6H), 1.68 (s, 6H).

[0199] .sup.13C NMR (CDCl.sub.3, 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 C.sub.17H.sub.22N.sub.2O: 270.17. found: 271.1 (MH.sup.+).

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

[0200] Phenylisocyanate or phenylthioisocyanate (0.75 mmol; 1.5 equiv.) and triethylamine (1.05 equiv.) are added, at 0° C., to a stirred suspension of 2-adamantylamine hydrochloride (0.5 mmol; 1 equiv.) in DMF (3 ml). The mixture is stirred for 24 h at ambient temperature, evaporated, placed in solution in Et.sub.2O and filtered, and then the filtrate is evaporated.

##STR00230##

[0201] A white solid is obtained (69%).

[0202] .sup.1H NMR (CDCl.sub.3, 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).

[0203] ESI+MS: calcd for C.sub.17H.sub.22N.sub.2O: 270.17. found: 271.1 (MH.sup.+).

[0204] 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 CH.sub.2Cl.sub.2 (4 ml). The mixture is stirred for 24 h at ambient temperature, washed with water, placed in a saturated solution of NH.sub.4Cl, dried over Na.sub.2SO.sub.4, filtered, evaporated and short-pad-purified.

##STR00231##

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

[0205] ##STR00232##

[0206] Starting from 1-adamantylamine and phenyl chloroformate, a white solid is obtained (13%).

[0207] .sup.1H NMR (CDCl.sub.3, 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).

[0208] .sup.13C NMR (CDCl.sub.3, 100 MHz): δ 150.9, 129.1, 125.0, 121.7, 51.2, 41.7, 36.3, 29.4.

[0209] ESI+MS: calcd for C.sub.17H.sub.21NO.sub.2: 271.16. found: 272.1 (MH.sup.+).

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

[0210] ##STR00233##

[0211] Starting from 2-adamantylamine hydrochloride and phenyl chloroformate, a white solid is obtained (17%).

[0212] .sup.1H NMR (CDCl.sub.3, 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).

[0213] .sup.13C NMR (CDCl.sub.3, 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.

[0214] ESI+MS: calcd for C.sub.17H.sub.21NO.sub.2: 271.16. found: 272.1 (MH.sup.+).

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

[0215] 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 CH.sub.2Cl.sub.2 (3 ml). The mixture is stirred for 24 h at ambient temperature, washed with water, placed in a saturated solution of NH.sub.4Cl, dried over Na.sub.2SO.sub.4, filtered, evaporated and short-pad-purified.

##STR00234##

[0216] Starting from acetyl chloride, a colorless oil is obtained (26%).

[0217] .sup.1H NMR (CDCl.sub.3, 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).

[0218] .sup.13C NMR (CDCl.sub.3, 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.

[0219] ESI+MS: calcd for C.sub.19H.sub.24BrNO: 361.10. found: 362.0 (MH.sup.+).

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

[0220] 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.

##STR00235##

[0221] Starting from phenylisocyanate, a colorless oil is obtained (51%).

[0222] .sup.1H NMR (CDCl.sub.3, 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).

[0223] .sup.13C NMR (CDCl.sub.3, 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.

[0224] ESI+MS: calcd for C.sub.24H.sub.27BrN.sub.2O: 438.13. found: 439.0 (MH.sup.+).

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

[0225] 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 CH.sub.2Cl.sub.2 (2 ml). The mixture is stirred for 24 h at ambient temperature, washed with water, placed in a saturated solution of NH.sub.4Cl, dried over Na.sub.2SO.sub.4, filtered, evaporated and short-pad-purified.

##STR00236##

[0226] Starting from benzoyl chloride, a white oil is obtained (17%).

[0227] .sup.1H NMR (CDCl.sub.3, 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).

[0228] .sup.13C NMR (CDCl.sub.3, 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.

[0229] ESI+MS: calcd for C.sub.24H.sub.26BrNO: 423.12. found: 424.8 (MH.sup.+).

[0230] Synthesis by Click Chemistry

##STR00237##

[0231] Et.sub.3N (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)

[0232] ##STR00238##

[0233] Starting from 1-azidoadamantane and phenylacetylene, a brown oil is obtained (96%).

[0234] .sup.1H NMR (CDCl.sub.3, 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).

[0235] .sup.13C NMR (CDCl.sub.3, 100 MHz): δ 146.5, 140.0, 128.6, 127.6, 125.4, 116.0, 59.4, 42.8, 35.7, 29.3.

[0236] ESI+MS: calcd for C.sub.18H.sub.21N.sub.3: 279.17. found: 280.2 (MH.sup.+).

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

[0237] ##STR00239##

[0238] Starting from 1-azidomethyladamantane and phenylacetylene, a brown oil is obtained (68%).

[0239] .sup.1H NMR (CDCl.sub.3, 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).

[0240] .sup.13C NMR (CDCl.sub.3, 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.

[0241] ESI+MS: calcd for C.sub.19H.sub.23N.sub.3: 293.19. found: 294.2 (MH.sup.+).

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

[0242] ##STR00240##

[0243] Starting from 1-azidoadamantane and 2-ethynylpyridine, a brown oil is obtained (39%).

[0244] .sup.1H NMR (CDCl.sub.3, 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).

[0245] .sup.13C NMR (CDCl.sub.3, 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.

[0246] ESI+MS: calcd for C.sub.17H.sub.20N.sub.4: 280.17. found: 281.2 (MH.sup.+).

[0247] Imidazolines and Oxazoline

##STR00241##

[0248] 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 Na.sub.2SO.sub.3 (5 ml), and extracted with chloroform (20 ml). The organic phases are washed with 2N NaOH (20 ml) and brine (20 ml), dried over Na.sub.2SO.sub.4, filtered and evaporated.

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

[0249] ##STR00242##

[0250] Starting from 1-adamantanemethanol and ethylenediamine, a colorless oil is obtained (66%).

[0251] .sup.1H NMR (CDCl.sub.3, 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)

[0252] ##STR00243##

[0253] Starting from 1-adamantanemethanol and 2-aminoethanol, a colorless oil is obtained (2.4%).

[0254] .sup.1H NMR (CDCl.sub.3, 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)

[0255] ##STR00244##

[0256] Starting from 1-adamantanemethanol and N-phenylethylenediamine, a yellow oil is obtained (15%).

[0257] .sup.1H NMR (CDCl.sub.3, 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).

[0258] .sup.13C NMR (CDCl.sub.3, 7100 MHz): δ 172.0, 145.0, 129.2, 127.1, 58.2, 52.1, 40.5, 37.5, 36.4, 28.2.

[0259] ESI+MS: calcd for C.sub.19H.sub.24N.sub.2: 280.19. found: 281.2 (MH.sup.+).

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

[0260] ##STR00245##

[0261] Starting from 1-adamantanemethanol and (1R,2R)-1,2-cyclohexanediamine, a yellow oil is obtained (10%).

[0262] .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 4.67 (bs, 1H), 2.84 (bs, 2H), 2.03 (s, 3H), 1.87 (s, 6H), 1.72 (m, 6H).

[0263] ESI+MS: calcd for C.sub.17H.sub.26N.sub.2: 258.21. found: 259.2 (MH.sup.+).

[0264] The synthesis of the amine compounds requires the prior preparation of the following synthesis intermediate: [0265] 2-amino-N-phenylbenzamide

[0266] 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).

[0267] .sup.1H NMR (400 MHz, DMSO d.sup.5)

[0268] δ: 9.95 (s, 1H, NH), 7.70-7.68 (d, J=7.6 Hz, 2H, H.sub.Ar 2′), 7.62-7.59 (d, J=8 Hz, 1H, H.sub.Ar 3), 7.33-7.29 (t, J=7.6 Hz, 2H, H.sub.Ar 3′), 7.20-7.16 (t, J=8.4 Hz, 1H, H.sub.Ar 4), 7.08-7.04 (t, J=7.2 Hz, 1H, H.sub.Ar 4′), 6.75-6.73 (d, J=8.4 Hz, 11-4, H.sub.Ar 6), 6.60-6.56 (t, J=8 Hz, 1H, H.sub.Ar 5), 6.29 (2H, NH.sub.2).

[0269] MS (ES) m/z 213 (M+H.sup.+), 120.

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

[0270] 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.

[0271] .sup.1H NMR (400 MHz, DMSO d.sup.6) δ: 8.40 (s, 1H, CH), 7.70-6.60 (m, 13H, H.sub.Ar),

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

[0272] 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.

[0273] .sup.1H NMR (400 MHz, DMSO d.sup.6) δ: 9.43 (s, 1H, CH), 7.62-6.72 (m, 13H, H.sub.Ar).

[0274] Amination

[0275] 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 CH.sub.2Cl.sub.2 (100 ml). The mixture is stirred for 4 days and evaporated. The solid is then solubilized in acetone and then filtered.

[0276] The brown filtrate is evaporated, to give a brown solid which is washed with Et.sub.2O to give 2-nitro-N-phenylbenzamide in the form of an orange solid (11.6 g; 71%).

[0277] 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.

[0278] 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.

[0279] This process makes it possible to prepare the following compounds:

##STR00246##

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

[0280] ##STR00247##

[0281] Starting from furan-2-carbaldehyde, a yellow solid is obtained (99%).

[0282] .sup.1H NMR (CDCl.sub.3, 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).

[0283] .sup.13C NMR (CDCl.sub.3, 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.

[0284] ESI+MS: calcd for C.sub.18H.sub.14N.sub.2O.sub.2: 290.11. found: 291.1 (MH.sup.+).

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

[0285] ##STR00248##

[0286] Starting from 5-methylfuran-2-carbaldehyde, a yellow solid is obtained (1000).

[0287] ESI+MS: calcd for C.sub.19H.sub.16N.sub.2O.sub.2: 304.12. found: 305.0 (MH.sup.+).

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

[0288] ##STR00249##

[0289] Starting from furan-3-carbaldehyde, a yellow solid is obtained (970).

[0290] .sup.1H NMR (CDCl.sub.3, 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).

[0291] .sup.13C NMR (CDCl.sub.3, 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.

[0292] ESI+MS: calcd for C.sub.18H.sub.14N.sub.2O.sub.2: 290.11. found: 291.1 (MH.sup.+).

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

[0293] ##STR00250##

[0294] Starting from 2-fluorobenzaldehyde, a yellow solid is obtained (53%).

[0295] ESI+MS: calcd for C.sub.20H.sub.15FN.sub.2O: 318.12. found: 319.1 (MH.sup.+).

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

[0296] ##STR00251##

[0297] Starting from 3-fluorobenzaldehyde, a yield of 100% is obtained.

[0298] ESI+MS: calcd for C.sub.20H.sub.15FN.sub.2O: 318.12. found: 319.1 (MH.sup.+).

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

[0299] ##STR00252##

[0300] Starting from 3-bromobenzaldehyde, a yield of 100% is obtained.

[0301] .sup.1H NMR (DMSO-d.sup.6, 400 MHz): δ 8.40 (s, 1H), 7.70-6.60 (m, 13H, H).

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

[0302] ##STR00253##

[0303] Starting from 4-fluorobenzaldehyde, a yellow oil is obtained (8%).

[0304] Purification Mode: Short Pad

[0305] .sup.1H NMR (DMSO d.sup.6, 400 MHz): δ 9.43 (s, 1H), 7.62-632 (m, 13H) ESI+MS: calcd for C.sub.20H.sub.15BrN.sub.2O: 318.12. found: 319.2 (MH.sup.+).

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

[0306] ##STR00254##

[0307] Starting from 5-fluoro-2-nitrobenzaldehyde, a yellow oil is obtained (2.9%).

[0308] Purification Mode: Short Pad

[0309] ESI+MS: calcd for C.sub.20H.sub.14FN.sub.3O.sub.3: 363.34. found: 364.1 (MW).

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

[0310] ##STR00255##

[0311] Starting from 5-bromo-2-hydroxybenzaldehyde, a yellow oil is obtained (92%).

[0312] ESI+MS: calcd for C.sub.20H.sub.15BrN.sub.2O.sub.2: 394.03. found: 395.0 (MH.sup.+).

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

[0313] ##STR00256##

[0314] Starting from 1-methyl-1H-indole-2-carbaldehyde, a yellow oil is obtained (12%).

[0315] Purification Mode: Short Pad

[0316] ESI+MS: calcd for C.sub.23H.sub.19N.sub.3O: 353.15. found: 354.2 (MH.sup.+).

[0317] Reductive Amination

##STR00257##

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

[0318] ##STR00258##

[0319] Starting from (E)-2-(3-fluorobenzylideneamino)-N-phenylbenzamide.

[0320] Yield=100%.

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

[0321] ##STR00259##

[0322] Starting from (E)-2-(2-fluorobenzylideneamino)-N-phenylbenzamide, a colorless oil is obtained (1%).

[0323] Purification Mode: Short Pad

[0324] ESI+MS: calcd for C.sub.20H.sub.17FN.sub.2O: 320.13. found: 321.0 (MH.sup.+).

[0325] Benzodiazepines

[0326] The synthesis of the compounds of general formula (II) requires the prior preparation of the following synthesis intermediates: [0327] tert-butyl N-[(phenylcarbamoyl)methyl]carbamate

[0328] 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%).

[0329] .sup.1H NMR (400 MHz, CDCl.sub.3)

[0330] δ: 9.89 (s, 1H, NH), 7.57-7.55 (d, J=7.6 Hz, 2H, H.sub.Ar), 7.30-7.26 (t, J=7.6 Hz, 2H, H.sub.Ar), 7.02-7.00 (d, J=7.2 Hz, 1H, H.sub.Ar), 5.19 (s, 1H, NH), 3.70-3.69 (d, J=6 Hz, 2H, CH.sub.2), 1.38 (s, 9H, (CH.sub.3).sub.3)

[0331] MS (ES) m/z 251 (M+H.sup.+), 195, 151, 94. [0332] tert-butyl (4-methoxyphenylcarbamoyl)methylcarbamate

[0333] 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%).

[0334] .sup.1H NMR (400 MHz, CDCl.sub.3)

[0335] δ: 9.74 (s, 1H, NH), 7.48-7.45 (d, J=9.2 Hz, 2H, H.sub.Ar), 7.00 (s, 1H, NH), 6.87-6.84 (d, J=8.8 Hz, 2H, H.sub.Ar), 3.70 (s, 3H, OCH.sub.3), 3.67-3.66 (d, J=6 Hz, 2H, CH.sub.2), 1.38 (s, 9H, (CH.sub.3).sub.3).

[0336] MS (ES) m/z 281 (M+H.sup.+), 225, 181, 124. [0337] 2-amino-N-phenylacetamide

[0338] 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.

[0339] MS (ES) m/z 151 (M+H.sup.+), 94. [0340] 2-amino-N-(4-methoxyphenyl)acetamide

[0341] 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.

[0342] MS (ES) m/z 181 (M+H.sup.+), 124. [0343] 2-benzoyl-4-bromoaniline

[0344] 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).

[0345] 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.

[0346] .sup.1H NMR (400 MHz, CDCl.sub.3)

[0347] 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, NH.sub.2).

[0348] MS (ES) m/z 276 (M+H.sup.+), 198, 105.

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

[0349] 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%.

[0350] .sup.1H NMR (400 MHz, CDCl.sub.3)

[0351] δ: 7.50-6.60 (m, 8H, H.sub.N), 6.44 (s, 1H, NH), 5.30 (s, 1H, CH), 3.82-3.72 (dd, J=10 et 15.6 Hz, 2H, CH.sub.2), 3.73 (s, 3H, OCH.sub.3), 3.49 (s, 1H, NH).

[0352] MS (ES) m/z 269 (M+H.sup.f), 222, 204, 145, 106.

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

[0353] 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% Na.sub.2CO.sub.3. The combined organic phases are washed with a saturated solution of sodium chloride and then dried with anhydrous Na.sub.2SO.sub.4 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%.

[0354] .sup.1H NMR (400 MHz, CDCl.sub.3)

[0355] δ: 8.45 (s, 1H, NH), 7.64-7.26 (m, 9H, H.sub.Ar), 4.34 (s, 2H, CH.sub.2).

[0356] MS (ES) m/z 237 (M+H.sup.+).

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

[0357] 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% Na.sub.2CO.sub.3. The combined organic phases are washed with a saturated solution of sodium chloride, then dried with anhydrous Na.sub.2SO.sub.4 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%).

[0358] .sup.1H NMR (400 MHz, CDCl.sub.3)

[0359] δ: 9.42 (s, 1H, NH), 7.78-7.16 (m, 8H, H.sub.Ar), 4.33 (s, 2H, CH.sub.2).

[0360] MS (ES) m/z 271 (M+H.sup.+).

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

[0361] 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% Na.sub.2CO.sub.3. The combined organic phases are washed with a saturated solution of sodium chloride, then dried over anhydrous Na.sub.2SO.sub.4 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%.

[0362] .sup.1H NMR (400 MHz, CDCl.sub.3)

[0363] δ: 9.26 (s, 1H, NH), 7.90-7.32 (m, 8H, H.sub.Ar), 4.37 (s, 2H, CH.sub.2).

[0364] MS (ES) m/z 315 (M+H.sup.+).

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

[0365] 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%.

[0366] .sup.1H NMR (400 MHz, CDCl.sub.3)

[0367] δ: 9.12 (s, 1H, NH), 7.35-6.67 (m, 9H, H.sub.Ar), 5.21 (s, 1H, CH), 3.35-3.25 (q, J=10−14.8 Hz, 2H, CH.sub.2), 3.21 (s, 1H, NH).

[0368] MS (ES) m/z 239 (M+H.sup.+), 182, 132, 91.

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

[0369] ##STR00260##

[0370] 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%.

[0371] .sup.1H NMR (400 MHz, CDCl.sub.3)

[0372] δ: 9.15 (s, 1H, NH), 7.40-6.86 (m, 8H, H.sub.Ar), 5.20 (s, 1H, CH), 3.45-3.36 (q, J=10-13.6 Hz, 2H, CH.sub.2), 3.10 (s, 1H, NH).

[0373] MS (ES) m/z 273 (M+H.sup.+), 221, 91.

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

[0374] 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%.

[0375] .sup.1H NMR (400 MHz, CDCl.sub.3)

[0376] δ: 8.48 (s, 1H, NH), 7.52-6.86 (m, 8H, H.sub.Ar), 5.18 (s, 1H, CH), 3.45-3.35 (q, J=10-14.8 Hz, 2H, CH.sub.2), 2.86 (s, 1H, NH).

[0377] MS (ES) m/z 317 (M+H.sup.+), 91.

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

[0378] 1,2-Diaminobenzene (1 eq., 2 mmol, 216 mg) and ethyl 3-oxo-3-phenylpropanoate (1 eq., 2 mmol, 384 mg) are mixed together in a pill bottle flask. The reaction mixture is then heated at 150° C. for 2 hours. The residue is then diluted in ethyl acetate and hydrochloric acid (pH˜5), and then the organic phase is washed with water and then with a saturated solution of sodium chloride. Finally, the solution is dried with Na.sub.2SO.sub.4 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%.

[0379] .sup.1H NMR (400 MHz, CDCl.sub.3)

[0380] δ: 12.88 (s, 1H, NH), 8.17-6.64 (m, 9H, H.sub.Ar), 5.50 (s, 2H, CH.sub.2).

[0381] MS (ES) m/z 237 (M+H.sup.+), 195.

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

[0382] 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%.

[0383] 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% Na.sub.2CO.sub.3 solution. The organic phase is extracted several times with the Na.sub.2CO.sub.3 solution, and then with a saturated solution of sodium chloride. Finally, the solution is dried with Na.sub.2SO.sub.4 and then evaporated.

[0384] 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).

[0385] .sup.1H NMR (400 MHz, CDCl.sub.3)

[0386] δ: 9.15 (s, 1H, NH), 7.40-6.72 (m, 9H, H.sub.Ar), 5.76 (s, 1H, NH), 4.91-4.89 (m, 1H, CH), 2.54-2.52 (d, J=6 Hz, 2H, CH.sub.2).

[0387] MS (ES) m/z 239 (M+H.sup.+), 197, 131.

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

[0388] 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%.

[0389] .sup.1H NMR (400 MHz, CDCl.sub.3)

[0390] δ: 9.10 (s, 1H, NH), 7.62-6.72 (m, 9H, H.sub.Ar), 5.10 (s, 1H, CH), 4.24 (m, 2H, CH.sub.2), 2.62-2.61 (d, J=6 Hz, 2H, CH.sub.2), 1.46 (t, J=8 Hz, 3H, CH.sub.3).

[0391] MS (ES) m/z 311 (M+H.sup.+), 269, 207, 135.

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

[0392] ##STR00261##

[0393] 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 Et.sub.2O to give the desired compound.

[0394] Starting from benzene-1,2-diamine:

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

[0395] Starting from ethyl 3-oxo-3-m-tolylpropanoate, a brown solid is obtained (31%).

[0396] .sup.1H NMR (CDCl.sub.3, 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).

[0397] ESI+MS: calcd for C.sub.16H.sub.14N.sub.2O: 250.11. found: 250.1 (MH.sup.+).

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

[0398] Starting from ethyl 3-(3-methoxyphenyl)-3-oxopropanoate, a brown solid is obtained (20%).

[0399] .sup.1H NMR (CDCl.sub.3, 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).

[0400] .sup.13C NMR (CDCl.sub.3, 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.

[0401] ESI+MS: calcd for C.sub.16H.sub.14N.sub.2O.sub.2: 266.11. found: 267.0 (MH.sup.+).

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

[0402] Starting from ethyl 3-(3-nitrophenyl)-3-oxopropanoate, a brown solid is obtained (23%).

[0403] .sup.1H NMR (CDCl.sub.3, 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).

[0404] ESI+MS: calcd for C.sub.15H.sub.11N.sub.3O.sub.3: 281.08. found: 282.0 (MH.sup.+).

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

[0405] Starting from ethyl 3-(3-chlorophenyl)-3-oxopropanoate, a brown solid is obtained (15%).

[0406] .sup.1H NMR (CDCl.sub.3, 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).

[0407] .sup.13C NMR (CDCl.sub.3, 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)

[0408] Starting from ethyl 3-(3-bromophenyl)-3-oxopropanoate, a brown solid is obtained (7%).

[0409] .sup.1H NMR (CDCl.sub.3, 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).

[0410] .sup.13C NMR (CDCl.sub.3, 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)

[0411] Starting from ethyl 3-(3-(trifluoromethyl)phenyl)-3-oxopropanoate, a brown solid is obtained (34%).

[0412] .sup.1H NMR (CDCl.sub.3, 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).

[0413] Starting from 4-bromobenzene-1,2-diamine

[0414] 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).

[0415] The mixture is stirred at reflux (120° C.) for 3 h. The mixture is diluted with EtOAc, acidified (pH 5), extracted with EtOAc, filtered, evaporated and washed with Et.sub.2O.

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

[0416] Starting from ethyl 3-oxo-3-m-tolylpropanoate, a brown solid is obtained (28%).

[0417] .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 7.89 (m, 3H), 7.40-7.32 (m, 4H), 3.58 (s, 2H), 2.44 (s, 3H).

[0418] ESI+MS: calcd for C.sub.16H.sub.13BrN.sub.2O: 328.02. found: 328.9 (MH.sup.+).

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

[0419] Starting from ethyl 3-(3-methoxyphenyl)-3-oxopropanoate, a brown solid is obtained (10%).

[0420] ESI+MS: calcd for C.sub.16H.sub.13BrN.sub.2O.sub.2: 344.02. found: 344.9 (MH.sup.+).

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

[0421] Starting from 3-(3-nitrophenyl)-3-oxopropanoate, a brown solid is obtained (6.5%).

[0422] ESI+MS: calcd for C.sub.15H.sub.10BrN.sub.3O.sub.3: 358.99. found: 359.8 (MH.sup.+).

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

[0423] Starting from ethyl 3-(3-chlorophenyl)-3-oxopropanoate, a brown solid is obtained (23%).

[0424] ESI+MS: calcd for C.sub.15H.sub.10BrClN.sub.2O: 347.97. found: 348.8 (MH.sup.+).

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

[0425] Starting from ethyl 3-(3-bromophenyl)-3-oxopropanoate, a brown solid is obtained (10%).

[0426] ESI+MS: calcd for C.sub.15H.sub.10Br.sub.2N.sub.2O: 391.92. found: 392.8 (MH.sup.+).

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

[0427] Starting from ethyl 3-(3-(trifluoromethyl)phenyl)-3-oxopropanoate, a brown solid is obtained (29%).

[0428] ESI+MS: calcd for C.sub.16H.sub.10BrF.sub.3N.sub.2O: 381.99. found: 382.8 (MH.sup.+).

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

[0429] 1) Principle of the High-Throughput Screening:

[0430] 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.

[0431] 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.

[0432] 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.sup.−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 [.sup.14C]-leucine (0.05 μCi/well). The incorporation of [.sup.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).

[0433] The yellow-colored wells are positive controls (A549 treated with ricin (10.sup.−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).

[0434] The results of the screening carried out are represented in the graph of FIG. 2.

[0435] 2) Implementation of the High-Throughput Screening:

[0436] 2.1. Protective Activity Against Ricin Toxin of the Compounds According to the Invention

[0437] The compounds were tested on A549 cells at the concentration of 30 μM by incubation with various ricin concentrations (10.sup.−9 to 10.sup.−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 EC.sub.50, i.e. the effective concentration for which 50% radioactive leucine assimilation is observed, which corresponds to 50% of viable cells. The higher the EC.sub.50 value, the greater the cell protection, since a higher concentration of ricin is then necessary in order to generate the same cytotoxicity.

[0438] The results, presented in the table below, are indicated in the form of a protective index (PI=EC.sub.50 compound/EC.sub.50 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).

TABLE-US-00015 N.sup.o Structures Bio 19 [00262] 1.31 3 [00263] 2.65 7 [00264] 1.07 9 [00265] 1.88 148 [00266] 2.82 21 [00267] 1.01 1 [00268] 1.58 123 [00269] 1.02 113 [00270] 1.09 121 [00271] 1.225 110 [00272] 3.13 32 [00273] 1.16 15 [00274] 4.64 111 [00275] 3.07 5 [00276] 2.13 124 [00277] 1.08 26 [00278] 1.06 27 [00279] 1.23 28 [00280] 2.52 24 [00281] 1.49 56 [00282] 1.09 36 [00283] 2.28/3.57 50 [00284] 1.22 53 [00285] 1.17 54 [00286] 1.17 55 [00287] 1.21 59 [00288] 1.30 132 [00289] 1.03 133 [00290] 1.10 51 [00291] 1.063 117 [00292] 2.199 118 [00293] 1.48 112 [00294] 3.54 192 [00295] 1.2 69 [00296] 1.84 69 [00297] 1.52 34 [00298] 1.93 39 [00299] 3.77 72 [00300] 1.27 40 [00301] 1.16 193 [00302] 4.1 122 [00303] 1.49 128 [00304] 1.30 64 [00305] 1.16 65 [00306] 1.61 94 [00307] 1.18 89 [00308] 1.41 109 [00309] 1.32 78 [00310] 1.09 79 [00311] 1.02 80 [00312] 1.05 81 [00313] 1.03 75 [00314] 1.62 86 [00315] 2.24 77 [00316] 1.15 84 [00317] 1.25 83 [00318] 1.05 [00319] 1.07 120 [00320] 1.09 102 [00321] 1.34 99 [00322] 1.09 105 [00323] 1.38 106 [00324] 3.64 108 [00325] 1.20 107 [00326] 2.33 165 [00327]   1 (a) 166 [00328] 1.14 (a) 166 [00329] 1.11 (a) 179 [00330] 1.04 149 [00331] 1.02 151 [00332] 1.04 154 [00333] 1.37 157 [00334] 1.27 138 [00335] 1.55 131 [00336] 1.43 139 [00337] 2.97 140 [00338] 2.62 141 [00339] 1.10 142 [00340] 1.41 143 [00341] 1.64 161 [00342] 2.98

[0439] 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.

[0440] These compounds are the first inhibitors that are active on human pulmonary and digestive epithelial cells with respect to the toxic activity of ricin.

[0441] 2.2. Protective Activity Against Diphtheria Toxin of the Compounds According to the Invention

[0442] 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.sup.−9 to 10.sup.−12 M) (Sigma), with the protocol described in point 2.1.

[0443] The results, presented in the table below, also represent a protective index (PI=EC.sub.50 compound/EC.sub.50 ricin ratio): the higher it is, the greater the protection of the cells against the action of diphtheria toxin.

TABLE-US-00016 Compound Structure Activity  5 [00343] 2.2  9 [00344] 1.7  39 [00345] 1.5 110 [00346] 2.6 111 [00347] 1.8 112 [00348] 3.6 139 [00349] 1.7 140 [00350] 3.0