COMPOUNDS, PHARMACEUTICAL COMPOSITION AND THEIR USE IN TREATING NEURODEGENERATIVE DISEASES

Abstract

The present invention is directed to novel compounds of Formula (I), pharmaceutically acceptable salts or solvates thereof, and their use.

##STR00001##

Claims

1-18. (canceled)

19. A method of treating and/or preventing a sigma-1 receptor related disease, comprising the step of administering an effective amount of a compound Formula I, ##STR00048## or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof, wherein X.sup.1 and X.sup.5 are independently selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, nitro, di(C1-C4-alkyl)amino, NHCOOR, and COOR, wherein R is methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or tert-butyl; X.sup.2, X.sup.3, X.sup.4 are independently selected from the group consisting of hydrogen, chloro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, cyano, nitro, di(C1-C4-alkyl)amino, NHCOOR, and COOR, wherein R is methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or tert-butyl; with the proviso that at least one of X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5 is not hydrogen and that at least one of X.sup.2, X.sup.3, X.sup.4 is not C1-C4-alkoxy; L is C(O)NH, NHC(O), SO.sub.2NH, NHSO.sub.2, or NH; n is 0, 1 or 2; m is 1, 2, 3, 4 or 5; R.sup.1 is H or alkyl, and R.sup.2 is 5- or 6-membered arylalkyl, 5- or 6-membered cycloalkylalkyl, wherein the cyclic moiety of said arylalkyl or cycloalkylalkyl is optionally substituted by one or more substituents independently selected from halogen; or R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached, form a 5-membered heterocyclyl group, which is fused to a 5- or 6-membered aryl group and which is optionally substituted by one or more substituents independently selected from C1-C3 alkyl, and wherein the resulting heterocyclic moiety is optionally substituted by one or more substituents independently selected from halogen.

20. The method according to claim 19, wherein the compound is selected from the group consisting of: N-[3-(benzylmethylamino)propyl]-4-propylbenzamide, N-[3-(benzylmethylamino)propyl]-4-butylbenzamide, N-[3-(benzylmethylamino)propyl]-4-tertbutylbenzamide, N-[3-(benzylmethylamino)propyl]-4-trifluoromethylbenzamide, N-[3-(benzylmethylamino)propyl]-4-fluorobenzamide, N-[3-(benzylmethylamino)propyl]-2-chlorobenzamide, N-[3-(benzylmethylamino)propyl]-3-chlorobenzamide, N-[3-(2-(N-methylbenzyl)amino)ethyl]-4-chlorobenzamide, N-[3-(benzylmethylamino)propyl]-4-chlorobenzamide, N-[4-(benzylmethylamino)butyl]-4-chlorobenzamide, N-[3-(N-methyl-2-phenylethylamino)propyl]-4-chlorobenzamide, N-[3-(isoindolin-2-yl)methylamino)propyl]-4-chlorobenzamide, N-[3-(benzylmethylamino)propyl]-2-bromobenzamide, N-[3-(benzylmethylamino)propyl]-2,3-dichlorobenzamide, N-[3-(benzylmethylamino)propyl]-2,4-dichlorobenzamide, N-[3-(benzylmethylamino)propyl]-3,4-dichlorobenzamide, N-[3-(benzylmethylamino)propyl]-3,5-dichlorobenzamide, N-[3-(benzylmethylamino)propyl]-3-methoxybenzamide, N-[3-(benzylmethylamino)propyl]-4-methoxybenzamide, N-[3-(benzylmethylamino)propyl]-3-dimethylaminobenzamide, N-[3-(benzylmethylamino)propyl]-4-cyanobenzamide, N-[3-(benzylmethylamino)propyl]-4-nitrobenzamide, N-(2-(benzyl(methyl)amino)ethyl)-3-chlorobenzamide, N-(2-(benzyl(methyl)amino)ethyl)-2,4-dichlorobenzamide, N-(2-(benzyl(methyl)amino)ethyl)-4-cyanobenzamide, N-(2-(benzyl(methyl)amino)ethyl)-4-nitrobenzamide, N-[3-(benzylmethylamino)propyl]-4-chlorobenzensulfonamide, 4-(benzylmethylamino)-N-(4-chlorophenyl)butanamide, N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamide, N-(4-nitrobenzyl)-3-(benzylmethylamino)propanamide, N-(4-cyanobenzyl)-3-(benzylmethylamino)propanamide, N-(2,4-dichlorobenzyl)-3-(benzylmethylamino)propanamide, N-(3-chlorobenzyl)-3-(benzylmethylamino)propanamide, and N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamine, or a pharmaceutically acceptable salt or solvate thereof.

21. The method according to claim 19, wherein the sigma-1 receptor related disease is a neurodegenerative disease.

22. The method according to claim 21, wherein the neurodegenerative disease is selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis.

23. A method of diagnosing of a sigma-1 receptor related disease, comprising the step of administering an effective amount of a compound of Formula I: ##STR00049## or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof, wherein X.sup.1 and X.sup.5 are independently selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, nitro, di(C1-C4-alkyl)amino, NHCOOR, and COOR, wherein R is methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or tert-butyl; X.sup.2, X.sup.3, X.sup.4 are independently selected from the group consisting of hydrogen, chloro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, cyano, nitro, di(C1-C4-alkyl)amino, NHCOOR, and COOR, wherein R is methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or tert-butyl; with the proviso that at least one of X.sup.2, X.sup.3, X.sup.4, X.sup.5 is not hydrogen and that at least one of X.sup.2, X.sup.3, X.sup.4 is not C1-C4-alkoxy; L is C(O)NH, NHC(O), SO.sub.2NH, NHSO.sub.2, or NH; n is 0, 1 or 2; m is 1, 2, 3, 4 or 5; R.sup.1 is H or alkyl, and R.sup.2 is 5- or 6-membered arylalkyl, 5- or 6-membered cycloalkylalkyl, wherein the cyclic moiety of said arylalkyl or cycloalkylalkyl is optionally substituted by one or more substituents independently selected from halogen; or R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached, form a 5-membered heterocyclyl group, which is fused to a 5- or 6-membered aryl group and which is optionally substituted by one or more substituents independently selected from C1-C3 alkyl, and wherein the resulting heterocyclic moiety is optionally substituted by one or more substituents independently selected from halogen.

24. The method according to claim 23, wherein the compound is selected from the group consisting of: N-[3-(benzylmethylamino)propyl]-4-propylbenzamide, N-[3-(benzylmethylamino)propyl]-4-butylbenzamide, N-[3-(benzylmethylamino)propyl]-4-tertbutylbenzamide, N-[3-(benzylmethylamino)propyl]-4-trifluoromethylbenzamide, N-[3-(benzylmethylamino)propyl]-4-fluorobenzamide, N-[3-(benzylmethylamino)propyl]-2-chlorobenzamide, N-[3-(benzylmethylamino)propyl]-3-chlorobenzamide, N-[3-(2-(N-methylbenzyl)amino)ethyl]-4-chlorobenzamide, N-[3-(benzylmethylamino)propyl]-4-chlorobenzamide, N-[4-(benzylmethylamino)butyl]-4-chlorobenzamide, N-[3-(N-methyl-2-phenylethylamino)propyl]-4-chlorobenzamide, N-[3-(isoindolin-2-yl)methylamino)propyl]-4-chlorobenzamide, N-[3-(benzylmethylamino)propyl]-2-bromobenzamide, N-[3-(benzylmethylamino)propyl]-2,3-dichlorobenzamide, N-[3-(benzylmethylamino)propyl]-2,4-dichlorobenzamide, N-[3-(benzylmethylamino)propyl]-3,4-dichlorobenzamide, N-[3-(benzylmethylamino)propyl]-3,5-dichlorobenzamide, N-[3-(benzylmethylamino)propyl]-3-methoxybenzamide, N-[3-(benzylmethylamino)propyl]-4-methoxybenzamide, N-[3-(benzylmethylamino)propyl]-3-dimethylaminobenzamide, N-[3-(benzylmethylamino)propyl]-4-cyanobenzamide, N-[3-(benzylmethylamino)propyl]-4-nitrobenzamide, N-(2-(benzyl(methyl)amino)ethyl)-3-chlorobenzamide, N-(2-(benzyl(methyl)amino)ethyl)-2,4-dichlorobenzamide, N-(2-(benzyl(methyl)amino)ethyl)-4-cyanobenzamide, N-(2-(benzyl(methyl)amino)ethyl)-4-nitrobenzamide, N-[3-(benzylmethylamino)propyl]-4-chlorobenzensulfonamide, 4-(benzylmethylamino)-N-(4-chlorophenyl)butanamide, N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamide, N-(4-nitrobenzyl)-3-(benzylmethylamino)propanamide, N-(4-cyanobenzyl)-3-(benzylmethylamino)propanamide, N-(2,4-dichlorobenzyl)-3-(benzylmethylamino)propanamide, N-(3-chlorobenzyl)-3-(benzylmethylamino)propanamide, and N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamine, or a pharmaceutically acceptable salt or solvate thereof.

25. A diagnostic imaging composition, comprising a compound of Formula I: ##STR00050## or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, wherein X.sup.1 and X.sup.5 are independently selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, nitro, di(C1-C4-alkyl)amino, NHCOOR, and COOR, wherein R is methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or ten-butyl; X.sup.2, X.sup.3, X.sup.4 are independently selected from the group consisting of hydrogen, chloro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, cyano, nitro, di(C1-C4-alkyl)amino, NHCOOR, and COOR, wherein R is methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or tert-butyl; with the proviso that at least one of X.sup.2, X.sup.3, X.sup.4, X.sup.5 is not hydrogen and that at least one of X.sup.2, X.sup.3, X.sup.4 is not C1-C4-alkoxy; L is C(O)NH, NHC(O), SO.sub.2NH, NHSO.sub.2, or NH; n is 0, 1 or 2; m is 1, 2, 3, 4 or 5; R.sup.1 is H or alkyl, and R.sup.2 is 5- or 6-membered arylalkyl, 5- or 6-membered cycloalkylalkyl, wherein the cyclic moiety of said arylalkyl or cycloalkylalkyl is optionally substituted by one or more substituents independently selected from halogen; or R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached, form a 5-membered heterocyclyl group, which is fused to a 5- or 6-membered aryl group and which is optionally substituted by one or more substituents independently selected from C1-C3 alkyl, and wherein the resulting heterocyclic moiety is optionally substituted by one or more substituents independently selected from halogen.

26. The diagnostic imaging composition according to claim 25, wherein the compound is selected from the group consisting of: N-[3-(benzylmethylamino)propyl]-4-propylbenzamide, N-[3-(benzylmethylamino)propyl]-4-butylbenzamide, N-[3-(benzylmethylamino)propyl]-4-tertbutylbenzamide, N-[3-(benzylmethylamino)propyl]-4-trifluoromethylbenzamide, N-[3-(benzylmethylamino)propyl]-4-fluorobenzamide, N-[3-(benzylmethylamino)propyl]-2-chlorobenzamide, N-[3-(benzylmethylamino)propyl]-3-chlorobenzamide, N-[3-(2-(N-methylbenzyl)amino)ethyl]-4-chlorobenzamide, N-[3-(benzylmethylamino)propyl]-4-chlorobenzamide, N-[4-(benzylmethylamino)butyl]-4-chlorobenzamide, N-[3-(N-methyl-2-phenylethylamino)propyl]-4-chlorobenzamide, N-[3-(isoindolin-2-yl)methylamino)propyl]-4-chlorobenzamide, N-[3-(benzylmethylamino)propyl]-2-bromobenzamide, N-[3-(benzylmethylamino)propyl]-2,3-dichlorobenzamide, N-[3-(benzylmethylamino)propyl]-2,4-dichlorobenzamide, N-[3-(benzylmethylamino)propyl]-3,4-dichlorobenzamide, N-[3-(benzylmethylamino)propyl]-3,5-dichlorobenzamide, N-[3-(benzylmethylamino)propyl]-3-methoxybenzamide, N-[3-(benzylmethylamino)propyl]-4-methoxybenzamide, N-[3-(benzylmethylamino)propyl]-3-dimethylaminobenzamide, N-[3-(benzylmethylamino)propyl]-4-cyanobenzamide, N-[3-(benzylmethylamino)propyl]-4-nitrobenzamide, N-(2-(benzyl(methyl)amino)ethyl)-3-chlorobenzamide, N-(2-(benzyl(methyl)amino)ethyl)-2,4-dichlorobenzamide, N-(2-(benzyl(methyl)amino)ethyl)-4-cyanobenzamide, N-(2-(benzyl(methyl)amino)ethyl)-4-nitrobenzamide, N-[3-(benzylmethylamino)propyl]-4-chlorobenzensulfonamide, 4-(benzylmethylamino)-N-(4-chlorophenyl)butanamide, N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamide, N-(4-nitrobenzyl)-3-(benzylmethylamino)propanamide, N-(4-cyanobenzyl)-3-(benzylmethylamino)propanamide, N-(2,4-dichlorobenzyl)-3-(benzylmethylamino)propanamide, N-(3-chlorobenzyl)-3-(benzylmethylamino)propanamide, and N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamine, or a pharmaceutically acceptable salt or solvate thereof.

27. A method of modulating sigma-1 receptor activity, comprising the step of administering an effective amount of a compound of Formula I: ##STR00051## or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof, wherein X.sup.1 and X.sup.5 are independently selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, nitro, di(C1-C4-alkyl)amino, NHCOOR, and COOR, wherein R is methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or tert-butyl; X.sup.2, X.sup.3, X.sup.4 are independently selected from the group consisting of hydrogen, chloro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, cyano, nitro, di(C1-C4-alkyl)amino, NHCOOR, and COOR, wherein R is methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or tert-butyl; with the proviso that at least one of X.sup.2, X.sup.3, X.sup.4, X.sup.5 is not hydrogen and that at least one of X.sup.2, X.sup.3, X.sup.4 is not C1-C4-alkoxy; L is C(O)NH, NHC(O), SO.sub.2NH, NHSO.sub.2, or NH; n is 0, 1 or 2; m is 1, 2, 3, 4 or 5; R.sup.1 is H or alkyl, and R.sup.2 is 5- or 6-membered arylalkyl, 5- or 6-membered cycloalkylalkyl, wherein the cyclic moiety of said arylalkyl or cycloalkylalkyl is optionally substituted by one or more substituents independently selected from halogen; or R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached, form a 5-membered heterocyclyl group, which is fused to a 5- or 6-membered aryl group and which is optionally substituted by one or more substituents independently selected from C1-C3 alkyl, and wherein the resulting heterocyclic moiety is optionally substituted by one or more substituents independently selected from halogen.

28. The method according to claim 27, wherein the compound is selected from the group consisting of: N-[3-(benzylmethylamino)propyl]-4-propylbenzamide, N-[3-(benzylmethylamino)propyl]-4-butylbenzamide, N-[3-(benzylmethylamino)propyl]-4-tertbutylbenzamide, N-[3-(benzylmethylamino)propyl]-4-trifluoromethylbenzamide, N-[3-(benzylmethylamino)propyl]-4-fluorobenzamide, N-[3-(benzylmethylamino)propyl]-2-chlorobenzamide, N-[3-(benzylmethylamino)propyl]-3-chlorobenzamide, N-[3-(2-(N-methylbenzyl)amino)ethyl]-4-chlorobenzamide, N-[3-(benzylmethylamino)propyl]-4-chlorobenzamide, N-[4-(benzylmethylamino)butyl]-4-chlorobenzamide, N-[3-(N-methyl-2-phenylethylamino)propyl]-4-chlorobenzamide, N-[3-(isoindolin-2-yl)methylamino)propyl]-4-chlorobenzamide, N-[3-(benzylmethylamino)propyl]-2-bromobenzamide, N-[3-(benzylmethylamino)propyl]-2,3-dichlorobenzamide, N-[3-(benzylmethylamino)propyl]-2,4-dichlorobenzamide, N-[3-(benzylmethylamino)propyl]-3,4-dichlorobenzamide, N-[3-(benzylmethylamino)propyl]-3,5-dichlorobenzamide, N-[3-(benzylmethylamino)propyl]-3-methoxybenzamide, N-[3-(benzylmethylamino)propyl]-4-methoxybenzamide, N-[3-(benzylmethylamino)propyl]-3-dimethylaminobenzamide, N-[3-(benzylmethylamino)propyl]-4-cyanobenzamide, N-[3-(benzylmethylamino)propyl]-4-nitrobenzamide, N-(2-(benzyl(methyl)amino)ethyl)-3-chlorobenzamide, N-(2-(benzyl(methyl)amino)ethyl)-2,4-dichlorobenzamide, N-(2-(benzyl(methyl)amino)ethyl)-4-cyanobenzamide, N-(2-(benzyl(methyl)amino)ethyl)-4-nitrobenzamide, N-[3-(benzylmethylamino)propyl]-4-chlorobenzensulfonamide, 4-(benzylmethylamino)-N-(4-chlorophenyl)butanamide, N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamide, N-(4-nitrobenzyl)-3-(benzylmethylamino)propanamide, N-(4-cyanobenzyl)-3-(benzylmethylamino)propanamide, N-(2,4-dichlorobenzyl)-3-(benzylmethylamino)propanamide, N-(3-chlorobenzyl)-3-(benzylmethylamino)propanamide, and N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamine, or a pharmaceutically acceptable salt or solvate thereof.

Description

FIGURES

[0095] FIG. 1. Results of the spontaneous alternation (a) and passive avoidance assays (b) for compound 3.1.10.

[0096] FIG. 2. Validation of al action of compound 3.1.10. Data are presented as meansem.

[0097] FIG. 3. Amelioration of EAE by compound 3.1.10, preventive treatment model. Data are presented as meansem.

[0098] FIG. 4. Amelioration of EAE by compound 3.1.10, curative treatment model. Data are presented as meansem.

EXAMPLES

Chemistry Examples

[0099] All temperatures are expressed in C. and all reactions were carried out at room temperature (RT) unless otherwise stated.

[0100] .sup.1H-, and .sup.13C spectra were recorded on a 300 MHz Bruker spectrometer. Chemical shifts (6) are given in ppm relative to the internal standard solvent. LC/MS chromatograms were recorded on a Waters Alliance 2695 system (X-Terra column, ionization mass spectrometer). For some compounds mass spectra were recorded on a MALDI-TOF Voyager-DE-STR (Applied Biosystems) apparatus.

[0101] Solvents, reagents and starting materials were purchased from well known chemical suppliers such as for example Sigma Aldrich, Acros Organics, Fluorochem, Eurisotop, VWR International, Sopachem and Polymer labs and the following abbreviations are used:

DCM: Dichloromethane,

DIEA: N,N-diisopropylethylamine,

DMF: N,N-dimethylformamide,

EtOH: Ethanol,

MeOH: Methanol,

[0102] RT: Room temperature,

HOBt: Hydroxybenzotriazole,

[0103] HBtu: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate,
LCMS: Liquid chromatographymass spectrometry,
TLC: Thin layer chromatography,
MW: Molecular weight,

eq: Equivalent.

[0104] ##STR00013##

Reagents: (a): di-tert-butylcarbonate, triethylamine, CH.sub.2Cl.sub.2; (b): HNR.sup.1R.sup.2, potassium carbonate, DMF or CH.sub.3CN; (c): 3M HCl in dry dioxane; (d): HNR.sup.1R.sup.2, potassium carbonate, DMF; (e): H.sub.2NNH.sub.2.H.sub.2O, EtOH 96; (f): bromochloroalkyl derivative, potassium carbonate, CH.sub.3CN; (g): HNCH.sub.3 40%, potassium carbonate, CH.sub.3CN.

##STR00014##

Reagents: (a): bromoalkylamine, CH.sub.2Cl.sub.2; (b): chloroalkylacyl chloride, CH.sub.2Cl.sub.2.

##STR00015## ##STR00016##

Reagents: (a): triethylamine, CH.sub.2Cl.sub.2 (YCl), Procedure E1; (b): HOBt, HBtu, DIEA, CH.sub.2Cl.sub.2 (YOH), Procedure E2; (c): HNR.sup.1R.sup.2, Procedure E3 (d): NaBH.sub.4, MeOH, Procedure E4.

2. Preparation of Diamine Intermediates (Compounds 1.4-1.7): Scheme 1

Step 1: Preparation of tert-butyl-3-bromopropylcarbamate (Compound 1.2)

[0105] 3-Bromopropylamine (13.70 mmol, 3.0 g) was dissolved in 80 mL of dichloromethane. After addition of triethylamine (16.4 mmol, 2.32 mL) and di-tert-butylcarbonate (13.70 mmol, 3.0 g) the resulting mixture was stirred at room temperature overnight. Then, it was washed with 260 mL of a citric acid solution (5%) and 50 mL of saturated brine solution. The organic fraction was dried over magnesium sulphate and concentrated to give the desired product as yellow oil of sufficient purity for use without purification in the next step. Yield: 97%.

Step 2: Preparation of Compounds 1.3

[0106] To a mixture of tert-butyl-3-bromopropylcarbamate 1.2 (5.6 mmol, 1.3 eq, 1.3 g) and N,N-disubstituted amine (4.3 mmol, 1 eq) in 30 mL of DMF was added potassium carbonate (13.0 mmol, 3 eq, 1.8 g). The resulting mixture was heated at 70 C. for 24 hours. Then, the solvent was removed under reduced pressure and water (80 mL) added to the residue. The crude product was extracted with 360 mL of dichloromethane. The combined organic fractions were washed with 60 mL of water and dried over magnesium sulphate. The solvent was evaporated and the crude product collected as yellow oil. Purification by column chromatography (DCM:MeOH(NH.sub.3), 9.7:0.3 (v/v)) was performed.

Example 1: Preparation of tert-butyl-3-[benzyl(methyl)amino]propyl carbamate (Compound 1.3a)

[0107] The compound 1.3a was synthesized according to the procedure by using tert-butyl-3-bromopropylcarbamate 1.2 (8.44 mmol, 2.0 g) and N-methylbenzylamine (6.50 mmol, 0.9 mL). Yield: 74%. LCMS m/z 279.1 [M+H].sup.+, 223.1 [M+HtertBut].sup.+.

Example 2: Preparation of tert-butyl-3-[N-methyl-N-(2-phenylethyl)amino] propyl carbamate (Compound 1.3b)

[0108] The compound 1.3b was synthesized according to the procedure by using tert-butyl-3-bromopropylcarbamate 1.2 (8.44 mmol, 2.0 g) and N-methylphenylethylamine (6.50 mmol, 1.0 mL). Yield: 81%. LCMS (ESI.sup.+tertBut): 237.0.

Example 3: Preparation of tert-butyl-3-(isoindolin-2-yl)propylcarbamate (Compound 1.3c)

[0109] The compound 1.3c was synthesized according to the procedure by using tert-butyl-3-bromopropylcarbamate 1.2 (8.44 mmol, 2.0 g) and 2-isoindoline (6.50 mmol, 0.9 mL). Yield: 65%. LCMS m/z 221.0 [M+HtertBut].sup.+.

Step 3: Preparation of Compounds 1.4

[0110] The compound 1.3 (1 eq) was dissolved in 72 mL of 3M HCl in dry 1,4-dioxane. The resulting mixture was stirred at room temperature overnight. Then, the solvent was removed under reduced pressure to give the desired product of sufficient purity for use without purification in the next step.

Example 1: Preparation of N.SUP.1.-benzyl-N.SUP.1.-methylpropane-1,3-diamine dihydrochloride (Compound 1.4a)

[0111] The compound 1.4a was synthesized according to the procedure by using tert-butyl-3-[benzylmethylamino]propylcarbamate 1.3a (7.18 mmol, 1.8 g). Yield 98%. LCMS m/z 179.0 [M+H]

Example 2: Preparation of N.SUP.1.-benzyl-N.SUP.1.-(2-phenylethyl)propane-1,3-diamine dihydrochloride (Compound 1.4b)

[0112] The compound 1.4b was synthesized according to the procedure by using tert-butyl-3-[N-methyl-N-(2-phenylethyl)amino]propylcarbamate 1.3b (7.18 mmol, 2.1 g). Yield: 88%. LCMS m/z 193.0 [M+H].sup.+

Example 3: Preparation of 3-(isoindolin-2-yl)propan-1-amine dihydrochloride (Compound 1.4c)

[0113] The compound 1.4c was synthesized according to the procedure by using tert-butyl-3-(isoindolin-2-yl)propylcarbamate 1.3c (7.18 mmol, 2.0 g). Yield: 83%. LCMS m/z 177.0 [M+H].sup.+.

Step 4: Preparation of Compounds 1.5

[0114] To a mixture of N-(bromoalkyl)phtalimide (1 eq) and N,N-disubstituted amine (1.2 eq) in 30 mL of DMF was added potassium carbonate (11.80 mmol, 2 eq, 1.6 g). The resulting mixture was heated at 90 C. for 16 hours. Then, inorganics were eliminated by filtration and the solvent was removed under reduced pressure. Purification by column chromatography (DCM:MeOH(NH.sub.3), 9.9:0.1 (v/v)) was performed.

Example 1: Preparation of 2-[2-(benzylmethylamino)ethyl]-2,3-dihydro-1H-isoindole-1,3-dione (Compound 1.5a)

[0115] The compound 1.5a was synthesized according to the procedure by using N-(2-bromoethyl)phtalimide (5.9 mmol, 1.50 g) and N-methylbenzylamine (7.1 mmol, 0.9 mL). Yield 52%. LCMS m/z 295.0 [M+H].sup.+.

Example 2: Preparation of 2-[4-(benzylmethylamino)butyl]-2,3-dihydro-1H-isoindole-1,3-dion (Compound 1.5b)

[0116] The compound 1.5b was synthesized according to the procedure by using N-(4-bromobutyl)phtalimide (5.9 mmol, 1.66 g) and N-methylbenzylamine (7.1 mmol, 0.9 mL). Yield 53%. LCMS m/z 323.0 [M+H]

Example 3: Preparation of 2-[2-(N-methyl-N-(2-phenylethyl)amino)ethyl]-2,3-dihydro-1H-isoindole-1,3-dione (Compound 1.5c)

[0117] The compound 1.5c was synthesized according to the procedure by using N-(2-bromoethyl)phtalimide (5.9 mmol, 1.50 g) and N-methyl-N-(2-phenylethyl)amine (7.1 mmol, 0.9 mL). Yield 64%. LCMS m/z 308.98 [M+H].sup.+.

Step 5: Preparation of Compounds 1.4

[0118] In 50 mL of ethanol 96, was added a mixture of 2-[N,N-disubstituted amino alkyl]-2,3-dihydro-1H-isoindole-1,3-dione (1 eq) and hydrazine hydrate (10 eq). The resulting mixture was heated at reflux for 16 hours. The solution was removed under reduced pressure. The mineral was eliminated by filtration and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to give an oily residue. Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Oily purified product was dissolved in EtOAc and ether saturated with gaseous HCl was added. The corresponding hydrochloride product was filtered.

Example 1: Preparation of N.SUP.1.-benzyl-N.SUP.1.-methylethane-1,2-diamine dihydrochloride (Compound 1.4d)

[0119] The compound 1.4d was synthesized according to the procedure by using 2-[2-(benzyl(methyl)amino)ethyl]-2,3-dihydro-1H-isoindole-1,3-dione (3.06 mmol, 0.9 g) and hydrazine hydrate (30.60 mmol, 1.5 mL). Yield 55%. LCMS mz 165.0 [M-F1-1].sup.+.

Example 2: Preparation of N.SUP.1.-benzyl-N.SUP.1.-methylbutane-1,4-diamine dihydrochloride (Compound 1.4e)

[0120] The compound 1.4e was synthesized according to the procedure by using 2-[4-(benzyl(methyl)amino)butyl]-2,3-dihydro-1H-isoindole-1,3-dione (6.2 mmol, 2.0 g) and hydrazine hydrate (62.0 mmol, 3.1 mL). Yield 73%. LCMS m/z 193.0 [M+H]

Example 3: Preparation of N.SUP.1.-(2-phenylethyl)-N.SUP.1.-methylethane-1,2-diamine dihydrochloride (Compound 1.4f)

[0121] The compound 1.4f was synthesized according to the procedure by using 2-[2-(N-methyl-N-(2-phenylethyl)amino)ethyl]-2,3-dihydro-1H-isoindole-1,3-dione (3.06 mmol, 0.94 g) and hydrazine hydrate (30.60 mmol, 1.5 mL). Yield 67%. LCMS m/z 179.09 [M+H].sup.+.

Step 6: Preparation of Compounds 1.6

[0122] To a mixture of N,N-disubstituted amine (1 eq) and bromochloroalkyl (1 eq) in 40 mL of DMF was added potassium carbonate (1 eq). The resulting mixture was stirred at room temperature for 1 day. Then, inorganics were eliminated by filtration and the solvent was removed under reduced pressure to give an oily residue. Purification by column chromatography (DCM:MeOH(NH.sub.3), 9.8:0.2 (v/v)) was performed.

Example 1: Preparation of 3-chloropropyl-N-benzylmethylamine (1.6a)

[0123] The compound 1.6a was synthesized according to the procedure by using N-methylbenzylamine (33.0 mmol, 4.0 mL) and 1-bromo-3-chloropropane (33.0 mmol, 9.7 mL). Yield: 95%. LCMS m/z 196.0, 198.0 [M+H].sup.+.

Step 7: Preparation of Compounds 1.7

[0124] In 5 mL of CH.sub.3CN was added a mixture of chloroalkyl-N,N-disubstituted amine (1 eq) and methylamine 40% (20 eq). The resulting mixture was heated at reflux for 18 hours. The solution was removed under reduced pressure to give an oily residue. Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed.

Example 1: Preparation of N.SUP.1.-benzyl-N.SUP.1.,N.SUP.2.-dimethylpropane-1,3-diamine (Compound 1.7a)

[0125] The compound 1.7a was synthesized according to the procedure by using 3-chloropropyl-N-benzylmethylamine (10.1 mmol, 2.0 g) and methylamine 40% (202.0 mmol, 15.6 mL). Yield 88%. LCMS m/z 193.0 [M+H].sup.+.

3. Preparation of Intermediates Aryle Derivatives (Compounds 2.1-2.3): Scheme 2

Preparation of N-(3-bromopropyl)-4-chlorobenzamide (Compound 2.1)

[0126] To a solution of 3-bromopropylamine hydrobromide (2.86 mmol, 625 mg) in 10 mL of dichloromethane at 0 C. was added slowly a solution of 4-chlorobenzoyl chloride (2.86 mmol, 363 L) in 5 mL of dichloromethane. The resulting mixture was stirred at room temperature for 12 hours. Then the solution was diluted with dichloromethane and washed successively with HCl (2M) solution, NaHCO.sub.3 saturated solution and NaCl solution. The organic layer was dried over magnesium sulfate and evaporated. The crude product 2.1 was purified by column chromatography (DCM:cyclohexane, 5:5 (v/v)). Yield: 65%.

Preparation of 4-chloro-N-(4-chlorophenyl)butyramide (Compound 2.2)

[0127] To a solution of 4-chloroaniline (7.8 mmol, 1.0 g) in 15 mL of dichloromethane at 0 C. was added slowly a solution of 4-chlorobutyryl chloride (7.8 mmol, 878 L) in 5 mL of dichloromethane. The resulting mixture was stirred at room temperature for 12 hours. Then the reaction was quenched with 25 mL of water and the product extract with 325 mL of DCM. The combined organic fractions were dried over magnesium sulphate and concentrated to give the desired product 2.2 with sufficient purity to be used without purification in the next step. Yield: 87%.

Preparation of Compounds 2.3

[0128] To a solution of substituted benzylamine (6.5 mmol, 1 eq) in AcOEt/H.sub.2O (20 mL/15 mL), was added potassium carbonate (13.1 mmol, 1.8 g, 2 eq) and 3-chloropropionyl chloride (7.8 mmol, 753 L). The resulting mixture was stirred at room temperature for 1 hour. The organic layer was washed successively with HCl (2M) solution (20 mL), water (20 mL) and dried over magnesium sulphate. The solution was removed under reduced pressure. The crude product 2.3 was washed with heptane and used in the next step.

Example 1: Preparation of N-(4-chlorobenzyl)-3-chloropropanamide (Compound 2.3a)

[0129] The compound 2.3.a was synthesized according to the procedure by using 4-chlorobenzylamine (6.5 mmol, 0.92 g). Yield: 60%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 7.35-7.30 (m, 2H, H.sub.aro); 7.25-7.20 (m, 2H, H.sub.aro); 5.94 (br s, 1H, NH); 4.45 (d, J=6 Hz, 2H, CH.sub.2); 3.84 (t, J=6 Hz, 2H, CH.sub.2); 2.67 (t, J=6 Hz, 2H, CH.sub.2).

Example 2: Preparation of N-(4-nitrobenzyl)-3-chloropropanamide (Compound 2.3b)

[0130] The compound 2.3.b was synthesized according to the procedure by using 4-nitrobenzylamine (6.5 mmol, 1.00 g). Yield: 69%. LCMS m/z 240.8 [MH].sup..

Example 3: Preparation of N-(4-cyanobenzyl)-3-chloropropanamide (Compound 2.3c)

[0131] The compound 2.3.c was synthesized according to the procedure by using 4-cyanobenzylamine (6.5 mmol, 0.86 g). Yield: 65%. LCMS m/z 220.9 [MH].sup..

Example 4: Preparation of N-(2,4-dichlorobenzyl)-3-chloropropanamide (Compound 2.3d)

[0132] The compound 2.3.d was synthesized according to the procedure by using 2,4-dichlorobenzylamine (6.5 mmol, 1.14 g). Yield: 79%. LCMS m/z 263.8, 265.8, 267.9 [MH].sup..

Example 5: Preparation of N-(3-chlorobenzyl)-3-chloropropanamide (Compound 2.3e)

[0133] The compound 2.3.e was synthesized according to the procedure by using 3-chlorobenzylamine (6.5 mmol, 0.92 g). Yield: 73%. LCMS m/z 231.9, 233.9, 235.9 [M+H].sup.+.

Example 6: Preparation of N-(3-Bromobenzyl)-3-chloropropanamide (Compound 2.30

[0134] The compound 2.3.f was synthesized according to the procedure by using 3-bromobenzylamine (6.5 mmol, 1.21 g). Yield: 67%. LCMS m/z 275.8, 277.8, 279.8 [M+H].sup.+.

4. General Procedures E: Synthesis of Compounds of the Invention: Scheme 3

General Procedure E1:

[0135] A solution of N,N-disubstituted alkyldiamine 1.4 (1 eq), and triethylamine (3 eq) in 10 mL of dichloromethane was cooled at 0 C. A solution of substituted-benzoylchloride (1 eq) in 5 mL of dichloromethane was added slowly. The resulting mixture was stirred at room temperature overnight. The solution was evaporated under reduced pressure. An aqueous solution of 3% sodium hydroxide (20 mL) was added and the mixture was stirred for 1 hour. The solution was extracted with dichloromethane. The organic fraction was dried over magnesium sulphate and concentrated to give an oily product. The residue was purified by thick layer chromatography or column chromatography.

General Procedure E2:

[0136] Reaction was carried out under nitrogen atmosphere. In 10 mL of dichloromethane, benzoic acid (1 eq), HOBt (1.2 eq) and HBtu (1.2 eq) were added and stirred at room temperature for 10 minutes. A solution of N,N-disubstituted alkyldiamine 1.4 (1 eq) and DIEA (15 eq) in dichloromethane was added to the reacting mixture. After stirring at room temperature for 24 hours, the solvent was removed under reduced pressure and dichloromethane was added to the residue. The solution was washed with a solution of NaHCO.sub.3 (5%) then saturated NaCl solution. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified by thick layer chromatography or column chromatography.

General Procedure E3:

[0137] A solution of compound 2.2 or 2.3 (1 eq) in disubstituted amine HNR.sup.1R.sup.2 (6 eq) was stirred at room temperature for 12 hours. A 5 mL amount of hexane was added and the white solid, identified as disubstituted amine hydrochloride, was filtered. The filtrate was concentrated and purified by thick layer chromatography or column chromatography.

General Procedure E4:

[0138] A solution of substituted benzoylchloride (1 eq) and N,N-disubstituted alkyldiamine 1.4 (1 eq) in MeOH (10 mL) was stirred at room temperature for 16 hours. Then, sodium borohydride (1.5 eq) was added and stirred for 3 hours. The mixture was quenched with water (5 mL) and evaporated under reduce pressure. The crude product was purified by thick layer chromatography or column chromatography.

Example 1: Synthesis of N-[3-(benzylmethylamino)propyl]-4-propylbenzamide (Compound 3.1.2)

[0139] The compound 3.1.2 was synthesized according to the procedure E1 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.55 mmol, 138 mg), and 4-propylbenzoylchloride (0.55 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 61%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 7.90 (br s, 1H, NH); 7.60 (d, J=8.2 Hz, 2H, H.sub.2, H.sub.6); 7.29-7.20 (m, 5H, H.sub.aro); 7.13 (d, J=8.1 Hz, 2H, H.sub.3, H.sub.5); 3.55 (t, J=6.0 Hz, 2H, CH.sub.2); 3.50 (s, 2H, CH.sub.2); 2.60 (m, 4H, 2 CH.sub.2); 2.23 (s, 3H, CH.sub.3); 1.80 (p, J=6.0 Hz, 2H, CH.sub.2); 1.62 (s, J=7.5 Hz, 2H, CH.sub.2); 0.95 (t, J=7.3 Hz, 2H, CH.sub.3). .sup.13C NMR (75 MHz, CDCl.sub.3) : 167.2 (CO); 146.1 (C.sub.aro); 138.4 (C.sub.aro); 132.2 (C.sub.aro); 129.3 (C.sub.aro); 128.5 (C.sub.aro); 128.4 (C.sub.aro); 127.2 (C.sub.aro); 126.9 (C.sub.aro); 63.3 (CH.sub.2); 57.1 (CH.sub.2); 42.1 (CH.sub.3); 40.2 (CH.sub.2); 37.9 (CH.sub.2); 25.5 (CH.sub.2); 24.3 (CH.sub.2); 14.2 (CH.sub.3). LCMS m/z 325.0 [M-EH].sup.+.

Example 2: Synthesis of N-[3-(benzylmethylamino)propyl]-4-butylbenzamide (Compound 3.1.3)

[0140] The compound 3.1.3 was synthesized according to the procedure E1 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.65 mmol, 163 mg), and 4-butylbenzoylchloride (0.65 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 30%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 7.97 (br s, 1H, NH); 7.60 (d, J=8.2 Hz, 2H, H.sub.2, H.sub.6); 7.29-7.23 (m, 5H, H.sub.aro); 7.13 (d, J=8.2 Hz, 2H, H.sub.3, H.sub.5); 3.56 (m, 4H, 2CH.sub.2); 2.64 (m, 4H, 2CH.sub.2); 2.28 (s, 3H, CH.sub.3); 1.83 (p, J=6.1 Hz, 2H, CH.sub.2); 1.62 (m, 2H, CH.sub.2); 1.35 (m, 2H, CH.sub.2); 0.97 (t, J=7.1 Hz, 2H, CH.sub.3). .sup.13C NMR (75 MHz, CDCl.sub.3) : 167.7 (CO); 146.7 (C.sub.aro); 138.0 (C.sub.aro); 132.5 (C.sub.aro); 129.8 (2 C.sub.aro); 128.8 (4 C.sub.aro); 127.9 (C.sub.aro); 127.3 (2 C.sub.aro); 63.5 (CH.sub.2); 57.1 (CH.sub.2); 41.9 (CH.sub.3); 40.3 (CH.sub.2); 35.9 (CH.sub.2); 33.7 (CH.sub.2); 25.7 (CH.sub.2); 22.6 (CH.sub.2); 14.3 (CH.sub.3). LCMS m/z 339.0 [M+H].sup.+.

Example 3: Synthesis of N-[3-(benzylmethylamino)propyl]-4-tert-butylbenzamide (Compound 3.1.4)

[0141] The compound 3.1.4 was synthesized according to the procedure E1 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.60 mmol, 150 mg), and 4-tertbutylbenzoylchloride (0.60 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 27%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 8.03 (br s, 1H, NH); 7.63 (d, J=8.5 Hz, 2H, H.sub.2, H.sub.6); 7.37 (d, J=8.5 Hz, 2H, H.sub.3, H.sub.5); 7.29-7.24 (m, 5H, H.sub.aro); 3.57 (m, 4H, 2CH.sub.2); 2.63 (t, J=6.0 Hz, 2H, CH.sub.2); 2.28 (s, 3H, NCH.sub.3); 1.84 (p, J=5.9 Hz, 2H, CH.sub.2); 1.32 (s, 9H, 3CH.sub.3). .sup.13C NMR (75 MHz, CDCl.sub.3) : 167.1 (CO); 154.4 (C.sub.aro); 137.8 (C.sub.aro); 131.8 (C.sub.aro); 129.5 (2 C.sub.aro); 128.4 (2 C.sub.aro); 127.4 (C.sub.aro); 126.8 (2 C.sub.aro); 125.3 (2 C.sub.aro); 63.1 (CH.sub.2); 56.9 (CH.sub.2); 41.5 (CH.sub.3); 40.1 (CH.sub.2); 34.8 (C); 31.2 (CH.sub.3); 25.3 (CH.sub.2). LCMS m/z 339.0 [M-F1-1]+.

Example 4: Synthesis of N-[3-(benzylmethylamino)propyl]-4-trifluoromethylbenzamide (Compound 3.1.5)

[0142] The compound 3.1.5 was synthesized according to the procedure E1 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.48 mmol, 120 mg), and 4-trifluoromethylbenzoylchloride (0.48 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 57%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 8.50 (br s, 1H, NH); 7.78 (d, J=8.2 Hz, 2H, H.sub.2, H.sub.6); 7.59 (d, J=8.2 Hz, 2H, H.sub.3, H.sub.5); 7.28-7.21 (m, 5H, H.sub.aro); 3.63-3.55 (m, 4H, 2 CH.sub.2); 2.68 (t, J=5.8 Hz, 2H, CH.sub.2); 2.30 (s, 3H, CH.sub.3); 1.85 (p, J=5.7 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 165.8 (CO); 138.0 (C.sub.aro); 129.5 (2 C.sub.aro); 128.5 (2 C.sub.aro); 127.7 (C.sub.aro); 127.4 (2 C.sub.aro); 125.5 (2 C.sub.aro); 125.4 (2 C.sub.aro); 62.9 (CH.sub.2); 57.1 (CH.sub.2); 41.3 (CH.sub.3); 40.5 (CH.sub.2); 24.8 (CH.sub.2). LCMS mz 351.0, 352.0 [M+H].sup.+.

Example 5: Synthesis of N-[3-(benzylmethylamino)propyl]-4-fluorobenzamide (Compound 3.1.6)

[0143] The compound 3.1.6 was synthesized according to the procedure E2 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.67 mmol, 170 mg), and 4-fluorobenzoic acid (0.67 mmol, 90 mg). Purification by thick layer chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 58%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 8.20 (br s, 1H, NH); 7.66 (m, 2H, H.sub.2, H.sub.6); 7.28-7.24 (m, 5H, H.sub.aro); 7.00 (t, J=9.1 Hz, 2H, H.sub.3, H.sub.5); 3.60-3.52 (m, 4H, 2 CH.sub.2); 2.65 (t, J=6.1 Hz, 2H, CH.sub.2); 2.28 (s, 3H, CH.sub.3); 1.83 (p, J=6.0 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 166.1 (CO); 164.5 (C.sub.aro); 137.6 (C.sub.aro); 130.8 (C.sub.aro); 129.5 (2 C.sub.aro); 129.2 (2 C.sub.aro); 128.5 (2 C.sub.aro); 127.6 (C.sub.aro); 115.3 (2 C.sub.aro); 63.1 (CH.sub.2); 57.1 (CH.sub.2); 41.4 (CH.sub.3); 40.3 (CH.sub.2); 25.0 (CH.sub.2). LCMS m/z 301.1, 302.1 [M+H].sup.+.

Example 6: Synthesis of N-[3-(benzylmethylamino)propyl]-2-chlorobenzamide (Compound 3.1.7)

[0144] The compound 3.1.7 was synthesized according to the procedure E1 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.57 mmol, 143 mg), and 2-chlorobenzoylchloride (0.57 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 46%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 7.52 (dd, J=7.0 Hz, J=1.9 Hz, 1H, H.sub.6); 7.39-7.25 (m, 4H, NH, H.sub.3, H.sub.4, H.sub.5); 7.17-7.09 (m, 5H, H.sub.aro); 3.54 (q, J=6.2 Hz, 2H, CH.sub.2); 3.49 (s, 2H, CH.sub.2); 2.58 (t, J=6.3 Hz, 2H, CH.sub.2); 2.21 (s, 3H, NCH.sub.3); 1.83 (p, J=6.2 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 166.7 (CO); 137.9 (C.sub.aro); 136.0 (C.sub.aro); 130.8 (C.sub.aro); 130.7 (C.sub.aro); 130.1 (C.sub.aro); 129.5 (C.sub.aro); 128.9 (2 C.sub.aro); 128.3 (2 C.sub.aro); 127.2 (C.sub.aro); 126.9 (C.sub.aro); 62.6 (CH.sub.2); 56.0 (CH.sub.2); 41.8 (CH.sub.3); 39.7 (CH.sub.2); 25.3 (CH.sub.2). LCMS m/z 317.0, 319.0 [M+H].sup.+.

Example 7: Synthesis of N-[3-(benzylmethylamino)propyl]-3-chlorobenzamide (Compound 3.1.8)

[0145] The compound 3.1.8 was synthesized according to the procedure E1 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.57 mmol, 143 mg), and 3-chlorobenzoylchloride (0.57 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 8%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 8.22 (br s, 1H, NH); 7.78 (dd, J=1.5 Hz, J=2.0 Hz, 1H, H.sub.2); 7.68 (d, J=8.0 Hz, 1H, H.sub.6); 7.52 (d, J=7.8 Hz, 1H, H.sub.4); 7.52 (t, J=7.3 Hz, 1H, H.sub.5); 7.32-7.22 (m, 5H, H.sub.aro); 3.58-3.51 (m, 4H, 2CH.sub.2); 2.63 (t, J=7.5 Hz, 2H, CH.sub.2); 2.30 (s, 3H, CH.sub.3); 1.84 (p, J=6.4 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 165.8 (CO); 136.5 (C.sub.aro); 134.6 (C.sub.aro); 131.2 (C.sub.aro); 129.7 (C.sub.aro); 129.4 (2 C.sub.aro); 128.5 (2 C.sub.aro); 127.7 (2 C.sub.aro); 127.5 (C.sub.aro); 125.0 (C.sub.aro); 63.1 (CH.sub.2); 56.7 (CH.sub.2); 41.6 (CH.sub.3); 40.4 (CH.sub.2); 24.8 (CH.sub.2). LCMS m/z 317.0, 319.0 [M+H].sup.+.

Example 8: Synthesis of N-[3-(2-(N-methylbenzyl)amino)ethyl]-4-chlorobenzamide (Compound 3.1.9)

[0146] The compound 3.1.9 was synthesized according to the procedure E1 by using N.sup.1-benzyl-N.sup.1-methylethane-1,2-diamine dihydrochloride 1.4d (0.57 mmol, 135 mg), and 4-chlorobenzoylchloride (0.57 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 20%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 7.67 (d, J=8.6 Hz, 2H, H.sub.2, H.sub.6); 7.41 (d, J=8.6 Hz, 2H, H.sub.3, H.sub.5); 7.23-7.33 (m, 5H, H.sub.aro); 6.78 (br s, 1H, NH); 3.56 (s, 2H, CH.sub.2); 3.51 (q, J=5.2 Hz, 2H, CH.sub.2); 2.62 (t, J=5.9 Hz, 2H, CH.sub.2); 2.31 (s, 3H, NCH.sub.3). .sup.13C NMR (75 MHz, CDCl.sub.3) : 166.4 (CO); 138.6 (C.sub.aro); 137.5 (C.sub.aro); 133.1 (C.sub.aro); 129.4 (2 C.sub.aro); 129.1 (2 C.sub.aro); 128.9 (2 C.sub.aro); 128.7 (2 C.sub.aro); 127.4 (C.sub.aro); 62.3 (CH.sub.2); 54.9 (CH.sub.2); 42.1 (CH.sub.3); 37.1 (CH.sub.2). LCMS m/z 303.0, 305.0 [M+H].sup.+.

Example 9: Synthesis of N-[3-(benzylmethylamino)propyl]-4-chlorobenzamide (Compound 3.1.10)

[0147] The compound 3.1.10 was synthesized according to the procedure E1 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.57 mmol, 143 mg), and 4-chlorobenzoylchloride (0.57 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 55%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 8.25 (br s, 1H, NH); 7.60 (d, J=9 Hz, 2H, H.sub.2, H.sub.6); 7.33-7.21 (m, 7H, H.sub.3, H.sub.5, H.sub.aro); 3.62-3.51 (m, 4H, 2CH.sub.2); 2.65 (t, J=5.4 Hz, 2H, CH.sub.2); 2.27 (s, 3H, NCH.sub.3); 1.83 (p, J=5.5 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 166.0 (CO); 137.8 (C.sub.aro); 137.3 (C.sub.aro); 133.1 (C.sub.aro); 129.4 (2 C.sub.aro); 128.6 (2 C.sub.aro); 128.5 (2 C.sub.aro); 128.4 (2 C.sub.aro); 127.5 (C.sub.aro); 63.2 (CH.sub.2); 57.2 (CH.sub.2); 41.5 (CH.sub.3); 40.5 (CH.sub.2); 25.0 (CH.sub.2). LCMS m/z 316.9, 318.9 [M+H].sup.+.

Example 10: Synthesis of N-[4-(benzylmethylamino)butyl]-4-chlorobenzamide (Compound 3.1.11)

[0148] The compound 3.1.11 was synthesized according to the procedure E1 by using N.sup.1-benzyl-N.sup.1-methylbutane-1,4-diamine dihydrochloride 1.4e (0.57 mmol, 151 mg), and 4-chlorobenzoylchloride (0.57 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 25%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 7.60 (d, J=9.2 Hz, 2H, H.sub.2, H.sub.6); 7.41 (br s, 1H, NH); 7.33-7.26 (m, 7H, H.sub.3, H.sub.5, H.sub.aro); 3.53 (s, 2H, CH.sub.2); 3.45 (q, J=6.2 Hz, 2H, CH.sub.2); 2.45 (t, J=6.4 Hz, 2H, CH.sub.2); 2.17 (s, 3H, NCH.sub.3); 1.73-1.62 (m, 4H, 2CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 166.6 (CO); 137.7 (C.sub.aro); 137.3 (C.sub.aro); 133.3 (C.sub.aro); 129.3 (2 C.sub.aro); 128.6 (2 C.sub.aro); 128.5 (2 C.sub.aro); 128.4 (2 C.sub.aro); 127.4 (C.sub.aro); 61.8 (CH.sub.2); 56.7 (CH.sub.2); 42.1 (CH.sub.3); 39.9 (CH.sub.2); 27.1 (CH.sub.2); 24.8 (CH.sub.2). LCMS m/z 331.0, 333.0 [M+H].sup.+.

Example 11: Synthesis of N-[3-(N-methyl-2-phenylethylamino)propyl]-4-chlorobenzamide (Compound 3.1.12)

[0149] The compound 3.1.12 was synthesized according to the procedure E1 by using N.sup.1-benzyl-N.sup.1-(2-phenylethyl)propane-1,3-diamine dihydrochloride 1.4b (0.57 mmol, 151 mg), and 4-chlorobenzoylchloride (0.57 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 69%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 8.25 (br s, 1H, NH); 7.58 (d, J=8.3 Hz, 2H, H.sub.2, H.sub.6); 7.34 (d, J=8.4 Hz, 2H, H.sub.3, H.sub.5); 7.26-7.12 (m, 5H, H.sub.aro); 3.53 (q, J=6.2 Hz, 2H, CH.sub.2); 2.82 (m, 2H, CH.sub.2); 2.75 (m, 2H, CH.sub.2); 2.66 (t, J=6.0 Hz, 2H, CH.sub.2); 2.35 (s, 3H, NCH.sub.3); 1.80 (p, J=5.9 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 165.9 (CO); 139.5 (C.sub.aro); 137.2 (C.sub.aro); 133.1 (C.sub.aro); 128.6 (4 C.sub.aro); 128.5 (2 C.sub.aro); 128.3 (2 C.sub.aro); 126.3 (C.sub.aro); 59.6 (CH.sub.2); 57.1 (CH.sub.2); 41.7 (CH.sub.3); 40.4 (CH.sub.2); 33.3 (CH.sub.2); 24.3 (CH.sub.2). LCMS mz 331.0, 333.0 [M+H].sup.+.

Example 12: Synthesis of N-[3-(isoindolin-2-yl)methylamino)propyl]-4-chlorobenzamide (Compound 3.1.15)

[0150] The compound 3.1.15 was synthesized according to the procedure E1 by using 3-(isoindolin-2-yl)propane-1-amine dihydrochloride 1.4c (0.57 mmol, 140 mg), and 4-chlorobenzoylchloride (0.57 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 36%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 9.00 (br s, 1H, NH); 7.48 (d, J=8.6 Hz, 2H, H.sub.2, H.sub.6); 7.31-7.21 (m, 4H, H.sub.aro); 7.03 (d, J=8.5 Hz, 2H, H.sub.3, H.sub.5); 4.02 (s, 4H, 2CH.sub.2); 3.63 (q, J=5.0 Hz, 2H, CH.sub.2); 3.05 (t, J=5.8 Hz, 2H, CH.sub.2); 1.89 (p, J=5.8 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 165.6 (CO); 139.2 (2 C.sub.aro); 137.1 (C.sub.aro); 132.6 (C.sub.aro); 128.4 (2 C.sub.aro); 128.2 (2 C.sub.aro); 127.2 (2 C.sub.aro); 122.4 (2 C.sub.aro); 58.6 (2 CH.sub.2); 55.3 (CH.sub.2); 40.8 (CH.sub.2); 25.9 (CH.sub.2). LCMS m/z 315.0, 317.0 [M-EH].sup.+.

Example 13: Synthesis of N-[3-(benzylmethylamino)propyl]-2-bromobenzamide (Compound 3.1.20)

[0151] The compound 3.1.20 was synthesized according to the procedure E1 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.45 mmol, 113 mg), and 2-bromobenzoylchloride (0.45 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 52%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 7.56 (dd, J=7.8 Hz, J=1.3 Hz, 1H, H.sub.6); 7.47 (br s, 1H, NH); 7.37 (dd, J=7.4 Hz, J=2.0 Hz, 1H, H.sub.3); 7.31 (td, J=7.3 Hz, J=1.2 Hz, 1H, H.sub.aro); 7.24 (td, J=7.4 Hz, J=1.9 Hz, 1H, H.sub.aro); 7.16-7.07 (m, 5H, H.sub.aro); 3.52 (q, J=6.2 Hz, 2H, CH.sub.2); 3.48 (s, 2H, CH.sub.2); 2.57 (t, J=6.1 Hz, 2H, CH.sub.2); 2.19 (s, 3H, NCH.sub.3); 1.80 (p, J=6.2 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 167.8 (CO); 138.6 (C.sub.aro); 138.0 (C.sub.aro); 133.2 (C.sub.aro); 130.8 (C.sub.aro); 129.0 (2 C.sub.aro); 128.9 (2 C.sub.aro); 128.3 (C.sub.aro); 127.4 (C.sub.aro); 127.1 (C.sub.aro); 119.5 (C.sub.aro); 62.6 (CH.sub.2); 56.1 (CH.sub.2); 41.8 (CH.sub.3); 39.6 (CH.sub.2); 25.3 (CH.sub.2). LCMS m/z 361.0, 363.0 [M+H].sup.+.

Example 14: Synthesis of N-[3-(benzylmethylamino)propyl]-3-bromobenzamide (Compound 3.1.21)

[0152] The compound 3.1.21 was synthesized according to the procedure E1 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.45 mmol, 113 mg), and 3-bromobenzoylchloride (0.45 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 53%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 8.27 (br s, 1H, NH); 7.82 (t, J=1.8 Hz, 2H, H.sub.2); 7.55 (m, 1H, H.sub.5); 7.28-7.17 (m, 7H, H.sub.4, H.sub.6, H.sub.aro); 3.55 (m, 4H, 2CH.sub.2); 2.62 (t, J=6.0 Hz, 2H, CH.sub.2); 2.30 (s, 3H, NCH.sub.3); 1.83 (p, J=5.9 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 165.7 (CO); 137.6 (C.sub.aro); 136.7 (C.sub.aro); 134.0 (C.sub.aro); 130.3 (C.sub.aro); 129.9 (C.sub.aro); 129.4 (2 C.sub.aro); 128.5 (2 C.sub.aro); 127.6 (C.sub.aro); 125.4 (C.sub.aro); 122.6 (C.sub.aro); 63.1 (CH2); 56.8 (CH.sub.2); 41.8 (CH.sub.3); 40.4 (CH.sub.2); 24.9 (CH.sub.2). LCMS m/z 361.0, 363.0 [M+H].sup.+.

Example 15: Synthesis of N-[3-(benzylmethylamino)propyl]-4-bromobenzamide (Compound 3.1.22)

[0153] The compound 3.1.22 was synthesized according to the procedure E2 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.65 mmol, 164 mg), and 4-fluorobenzoic acid (0.65 mmol, 130 mg). Purification by thick layer chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 67%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 8.29 (br s, 1H, NH); 7.54 (d, J=9.1 Hz, 2H, H.sub.2, H.sub.6); 7.46 (d, J=9.2 Hz, 2H, H.sub.3, H.sub.5); 7.33-7.20 (m, 5H, H.sub.aro); 3.65-3.47 (m, 4H, 2 CH.sub.2); 2.66 (t, J=5.9 Hz, 2H, CH.sub.2); 2.29 (s, 3H, CH.sub.3); 1.84 (p, J=5.8 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 166.2 (CO); 137.5 (C.sub.aro); 133.5 (C.sub.aro); 131.6 (2 C.sub.aro); 129.5 (2 C.sub.aro); 128.6 (2 C.sub.aro); 128.5 (2 C.sub.aro); 127.7 (C.sub.m); 125.7 (C.sub.aro); 63.0 (CH.sub.2); 57.0 (CH.sub.2); 41.4 (CH.sub.3); 40.3 (CH.sub.2); 24.9 (CH.sub.2). LCMS m/z 360.9, 362.9 [M+H].sup.+.

Example 16: Synthesis of N-[3-(benzylmethylamino)propyl]-2,3-dichlorobenzamide (Compound 3.1.23)

[0154] The compound 3.1.23 was synthesized according to the procedure E1 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.48 mmol, 120 mg), and 2,3-dichlorobenzoylchloride (0.48 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 66%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 7.58 (br s, 1H, NH); 7.51 (dd, J=7.9 Hz, J=1.6 Hz, 1H, H.sub.6); 7.32 (dd, J=7.7 Hz, J=1.6 Hz, 1H, H.sub.4); 7.25 (m, 1H, H.sub.5); 7.17-7.07 (m, 5H, H.sub.aro); 3.55 (q, J=6.7 Hz, 2H, CH.sub.2); 3.48 (s, 2H, CH.sub.2); 2.58 (t, J=5.9 Hz, 2H, CH.sub.2); 2.21 (s, 3H, NCH.sub.3); 1.82 (p, J=6.0 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 166.2 (CO); 138.6 (C.sub.aro); 137.8 (C.sub.aro); 133.7 (C.sub.aro); 131.3 (C.sub.aro); 128.9 (C.sub.aro); 128.3 (2 C.sub.aro); 127.6 (2 C.sub.aro); 127.5 (C.sub.aro); 127.3 (C.sub.aro); 127.0 (C.sub.aro); 62.7 (CH.sub.2); 56.0 (CH.sub.2); 41.8 (CH.sub.3); 39.7 (CH.sub.2); 25.1 (CH.sub.2). LCMS m/z 351.0, 353.0 [M+H].sup.+.

Example 17: Synthesis of N-[3-(benzylmethylamino)propyl]-2,4-dichlorobenzamide (Compound 3.1.24)

[0155] The compound 3.1.24 was synthesized according to the procedure E1 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.48 mmol, 120 mg), and 2,4-dichlorobenzoylchloride (0.48 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 41%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 7.70 (br s, 1H, NH); 7.45 (d, J=8.3 Hz, 1H, H.sub.6); 7.38 (d, J=2.0 Hz, 1H, H.sub.3); 7.26 (dd, J=8.3 Hz, J=2.0 Hz 1H, H.sub.5); 7.19-7.07 (m, 5H, H.sub.aro); 3.53 (q, J=5.6 Hz, 2H, CH.sub.2); 3.47 (s, 2H, CH.sub.2); 2.56 (t, J=6.2 Hz, 2H, CH.sub.2); 2.20 (s, 3H, NCH.sub.3); 1.81 (p, J=6.0 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 165.7 (CO); 137.9 (C.sub.aro); 136.1 (C.sub.aro); 134.5 (C.sub.aro); 131.6 (C.sub.aro); 130.5 (C.sub.aro); 129.9 (C.sub.aro); 128.9 (2 C.sub.aro); 128.3 (2 C.sub.aro); 127.3 (C.sub.aro); 127.2 (C.sub.aro); 62.6 (CH.sub.2); 56.2 (CH.sub.2); 41.8 (CH.sub.3); 39.9 (CH.sub.2); 25.1 (CH.sub.2). LCMS mz 351.0, 353.0 [M+H].sup.+.

Example 18: Synthesis of N-[3-(benzylmethylamino)propyl]-3,4-dichlorobenzamide (Compound 3.1.25)

[0156] The compound 3.1.25 was synthesized according to the procedure E2 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.78 mmol, 197 mg), and 3,4-dichlorobenzoic acid (0.78 mmol, 150 mg). Purification by thick layer chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 31%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 8.44 (br s, 1H, NH); 7.82 (d, 0.1=2.0 Hz, 1H, H.sub.2); 7.47 (dd, J=8.2 Hz, J=2.0 Hz, 1H, H.sub.6); 7.38 (d, J=8.3 Hz, 1H, H.sub.5); 7.31-7.22 (m, 5H, H.sub.aro); 3.60 (s, 2H, CH.sub.2); 3.56 (q, J=6.1 Hz, 2H, CH.sub.2); 2.68 (t, J=6.1 Hz, 2H, CH.sub.2); 2.33 (s, 3H, CH.sub.3); 1.86 (p, J=6.2 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 164.9 (CO); 135.4 (C.sub.aro); 134.5 (C.sub.aro); 132.9 (C.sub.aro); 130.4 (2 C.sub.aro); 129.5 (2 C.sub.aro); 129.3 (C.sub.aro); 128.6 (2 C.sub.aro); 127.8 (C.sub.aro); 126.1 (C.sub.aro); 62.8 (CH.sub.2); 56.7 (CH.sub.2); 41.4 (CH.sub.3); 40.3 (CH.sub.2); 24.7 (CH.sub.2). LCMS m/z 350.9, 352.9 [M+H].sup.+.

Example 19: Synthesis of N-[3-(benzylmethylamino)propyl]-3,5-dichlorobenzamide (Compound 3.1.26)

[0157] The compound 3.1.26 was synthesized according to the procedure E2 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.78 mmol, 197 mg), and 3,5-dichlorobenzoic acid (0.78 mmol, 150 mg). Purification by thick layer chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 34%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 8.42 (br s, 1H, NH); 7.55 (m, 2H, H.sub.2, H.sub.6); 7.44 (m, 1H, H.sub.4); 7.28-7.20 (m, 5H, H.sub.aro); 3.57-3.51 (m, 4H, 2 CH.sub.2); 2.63 (t, J=6.1 Hz, 2H, CH.sub.2); 2.32 (s, 3H, CH.sub.3); 1.82 (p, J=6.0 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 164.6 (CO); 137.7 (C.sub.aro); 137.5 (C.sub.aro); 135.3 (C.sub.aro); 130.9 (2 C.sub.aro); 129.3 (2 C.sub.aro); 128.5 (2 C.sub.aro); 127.6 (C.sub.aro); 125.7 (2 C.sub.aro); 63.0 (CH.sub.2); 56.7 (CH.sub.2); 41.8 (CH.sub.3); 40.7 (CH.sub.2); 24.8 (CH.sub.2). LCMS m/z 351.0, 353.0 [M+H].sup.+.

Example 20: Synthesis of N-[3-(benzylmethylamino)propyl]-4-bromo-2-fluorobenzamide (Compound 3.1.27)

[0158] The compound 3.1.27 was synthesized according to the procedure E1 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.42 mmol, 105 mg), and 4-bromo-2-fluorobenzoylchloride (0.42 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 22%. .sup.1H NMR (300 MHz, MeOD), : 7.60 (d, J=8.2 Hz, 1H, H.sub.6); 7.50 (m, 1H, H.sub.aro); 7.44 (m, 1H, H.sub.aro); 7.22-7.34 (m, 5H, H.sub.aro); 3.59 (s, 2H, CH.sub.2); 3.43 (t, J=6.7 Hz, 2H, CH.sub.2); 2.56 (t, J=7.1 Hz, 2H, CH.sub.2); 2.28 (s, 3H, CH.sub.3); 1.85 (p, J=7.0 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 162.5 (CO); 132.9 (C.sub.aro); 129.5 (C.sub.aro); 128.7 (C.sub.aro); 128.4 (2 C.sub.aro); 128.1 (2 C.sub.aro); 125.1 (C.sub.aro); 119.8 (C.sub.aro); 119.4 (C.sub.aro); 62.4 (CH.sub.2); 55.3 (CH.sub.2); 41.4 (CH.sub.3); 29.7 (CH.sub.2); 25.4 (CH.sub.2). LCMS m/z 379.0, 381.0 [M+H].sup.+.

Example 21: Synthesis of N-[3-(benzylinethylamino)propyl]-3-methoxybenzamide (Compound 3.1.28)

[0159] The compound 3.1.28 was synthesized according to the procedure E1 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.59 mmol, 148 mg), and 3-methoxybenzoylchloride (0.59 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 35%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 8.10 (br s, 1H, NH); 7.35 (m, 1H, H.sub.2); 7.28-7.14 (m, 7H, H.sub.5, H.sub.6, H.sub.aro); 7.11 (m, 1H, H.sub.4); 3.78 (s, 3H, OCH.sub.3); 3.55 (m, 4H, 2CH.sub.2); 2.63 (t, 0.1=6.2 Hz, 2H, CH.sub.2); 2.28 (s, 3H, NCH.sub.3); 1.83 (p, J=6.4 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 165.3 (CO); 159.7 (C.sub.aro); 137.6 (C.sub.aro); 136.2 (C.sub.aro); 129.4 (3 C.sub.aro); 128.4 (2 C.sub.aro); 127.4 (C.sub.aro); 118.8 (C.sub.aro); 117.6 (C.sub.aro); 112.1 (C.sub.aro); 63.0 (CH.sub.2); 56.8 (CH.sub.2); 55.3 (OCH.sub.3); 41.5 (NCH.sub.3); 40.2 (CH.sub.2); 25.2 (CH.sub.2). LCMS m/z 313.0 [M+H].sup.+.

Example 22: Synthesis of N-[3-(benzylmethylamino)propyl]-4-methoxybenzamide (Compound 3.1.29)

[0160] The compound 3.1.29 was synthesized according to the procedure E2 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.98 mmol, 247 mg), and 4-methoxybenzoic acid (0.98 mmol, 150 mg). Purification by thick layer chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 73%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 7.97 (br s, 1H, NH); 7.67 (m, 2H, H.sub.2, H.sub.6); 7.32-7.24 (m, 5H, H.sub.aro); 6.84 (m, 2H, H.sub.3, H.sub.5); 3.84 (s, 3H, OCH.sub.3); 3.60-3.52 (m, 4H, 2 CH.sub.2); 2.65 (t, J=6.0 Hz, 2H, CH.sub.2); 2.29 (s, 3H, CH.sub.3); 1.85 (p, J=6.1 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 166.9 (CO); 162.0 (C.sub.aro); 137.2 (C.sub.aro); 129.6 (2 C.sub.aro); 128.8 (2 C.sub.aro); 128.5 (2 C.sub.aro); 127.7 (C.sub.aro); 125.0 (C.sub.aro); 113.6 (2 C.sub.aro); 62.9 (CH.sub.2); 56.7 (CH.sub.2); 55.4 (OCH.sub.3); 41.4 (CH.sub.3); 39.9 (CH.sub.2); 25.3 (CH.sub.2). LCMS m/z 313.1 [M+1-1].sup.+.

Example 23: Synthesis of N-[3-(benzylmethylamino)propyl]-3-dimethylaminobenzamide (Compound 3.1.30)

[0161] The compound 3.1.30 was synthesized according to the procedure E1 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.55 mmol, 138 mg), and 3-dimethylaminobenzoylchloride (0.55 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 11%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 7.90 (br s, 1H, NH); 7.28-7.24 (m, 5H, H.sub.aro); 7.22-7.19 (m, 2H, H.sub.2, H.sub.5); 6.92 (d, J=7.5 Hz, 1H, H.sub.6); 6.82 (dd, J=8.1 Hz, J=2.2 Hz, 1H, H.sub.4); 3.62-3.51 (m, 4H, 2 CH.sub.2); 2.95 (s, 6H, 2 CH.sub.3); 2.64 (t, =6.0 Hz, 2H, CH.sub.2); 2.31 (s, 3H, CH.sub.3); 1.85 (p, J=5.8 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 162.4 (CO); 138.5 (C.sub.aro); 133.1 (2 C.sub.aro); 129.0 (2 C.sub.aro); 128.2 (2 C.sub.aro); 128.0 (2 C.sub.aro); 127.1 (C.sub.aro); 119.7 (C.sub.aro); 119.4 (C.sub.aro); 63.0 (CH.sub.2); 55.9 (CH.sub.2); 50.9 (CH2); 41.9 (3 CH.sub.3); 39.9 (CH.sub.2); 25.6 (CH.sub.2). LCMS m/z 326.0 [M-F1-1].sup.+.

Example 24: Synthesis of N-[3-(benzylmethylamino)propyl]-4-cyanobenzamide (Compound 3.1.31)

[0162] The compound 3.1.31 was synthesized according to the procedure E1 by using N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.60 mmol, 150 mg), and 4-cyanobenzoylchloride (0.60 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 7%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 8.61 (br s, 1H, NH); 7.71 (d, J=8.2 Hz, 2H, H.sub.2, H.sub.6); 7.61 (d, J=8.3 Hz, 2H, H.sub.3, H.sub.5); 7.30-7.20 (m, 5H, H.sub.aro); 3.62 (q, J=6.4 Hz, 2H, CH.sub.2); 3.55 (s, 2H, CH.sub.2); 2.69 (t, J=5.8 Hz, 2H, CH.sub.2); 2.27 (s, 3H, CH.sub.3); 1.84 (p, J=6.0 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 165.3 (CO); 138.4 (C.sub.aro); 136.8 (C.sub.aro); 132.2 (2 C.sub.aro); 129.6 (2 C.sub.aro); 128.6 (2 C.sub.aro); 127.7 (2 C.sub.aro); 118.2 (C.sub.aro); 114.6 (C.sub.aro); 63.3 (CH.sub.2); 57.6 (CH.sub.2); 41.5 (CH.sub.3); 40.9 (CH.sub.2); 25.1 (CH.sub.2). LCMS m/z 308.0 [M+H].sup.+.

Example 25: Synthesis of N-[3-(benzylmethylamino)propyl]-4-nitrobenzamide (Compound 3.1.32)

[0163] The compound 3.1.32 was synthesized according to the procedure E1 by using N.sup.1-dihydrochloride 1.4a (0.53 mmol, 133 mg), and 4-nitrobenzoylchloride (0.53 mmol, 100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 50%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 8.68 (br s, 1H, NH); 8.17 (d, J=8.8 Hz, 2H, H.sub.2, H.sub.6); 7.79 (d, J=8.8 Hz, 2H, H.sub.3, H.sub.5); 7.32-7.22 (m, 5H, H.sub.aro); 3.65-3.56 (m, 4H, 2CH.sub.2); 2.72 (t, J=5.6 Hz, 2H, CH.sub.2); 2.32 (s, 3H, NCH.sub.3); 1.88 (p, J=5.7 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 166.7 (CO); 149.3 (C.sub.aro); 140.1 (C.sub.aro); 137.1 (C.sub.aro); 129.6 (2 C.sub.aro); 128.6 (2 C.sub.aro); 128.1 (2 C.sub.aro); 127.8 (C.sub.aro); 123.6 (2 C.sub.aro); 63.5 (CH.sub.2); 57.6 (CH.sub.2); 41.7 (CH.sub.3); 41.1 (CH.sub.2); 25.0 (CH.sub.2). LCMS m/z 328.0 [M+H].sup.+.

Example 26: Synthesis of N-[3-(benzylmethylamino)propyl]-4-chlorobenzensulfonamide (Compound 3.2a)

[0164] The compound 3.2a was synthesized according to the procedure E1 by using of M-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride 1.4a (0.47 mmol, 118 mg), and 4-chlorobenzo sulfonamide chloride (0.47 mmol, 100 mg). Purification by column chromatography (petroleum ether:DCM:MeOH(NH.sub.3), 5:4:1 (v/v)) was performed. Yield: 60%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 7.76 (d, J=9.1 Hz, 2H, H.sub.2, H.sub.6); 7.47 (d, J=9.2 Hz, 2H, H.sub.3, H.sub.5); 7.36-7.22 (m, 5H, H.sub.aro); 3.46 (s, 2H, CH.sub.2); 3.05 (t, J=7.2 Hz, 2H, CH.sub.2); 2.45 (t, J=7.1 Hz, 2H, CH.sub.2); 2.18 (s, 3H, CH.sub.3); 1.67 (p, J=7.0 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 138.8 (C.sub.aro); 138.7 (C.sub.aro); 137.9 (C.sub.aro); 129.3 (2 C.sub.aro); 129.0 (2 C.sub.aro); 128.6 (2 C.sub.aro); 128.5 (2 C.sub.aro); 127.4 (C.sub.aro); 62.8 (CH.sub.2); 56.8 (CH.sub.2); 44.0 (CH.sub.3); 41.9 (CH.sub.2); 24.7 (CH.sub.2). LCMS m/z 353.0, 355.0 [M+H].sup.+.

Example 27: Synthesis of 4-(benzylmethylamino)-N-(4-chlorophenyl)butanamide (Compound 3.3a)

[0165] The compound 3.3a was synthesized according to the procedure E3 by using of 4-chloro-N-(4-chlorophenyl)butyramide 2.2 (1.29 mmol, 300 mg) and N-benzylmethylamine (7.75 mmol, 1 mL). Purification by thick layer chromatography (cyclohexane:ethyl acetate:MeOH(NH.sub.3), 4.5:4.5:1 (v/v)) was performed. Yield: 70%. .sup.1H NMR (300 MHz, CDCl.sub.3), 9.63 (br s, 1H, NH); 7.45 (d, J=9.1 Hz, 2H, H.sub.2, H.sub.6); 7.34-7.27 (m, 5H, H.sub.aro); 7.21 (d, J=9.0 Hz, 2H, H.sub.3, H.sub.5); 3.69 (s, 2H, CH.sub.2); 2.62 (t, 0.1=6.2 Hz, 2H, CH.sub.2); 2.51 (t, 0.1=7.0 Hz, 2H, CH.sub.2); 2.35 (s, 3H, CH.sub.3); 1.96 (p, J=6.1 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 171.4 (CO); 137.2 (C.sub.aro); 135.9 (C.sub.aro); 129.7 (2 C.sub.aro); 128.8 (2 C.sub.aro); 128.7 (2 C.sub.aro); 128.5 (2 C.sub.aro); 128.0 (C.sub.aro); 120.8 (C.sub.aro); 62.2 (CH.sub.2); 56.5 (CH.sub.2); 41.4 (CH.sub.3); 36.2 (CH.sub.2); 22.2 (CH.sub.2). LCMS m/z 317.2, 319.2 [M+H].sup.+.

Example 28: Synthesis of N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamide (Compound 3.4a)

[0166] The compound 3.4a was synthesized according to the procedure E3 by using of N-(4-chlorobenzyl)-3-chloropropanamide 2.3 (0.21 mmol, 50 mg) and N-benzylmethylamine (1.29 mmol, 166 L). Purification by thick layer chromatography (cyclohexane:ethyl acetate:MeOH(NH.sub.3), 4.5:4.5:1 (v/v)). Yield: 67%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 8.65 (br s, 1H, NH); 7.34-7.19 (m, 7H, H.sub.2, H.sub.6, H.sub.aro); 7.09 (d, J=9.3 Hz, 2H, H.sub.3, H.sub.5); 4.38 (d, J=6.1 Hz, 2H, CH.sub.2); 3.57 (s, 2H, CH.sub.2); 2.79 (t, J=6.2 Hz, 2H, CH.sub.2); 2.56 (t, J=6.0 Hz, 2H, CH.sub.2); 2.25 (s, 3H, CH.sub.3). .sup.13C NMR (75 MHz, CDCl.sub.3) : 171.9 (CO); 137.2 (C.sub.aro); 133.1 (C.sub.aro); 129.3 (2 C.sub.aro); 129.2 (3 C.sub.aro); 128.8 (2 C.sub.aro); 128.6 (2 C.sub.aro); 127.9 (C.sub.aro); 62.0 (CH.sub.2); 53.0 (CH.sub.2); 42.6 (CH.sub.2); 40.7 (CH.sub.3); 32.4 (CH.sub.2). LCMS m/z 316.9, 318.9 [M+H].sup.+.

Example 29: Synthesis of N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamine (Compound 3.5a)

[0167] The compound 3.5a was synthesized according to the procedure E4 by using commercially 4-chlorobenzaldehyde (0.55 mmol, 77 mg) and N.sup.1-benzyl-/V-methylpropane-1,3-diamine 1.4a (0.55 mmol, 100 mg). Purification by thick layer chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)). Yield: 35%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 7.80 (br s, 1H, NH); 7.48 (d, J=8.4 Hz, 2H, H.sub.2, H.sub.6); 7.33 (d, J=8.5 Hz, 2H, H.sub.3, H.sub.5); 7.30-7.26 (m, 3H, H.sub.aro); 7.13 (m, 2H, H.sub.aro); 4.00 (s, 2H, CH.sub.2); 3.53 (s, 2H, CH.sub.2); 2.94 (t, J=6.5 Hz, 2H, CH.sub.2); 2.60 (t, J=6.3 Hz, 2H, CH.sub.2); 2.27 (s, 3H, CH.sub.3); 2.02 (p, J=6.2 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) : 136.5 (C.sub.aro); 135.3 (C.sub.aro); 131.2 (2 C.sub.aro); 130.3 (C.sub.aro); 129.4 (2 C.sub.aro); 129.3 (2 C.sub.aro); 128.6 (2 C.sub.aro); 127.8 (C.sub.aro); 62.2 (CH.sub.2); 55.4 (CH.sub.2); 50.9 (CH.sub.2); 47.3 (CH.sub.2); 41.5 (CH.sub.3); 22.6 (CH.sub.2). LCMS m/z 303.0, 305.0 [M+H].sup.+.

Example 30 Synthesis of N-(2-(benzyl(methyl)amino)ethyl)-3-chlorobenzamide (Compound 3.1.33)

[0168] The compound 3.1.33 was synthesized according to the procedure E3 by using N-(2-aminoethyl)benzamide (0.91 mmol, 150 mg) and 3-chlorobenzoyl chloride (0.91 mmol, 117 L). Purification by thick layer chromatography (DCM:MeOH(NH.sub.3), 9.1:1 (v/v)). Yield 35%. .sup.1H NMR (300 MHz, CDCl.sub.3) : 2.26 (s, 3H), 2.56 (t, 2H, J=7.1 Hz), 3.56 (q, 2H, J=5.0 Hz, J=7.5 Hz), 3.60 (s, 2H), 6.85 (s, 1H), 7.31 (m, 5H), 7.35 (t, 1H, J=7.5 Hz, J=7.5 Hz), 7.74 (m, 1H), 7.56 (d, 1H, J=1.5 Hz), 7.93 (m, 2H).sup.13C NMR (75 MHz, CDCl.sub.3) : 44.1, 57.6, 57.9, 64.9, 127.1, 127.8, 128.6, 128.2, 129.7, 130.0, 132.2, 134.4, 135.6, 138.6, 167.3 LCMS m/z 302.1; 303.1 [M+H].sup.+.

Example 31: Synthesis of N-(2-(benzyl(methyl)amino)ethyl)-2,4-dichlorobenzamide (Compound 3.1.34)

[0169] The compound 3.1.34 was synthesized according to the procedure E3 by using N-(2-aminoethyl)benzamide (0.91 mmol, 150 mg) and 2,4-dichlorobenzoyl chloride (0.91 mmol, 107 L). Purification by thick layer chromatography (DCM:MeOH(NH.sub.3), 9.1:1 (v/v)). Yield 35%. .sup.1H NMR (300 MHz, CDCl.sub.3) : 2.26 (s, 3H), 2.56 (t, 2H, J=7.1 Hz), 3.56 (q, 2H, J=5.0 Hz, J=7.5 Hz), 3.60 (s, 2H), 6.85 (s, 1H), 7.31 (m, 5H), 7.35 (t, 1H, J=7.5 Hz, J=7.5 Hz), 7.74 (m, 1H), 7.56 (d, 1H, J=1.5 Hz), 7.93 (m, 2H).sup.13C NMR (75 MHz, CDCl.sub.3) : 44.1, 57.6, 57.9, 64.9, 127.1, 127.8, 128.6, 128.2, 129.7, 130.0, 132.2, 134.4, 135.6, 138.6, 167.3 LCMS m/z 302.1; 303.1 [M+H].sup.+.

Example 32: Synthesis of N-(2-(benzyl(methyl)amino)ethyl)-4-cyanobenzamide (Compound 3.1.36)

[0170] The compound 3.1.36 was synthesized according to the procedure E3 by using N-(2-aminoethyl)benzamide (0.91 mmol, 150 mg) and 4-cyanobenzolyl chloride (0.91 mmol, 150 mg). Purification by thick layer chromatography (DCM:MeOH(NH.sub.3), 9.1:1 (v/v)). Yield 33%. .sup.1H NMR (300 MHz, CDCl.sub.3) : 2.34 (s, 3H), 2.65 (t, 2H, J=5.7 Hz), 3.55 (q, 2H, J=5.1 Hz, J=6.3 Hz), 3.59 (s, 2H), 6.96 (s, 1H), 7.35 (m, 5H), 7.52 (d, 2H, J=4.8 Hz), 8.29 (d, 2H, J=9 Hz).sup.13C NMR (75 MHz, CDCl.sub.3) : 43.9, 57.5, 58.0, 64.7, 115.7, 118.0, 126.9, 128.0, 128.5, 131.7, 139.1, 167.9 LCMS m/z 294.1[M+H].sup.+.

Example 33: Synthesis of N-(2-(benzyl(methyl)amino)ethyl)-4-nitrobenzamide (Compound 3.1.37)

[0171] The compound 3.1.37 was synthesized according to the procedure E3 by using N-(2-aminoethyl)benzamide (0.91 mmol, 150 mg) and 4-nitrobenzoyl chloride (0.91 mmol, 110 mg). Purification by thick layer chromatography (DCM:MeOH(NH.sub.3), 9.1:1 (v/v)). Yield 52%. .sup.1H NMR (300 MHz, CDCl.sub.3) : 2.34 (s, 3H), 2.65 (t, 2H, J=5.7 Hz), 3.55 (q, 2H, J=5.1 Hz, J=6.3 Hz), 3.59 (s, 2H), 6.96 (s, 1H), 7.35 (m, 5H), 7.52 (d, 2H, J=4.8 Hz), 8.29 (d, 2H, J=9 Hz).sup.13C NMR (75 MHz, CDCl.sub.3) : 43.9, 57.5, 58.0, 64.7, 115.7, 118.0, 126.9, 128.0, 128.5, 131.7, 139.1, 167.9 LCMS m/z 294.1[M+H].sup.+.

Example 34: Synthesis of N-(4-Nitrobenzyl)-3-(benzylmethylamino)propanamide (Compound 3.4b)

[0172] The compound 3.4b was synthesized according to the procedure E3 by using N-(4-chlorobenzyl)-3-chloropropanamide 2.3b (0.41 mmol, 100 mg) and N-benzylmethylamine (4.1 mmol, 531 L). Purification by thick layer chromatography (DCM:MeOH(NH.sub.3), 9.7:0.3 (v/v)). Yield: 37%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 9.00 (br s, 1H, NH); 8.15 (d, J=8.7 Hz, 2H, H.sub.aro); 7.40 (d, J=8.4 Hz, 2H, H.sub.aro); 7.20 (m, 3H, H.sub.aro); 7.10 (m, 2H, H.sub.aro); 4.50 (d, J=6.0 Hz, 2H, CH.sub.2); 3.50 (s, 2H, CH.sub.2); 2.70 (t, J=6.2 Hz, 2H, CH.sub.2); 2.50 (t, J=6.2 Hz, 2H, CH.sub.2); 2.25 (s, 3H, CH.sub.3). .sup.13C NMR (75 MHz, CDCl.sub.3) : 172.6 (CO); 146.5 (C.sub.aro); 146.2 (C.sub.aro); 137.3 (C.sub.aro); 129.1 (C.sub.aro); 128.5 (C.sub.aro); 128.1 (C.sub.aro); 127.6 (C.sub.aro); 123.8 (C.sub.aro); 62.2 (CH.sub.2); 52.8 (CH.sub.2); 42.3 (CH.sub.3); 41.1 (CH.sub.2); 32.5 (CH.sub.2); 29.7 (CH.sub.2). LCMS m/z 328.9 [M+H].sup.+.

Example 35: Synthesis of N-(4-Cyanobenzyl)-3-(benzylmethylamino)propanamide (Compound 3.4c)

[0173] The compound 3.4c was synthesized according to the procedure E3 by using N-(4-chlorobenzyl)-3-chloropropanamide 2.3c (0.44 mmol, 100 mg) and N-benzylmethylamine (4.4 mmol, 579 L). Purification by thick layer chromatography (DCM:MeOH(NH.sub.3), 9.7:0.3 (v/v)). Yield: 80%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 8.90 (br s, 1H, NH); 7.58 (d, J=6.3 Hz, 2H, H.sub.aro); 7.32 (d, J=8.1 Hz, .sup.2H, H.sub.aro); 7.21 (m, 3H, H.sub.aro); 7.07 (m, 2H, H.sub.aro); 4.43 (d, J=5.9 Hz, 2H, CH.sub.2); 3.48 (s, 2H, CH.sub.2); 2.68 (t, J=5.6 Hz, 2H, CH.sub.2); 2.47 (t, J=5.5 Hz, 2H, CH.sub.2); 2.21 (s, 3H, CH.sub.3). .sup.13C NMR (75 MHz, CDCl.sub.3) : 172.7 (CO); 144.4 (C.sub.aro); 137.5 (C.sub.aro); 132.4 (C.sub.aro); 129.0 (C.sub.aro); 128.5 (C.sub.aro); 128.1 (C.sub.aro); 127.5 (C.sub.aro); 118.8 (C.sub.aro); 110.9 (C.sub.aro); 62.2 (CH.sub.2); 52.9 (CH.sub.2); 42.5 (CH.sub.3); 41.1 (CH.sub.2); 32.6 (CH.sub.2). LCMS m/z 308.0 [M+H].sup.+.

Example 36: Synthesis of N-(2,4-Dichlorobenzyl)-3-(benzylmethylamino)propanamide (Compound 3.4d)

[0174] The compound 3.4d was synthesized according to the procedure E3 by using N-(4-chlorobenzyl)-3-chloropropanamide 2.3d (0.37 mmol, 100 mg) and N-benzylmethylamine (3.7 mmol, 483 L). Purification by thick layer chromatography (DCM:MeOH(NH.sub.3), 9.7:0.3 (v/v)). Yield: 80%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 8.90 (br s, 1H, NH); 7.38 (d, J=1.9 Hz, 1H, H.sub.aro); 7.28 (d, J=8.3 Hz, .sup.1H, H.sub.aro); 7.27-7.15 (m, 4H, H.sub.aro); 7.10 (m, 2H, H.sub.aro); 4.45 (d, J=5.8 Hz, 2H, CH.sub.2); 3.50 (s, 2H, CH.sub.2); 2.70 (t, J=6.1 Hz, 2H, CH.sub.2); 2.45 (t, J=5.6 Hz, 2H, CH.sub.2); 2.18 (s, 3H, CH.sub.3). .sup.13C NMR (75 MHz, CDCl.sub.3) : 172.5 (CO); 137.5 (C.sub.aro); 134.8 (C.sub.aro); 134.3 (C.sub.aro); 133.7 (C.sub.aro); 131.1 (C.sub.aro); 129.2 (C.sub.aro); 129.0 (C.sub.aro); 128.4 (C.sub.aro); 127.5 (C.sub.aro); 127.3 (C.sub.aro); 62.2 (CH.sub.2); 53.1 (CH.sub.2); 41.0 (CH.sub.3); 40.5 (CH.sub.2); 32.6 (CH.sub.2). LCMS m/z 350.97, 354.96, 352.93 [M+H].sup.+.

Example 37: Synthesis of N-(3-Chlorobenzyl)-3-(benzylmethylamino)propanamide (Compound 3.4e)

[0175] The compound 3.4e was synthesized according to the procedure E3 by using N-(4-chlorobenzyl)-3-chloropropanamide 2.3e (0.43 mmol, 100 mg) and N-benzylmethylamine (4.3 mmol, 555 L). Purification by thick layer chromatography (DCM:MeOH(NH.sub.3), 9.7:0.3 (v/v)). Yield: 68%. .sup.1H NMR (300 MHz, CDCl.sub.3), : 8.80 (br s, 1H, NH); 7.30-7.00 (m, 9H, H.sub.aro); 4.40 (d, =5.6 Hz, 2H, CH.sub.2); 3.50 (s, 2H, CH.sub.2); 2.70 (t, J=6.0 Hz, 2H, CH.sub.2); 2.48 (t, J=5.6 Hz, 2H, CH.sub.2); 2.20 (s, 3H, CH.sub.3). .sup.13C NMR (75 MHz, CDCl.sub.3) : 172.5 (CO); 140.8 (C.sub.aro); 137.5 (C.sub.aro); 134.4 (C.sub.aro); 129.9 (C.sub.aro); 129.0 (C.sub.aro); 128.5 (C.sub.aro); 127.8 (C.sub.aro); 127.5 (C.sub.aro); 127.4 (C.sub.aro); 125.9 (C.sub.aro); 62.2 (CH.sub.2); 53.1 (CH.sub.2); 42.5 (CH.sub.3); 40.1 (CH.sub.2); 32.6 (CH.sub.2). LCMS m/z 317.1, 319.1 [M+H].sup.+.

[0176] Compounds have been transformed into their hydrochloride salts by solubilizing in MeOH, treating with HCl 1M until pH=1 and then lyophilizing.

Biology Examples

1. Binding Assay to a Receptors

[0177] The binding assays were performed according to Ganapathy et al. (Ganapathy, M. E.; Prasad, P. D.; Huang, W.; Seth, P.; Leibach, F. H.; Ganapathy, V. Molecular and ligand-binding characterization of the sigma-receptor in the Jurkat human T lymphocyte cell line. J. Pharmacol. Exp. Ther. 1999, 289, 251-260). The .sub.1 binding assay was carried out by incubating Jurkat cell membranes (10-20 mg protein per tube) with [.sup.3H](+)-pentazocine (15 nM) and a range of concentrations of tested compounds, at 37 C. for 2 hours, in 5 mM Tris/HCl buffer (pH=7.4). The .sub.2 binding assay was performed by incubating Jurkat cell membranes (10-20 mg protein per tube) with [.sup.3H]-DTG (25 nM) in presence of (+)-pentazocine (1 M) to saturate .sub.1 receptors, and a range of concentrations of tested compounds, at room temperature for 1 hour in 5 mM Tris/HCl buffer (pH=7.4). The final assay volume was 0.5 mL. Binding was terminated by rapid filtration through Wathman GF/B filters, which were then washed with 51 mL ice-cold NaCl solution and allowed to dry before bound radioactivity was measured using liquid scintillation counting. Nonspecific binding was determined, in both assays, under similar conditions, but in presence of 10 M unlabeled haloperidol. Inhibition constants (KO were calculated from the IC.sub.50 values according to the method of Cheng and Prusoff (Cheng, Y.; Prusoff, W. H. Relationship between the inhibition constant (KO and the concentration of inhibitor which causes 50 percent inhibition (IC.sub.50) of an enzymatic reaction. Biochem Pharmacol. 1973, 22 (23), 3099-108):

[00001]$K_t=\frac{{\mathrm{IC}}_{50}}{1*\frac{L}{K_d}}$

Where IC.sub.50=Inhibitory concentration at 50% [0178] L=Concentration of radioligand [0179] Kd=Affinity constant of radioligand

[0180] The .sub.1 binding assay was carried out with [.sup.3H]()-pentazocine (L=15 nM, K.sub.d=16 nM) as radioligand and the .sub.2 binding assay with [.sup.3H]-DTG (L=25 nM, K.sub.d=80.84 nM).

[0181] The results of the sigma-1 and sigma-2 binding assays (i.e. the mean K.sub.i values for 2 or 3 independent experiments with less than 10% deviation) are shown in Tables 2, 3 and 4 hereafter:

TABLE-US-00002 TABLE 2 [00017] Com- Sigma 1 Sigma 2 pound K.sub.i K.sub.i Ratio No.* X m NR.sub.1R.sub.2 (nM) (nM) .sub.2/.sub.1 3.1.2 4-n-Pr 3 [00018] 3.7 160 43 3.1.3 4-n-Bu 3 [00019] 7.3 49 7 3.1.4 4-t-Bu 3 [00020] 1.6 nd 3.1.5 4-CF.sub.3 3 [00021] 1.4 98 70 3.1.6 4-F 3 [00022] 20 470 24 3.1.7 2-Cl 3 [00023] 47 >1200 >26 3.1.8 3-Cl 3 [00024] 10 340 34 3.1.9 4-Cl 2 [00025] 3.6 850 236 3.1.10 4-Cl 3 [00026] 3.2 190 60 3.1.11 4-Cl 4 [00027] 1.7 20 12 3.1.12 4-Cl 3 [00028] 4.3 200 47 3.1.15 4-Cl 3 [00029] 19 nd 3.1.20 2-Br 3 [00030] 42 >1200 >29 3.1.21 3-Br 3 [00031] 3.9 350 90 3.1.22 4-Br 3 [00032] 2.1 160 76 3.1.23 2,3-Cl 3 [00033] 10 310 31 3.1.24 2,4-Cl 3 [00034] 1.3 310 238 3.1.25 3,4-Cl 3 [00035] 1.1 59 54 3.1.26 3,5-Cl 3 [00036] 23 48 2 3.1.27 2-F-4-Br 3 [00037] 2.9 Nd 3.1.28 3-OCH.sub.3 3 [00038] 40 >1200 >30 3.1.29 4-OCH.sub.3 3 [00039] 37 >1000 >27 3.1.30 3-N(CH.sub.3).sub.2 3 [00040] 1.9 3.1.31 4-CN 3 [00041] 24 >1200 >50 3.1.32 4-NO.sub.2 3 [00042] 4.3 360 84 3.1.34 3,4-Cl 2 [00043] 6.5 110 17 3.1.36 4-CN 2 [00044] 1.2 170 142 3.1.37 4-NO.sub.2 2 [00045] 3.6 1400 389 *compounds are evaluated as their hydrochloride salts.

TABLE-US-00003 TABLE 3 [00046] Compound Sigma 1 Sigma 2 Ratio No.* L m K.sub.i (nM) K.sub.i (nM) .sub.2/.sub.1 3.2a SO.sub.2NH 3 5.8 200 35 3.3a NHCO 3 6.5 170 26 3.4a CH.sub.2NHCO 2 1.7 410 241 3.5a CH.sub.2NH 3 2.9 nd *compounds are evaluated as their hydrochloride salts.

TABLE-US-00004 TABLE 4 [00047] Compound Sigma 1 Sigma 2 Ratio No.* (X).sub.n K.sub.i (nM) K.sub.i (nM) .sub.2/.sub.1 3.4b 4-NO.sub.2 2.3 6500 2826 3.4c 4-CN 5.6 1800 321 3.4d 2,4-Cl 2.3 120 52 3.4e 3-Cl 0.63 200 317 *compounds are evaluated as their hydrochloride salts.

[0182] The present study shows that the compounds of the invention have good signal affinities and are selective over sigma 2. Especially compounds 3.1.9, 3.1.24, 3.4b and 3.5a have sigma 1 affinities in the nanomolecular range (1.3 to 3.6 nM) and excellent sigma 2/sigma 1 selectivities between 236 and 2826.

2. Agonist Activity of Sigma-1 Receptor Ligand 3.1.10 in the Dizocilpine-Induced Learning Deficits Test

[0183] The activity of compound 3.1.10 was evaluated on the prevention of the dizocilpine-induced learning deficits measured using two behavioral tests. The present experiment tested if its anti-amnesic activity could be blocked by pre-treatment with the reference sigma-1 receptor antagonist NE-100.

2.1 Study Plan Protocols and Materials

2.1.1. Experimental Design

[0184] Sixty (60) mice were used. Behavioral testing started one week after the arrival of the animals in the AMYLGEN animal facility. [0185] 5 treatment groups were designed and used as follows:

TABLE-US-00005 Treatment group n 1. vehicle 1 + vehicle 2 12 2. dizocilpine + vehicle 2 12 3. dizocilpine (0.15 mg/kg i.p.) + Cpd. 3.1.10 (0.5 mg/kg) 12 4. dizocilpine (0.15 mg/kg i.p.) + Cpd. 3.1.10 (0.5 mg/kg) + 12 5. dizocilpine (0.15 mg/kg i.p.) + NE-100 (3 mg/kg) 12 Total mice 60 [0186] Vehicle 1 was physiological saline for dizocilpine, DMSO 2% in water for compound 3.1.10 [0187] Animals were used at day 1 in the Y-maze test and at days 2 and 3 in the passive avoidance test, with training at day 2 and retention at day 3. [0188] Test compounds, compound 3.1.10 and/or NE-100 were administered 10 min before dizocilpine (at 0.15 mg/kg i.p.) or vehicle. [0189] Dizocilpine or vehicle 1 was administered 20 min before the Y-maze test session on day 1. [0190] Dizocilpine or vehicle 1 was administered 20 min before the passive avoidance training session on day 2. [0191] Drugs were not injected before the retention session on day 3. [0192] The whole experiment program was performed in a single series experiment. [0193] Treatments were randomized.

2.1.2. Animals

[0194] Male Swiss mice, 6 weeks old and weighing 30-35 g, from JANVIER (Saint Berthevin, France), were housed in groups with access to food and water ad libitum, except during experiments. They were kept in a temperature and humidity controlled animal facility on a 12 h/12 h light:dark cycle (lights on at 7:00 am). Behavioral experiments were carried out between 09:00 am and 05:00 pm, in a sound attenuated and air-regulated experimental room, to which mice were habituated at least 30 min. Mice were numbered by marking their tail using permanent markers ad sacrificed immediately after the passive avoidance retention session.

2.1.3. Test compounds [0195] Compound 3.1.10 of Example 10 above. [0196] Dizocilpine ((+)-MK-801 maleate, CAS #77086-22-7, batch 9A/124751) was from Tocris Bioscience. [0197] NE-100 hydrochloride (CAS #149409-57-4, batch 1B/124951) was from Tocris Bioscience.

[0198] All compounds were injected intraperitoneally (i.p.) in a volume of 100 L, per 20 g of body weight, corresponding to 5 mL/kg.

2.1.4. Randomization of the Treatments

[0199] Treatment received by animals tested in series were conterbalanced.

2.1.5. Mortality

[0200] No animal deceased following injection or during the behavioral testing.

2.2. Behavioral Analyses

2.2.1. Spontaneous Alternation Performances

[0201] Animals were tested for spontaneous alternation performance in the Y-maze, an index of spatial working memory. The Y-maze is made of grey polyvinylchloride. Each arm is 40 cm long, 13 cm high, 3 cm wide at the bottom, 10 cm wide at the top, and converging at an equal angle. Each mouse was placed at the end of one arm and allowed to move freely through the maze during an 8 min session. The series of arm entries, including possible returns into the same arm, were checked visually. An alternation was defined as entries into all three arms on consecutive occasions. The number of maximum alternations was therefore the total number of arm entries minus two and the percentage of alternation was calculated as: (actual alternations/maximum alternations)100. Parameters included the percentage of alternation (memory index) and total number of arm entries (exploration index).

[0202] Animals showing an extreme behavior (alternation <20% or >90% or number of arm entries <10) are usually discarded from the calculations. 2 animals were discarded accordingly.

2.2.2. Step-Through Passive Avoidance Test

[0203] The apparatus is a two-compartments (152015 cm high) box with one illuminated with white polyvinylchloride walls and the other darkened with black polyvinylchloride walls and a grid floor. A guillotine door separates each compartment. A 60 W lamp positioned 40 cm above the apparatus lights up the white compartment during the experiment. Scrambled footshocks (0.3 mA for 3 s) could be delivered to the grid floor using a shock generator scrambler (Lafayette Instruments, Lafayette, USA). The guillotine door is initially closed during the training session. Each mouse was placed into the white compartment. After 5 s, the door was raised. When the mouse entered the dark compartment and placed all its paws on the grid floor, the door was closed and the footshock delivered for 3 s. The step-through latency (the latency spent to enter the dark compartment) and the number of vocalizations was recorded. The retention test was carried out after 24 h. Each mouse was placed again into the white compartment. After 5 s, the door was opened. The step-through latency was recorded up to 300 s. When the mouse entered the dark compartment or 300 s has elapsed (they were therefore manually placed in it), the escape latency (latency to exit from the dark compartment) was recorded up to 300 s.

2.2.3. Statistical Analyses

[0204] All values, except passive avoidance latencies, were expressed as meanS.E.M. Statistical analyses were performed using two-way ANOVA (F value), with genotype and peptide treatment as independent factors, followed by a Dunn's post-hoc multiple comparison test.

[0205] Passive avoidance latencies do not follow a Gaussian distribution, since upper cut-off times are set. They were therefore analyzed using a Kruskal-Wallis non-parametric ANOVA (H value), followed by a Dunn's multiple comparison test.

[0206] p<0.05 was considered as statistically significant.

2.3. Results

[0207] The results of the spontaneous alternation and passive avoidance assays are represented in FIGS. 1a and 1b.

[0208] Compound 3.1.10 significantly attenuated the dizocilpine-induced learning deficits, at 0.5 mg/kg in the Y-maze test and in the passive avoidance test. The beneficial effect of compound 3.1.10 in the two tests was prevented by treatment with the sigma-1 antagonist NE-100 at 3 mg/kg, devoid of effect by itself.

[0209] These results thus demonstrate the sigma-1 receptor effect of compound 3.1.10.

3. In Vivo Assay to Assess Activity of Compound 3.1.10 in Rodent MS Model

[0210] Experimental autoimmune encephalomyelitis (EAE) is an unequivocal animal model of multiple sclerosis (MS), a demyelitating disabling disease of the central nervous system characterized by the inappropriate effect of reactive T and B cells.

Materials and Methods

[0211] Animals. SJL/J mice were purchased from Janvier (Le Genest-St-Isle, France) and bred under conventional barrier protection at the Pasteur Institute (Lille, France). All experiment protocols and procedures were in compliance with the European Communities Council Directives of 24 Nov. 1986 (86/609/EEC) and were approved by the local ethical committee (CEEA 102009R). Efforts were made to minimize the number of animals used and their suffering. Animals that reached severe hind limb paresis (clinical grade 3) were isolated, and hydration and food access were facilitated.

[0212] EAE induction and treatment. The method of EAE induction was similar to previously published methods (Lee-Chang et al., Immunol Lett. 2011 Mar. 30; 135(1-2):108-17). Randomized 9-week-old female SJL/J mice were inoculated subcutaneously (s.c.) in the neck with an emulsion containing 100 g of myelin proteolipid protein (PLP).sub.139-151 peptide and an equal volume of Freund's complete adjuvant (FCA) containing 4 mg/ml of heat-inactivated Mycobacterium tuberculosis H37RA (Difco Laboratories, Detroit, Mich., USA) on day 0. Additionally, mice received 0.3 g of Bordetella pertussis toxin (BPT) (Sigma-Aldrich, Saint Louis, Mich., USA) intraperitoneally (i.p.) on days 0 and 3. Sham animals only received saline injection. SJL/J mice that only received FCA and BPT were also included in the experiments.

[0213] Compound 3.1.10 was dissolved in physiological saline. Control animals received one administration of saline solution (vehicle).

[0214] For validation of the 1 action, pretreatment BD1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N,N,N-trimethylethane-1,2-diamine; Costa B. R., Radesca L., Di Paolo L., Bowen W. D. J. Med. Chem. 1992, 35, 38-47) or saline, i.p.) was administered 20 min prior to receiving compound 3.1.10 (i.p.). Injections were performed on the onset of EAE (i.e. grade=2) and continued for the following 14 days. The clinical course was followed for 35 days. Three different groups, EAE-vehicle, EAE-compound 3.1.10 (1 mg/kg), and EAE-DB1047 (10 mg/kg) compound 3.1.10 (1 mg/kg) were used per experiment with 7 animals per treatment group.

[0215] For preventive treatment, single compound 3.1.10 i.p. injection was performed on day 0 (D0). Three different groups, EAE-vehicle, EAE-compound 3.1.10 (0.5 mg/kg), and EAE-compound 3.1.10 (1 mg/kg), were used per experiment with 13-15 animals per treatment group.

[0216] For curative treatment, p.o. administrations were performed on the onset of EAE (i.e. grade=2) and treatment was continued for the following 14 days. The clinical course was followed for 70 days. Three different groups, EAE-vehicle, EAE-compound 3.1.10 (0.5 mg/kg), and EAE-compound 3.1.10 (1 mg/kg), were used per experiment with 7 animals per treatment group.

[0217] Mice showed no apparent toxic side effects of any treatment protocols.

[0218] Clinical evaluation. Body weight and clinical signs of EAE were monitored daily. The severity of clinical symptoms was scored based on a standard neurological scoring system for EAE, as follows: grade 0, no disease; grade 1, moderate tail hypotonia and/or slight clumsy gait; grade 2, tail atony and/or clumsy gait; grade 3, severe hind limb paresis; grade 4, paraplegia; grade 5, tetraplegia. Scoring was performed in a blind fashion.

[0219] Serum anti-PLP enzyme-linked immunosorbent assay (ELISA). Mice were deeply anesthetized with an i.p. injection of pentobarbital. Serum samples were prepared from peripheral blood obtained by cardiac puncture immediately before perfusion. Active immunizations were verified by measuring anti-PLP.sub.139-151 IgG antibody (Ab), as previously described (El Behi et al., (2007), J Neuroimmunol 182:80-8).

Results

[0220] The validation of al action assay confirms that compounds of the invention are active via the al receptor. The results are represented in FIG. 2.

[0221] The assay using compound 3.1.10 in preventive treatment demonstrates that compounds of the invention are useful in delaying the onset of EAE in mice. The results are represented in FIG. 3.

[0222] The assay using compound 3.1.10 in curative treatment demonstrates that compounds of the invention are useful in alleviating the symptoms of EAE in mice. The results are represented in FIG. 4.

[0223] EAE being an unequivocal animal model of multiple sclerosis (MS), a demyelitating disabling disease of the central nervous system characterized by the inappropriate effect of reactive T and B cells, the above results show the usefulness of the compounds of the invention, especially of compound 3.1.10, in the treatment and prevention of multiple sclerosis (MS) in particular and 61 receptor related diseases in general.

[0224] While embodiments of the invention have been illustrated and described, it is not intended that these embodiments illustrate and describe all possible forms of the invention. Rather, the words used in the specification are words of description rather than limitation ant it is understood that various changes may be made without departing from the spirit and scope of the invention.