Dream neuronal calcium sensor-modulating compounds, and therapeutic uses thereof

Abstract

The present invention relates to a group of compounds with a structural nucleus derived from phenylacetamide, having the following formula (I): ##STR00001##
that can modulate the DREAM neuronal calcium sensor. Consequently, the present invention also relates to the use of these compounds for the treatment or prevention of disorders or diseases in which DREAM levels are above or below physiologically normal levels.

Claims

1. A compound selected from the group consisting of: 2-[2-(3,4-dichlorophenyl)acetylamino]-4-methoxybenzoic acid, 4-chloro-2-[2-(3-phenoxyphenyl)acetylamino]benzoic acid, 4-chloro-2-[2-(4-chloro-2-fluorophenyl)acetylamino]benzoic acid, 4-chloro-2-[2-(3,4-dichlorophenyl)acetylamino]methyl benzoate, 4-chloro-2-[2-(3,4-dihydroxyphenyl)acetylamino]benzoic acid, 4-chloro-2-[3-(3,4-dichlorophenyl)propanoylamino] benzoic acid, 4-chloro-2-[2-(3,4-dichlorophenyl)acetylamino]-N-methylbenzamide, 3-[2-(3-phenoxyphenyl)acetylamino]-2-naphthoic acid, 3-[3-(3,4-dichlorophenyl)propanoylamino]-2-naphthoic acid, 4-bromo-2-[2-(3,4-diclorophenyl)acetylamino]benzoic acid, 2-[2-(3,4-dichlorophenyl)acetylamino]-5-(4-n-butylphenyl)benzoic acid, 2-[2-(3,4-dichlorophenyl)acetylamino]-4-(4-n-butylphenyl)benzoic acid, 2-[2-(3,4-dichlorophenyl)acetylamino]-5-(4-tert-butylphenyl)benzoic acid, 2-[2-(3,4-dichlorophenyl)acetylamino]-5-(2-methylphenyl)benzoic acid, 2-[3-(3,4-dichlorophenyl)propanoylamino]-5-(4-n-butylphenyl)benzoic acid, 2-[2-(3,4-dichlorophenyl)acetylamino]-4-phenylbenzoic acid, 2-[2-(3,4-dichlorophenyl)acetylamino]-4-(2-methylphenyl)benzoic acid, 2-[3-(3,4-dichlorophenyl)propanoylamino]-4-phenylbenzoic acid, 2-[2-(3,4-dichlorophenyl)acetylamino]-5-phenylbenzoic acid, 2-[3-(3,4-dichlorophenyl)propanoylamino]-5-(4-tert-butylphenyl)benzoic acid, 2-[3-(3,4-dichlorophenyl)propanoylamino]-5-(2-methylphenyl)benzoic acid, 2-[3-(3,4-dichlorophenyl)propanoylamino]-4-(2-methylphenyl)benzoic acid, 2-[2-(3,4-dichlorophenyl)acetylamino]-4-ethynylbenzoic acid, 2-[2-(3,4-dichlorophenyl)acetylamino]-methyl 5-phenylbenzoate, 2-[2-(3,4-dichlorophenyl)acetylamino]-5-(2-methylphenyl)methyl benzoate, 2-[2-(3,4-dichlorophenyl)acetylamino]-5-(4-tert-butylphenyl)methyl benzoate, 2-[2-(3,4-dichlorophenyl)acetylamino]-5-(4-n-butylphenyl)methyl benzoate, 2-[2-(3,4-dichlorophenyl)acetylamino]-methyl 4-phenylbenzoate, 2-[2-(3,4-dichlorophenyl)acetylamino]-4-(2-methylphenyl)methyl benzoate, 2-[2-(3,4-dichlorophenyl)acetylamino]-4-(4-n-butylphenyl)methyl benzoate, 2-[3-(3,4-dichlorophenyl)propanoylamino]-methyl 5-phenylbenzoate, 2-[3-(3,4-dichlorophenyl)propanoylamino]-5-(2-methylphenyl)methyl benzoate, 2-[3-(3,4-dichlorophenyl)propanoylamino]-5-(4-n-butylphenyl)methyl benzoate, 2-[3-(3,4-dichlorophenyl)propanoylamino]-methyl 4-phenylbenzoate, 2-[3-(3,4-dichlorophenyl)propanoylamino]-4-(2-methylphenyl)methyl benzoate, 2-[3-(3,4-dichlorophenyl)propanoylamino]-4-(4-n-butyl phenyl)methyl benzoate, 2-[3-(3,4-dichlorophenyl)propanoylamino]-5-phenylbenzoic acid, N-(2-benzoylphenyl)-2-(3,4-dichlorophenyl)acetamide and 2-[3-(3,4-dichlorophenyl)propanoylamino]-4-(4-n-butylphenyl)benzoic acid.

2. A compound of the formula (2R)-2-[2-(3,4-dichlorophenyl)acetylamino]-3-(1-trityl-1H-imidazol-4-yl)methyl propanoate.

3. A pharmaceutical composition comprising the compound of claim 2.

4. A pharmaceutical composition comprising the compound of claim 1.

5. A method for treating a disease or disorder in which the DREAM protein has altered expression levels comprising administering to a person in need thereof the pharmaceutical composition according to claim 4 and wherein the disease or disorder in which expression levels of the DREAM protein are altered is selected from neurodegenerative disorders, cognitive disorders, sensory perception disorders, inflammatory response disorders and auto inflammatory diseases.

6. The method according to claim 5 wherein the disease or disorder in which expression levels of the DREAM protein are altered is selected from Alzheimer's disease and other types of dementia, schizophrenia, Huntington's disease, dyskinesia, depression, Down's syndrome, chronic pain, neuropathic pain, allodynia, atherosclerosis, type-2 diabetes, rheumatoid arthritis, gout or acute respiratory distress syndrome.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1. A: Shows the representative example of the currents generated after the activation of Kv4.3 or Kv4.3+DREAM channels in the absence (black line) and presence (grey line) of the compound (35) at 100 nM. B: shows the bar chart in which the inhibitory effect of the Kv4.3 and Kv4.3+DREAM current produced by (35), (42) and (62) at 100 nM is compared.

(2) FIG. 2. Shows the analysis of the neuroprotective effect shown by compounds 9, 16, 22, 23 and 62 (100 nM) against the rupture the cell membrane mediated by H.sub.2O.sub.2 (0.66 mM) and subsequent release of LDH (lactate dehydrogenase) in STHdh.sup.Q111/Q111 cells infected with lentivirus expressing the complete human DREAM protein. RP: Repaniglida.

(3) FIG. 3. Analysis of the neuroprotective effect of compounds 9, 16, 22, 23 and 62 (100 nM) against the activation of caspase-3 mediated by staurosporine in .sup.Q111/Q111 cells infected with lentivirus expressing the complete human DREAM protein. The caspase-3 activity was measured after 1 h of pre-incubation of the compounds (100 nM) and subsequent exposure for 5 h of staurosporine at 1 M. RP: Repaniglida.

EXAMPLES

(4) The invention is illustrated below by means of tests carried out by the inventors, which reveal the effectiveness of the product of the invention.

Example 1: Synthesis of the Compounds of the Invention. General Procedure

(5) The compounds of general formula (I) of the present invention can be synthesised in two steps following the general methods A-D. In methods A-C, the first step consists in the formation of the necessary acid chlorides; and the second, in the generation of the amide, by reaction of the different acid chlorides and the amine of interest. Method D consists of the use of peptide coupling agents. These methods are described in detail below:

(6) Method A

(7) 2.4 mmol of oxalyl chloride and a drop of DMF as a catalyst are added to a solution of the corresponding carboxylic acid (1 mmol) in anhydrous THF (3 ml) at 0 C. The reaction mixture is stirred for two hours at room temperature. The acid chloride formed is dissolved in anhydrous THF (3 mL) and the corresponding amine (1.1 mmol) is added. Then 3 equivalents of anhydrous Et.sub.3N (3 mmol) are added, drop-by-drop, at 0 C. and stirred overnight at room temperature. The solvent is removed in a vacuum and the crude reaction product is suspended in water, it is acidified with 1N HCl to pH=3 or 4, extracted with AcOEt and washed with a solution saturated with NaCl (315 mL). The organic phase is dried over NA.sub.2SO.sub.4 and concentrated in a vacuum. As indicated in each case, the resulting residue is purified by medium pressure chromatography or crystallisation.

(8) Method B

(9) The procedure for synthesising acid chloride is that which is described in method A. The formation of the amide is carried out by microwave heating at 100 C. for 5 min using THF as a solvent.

(10) Method C

(11) A solution of the corresponding carboxylic acid (0.75 mmol) in thionyl chloride (1.5 mL) is heated under reflux for 6 h. After this time, excess thionyl chloride is evaporated to dryness. The residue is then dissolved in anhydrous THF (2 mL), and the corresponding amine (0.5 mmol) and propylene oxide (7.5 mmol) are added to the solution. The reaction is stirred at room temperature overnight. Finally, the excess solvent is removed in a vacuum and the solid formed is washed with water. The synthesised product is purified by successive washings with the appropriate solvent or by medium pressure chromatography.

(12) Method D

(13) 2.2 mmol of DIPEA or NMM are added to a solution of the corresponding amine (0.7 mmol) in DMF (2 mL). The solution is stirred at room temperature for 10 min. A coupling reagent (1.1 mmol, HATU, COMU, PyAOP-HOAt, EDC, DIC, HOBt) and the corresponding acid (1.1 mmol) are then added. After 12 hours of stirring at room temperature, the solvent is removed under reduced pressure. The reaction crude is suspended in water, acidified with 1N HCl to pH=3 or 4, extracted with AcOEt (315 mL) and washed with a solution saturated with NaCl (315 mL). The organic phase is dried over NA.sub.2SO.sub.4 and the solvent is evaporated to dryness. The resulting residue is purified by medium pressure chromatography.

(14) Functionalisation of the Aryl Ring. General Procedure.

(15) Cross coupling technology enables functionalising an aryl ring through reactions catalysed by a transition metal. For example, a Suzuki coupling may be carried out using aryl bromide and a boronic acid coupling partner. Alternatively, couplings can be carried out between an acetylene terminal and an aryl halide by Sonogashira reaction.

(16) a. Suzuki Coupling.

(17) An aryl halide (0.4 mmol), the corresponding derivative of boronic acid (0.6 mmol), K.sub.2CO.sub.3 (2.6 mmol), [Pd(PPh.sub.3).sub.4] (2% by weight) and 7 mL of a THF/H.sub.2O (4/1) mixture are added in a microwave tube. The reaction mixture is purged with argon and heated by irradiating at 125 C. for 15 min in a microwave reactor. Then, a further 0.6 mmol of the corresponding boronic acid is added and the procedure described is repeated. The solvent is removed to dryness, water is added and extracted with DCM (310 mL). The organic phases are washed with H.sub.2O (310 mL), they are dried over Na.sub.2SO.sub.4, and are concentrated under reduced pressure. The crude reaction product is purified by medium pressure chromatography.

(18) b. Sonogashira Reaction

(19) The corresponding brominated derivative (0.22 mmol), CuI (0.06 mmol), [Pd(PPh.sub.3).sub.4] (20% by weight), Et.sub.3N (1.74 mmol), trimethylsilylalkyne (0.67 mmol) and 1.5 of a THF/DMF mixture (10/3) are added to a sealed 25 mL tube. The reaction mixture is heated at 45 C. for 12 hours. The solvent is evaporated to dryness and the residue is extracted with AcOEt (310 mL). The organic phases are washed with H.sub.2O (310 mL), dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The crude reaction product is purified by medium pressure chromatography (hexane/AcOEt).

(20) Saponification of the Ester Group. General Procedure.

(21) A solution of NaOH 2N (0.2 mL) is added, drop-by-drop, to a solution of the corresponding ester (0.09 mmol) in 1.2 mL of THF and 0.6 mL of MeOH. After 12 hours of stirring at room temperature, the solvent is removed under reduced pressure, water is added and acidified with 1N HCl at pH 3 or 4. The aqueous phase is extracted with AcOEt (310 mL). The organic extracts are washed with water and solution saturated with NaCl, dried over Na.sub.2SO.sub.4, the solvent is removed to dryness and lyophilised. The product is obtained pure without the need for further purification.

(22) Detailed Description of the New Prepared Compounds:

2-[2-(3,4-dichlorophenyl)acetylamino]-4-methoxybenzoic acid. (7)

(23) White amorphous solid. Yield 60%. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) : 3.78 (3H, s), 3.71 (2H, s), 6.69 (1H, dd, J=8.9, 2.6 Hz), 7.34 (1H, dd, J=8.3, 2.1 Hz), 7.60 (1H, d, J=8.3 Hz), 7.65 (1H, d, J=2.1 Hz), 7.90 (1H, d, J=8.9 Hz), 8.18 (1H, d, J=2.6 Hz), 11.33 (1H, s), 13.26 (1H, s). .sup.13C-NMR (75 MHz, DMSO-d.sub.6) : 43.0, 55.4, 104.4, 108.3, 108.6, 129.6, 130.2, 130.5, 130.9, 131.8, 132.9, 135.7, 142.7, 163.5, 168.9, 169.2. LC-MS (m/z): 354.4 ([M+H].sup.+).

4-chloro-2-[2-(3-phenoxyphenyl)acetylamino]benzoic acid. (9)

(24) White crystalline solid. Yield 16%. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) : 3.80 (2H, s), 6.93 (1H, ddd, J=8.2, 2.5, 0.9 Hz), 7.02 (3H, m), 7.12 (2H, m), 7.21 (1H, dd, J=8.6, 2.2 Hz), 7.36 (3H, m), 7.96 (1H, d, J=8.6 Hz), 8.63 (1H, d, J=2.2 Hz), 11.21 (1H, s), 13.87 (1H, s). .sup.13C-NMR (75 MHz, DMSO-d.sub.6) : 44.5, 115.3, 118.9, 119.4, 120.4, 123.0, 123.7, 125.3, 130.4, 130.6, 133.2, 136.8, 138.8, 142.1, 157.1, 169.0, 170.2. LC-MS: 382.5 ([M+H].sup.+).

4-chloro-2-[2-(4-chloro-2-fluorophenyl)acetylamino]benzoic acid. (10)

(25) White crystalline solid. Yield 24%. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) : 3.86 (2H, s), 7.20 (1H, dd, J=8.6, 2.2 Hz), 7.25 (1H, m), 7.32 (1H, m), 7.36 (1H, m), 7.94 (1H, d, J=8.6 Hz), 8.59 (1H, d, J=2.2 Hz), 11.16 (1H, s), 13.85 (1H, s). .sup.13C-NMR (75 MHz, DMSO-d.sub.6) : 43.1, 114.7 (d, J=25.1 Hz), 115.1, 115.8 (d, J=21.7 Hz), 119.2, 122.7, 126.2, 132.7, 133.8 (d, J=11.3 Hz), 138.4, 138.6 (d, J=9.0 Hz), 141.5, 162.0 (d, J=247.0 Hz), 168.6, 168.9. LC-MS: 342.3 ([M+H].sup.+).

4-chloro-2-[2-(3,4-dichlorophenyl)acetylamino]methyl benzoate. (13)

(26) White amorphous solid. Yield 55%. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) : 3.79 (3H, s), 3.82 (2H, s), 7.25 (1H, dd, J=8.6, 2.2 Hz), 7.33 (1H, dd, J=8.3, 2.0 Hz), 7.60 (1H, d, J=8.3 Hz), 7.63 (1H, d, J=2.0 Hz), 7.88 (1H, d, J=8.6 Hz), 8.33 (1H, d, J=2.2 Hz), 10.7 (1H, s). .sup.13C-NMR (75 MHz, DMSO-d.sub.6) : 43.1, 55.2, 117.1, 121.1, 124.0, 130.4, 130.7, 131.2, 131.6, 132.4, 133.0, 136.5, 139.0, 141.1, 167.4, 169.7. LC-MS (m/z): 324.2 ([M+H].sup.+).

N-(2-benzoylphenyl)-2-(3,4-dichlorophenyl) acetamide. (63)

(27) White amorphous solid. Yield 35%. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) : 3.41 (2H, s), 7.02 (1H, dd, J=8.3, 2.1 Hz), 7.27 (1H, td, J=7.7, 1.0 Hz), 7.32 (1H, d, J=2.1 Hz), 7.37 (1H, dd, J=7.7, 1.5 Hz), 7.42 (2H, td, J=7.7, 1.0 Hz), 7.47 (1H, d, J=8.3 Hz), 7.51 (1H, dd, J=7.7, 1.0 Hz), 7.55 (1H, dd, J=7.7, 1.0 Hz), 7.59 (2H, m), 10.24 (1H, s). .sup.13C-NMR (75 MHz, DMSO-d.sub.6) : 41.8, 124.5, 125.3, 124.0, 128.8, 129.9, 130.1, 130.2, 130.5, 130.9, 131.3, 131.8, 131.9, 132.4, 133.3, 136.4, 136.9, 137.6, 168.7, 195.6. LC-MS (m/z): 384.2 ([M+H].sup.+).

4-chloro-2-[2-(3,4-dihydroxyphenyl)acetylamino]benzoic acid. (15)

(28) White amorphous solid. Yield 52%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.56 (2H, s), 6.59 (1H, dd, J=8.0, 2.1 Hz), 6.69 (1H, d, J=8.0 Hz), 6.71 (1H, d, J=2.1 Hz), 7.19 (1H, dd, J=8.5, 2.2 Hz), 7.95 (1H, d, J=8.5 Hz), 8.67 (1H, d, J=2.2 Hz), 8.85 (1H, s), 8.92 (1H, s), 11.36 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 45.2, 116.4, 117.4, 119.4, 121.1, 123.1, 125.6, 133.5, 139.0, 142.7, 145.1, 146.0, 169.4, 171.5. LC-MS (m/z): 322.1 ([M+H].sup.+).

4-chloro-2-[3-(3,4-dichlorophenyl)propanoylamino] benzoic acid. (16)

(29) White amorphous solid. Yield 22%. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) : 2.74 (2H, t, J=7.4 Hz), 2.89 (2H, t, J=7.4 Hz), 7.17 (1H, dd, J=8.6, 2.2 Hz), 7.24 (1H, td, J=8.3, 2.1 Hz), 7.49 (1H, d, J=8.3 Hz), 7.53 (1H, d, J=2.1 Hz), 7.93 (1H, d, J=8.6 Hz), 8.54 (1H, d, J=2.2 Hz), 11.19 (1H, s). .sup.13C-NMR (75 MHz, DMSO-d.sub.6) : 29.9, 38.7, 115.7, 119.8, 123.2, 129.3, 129.6, 131.0, 131.4, 133.5, 139.1, 142.3, 142.6, 169.1, 171.3. LC-MS (m/z): 372.1 ([M+H].sup.+).

4-chloro-2-[2-(3,4-dichlorophenyl)acetylamino]-N-methylbenzamide. (21)

(30) White amorphous solid. Yield 23% .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 2.76 (3H, d, J=4.5 Hz), 3.80 (2H, s), 7.23 (1H, dd, J=8.5, 2.2 Hz), 7.33 (1H, dd, J=8.3, 2.1 Hz), 7.60 (1H, d, J=8.3 Hz), 7.63 (1H, d, J=2.1 Hz), 7.71 (1H, d, J=8.5 Hz), 8.45 (1H, d, J=2.2 Hz), 8.76 (1H, d, J=4.5 Hz), 11.51 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 26.9, 43.2, 120.3, 120.4, 123.6, 130.3, 130.7, 131.1, 131.5, 132.4, 136.7, 136.7, 140.5, 168.2, 169.5. LC-MS (m/z): 371.1 ([M+H].sup.+).

3-[2-(3-phenoxyphenyl)acetylamino]-2-naphthoic acid. (22)

(31) White amorphous solid. Yield 61%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.79 (2H, s), 6.92 (1H, ddd, J=8.2, 2.5, 0.9 Hz), 7.01 (2H, m), 7.05 (1H, t, J=2.5 Hz), 7.10 (1H, tt, J=7.7, 1.1 Hz), 7.15 (1H, dt, J=8.2, 0.9 Hz), 7.36 (3H, m), 7.45 (1H, ddd, J=8.1, 6.9, 1.1 Hz), 7.58 (1H, ddd, J=8.1, 6.9, 1.1 Hz), 7.84 (1H, d, J=8.1 Hz), 7.99 (1H, d, J=8.1 Hz), 8.65 (1H, s), 8.92 (1H, s), 11.11 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 44.3, 116.6, 117.3, 117.4, 118.5, 120.0, 123.4, 124.9, 125.6, 127.1, 128.2, 129.1, 129.3, 130.0, 130.2, 133.1, 135.5, 136.0, 137.0, 156.7, 169.3, 169.4. LC-MS (m/z): 398.2 ([M+H].sup.+).

3-[3-(3-(3,4-dichlorophenyl)propanoylamino)]-2-naphthoic acid. (23)

(32) White amorphous solid. Yield 71%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 2.79 (2H, s), 2.97 (2H, s), 7.30 (1H, dd, J=8.3; 2.0 Hz), 7.47 (1H, td, J=8.1, 6.9 Hz), 7.53 (1H, t, J=8.3 Hz), 7.59 (1H, m), 7.86 (1H, d, J=8.1 Hz), 8.01 (1H, d, J=8.1 Hz), 8.67 (1H, s), 8.88 (1H, s), 11.15 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 29.6, 38.2, 116.7, 117.7, 125.5, 127.1, 128.2, 128.6, 129.0, 129.2, 130.4, 130.5, 130.8, 133.1, 135.5, 135.9, 142.3, 169.5, 170.1. LC-MS (m/z): 388.2 ([M+H].sup.+).

4-bromo-2-[2-(3,4-diclorophenyl)acetylamino]benzoic acid. (32)

(33) White amorphous solid. Yield 69%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.85 (2H, s), 7.36 (2H, dd, J=8.4, 2.0 Hz), 7.61 (1H, d, J=8.4 Hz), 7.66 (1H, d, J=2.0 Hz), 7.87 (1H, d, J=8.4 Hz), 8.74 (1H, d, J=2.0 Hz), 11.15 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 42.8, 116.2, 122.2, 125.8, 127.5, 129.8, 130.3, 130.6, 131.0, 131.9, 132.9, 135.6, 141.6, 168.8, 169.2. LC-MS (m/z): 403.0 ([M+H].sup.+).

2-[2-(3,4-dichlorophenyl)acetylamino]-4-ethynylbenzoic acid. (46)

(34) White amorphous solid. Yield 35%. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) : 3.84 (2H, s), 4.44 (1H, s), 7.22 (1H, dd, J=8.1, 1.6 Hz), 7.36 (1H, dd, J=8.3, 2.1 Hz), 7.61 (1H, d, J=8.2 Hz), 7.66 (1H, d, J=2.1 Hz), 7.92 (1H, d, J=8.1 Hz), 8.57 (1H, d, J=1.6 Hz), 11.24 (1H, s). .sup.13C-NMR (125 MHz, DMSO-d.sub.6) : 42.8, 82.6, 83.5, 122.7, 125.8, 126.7, 129.7, 130.2, 130.6, 130.9, 131.4, 131.8, 135.8, 140.5, 168.7, 169.0. LC-MS (m/z): 348.1 ([M+H].sup.+).

2-[2-(3,4-dichlorophenyl)acetylamino]-methyl 5-phenylbenzoate. (48)

(35) White amorphous solid. Yield 80%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.82 (3H, s), 3.83 (2H, s), 7.38 (2H, m), 7.47 (2H, m), 7.63 (1H, d, J=8.3 Hz), 7.67 (3H, m), 7.92 (1H, dd, J=8.7, 2.3 Hz), 8.12 (1H, d, J=2.3 Hz), 8.25 (1H, d, J=8.7 Hz), 10.64 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 42.4, 52.4, 119.2, 122.2, 126.4, 127.7, 128.2, 129.1, 129.6, 130.0, 130.5, 130.9, 131.6, 131.8, 135.2, 136.3, 138.2, 138.5, 167.3, 168.7. LC-MS (m/z): 414.2 ([M+H].sup.+).

2-[2-(3,4-dichlorophenyl)acetylamino]-5-(2-methylphenyl)methyl benzoate. (49)

(36) White amorphous solid. Yield 84%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 2.21 (3H, s), 3.78 (3H, s), 3.83 (2H, s), 7.20 (1H, m), 7.28 (3H, m), 7.37 (1H, dd, J=8.3, 2.0 Hz), 7.60 (1H, dd, J=8.5, 2.2 Hz), 7.63 (1H, d, J=8.3 Hz), 7.67 (1H, d, J=2.0 Hz), 7.78 (1H, d, J=2.2 Hz), 8.22 (1H, d, J=8.5 Hz), 10.64 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 20.1, 42.4, 52.4, 118.6, 121.4, 126.1, 127.7, 129.4, 129.6, 130.0, 130.4, 130.5, 130.6, 130.9, 131.6, 134.2, 134.8, 140.2, 136.3, 137.8, 139.7, 167.2, 168.7. LC-MS (m/z): 428.3 ([M+H].sup.+).

2-[2-(3,4-dichlorophenyl)acetylamino]-5-(4-tert-butylphenyl)methyl benzoate. (50)

(37) White amorphous solid. Yield 63%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 1.30 (9H, s), 3.81 (2H, s), 7.36 (1H, dd, J=8.2, 2.0 Hz), 7.48 (2H, d, J=8.6 Hz), 7.58 (2H, d, J=8.6 Hz), 7.62 (1H, d, J=8.2 Hz), 7.65 (1H, d, J=2.0 Hz), 7.88 (1H, dd, J=8.6, 2.3 Hz), 8.08 (1H, d, J=2.3 Hz), 8.20 (1H, d, J=8.6 Hz), 10.61 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 31.1, 34.4, 42.5, 52.5, 119.5, 122.4, 126.0, 126.2, 128.1, 129.7, 130.1, 130.6, 131.0, 131.6, 131.7, 135.6, 135.7, 136.4, 138.0, 150.3, 167.4, 168.8. LC-MS (m/z): 470.3 ([M+H].sup.+).

2-[2-(3,4-dichlorophenyl)acetylamino]-5-(4-n-butylphenyl)methyl benzoate. (51)

(38) White amorphous solid. Yield 67%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 0.90 (3H, t, J=7.3 Hz), 1.32 (2H, sx, J=7.3 Hz), 1.96 (2H, q, J=7.3 Hz), 2.61 (2H, t, J=7.3 Hz), 3.82 (3H, s), 3.82 (2H, s), 7.29 (2H, d, J=8.4 Hz), 7.36 (1H, dd, J=8.2, 2.0 Hz), 7.57 (2H, d, J=8.4 Hz), 7.64 (1H, d, J=8.2 Hz), 7.66 (1H, d, J=2.0 Hz), 7.89 (1H, dd, J=8.7, 2.3 Hz), 8.09 (1H, d, J=2.3 Hz), 8.23 (1H, d, J=8.7 Hz), 10.62 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 13.8, 21.7, 33.1, 34.1, 42.4, 52.4, 119.2, 122.2, 126.2, 127.9, 129.0, 129.6, 130.0, 130.5, 130.9, 131.5, 131.6, 135.2, 135.8, 136.3, 138.0, 142.0, 167.3, 168.6. LC-MS (m/z): 470.2 ([M+H].sup.+).

2-[2-(3,4-dichlorophenyl)acetylamino]-methyl 4-phenylbenzoate. (52)

(39) White amorphous solid. Yield 71%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.83 (3H, s), 3.85 (2H, s), 7.37 (1H, dd, J=8.3, 2.0 Hz), 7.44 (1H, m), 7.51 (3H, m), 7.62 (1H, d, J=8.3 Hz), 7.67 (3H, m), 7.98 (1H, d, J=8.3 Hz), 8.56 (1H, d, J=1.8 Hz), 11.73 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 43.1, 53.0, 117.5, 119.9, 122.4, 127.5, 129.3, 129.8, 130.3, 130.8, 131.2, 131.5, 131.9, 132.4, 136.8, 139.3, 140.5, 146.0, 167.9, 169.6. LC-MS (m/z): 414.1 ([M+H].sup.+).

2-[2-(3,4-dichlorophenyl)acetylamino]-4-(2-methylphenyl)methyl benzoate. (53)

(40) White amorphous solid. Yield 47%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 2.23 (3H, s), 3.82 (5H, s), 7.19 (1H, dd, J=8.1, 1.8 Hz), 7.20 (1H, m), 7.28 (1H, m), 7.32 (2H, m), 7.35 (1H, dd, J=8.2, 1.9 Hz), 7.61 (1H, d, J=8.2 Hz), 7.65 (1H, d, J=1.9 Hz), 7.95 (1H, d, J=8.1 Hz), 8.20 (1H, d, J=1.8 Hz), 10.70 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 20.1, 42.5, 52.4, 116.6, 121.8, 126.2, 126.2, 128.1, 129.2, 129.6, 130.1, 130.5, 130.6, 130.9, 131.7, 134.6, 136.2, 139.1, 140.0, 146.7, 167.3, 168.9. LC-MS (m/z): 428.3 ([M+H].sup.+).

2-[2-(3,4-dichlorophenyl)acetylamino]-4-(4-n-butylphenyl)methyl benzoate. (54)

(41) White amorphous solid. Yield 72%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 0.90 (3H, t, J=7.3 Hz), 1.31 (2H, sx, J=7.3 Hz), 1.57 (2H, q, J=7.3 Hz), 2.62 (2H, t, J=7.3 Hz), 3.83 (3H, s), 3.85 (2H, s), 7.32 (1H, d, J=8.4 Hz), 7.37 (1H, dd, J=8.3, 2.1 Hz), 7.49 (1H, dd, J=8.3, 1.9 Hz), 7.58 (2H, d, J=8.4 Hz), 7.62 (1H, d, J=8.3 Hz), 7.67 (1H, d, J=2.1 Hz), 7.96 (1H, d, J=8.3 Hz), 8.55 (1H, d, J=1.9 Hz), 10.73 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 13.8, 21.8, 33.0, 34.5, 42.5, 52.4, 116.4, 118.9, 121.4, 126.8, 129.1, 129.6, 130.1, 130.5, 130.9, 131.2, 131.7, 136.0, 136.2, 139.9, 143.1, 145.3, 167.3, 168.9. LC-MS (m/z): 470.2 ([M+H].sup.+).

2-[3-(3,4-dichlorophenyl)propanoylamino]-methyl 5-phenylbenzoate. (55)

(42) White amorphous solid. Yield 62%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 2.76 (2H, t, J=7.5 Hz), 2.94 (2H, t, J=7.5 Hz), 3.86 (3H, s), 7.28 (1H, dd, J=8.2, 2.0 Hz), 7.38 (1H, t, J=7.6 Hz), 7.48 (2H, t, J=7.6 Hz), 7.53 (1H, d, J=8.2 Hz), 7.57 (1H, d, J=2.0 Hz), 7.66 (2H, d, J=7.6 Hz), 7.91 (1H, dd, J=8.7, 2.3 Hz), 8.12 (1H, d, J=2.3 Hz), 8.27 (1H, d, J=8.7 Hz), 10.54 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 29.7, 37.9, 52.6, 118.7, 122.0, 126.4, 127.7, 128.2, 128.7, 129.0, 129.2, 130.4, 130.5, 130.9, 131.9, 135.0, 138.6, 142.2, 167.4, 170.4. LC-MS (m/z): 428.2 ([M+H].sup.+).

2-[3-(3,4-dichlorophenyl)propanoylamino]-5-(2-methylphenyl)methyl benzoate. (56)

(43) White amorphous solid. Yield 99%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 2.22 (3H, s), 2.77 (2H, t, J=7.5 Hz), 2.95 (2H, t, J=7.5 Hz), 3.83 (2H, s), 7.20 (1H, m), 7.28 (4H, m), 7.54 (1H, d, J=8.2 Hz), 7.58 (1H, d, J=2.0 Hz), 7.59 (1H, dd, J=8.6, 2.1 Hz), 7.79 (1H, d, J=2.1 Hz), 8.25 (1H, d, J=8.6 Hz), 10.55 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 20.1, 29.6, 37.9, 52.5, 118.0, 121.2, 126.1, 127.7, 128.6, 129.0, 129.5, 130.4, 130.5, 130.5, 130.6, 130.8, 134.3, 134.8, 136.0, 138.0, 139.7, 142.2, 167.4, 170.3. LC-MS (m/z): 442.2 ([M+H].sup.+).

2-[3-(3,4-dichlorophenyl)propanoylamino]-5-(4-n-butylphenyl)methyl benzoate. (57)

(44) White amorphous solid. Yield 81%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 0.90 (3H, t, J=7.3 Hz), 1.32 (2H, sx, J=7.3 Hz), 1.56 (2H, q, J=7.3 Hz), 2.61 (2H, t, J=7.3 Hz), 2.76 (2H, t, J=7.5 Hz), 2.94 (2H, t, J=7.5 Hz), 3.86 (3H, s), 7.28 (1H, dd, J=8.2, 2.4 Hz), 7.29 (2H, d, J=8.2 Hz), 7.54 (1H, d, J=8.2 Hz), 7.56 (1H, d, J=2.4 Hz), 7.57 (2H, d, J=8.2 Hz), 7.89 (1H, dd, J=8.7, 2.3 Hz), 8.10 (1H, d, J=2.3 Hz), 8.26 (1H, d, J=8.7 Hz), 10.53 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 13.8, 21.8, 29.6, 33.2, 34.4, 37.9, 52.5, 118.6, 121.9, 126.2, 129.7, 128.6, 128.9, 129.0, 130.4, 130.5, 130.8, 131.7, 134.9, 135.9, 138.3, 141.9, 142.2, 167.4, 170.2. LC-MS (m/z): 484.4 ([M+H].sup.+).

2-[3-(3,4-dichlorophenyl)propanoylamino]-methyl 4-phenylbenzoate. (58)

(45) White amorphous solid. Yield 70%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 2.78 (2H, t, J=7.4 Hz), 2.95 (2H, t, J=7.4 Hz), 3.86 (3H, s), 7.28 (1H, dd, J=8.3, 2.0 Hz), 7.45 (1H, tt, J=7.4, 1.3 Hz), 7.50 (4H, m), 7.58 (1H, d, J=2.0 Hz), 7.67 (2H, dd, J=8.3, 1.3 Hz), 7.98 (1H, d, J=8.3 Hz), 8.56 (1H, d, J=1.8 Hz), 10.63 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 29.6, 38.0, 52.5, 116.4, 119.1, 121.5, 126.9, 128.6, 128.7, 128.9, 129.2, 130.4, 130.5, 130.5, 130.8, 131.3, 138.8, 140.1, 142.1, 145.4, 167.4, 170.5. LC-MS (m/z): 428.3 ([M+H].sup.+).

2-[3-(3,4-dichlorophenyl)propanoylamino]-4-(2-methylphenyl)methyl benzoate. (59)

(46) White amorphous solid. Yield 67%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 2.24 (3H, s), 2.76 (2H, t, J=7.5 Hz), 2.93 (2H, t, J=7.5 Hz), 3.86 (3H, s), 7.17 (1H, dd, J=8.1, 1.8 Hz), 7.21 (1H, d, J=7.9 Hz), 7.27 (1H, dd, J=8.3, 2.0 Hz), 7.30 (1H, m), 7.32 (2H, m), 7.52 (1H, d, J=8.3 Hz), 7.56 (1H, d, J=2.0 Hz), 7.96 (1H, d, J=8.1 Hz), 8.23 (1H, d, J=1.8 Hz), 10.62 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 20.1, 29.5, 37.9, 52.4, 116.1, 121.6, 123.9, 126.1, 128.1, 128.6, 128.9, 129.1, 130.4, 130.5, 130.5, 130.6, 130.8, 134.6, 139.4, 140.0, 142.1, 146.7, 167.4, 170.4. LC-MS (m/z): 442.2 ([M+H].sup.+).

2-[3-(3,4-dichlorophenyl)propanoylamino]-4-(4-n-butylphenyl)methyl benzoate. (60)

(47) White amorphous solid. Yield 78%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 0.91 (3H, t, J=7.3 Hz), 1.32 (2H, sx, J=7.3 Hz), 1.58 (2H, q, J=7.3 Hz), 2.63 (2H, t, J=7.3 Hz), 2.78 (2H, t, J=7.5 Hz), 2.95 (2H, t, J=7.5 Hz), 3.86 (3H, s), 7.29 (1H, dd, J=8.2, 2.0 Hz), 7.33 (2H, d, J=8.3 Hz, 2H), 7.47 (1H, dd, J=8.3, 1.9 Hz), 7.53 (1H, d, J=8.2 Hz), 7.58 (2H, d, J=8.3 Hz), 7.58 (1H, d, J=2.0 Hz), 7.97 (1H, d, J=8.3 Hz), 8.57 (1H, d, J=1.9 Hz), 10.64 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 13.8, 21.8, 29.6, 33.0, 34.5, 37.9, 52.4, 115.9, 118.7, 121.1, 126.7, 128.6, 128.9, 129.1, 130.4, 130.5, 130.8, 131.2, 136.1, 140.1, 142.1, 143.1, 145.3, 167.4, 170.4. LC-MS (m/z): 484.3 ([M+H].sup.+).

2-[2-(3,4-dichlorophenyl)acetylamino]-5-phenylbenzoic acid. (42)

(48) White amorphous solid. Yield 91%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.86 (2H, s), 7.38 (2H, m), 7.47 (2H, m), 7.62 (1H, d, J=8.2 Hz), 7.67 (3H, m), 7.91 (1H, dd, J=8.7, 2.4 Hz), 8.20 (1H, d, J=2.4 Hz), 8.56 (1H, d, J=8.7 Hz), 11.14 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 42.9, 117.4, 120.7, 126.3, 127.6, 128.7, 129.1, 129.7, 130.2, 130.6, 130.9, 131.8, 132.0, 134.5, 136.0, 138.6, 139.8, 168.7, 169.2. LC-MS (m/z): 400.1 ([M+H].sup.+).

2-[2-(3,4-dichlorophenyl)acetylamino]-5-(2-methylphenyl)benzoic acid. (37)

(49) White amorphous solid. Yield 92%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 2.22 (2H, s), 3.86 (3H, s), 7.20 (1H, m), 7.27 (3H, m), 7.38 (1H, dd, J=8.3, 2.1 Hz), 7.59 (1H, dd, J=8.6, 2.2 Hz), 7.62 (1H, d, J=8.3 Hz), 7.69 (1H, d, J=2.1 Hz), 7.86 (1H, d, J=2.2 Hz), 8.53 (1H, d, J=8.6 Hz), 11.12 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 20.1, 42.9, 116.7, 120.0, 126.1, 127.6, 129.4, 129.7, 130.2, 130.5, 130.6, 131.0, 131.2, 131.8, 134.5, 134.7, 135.6, 136.0, 139.3, 139.8, 168.7, 169.2. LC-MS (m/z): 414.2 ([M+H].sup.+).

2-[2-(3,4-dichlorophenyl)acetylamino]-5-(4-tert-butylphenyl)benzoic acid. (36)

(50) White amorphous solid. Yield 96%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 1.30 (9H, s), 3.88 (2H, s), 7.38 (1H, dd, J=8.3, 2.1 Hz), 7.47 (2H, d, J=8.6 Hz), 7.58 (2H, d, J=8.6 Hz), 7.62 (1H, d, J=8.3 Hz), 7.68 (1H, d, J=2.1 Hz), 7.88 (1H, dd, J=8.7, 2.4 Hz), 8.18 (1H, d, J=2.4 Hz), 8.53 (1H, d, J=8.7 Hz), 11.17 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 31.0, 34.3, 42.9, 118.2, 121.3, 126.5, 126.7, 129.2, 130.3, 130.9, 131.3, 131.6, 132.4, 132.5, 135.0, 136.5, 136.7, 140.2, 150.0, 169.4, 169.9. LC-MS (m/z): 456.1 ([M+H].sup.+).

2-[2-(3,4-dichlorophenyl)acetylamino]-5-(4-n-butylphenyl)benzoic acid. (34)

(51) White amorphous solid. Yield 92%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 0.90 (3H, t, J=7.3 Hz), 1.31 (2H, sx, J=7.3 Hz), 1.56 (2H, q, J=7.3 Hz), 2.60 (2H, t, J=7.3 Hz), 3.85 (2H, s), 7.27 (2H, d, J=8.3 Hz), 7.38 (1H, dd, J=8.3, 2.0 Hz), 7.56 (2H, d, J=8.3 Hz), 7.62 (1H, d, J=8.3 Hz), 7.68 (1H, d, J=2.0 Hz), 7.88 (1H, dd, J=8.8, 2.4 Hz), 8.17 (1H, d, J=2.4 Hz), 8.54 (1H, d, J=8.8 Hz), 11.10 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 13.8, 21.8, 33.1, 34.4, 42.9, 117.3, 120.7, 126.2, 128.5, 129.0, 129.7, 130.2, 130.6, 131.0, 131.8, 131.8, 134.5, 136.0, 139.5, 141.8, 168.7, 169.3. LC-MS (m/z): 456.4 ([M+H].sup.+).

2-[2-(3,4-dichlorophenyl)acetylamino]-4-phenylbenzoic acid. (39)

(52) White amorphous solid. Yield 91%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.87 (2H, s), 7.38 (1H, dd, J=8.3, 2.0 Hz), 7.44 (1H, m), 7.46 (1H, dd, J=8.2, 1.8 Hz), 7.50 (2H, t, J=7.4 Hz), 7.62 (1H, d, J=8.3 Hz), 7.65 (1H, d, J=2.0 Hz), 7.68 (2H, dd, J=7.4, 1.8 Hz), 8.03 (1H, d, J=8.2 Hz), 8.83 (1H, d, J=1.8 Hz), 11.21 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 42.9, 115.4, 117.9, 121.1, 126.9, 128.6, 129.1, 129.7, 130.3, 130.5, 130.9, 131.8, 131.9, 135.9, 138.9, 141.1, 145.4, 169.0, 169.2. LC-MS (m/z): 400.1 ([M+H].sup.+).

2-[2-(3,4-dichlorophenyl)acetylamino]-4-(2-methylphenyl)benzoic acid. (40)

(53) White amorphous solid. Yield 85%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 2.23 (3H, s), 3.84 (2H, s), 7.13 (1H, dd, J=8.1, 1.8 Hz), 7.20 (1H, m), 7.27 (3H, m), 7.36 (1H, dd, J=8.3, 2.1 Hz), 7.61 (1H, d, J=8.3 Hz), 7.67 (1H, d, J=2.1 Hz), 8.01 (1H, d, J=8.1 Hz), 8.49 (1H, d, J=1.8 Hz), 11.20 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 20.1, 42.9, 115.1, 120.5, 123.5, 126.1, 128.0, 129.1, 129.7, 130.3, 130.5, 130.9, 131.0, 131.9, 134.6, 135.9, 140.2, 140.4, 146.8, 168.9, 169.2. LC-MS (m/z): 414.2 ([M+H].sup.+).

2-[2-(3,4-dichlorophenyl)acetylamino]-4-(4-n-butylphenyl)benzoic acid. (35)

(54) White amorphous solid. Yield 94%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 0.90 (3H, t, J=7.3 Hz), 1.31 (2H, sx, J=7.3 Hz), 1.57 (2H, q, J=7.3 Hz), 2.62 (2H, t, J=7.3 Hz), 3.87 (2H, s), 7.31 (2H, d, J=8.3 Hz), 7.38 (1H, dd, J=8.3, 2.0 Hz), 7.43 (1H, dd, J=8.3, 1.9 Hz), 7.57 (2H, d, J=8.3 Hz), 7.62 (1H, d, J=8.3 Hz), 7.68 (1H, d, J=2.0 Hz), 8.01 (1H, d, J=8.3 Hz), 8.82 (1H, d, J=1.9 Hz), 11.21 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 13.8, 21.8, 33.0, 34.5, 42.9, 115.0, 117.6, 120.8, 126.7, 129.1, 129.7, 130.3, 130.6, 130.9, 131.8, 131.9, 135.9, 136.2, 141.2, 143.0, 145.4, 168.9, 169.3. LC-MS (m/z): 456.1 ([M+H].sup.+).

2-[3-(3,4-dichlorophenyl)propanoylamino]-5-phenylbenzoic acid. (61)

(55) White amorphous solid. Yield 99%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 2.76 (2H, t, J=7.5 Hz), 2.93 (2H, t, J=7.5 Hz), 7.27 (1H, dd, J=8.3, 2.1 Hz), 7.35 (1H, tt, J=7.6, 1.1 Hz), 7.45 (2H, t, J=7.6 Hz), 7.51 (1H, d, J=8.3 Hz), 7.56 (1H, d, J=2.1 Hz), 7.64 (2H, dd, J=7.6, 1.1 Hz), 7.88 (1H, dd, J=8.7, 2.4 Hz), 8.19 (1H, d, J=2.4 Hz), 8.52 (1H, d, J=8.7 Hz), 11.20 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 30.2, 38.4, 117.9, 121.4, 127.0, 128.2, 129.3, 129.4, 129.6, 129.7, 131.0, 131.2, 131.5, 132.7, 134.9, 139.4, 140.5, 142.8, 170.0, 170.9. LC-MS: 414.1 (M+H)+. LC-MS (m/z): 414.2 ([M+H].sup.+).

2-[3-(3,4-dichlorophenyl)propanoylamino]-5-(2-methylphenyl)benzoic acid. (44)

(56) White amorphous solid. Yield 66%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 2.23 (3H, s), 2.78 (2H, t, J=7.5 Hz), 2.96 (2H, t, J=7.5 Hz), 7.21 (1H, m), 7.29 (4H, m), 7.54 (1H, d, J=8.2 Hz), 7.58 (1H, d, J=2.0 Hz), 7.59 (1H, dd, J=8.5, 2.2 Hz), 7.88 (1H, d, J=2.2 Hz), 8.51 (1H, d, J=8.5 Hz), 11.16 (1H, s), 13.68 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 20.1, 29.5, 38.1, 116.7, 120.0, 126.1, 127.5, 128.6, 128.9, 129.4, 130.4, 130.4, 130.5, 130.8, 131.1, 134.4, 134.7, 135.3, 139.4, 139.8, 142.1, 169.3, 170.2. LC-MS (m/z): 428.2 ([M+H].sup.+).

2-[3-(3,4-dichlorophenyl)propanoylamino]-5-(4-tert-butylphenyl)benzoic acid. (43)

(57) White amorphous solid. Yield 91%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 1.31 (3H, s), 2.77 (2H, t, J=7.5 Hz), 2.95 (2H, t, J=7.5 Hz), 7.29 (1H, dd, J=8.3, 2.1 Hz), 7.48 (2H, d, J=8.4 Hz), 7.53 (1H, d, J=8.3 Hz), 7.58 (3H, m), 7.88 (1H, dd, J=8.7, 2.3 Hz), 8.19 (1H, d, J=2.3 Hz), 8.53 (1H, d, J=8.7 Hz), 11.10 (1H, s), 13.70 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 29.6, 31.2, 34.4, 38.3, 117.2, 120.7, 125.8, 126.0, 128.5, 128.9, 130.4, 130.5, 130.8, 131.9, 134.2, 135.9, 139.6, 142.1, 150.0, 169.3, 170.2. LC-MS (m/z): 470.3 ([M+H].sup.+).

2-[3-(3,4-dichlorophenyl)propanoylamino]-5-(4-n-butylphenyl)benzoic acid. (38)

(58) White amorphous solid. Yield 91%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 0.90 (3H, t, J=7.3 Hz), 1.32 (2H, sx, J=7.3 Hz), 1.57 (2H, q, J=7.3 Hz), 2.69 (2H, t, J=7.3 Hz), 2.77 (2H, t, J=7.5 Hz), 2.95 (2H, t, J=7.5 Hz), 7.29 (3H, m), 7.53 (1H, d, J=8.3 Hz), 7.56 (2H, d, J=8.2 Hz), 7.58 (1H, d, J=2.0 Hz), 7.88 (1H, dd, J=8.7, 2.3 Hz), 8.19 (1H, d, J=2.3 Hz), 8.53 (1H, d, J=8.7 Hz), 11.10 (1H, s), 13.76 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 13.8, 21.8, 29.5, 33.1, 34.4, 38.2, 117.2, 120.7, 126.2, 128.5, 128.6, 128.9, 129.0, 130.4, 130.5, 130.8, 131.8, 134.2, 136.1, 139.6, 141.8, 142.2, 169.4, 170.2. LC-MS (m/z): 470.2 ([M+H].sup.+).

2-[3-(3,4-dichlorophenyl)propanoylamino]-4-phenylbenzoic acid. (41)

(59) White amorphous solid. Yield 89%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 2.79 (2H, t, J=7.5 Hz), 2.96 (2H, t, J=7.4 Hz), 7.30 (1H, dd, J=8.3, 2.1 Hz), 7.44 (1H, m), 7.50 (4H, m), 7.58 (1H, d, J=2.1 Hz), 7.67 (2H, dd, J=8.2, 1.3 Hz), 8.05 (1H, d, J=8.3 Hz), 8.81 (1H, d, J=1.8 Hz), 11.20 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 29.4, 38.2, 115.3, 117.9, 120.9, 126.9, 128.6, 128.7, 128.9, 129.2, 130.4, 130.5, 130.8, 131.8, 139.0, 141.2, 142.1, 145.4, 169.3, 170.4. LC-MS (m/z): 414.2 ([M+H].sup.+).

2-[3-(3,4-dichlorophenyl)propanoylamino]-4-(2-methylphenyl)benzoic acid. (45)

(60) White amorphous solid. Yield 94%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 2.24 (3H, s), 2.77 (2H, t, J=7.5 Hz), 2.93 (2H, t, J=7.5 Hz), 7.12 (1H, dd, J=8.1, 1.8 Hz), 7.21 (1H, m), 7.29 (2H, dd, J=8.2, 2.1 Hz), 7.32 (2H, m), 7.52 (1H, d, J=8.2 Hz), 7.56 (1H, d, J=2.1 Hz), 8.02 (1H, d, J=8.1 Hz), 8.47 (1H, d, J=1.8 Hz), 11.17 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 20.1, 29.4, 38.2, 114.9, 120.4, 123.3, 126.1, 128.0, 128.6, 128.9, 129.1, 130.4, 130.5, 130.5, 130.7, 131.0, 134.6, 140.2, 140.0, 140.5, 142.1, 169.3, 170.3. LC-MS (m/z): 428.2 ([M+H].sup.+).

2-[3-(3,4-dichlorophenyl)propanoylamino]-4-(4-n-butylphenyl)benzoic acid. (64)

(61) White amorphous solid. Yield 89%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 0.90 (3H, t, J=7.3 Hz), 1.32 (2H, sx, J=7.3 Hz), 1.57 (2H, q, J=7.3 Hz), 2.63 (2H, t, J=7.3 Hz), 2.79 (2H, t, J=7.5 Hz), 2.96 (2H, t, J=7.5 Hz), 7.29 (1H, dd, J=8.2, 2.1 Hz), 7.33 (2H, d, J=8.3 Hz), 7.42 (1H, dd, J=8.3, 1.9 Hz), 7.53 (1H, d, J=8.2 Hz), 7.58 (2H, d, J=8.3 Hz), 7.58 (1H, d, J=2.1 Hz), 8.03 (1H, d, J=8.3 Hz), 8.80 (1H, d, J=1.9 Hz), 11.19 (1H, s), 13.59 (1H, s). .sup.13C-NMR (100 MHz, DMSO-d.sub.6) : 13.8, 21.8, 29.4, 33.0, 34.5, 38.2, 114.9, 117.6, 120.6, 126.7, 128.6, 128.9, 129.1, 130.4, 130.5, 130.8, 131.8, 136.3, 141.2, 142.1, 143.0, 145.4, 169.3, 170.4. LC-MS (m/z): 470.3 ([M+H].sup.+).

(2R)-2-[2-(3,4-dichlorophenyl)acetylamino]-3-(1-trityl-1H-imidazol-4-yl)methyl propanoate. (62)

(62) White amorphous solid. Yield 71%. .sup.1H-NMR (300 MHz, CD.sub.3Cl) : 2.91 (1H, dd, J=14.7, 4.5 Hz), 3.00 (1H, dd, J=14.7, 5.8 Hz), 3.51 (3H, s), 4.04 (1H, d, J=14.3 Hz), 4.06 (1H, d, J=14.3 Hz), 4.66 (1H, ddd, J=7.8, 5.8, 4.5 Hz), 6.50 (1H, s), 6.99 (6H, m), 7.09 (1H, dd, J=8.2, 2.1 Hz), 7.19 (1H, s), 7.28 (10H, m), 7.37 (1H, d, J=2.1 Hz), 7.68 (1H, d, J=7.8 Hz). .sup.13C-NMR (75 MHz, CD.sub.3Cl) : 28.0, 41.0, 51.4, 52.0, 75.0, 119.0, 119.1, 119.3, 127.3, 128.0, 129.0, 129.7, 130.0, 130.5, 131.0, 134.5, 136.5, 141.0, 169.0, 171.0. LC-MS (m/z): 599.1 ([M+H].sup.+).

Example 2. Trials on the Effect of the Compounds of the Invention on the Kv4.3 Channel Modulation by DREAM

(63) The new compounds synthesised according to this invention have been evaluated in vitro in voltage-binding assays in CHO cells transiently transfected with cDNA encoding Kv4.3 only or Kv4.3 in the presence of DREAM (Kv4.3+DREAM) using the patch-clamp technique. Some of the compounds inhibit Kv4.3 channel modulation by DREAM. For some of the compounds evaluated, this effect is selective and is only observed in the presence of the DREAM channel modulator. Thus, as shown in FIG. 1B, compounds (35) and (42) only inhibit the Kv4.3 current in the presence of DREAM, measured as the % decrease of the amount of charge passing through the membrane and estimated based on the integral of the current. However, (62) has no selectivity, joining the channel in the absence of DREAM, since it similarly inhibits the current generated by the Kv4.3 channels to that of the Kv4.3 channels in the presence of DREAM. FIG. 1A shows a representative example of the effects of (35) (100 nM) on Kv4.3 or Kv4.3+DREAM channels. Graph B of FIG. 1 shows a bar chart comparing the inhibitory effect of the Kv4.3 and Kv4.3+DREAM current produced by (35), (42) and (62) at 100 nM.

Example 3: Neuroprotective Effect of the Compounds of the Invention on Q111DR Cells

(64) In an immortalized cell line of mouse striatum infected with lentivirus STHdh.sup.Q111/Q111 expressing the complete human DREAM protein (Q111DR), the neuroprotective effect of the compounds was tested against necrosis mediated by H.sub.2O.sub.2 and apoptosis mediated by staurosporine.

(65) FIG. 2 shows a representative example of the ability of the compounds to inhibit the release of the lactate dehydrogenase enzyme, which is a reflection of their inhibitory effect of cell death caused by oxidative stress in response to exposure to H.sub.2O.sub.2. It is clearly the lowest LDH release and therefore the neuroprotective effect of compound (62).

(66) FIG. 3 shows a representative example of the effect of the compounds on the activation of caspase-3 associated with induced cell death due to treatment with staurosporine. It is clearly the lowest activation of caspase-3 and therefore the inhibition of apoptosis and the neuroprotective effect of compound (62) compared with repaglinide (RP), a previously described neuroprotective agent.