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LRRK2 INHIBITING COMPOUNDS AND USE THEREOF FOR TREATING NEURODEGENERATIVE DISEASES

20210323936 · 2021-10-21

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention relates to a series of compounds having a structural benzothiazole-benzamide core with capacity to inhibit the LRRK2 enzyme, due to which the invention also relates to the use of these compounds for treating neurodegenerative diseases in which this enzyme is involved, such as Parkinson's Disease or Alzheimer's Disease.

    Claims

    1. A compound of formula (I): ##STR00002## wherein R.sub.1 is selected from H, C.sub.1-C.sub.6 alkyl, halogen, CF.sub.3 and —O—C.sub.1-C.sub.6 alkyl.

    2. The compound according to claim 1, wherein R.sub.1 is H.

    3. The compound according to claim 1, wherein R.sub.1 is a C.sub.1-C.sub.4 alkyl.

    4. The compound according to claim 3, wherein R.sub.1 is selected from methyl or isopropyl.

    5. The compound according to claim 1, wherein R.sub.1 is selected from F, Cl or Br.

    6. The compound according to claim 1, wherein R.sub.1 is a —O—C.sub.1-C.sub.4 alkyl.

    7. The compound according to claim 6, wherein R.sub.1 is selected from —O-methyl, —O-ethyl and —O-propyl.

    8. The compound according to claim 1, wherein R.sub.1 is CF.sub.3.

    9. The compound according to claim 1, which is selected from the following list: N-(benzothiazole-2-yl)-4-morpholinobenzamide, N-(6-methoxybenzothiazole-2-yl)-4-morpholinobenzamide, N-(6-trifluoromethylbenzothiazole-2-yl)-4-morpholinobenzamide, N-(6-methylbenzothiazole-2-yl)-4-morpholinobenzamide, N-(6-chlorobenzothiazole-2-yl)-4-morpholinobenzamide, N-(6-fluorobenzothiazole-2-yl)-4-morpholinobenzamide, N-(6-ethoxybenzothiazole-2-yl)-4-morpholinobenzamide, N-(6-bromobenzothiazole-2-yl)-4-morpholinobenzamide, N-(6-propoxybenzothiazole-2-yl)-4-morpholinobenzamide, N-(6-isopropylbenzothiazole-2-yl)-4-morpholinobenzamide.

    10. (canceled)

    11. A method of treatment of a neurodegenerative disease in a subject, comprising administering to said subject an effective amount of a compound of formula (I) according to claim 1, wherein the neurodegenerative disease is selected from Alzheimer's Disease, Parkinson's Disease, Pick's Disease, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia, parkinsonism linked to chromosome 17, argyrophilic dementia, post-encephalitic parkinsonism and primary age-related tauopathy.

    12. The method according to claim 11, wherein the neurodegenerative disease is Parkinson's Disease.

    13. The method according to claim 11, wherein the neurodegenerative disease is Alzheimer's Disease.

    14. A pharmaceutical composition comprising a compound of formula (I) according to claim 1.

    15. The pharmaceutical composition according to claim 14, which further comprises another active ingredient.

    Description

    BRIEF DESCRIPTION OF THE FIGURES

    [0042] FIG. 1. Shows neuroprotection against the hyperphosphorylation of tau of LRRK2 inhibiting compounds 1-10 of the invention.

    [0043] FIG. 2. Shows the linear correlation between the described and experimental permeability of ten commercial compounds using PAMPA-Blood-brain barrier methodology.

    EXAMPLES

    [0044] The invention is illustrated below by means of assays performed by the inventors, which demonstrates the effectiveness of the product of the invention.

    Example 1. Synthesis and Characterisation of the Compounds of the Invention

    N-(benzothiazole-2-yl)-4-morpholinobenzamide (1)

    [0045] 276.0 mg of 4-morpholinobenzoic acid (1.3 mmol), 331.00 mg of EDCl (1.4 mmol), 24.4 mg of DMAP (0.3 mmol) and 335 μL (2.4 mmol) of triethylamine were dissolved in dichloromethane. After stirring for 1 hour at room temperature, 200 mg of 2-aminobenzothiazole (1.3 mmol) were added. The reaction is left under stirring at room temperature during the night. After this time period the crude was washed with saturated solutions of NaHCO.sub.3 and NaCl, respectively. Next, the organic phase is dried on anhydrous magnesium sulfate, the solvent is evaporated at low pressure and is purified by chromatography in a flash column using a mixture of eluents CH.sub.2Cl.sub.2/MeOH (20:1) to obtain a yellow solid (72 mg, 16%). HPLC Purity >95%. MS: m/z 340 [M+1].sup.+. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 10.21 (s, 1H, NH), 7.90 (d, J=9.0 Hz, 2H), 7.84 (dd, J=8.5, 1.5 Hz, 1H), 7.62 (dd, J=8.3, 1.2 Hz, 1H), 7.44-7.35 (m, 1H), 7.35-7.27 (m, 1H), 4.01-3.71 (m, 4H), 3.49-3.16 (m, 4H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) δ 164.6, 159.1, 154.3, 148.2, 132.2, 129.4, 126.0, 123.7, 121.3, 121.1, 120.7, 113.8, 66.5, 47.4.

    N-(6-methoxybenzothiazole-2-yl)-4-morpholinobenzamide (2)

    [0046] 230.0 mg of 4-morpholinobenzoic acid (1.1 mmol), 276.6 mg of EDCl (1.4 mmol), 24.43 mg of DMAP (0.2 mmol) and 248 μL (1.7 mmol) of triethylamine were dissolved in dichloromethane. After stirring for 1 hour at room temperature, 200 mg of 2-amino-6-methoxybenzothiazole (1.1 mmol) were added. The reaction is left under stirring at room temperature during the night. After this time period the crude was washed with saturated solutions of NaHCO.sub.3 and NaCl, respectively. Next, the organic phase is dried on anhydrous magnesium sulfate, the solvent is evaporated at low pressure and is purified by flash column chromatography using a mixture of eluents CH.sub.2Cl.sub.2/MeOH (50:1) to obtain a yellow solid (36 mg, 9%). P.f.: 237.6-240.0° C. HPLC Purity: 95%. MS: m/z 370 [M+H].sup.+. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 9.47 (s, 1H), 7.88 (d, J=9.0 Hz, 2H), 7.64 (d, J=8.8 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.04 (dd, J=8.8, 2.6 Hz, 1H), 6.94 (d, J=9.0 Hz, 2H), 3.93-3.83 (m, 7H), 3.36-3.31 (m, 4H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) δ 164.8, 156.9, 156.0, 153.8, 142.7, 132.8, 129.8, 120.8, 120.5, 114.80, 113.1, 104.6, 65.8, 55.6, 46.8.

    N-(6-trifluoromethylbenzothiazole-2-yl)-4-morpholinobenzamide (3)

    [0047] 189.9 mg of 4-morpholinobenzoic acid (0.9 mmol), 228.53 mg of EDCl (1.2 mmol), 22.41 mg of DMAP (0.2 mmol) and 223 μL (1.5 mmol) of triethylamine were dissolved in dichloromethane. After stirring for 1 hour at room temperature, 200 mg of 2-amino-6-trifluorobenzothiazole (0.9 mmol) were added. The reaction is left under stirring at room temperature during the night. After this time period the crude was washed with saturated solutions of NaHCO.sub.3 and NaCl, respectively. Next, the organic phase is dried on anhydrous magnesium sulfate, the solvent is evaporated at low pressure and is purified by automatic flash column chromatography (Biotage®Isolera One) using a mixture of eluents hexane/AcOEt to obtain a yellow solid (79 mg, 26%). P.f.: 218.5-218.5° C. HPLC Purity: 95%. MS: m/z 408 [M+H].sup.+. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 10.85 (s, 1H), 8.13 (s, 1H), 7.89 (d, J=9.0 Hz, 1H), 7.57-7.53 (m, 2H), 6.84 (d, J=9.0 Hz, 2H), 3.87-3.83 (m, 4H), 3.31-3.26 (m, 4H). .sup.13C NMR (75 MHz, CDCl.sub.3) δ 163.8, 160.8, 153.4, 149.4, 131.2, 128.5, 124.9 (d, J=32.5 Hz), 124.3, 122.1 (d, J=3.4 Hz), 119.6 (d, J=32.2 Hz), 118.0 (d, J=4.2 Hz), 112.7, 65.4, 46.3, 28.6. C.sub.19H.sub.16F.sub.3N.sub.3O.sub.2S: Theoretical (%) C, 56.01; H, 3.96; N, 10.31; S, 7.87. Found (%) C, 56.13; H, 3.98; N, 10.38; S, 7.59.

    N-(6-methylbenzothiazole-2-yl)-4-morpholinobenzamide (4)

    [0048] 252.4 mg of 4-morpholinobenzoic acid (1.2 mmol), 303.5 mg of EDCl (1.58 mmol), 20.06 mg of DMAP (0.2 mmol) and 272 μL (1.9 mmol) of triethylamine were dissolved in dichloromethane. After stirring for 1 hour at room temperature, 200 mg of 2-amino-6-methylbenzothiazole (1.2 mmol) were added. The reaction is left under stirring at room temperature during the night. After this time period the crude was washed with solutions of HCl (0.1M), saturated NaHCO.sub.3 and saturated NaCl, respectively. Next, the organic phase is dried on anhydrous magnesium sulfate, the solvent is evaporated at low pressure and is purified by automatic flash column chromatography (Biotage®Isolera One) using a mixture of eluents hexane/AcOEt to obtain a yellow solid (43 mg, 10%). P.f.: 287.7-288.8° C. MS (ESI+): m/z 354 [M+H].sup.+. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 10.56 (s, 1H), 7.89 (d, J=8.9 Hz, 2H), 7.63 (s, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.16 (dd, J=8.3, 1.7 Hz, 1H), 6.85 (d, J=8.9 Hz, 1H), 3.87-3.83 (m, 4H), 3.29-3.26 (m, 4H), 2.46 (s, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3) δ 164.7, 158.5, 154.2, 146.1, 133.7, 132.3, 129.4, 127.5, 121.3, 121.1, 120.3, 113.8, 66.5, 47.5, 21.4. C.sub.19H.sub.19N.sub.3O.sub.2S: Theoretical (%) C, 64.57; H, 5.42; N, 11.89; S, 9.07. Found (%) C, 64.33; H, 5.38; N, 11.85; S, 8.96.

    N-(6-chlorobenzothiazole-2-yl)-4-morpholinobenzamide (5)

    [0049] 224.4 mg of 4-morpholinobenzoic acid (1.1 mmol), 269.89 mg of EDCl (1.4 mmol), 26.4 mg of DMAP (0.2 mmol) and 242 μL (1.7 mmol) of triethylamine were dissolved in dichloromethane. After stirring for 1 hour at room temperature, 200 mg of 2-amino-6-chlorobenzothiazole (1.1 mmol) were added. The reaction is left under stirring at room temperature during the night. After this time period the crude was washed with solutions of HCl (0.1M), saturated NaHCO.sub.3 and saturated NaCl, respectively. Next, the organic phase is dried on anhydrous magnesium sulfate, the solvent is evaporated at low pressure and is purified by automatic flash column chromatography (Biotage®Isolera One) using a mixture of eluents hexane/AcOEt to obtain a white solid (96 mg, 24%). P.f.: 245.4-246.4° C. HPLC Purity: 97%. MS: m/z 374 [M+H].sup.+. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 10.25 (s, 1H), 7.89 (d, J=8.9 Hz, 2H), 7.81 (d, J=2.1 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.33 (dd, J=8.7, 2.1 Hz, 1H), 6.89 (d, J=9.0 Hz, 2H), 3.92-3.82 (m, 4H), 3.33-3.30 (m, 4H). .sup.13C NMR (75 MHz, CDCl.sub.3) δ 164.5, 159.3, 154.4, 146.8, 139.7, 133.5, 129.4, 126.7, 121.5, 121.0, 120.8, 113.7, 66.5, 47.4. C.sub.18H.sub.16ClN.sub.3O.sub.2S: Theoretical (%) C, 57.83; H, 4.31; N, 11.24; S, 8.58. Found (%) C, 57.56; H, 4.09; N, 11.43; S, 8.40.

    N-(6-fluorobenzothiazole-2-yl)-4-morpholinobenzamide (6)

    [0050] 168.20 mg of 4-morpholinobenzoic acid (1.2 mmol), 296.3 mg of EDCl (1.5 mmol), 29.05 mg of DMAP (0.2 mmol) and 265 μL (1.9 mmol) of triethylamine were dissolved in dichloromethane. After stirring for 1 hour at room temperature, 200 mg of 2-amino-6-fluorobenzothiazole (1.2 mmol) were added. The reaction is left under stirring at room temperature during the night. After this time period the crude was washed with solutions of HCl (0.1M), saturated NaHCO.sub.3 and saturated NaCl, respectively. Next, the organic phase is dried on anhydrous magnesium sulfate, the solvent is evaporated at low pressure and is purified by automatic flash column chromatography (Biotage®Isolera One) using a mixture of eluents hexane/AcOEt to obtain a white solid (79 mg, 19%). P.f.: 228.3-229.3° C. HPLC Purity: 98%. MS: m/z 358 [M+H].sup.+. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 9.96 (s, 1H), 7.81 (d, J=8.9 Hz, 2H), 7.74 (d, J=2.1 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.28 (dd, J=8.7, 2.1 Hz, 1H), 6.84 (d, J=8.7 Hz, 2H), 3.87-3.85 (m, 4H), 3.34-3.30 (m, 4H). .sup.13C NMR (75 MHz, CDCl.sub.3) δ 164.4, 159.2, 154.4, 147.0, 138.7, 133.6, 129.3, 126.8, 121.6, 121.0, 120.8, 113.8, 66.5, 47.4. C.sub.18H.sub.16FN.sub.3O.sub.2S: Theoretical (%) C, 60.49; H, 4.51; N, 11.76; S, 8.97. Found (%) C, 60.68; H, 4.50; N, 11.55; S, 8.72.

    N-(6-ethoxybenzothiazole-2-yl)-4-morpholinobenzamide (7)

    [0051] 213.1 mg of 4-morpholinobenzoic acid (1.0 mmol), 256.2 mg of EDCl (1.3 mmol), 25.12 mg of DMAP (0.2 mmol) were dissolved in dichloromethane. After stirring for 6 hours at room temperature, 200 mg of 2-amino-6-ethoxybenzothiazole (1.0 mmol) and 229 μL of triethylamine (1.9 mmol) were added. The reaction is left under stirring at room temperature during the night. After this time period the crude was washed with solutions of HCl (0.1M), saturated NaHCO.sub.3 and saturated NaCl, respectively. Next, the organic phase is dried on anhydrous magnesium sulfate, the solvent is evaporated at low pressure and is purified by automatic flash column chromatography (Biotage®Isolera One) using a mixture of eluents hexane/AcOEt to obtain a yellow solid (20 mg, 5%). P.f.: 222.8-223.8° C. HPLC Purity: 95%. MS: m/z 384 [M+H].sup.+. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.07 (d, J=8.6 Hz, 2H), 7.54 (d, J=8.9 Hz, 1H), 7.35-7.18 (m, 1H), 7.04 (dd, J=8.9, 2.4 Hz, 1H), 6.89 (d, J=8.6 Hz, 2H), 4.07 (q, J=6.9 Hz, 2H), 3.89-3.69 (m, 4H), 3.38-3.25 (m, 4H), 1.43 (t, J=6.9 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3) δ 164.4, 157.1, 156.0, 154.2, 142.3, 133.3, 129.3, 121.3, 121.2, 119.7, 115.5, 114.2, 113.8, 106.0, 104.9, 99.5, 66.5, 64.1, 64.1, 47.5, 14.8.

    N-(6-bromobenzothiazole-2-yl)-4-morpholinobenzamide (8)

    [0052] 180.9 mg of 4-morpholinobenzoic acid (0.9 mmol), 217.6 mg of EDCl (1.1 mmol), 21.33 mg of DMAP (0.2 mmol) were dissolved in dichloromethane. After stirring for 6 hours at room temperature, 200 mg of 2-amino-6-bromobenzothiazole (0.9 mmol) and 195 μl of triethylamine (1.4 mmol) were added. The reaction is left under stirring at room temperature during the night. After this time period the crude was washed with solutions of HCl (0.1M), saturated NaHCO.sub.3 and saturated NaCl, respectively. Next, the organic phase is dried on anhydrous magnesium sulfate, the solvent is evaporated at low pressure and is purified by automatic flash column chromatography (Biotage®Isolera One) using a mixture of eluents hexane/AcOEt to obtain a yellow solid (41 mg, 11%). P.f.: 237.5-238.5° C. HPLC Purity: 98%. MS: m/z 418 [M+H]+. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 10.51 (s, 1H), 7.96 (s, 1H), 7.87 (d, J=9.0 Hz, 3H), 7.44 (dd, J=8.6, 1.9 Hz, 2H), 7.38 (d, J=8.6 Hz, 2H), 6.86 (d, J=9.0 Hz, 3H), 3.89-3.83 (m, 11H), 3.33-3.26 (m, 11H). .sup.13C NMR (75 MHz, CDCl.sub.3) δ 165.2, 160.4, 154.8, 147.1, 134.1, 130.0, 129.9, 124.3, 122.1, 121.1, 117.2, 114.1, 66.9, 47.8.

    N-(6-propoxybenzothiazole-2-yl)-4-morpholinobenzamide (9)

    [0053] 248.8 mg of 4-morpholinobenzoic acid (1.2 mmol), 299.00 mg of EDCl (1.6 mmol), 29.3 mg of DMAP (0.2 mmol) were dissolved in dichloromethane. After stirring for 6 hours at room temperature, 250 mg of 2-amino-6-propoxybenzothiazole (1.2 mmol) and 267.6 μL (1.9 mmol) of triethylamine were added. The reaction is left under stirring at room temperature during the night. After this time period the crude was washed with a HCl solution (0.1M). Next, the organic phase is dried on anhydrous magnesium sulfate, the solvent is evaporated at low pressure and is purified by flash column chromatography using a mixture of eluents CH.sub.2Cl.sub.2/MeOH (50:1) to obtain a yellow solid (127 mg, 27%). HPLC Purity>95%. MS: m/z 398 [M+H]+. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.88 (d, J=9.0 Hz, 2H), 7.46 (d, J=8.9 Hz, 1H), 7.31 (d, J=2.5 Hz, 1H), 6.96 (dd, J=8.9, 2.5 Hz, 1H), 6.88 (d, J=9.0 Hz, 2H), 3.98 (t, J=6.6 Hz, 2H), 3.89-3.83 (m, 4H), 3.32-3.27 (m, 4H), 1.85 (h, J=7.3 Hz, 2H), 1.06 (t, J=7.4 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) δ 163.6, 156.3, 155.2, 153.3, 141.27, 132.2, 128.4, 120.4, 120.3, 114.5, 112.8, 103.9, 69.2, 65.5, 46.5, 21.6, 9.5. C.sub.21H.sub.23N.sub.3O.sub.3S: Theoretical (%) C, 63.46; H, 5.83; N, 10.57; S, 8.07. Found (%) C, 63.73; H, 5.74, N, 10.09; S, 7.71.

    N-(6-isopropylbenzothiazole-2-yl)-4-morpholinobenzamide (10)

    [0054] 269.4 mg of 4-morpholinobenzoic acid (1.3 mmol), 324.00 mg of EDCl (1.7 mmol), 32.00 mg of DMAP (0.3 mmol) were dissolved in dichloromethane. After stirring for 6 hours at room temperature, 250 mg of 2-amino-6-isopropylbenzothiazole (1.3 mmol) and 290.0 μL (2.1 mmol) of triethylamine were added. The reaction is left under stirring at room temperature during the night. After this time period the crude was washed with a HCl solution (0.1M). Next, the organic phase is dried on anhydrous magnesium sulfate, the solvent is evaporated at low pressure and is purified by flash column chromatography using a mixture of eluents CH.sub.2Cl.sub.2/MeOH (50:1) to obtain a yellow solid (218.4 mg, 44%). HPLC Purity>95%. MS: m/z 382 [M+H].sup.+. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 10.35 (s, 1H), 7.89 (d, J=9.0 Hz, 2H), 7.68 (d, J=1.7 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.26-7.22 (m, 1H), 6.88 (d, J=9.0 Hz, 2H), 3.89-3.81 (m, 4H), 3.33-3.25 (m, 4H), 3.03 (p, J=6.9 Hz, 1H), 1.31 (d, J=6.9 Hz, 6H). .sup.13C NMR (75 MHz, CDCl.sub.3) δ 163.7, 157.7, 153.2, 145.3, 143.9, 131.3, 128.4, 124.0, 120.4, 119.4, 119.1, 117.5, 112.8, 65.5, 46.5, 33.2, 23.3. C.sub.21H.sub.23N.sub.3O.sub.2S: Theoretical (%) C, 66.12; H, 6.08; N, 11.00; S, 8.40. Found (%) C, 66.09; H, 6.13; N, 10.69; S, 8.54.

    Example 2. Inhibition of LRRK2 and LRRK2 G2019S

    [0055] The compounds were evaluated in LRRK2 and in the mutated form LRRK2 G2019S. This mutation is more frequent in the familial forms of Parkinson's Disease and has a significant increase in kinase activity. The experimental determination of the inhibition of both enzymes was carried out using the Adapta® method, which is an evaluation method of fluorescent kinase activity that determines ADP in a highly sensitive manner. The methodology can be divided into two stages: kinase reaction and ADP determination. In the first stage, all the components for the kinase reaction are added to the well and incubated for 60 min. After the reaction, the ADP detection solution which contains a Europium-labeled anti-ADP antibody (Alexa Fluor® 647 labeled ADP tracer) and EDTA, to stop the kinase reaction, are added to the reaction well. The ADP formed in the kinase reaction without inhibitor will displace the Alexa Fluor® 647 labeled ADP tracer of the antibody, resulting in the TR-FRET signal decrease. In the presence of the inhibitor, the amount of ADP formed is reduced, which does not modify the antibody-tracer interaction and, therefore, has a higher TR-FRET signal.

    [0056] The assay is performed in 384-well plates. Adding 100 nL of the solution with the compound to be evaluated in 1% DMSO, 2.4 μL of HEPES solution, 2.5 μL of ATP solution, 4.5 μL of substrate solution. The 10 μl of the kinase reaction contain: 75-70 ng LRRK2 and 200 μM ERM (LRRKtide) in 25 mM Tris/7.5 mM HEPES pH 8.2, 0.005% BRIJ-35, 5 mM MgCl.sub.2, 0.5 mM EGTA, 0.01% NaN.sub.3 or 3-12 ng LRRK2 G2019S and 200 μM ERM (LRRKtide) in 25 mM Tris/7.5 mM HEPES pH 8.2, 0.005% BRIJ-35, 5 mM MgCl.sub.2, 0.5 mM EGTA, 0.01% NaN.sub.3. The plate is stirred for 30 s on a stirring plate and centrifuged for 1 min in a centrifuge at 1,000×g. The reaction is incubated at room temperature for 60 min. After this time period, 5 μL of the detection mixture is added, the plate is stirred for 30 s on a stirring plate and centrifuged for 1 min at 1,000×g. Fluorescence is determined in a plate reader and the data are analysed.

    TABLE-US-00001 TABLE 1 Inhibition of LRRK2 and LRRK2 G2019S of heterocyclic compounds Compound LRRK2 LRRK2 G2019S No. IC.sub.50 (μM) IC.sub.50 (μM) 1 0.696 0.360 2 0.368 0.108 3 1.060 0.293 4 0.523 0.332 5 0.777 n.d. 6 0.190 0.426 7 0.308 0.158 8 0.474 1.380 9 4.000 1.190 10 1.950 1.170 n.d. not determined

    Example 3. Neuroprotection Against Tau Hyperphosphorylation

    [0057] The neuroprotective potential of the compounds was evaluated in an okadaic acid (OA)-induced neurodegeneration cell model. OA is an inhibitor of phosphatase 1 and 2 and is normally used to induce tau hyperphosphorylation in different cell lines. In this case, the human neuronal line SH-SY5Y is used. The cells are cultured in DMEM medium supplemented with 10% FBS and 1% penicillin/streptomycin at 37° C. and in an incubator with 5% CO.sub.2. The SH-SY5Y cells are sown on a 96-well plate at a density of 60,000 cells per well for 48 hours. After this time period, the cells are pre-incubated with the compounds to be studied at a concentration of 1, 5 and 10 μM for 1 hour. After that time period, OA is added at a concentration of 30 nM, letting the plate incubate for a further 24 hours. Next, the cells were incubated with an MTT solution at 0.5 mg.Math.mL.sup.−1 for at least 4 hours at 37° C. and 5% CO.sub.2. Next, the culture medium is removed and the formazan crystals joined to the base of the plate are dissolved with 200 μL of DMSO. Lastly, UV absorbance was measured at 595 nM in a plate reader (Varioskan Flash Microplate reader, Thermo Scientific). The neuroprotection results shown by the compounds studied (1, 2, 3, 4, 5, 6, 7, 8, 9 and 10) are shown in FIG. 1. In all cases, the treatment of the compounds prevents the damage caused by the okadaic acid and consequently phosphorylation of the tau protein. These data indicate that the compounds used are probably capable of reducing this phosphorylation and increasing neuronal viability, i.e. they protect the neurons in culture.

    Example 4. Physico-Chemical Properties Compatible with the Blood-Brain Barrier Passage

    [0058] The physico-chemical properties of the synthesised compounds were determined using the LigPrep module and the QikProp tool, both of the Maestro® program (Maestro version 11.0.015 release 2016-4, Maestro, Schrödinger, LLC, New York, N.Y., 2016). Using these cheminformatics tools, the structures were prepared in a medium similar to the first physiological medium; and, once obtained, the physico-chemical properties were calculated. The physico-chemical properties of a compound are important to achieve therapeutic effectiveness, since they condition many of the processes of the ADME series (absorption, distribution, metabolism and excretion). Therefore, a prediction was made on the following features: the prediction of the blood-brain barrier passage (QP log BB), the polar surface area (PSA) and the octanol/water partition coefficient (QP log P o/w) (Table 2). According to these data, all the compounds fall within the adequate intervals; therefore, they all have good lipophilicity features, and capacity to form hydrogen bridges and penetrate the blood-brain barrier.

    TABLE-US-00002 TABLE 2 Calculated physico-chemical properties: QPlogBB (brain/blood partition coefficient, interval (−3.0 to 1.2)); PSA (polar surface area, interval (7.0 to 200.0)); QPlogP o/w (octanol/water partition coefficient, interval (−2.0 to 6.5)). Compound QPlogBB PSA QPLogP o/w 1 −0.156 63.022 3.112 2 −0.235 71.307 2.910 3 0.100 63.025 4.084 4 −0.177 63.023 3.150 5 0.004 63.020 3.599 6 −0.047 63.020 3.345 7 −0.337 70.765 3.635 8 0.014 63.020 3.674 9 −0.420 70.765 3.997 10 −0.265 63.024 4.060

    Example 5. Permeability in the Central Nervous System (CNS) Using Parallel Artificial Membranes (PAMPA)

    [0059] The permeability prediction of the different compounds on the central nervous system (CNS), blood-brain barrier passage, was determined using the parallel artificial membrane methodology (PAMPA) [Di, L.; Kerns, E. H.; Fan, K.; McConnell, O. J.; Carter, G. T. “High throughput artificial membrane permeability assay for blood-brain barrier” Eur. J. Med. Chem., 2003, 38 (3), 223-232]. The above-referenced commercial compounds, phosphate buffer at pH=7.4 (PBS), Ethanol and dodecane were obtained from the commercial houses Sigma, Acros organics, Merck, Aldrich and Fluka, respectively. The pig brain lipid (catalogue reference 141101) was acquired at Avanti Polar Lipids. Both the 96-well donor plate (Multiscreen® IP Sterile Plate PVDF membrane, 0.45 μM pore size, catalogue reference MAIPS4510) and the 96-well acceptor plate (Multiscreen®, catalogue reference MAMCS9610) were acquired at Millipore. To filter the samples, PVDF membrane filters were used (30 mm diameter, 0.45 μm pore size) from the company Symta. The equipment used to measure UV absorbance in 96-well plates was a Thermoscientific Multiskan spectrum.

    [0060] Ten reference compounds were selected, whose blood-brain barrier passage is known, in order to validate the experiment. Different amounts thereof were taken [(3-5 mg of caffeine, enoxacin, hydrocortisone, desipramine, ofloxacin, piroxicam, testosterone), (12 mg of promazine) and 25 mg of verapamil and atenolol], which were dissolved in ethanol (1,000 μl). 100 microlitres of these solutions were taken and 1,400 μL of EtOH and 3,500 μL of PBS phosphate buffer (pH=7.4) were added, in order to obtain a final concentration of EtOH of 30% in the solution. The solutions were filtered. Next, 180 μL of a PBS/EtOH (70/30) solution were added to each well of the acceptor plate. The donor plate was impregnated with 4 μL of a pig brain lipid solution dissolved in dodecane (20 mg mL.sup.−1). After 5 minutes, 180 μL of solution of each compound were added on this plate. Of the compounds whose penetration in the central nervous system is being evaluated, between 1-2 mg were taken and dissolved in 1,500 μL of EtOH and 3,500 μL of PBS phosphate buffer (pH=7.4), filtered and added to the 96-well donor plate. Next, the donor plate was placed on top of the acceptor plate forming a kind of “sandwich” and left to incubate for 2 h and 30 min at 25° C. The passive transport compounds pass from the donor plate through the pig brain lipid to the acceptor plate. After 2 h and 30 min, the donor plate is carefully removed. The concentration and absorbance of both the commercial compounds and the synthesised derivatives that were evaluated in the acceptor and donor plates were determined using a UV absorbance reader. Each sample was analysed at 2 to 5 wavelengths, in at least three wells and in two independent experiments. The results are the average of the measurements [standard deviation (SD)] of the different experiments carried out. Ten reference commercial compounds whose penetration in the central nervous system is known were used in each experiment in order to validate the method. A good correlation was found between the experimental and described permeability (Pe) values, Pe (exptl)=1.3711 (desc)−1.4509 (R.sup.2=0.972) (FIG. 2). Based on this equation and following the pattern described in the bibliography [Crivori, P.; Cruciani, G.; Testa, B. “Predicting Blood-Brain Barrier Permeation from Three-Dimensional Molecular Structure.” J. Med. Chem., 2000, 43, 2204-2216] for predicting the permeability of the blood-brain barrier, the compounds can be classified as permeable to the central nervous system (CNS) when they have a permeability >4.03×10.sup.−6 cm s.sup.−1. The results are shown in Table 3, where it can be observed how some of the evaluated compounds (1, 4, 6) are capable of penetrating the blood-brain barrier by passive diffusion.

    TABLE-US-00003 TABLE 3 Permeability (Pe 10.sup.−6 cm s.sup.−1) in the PAMPA-Blood-brain barrier experiment for ten commercial compounds, used to validate the experiment, and different synthesised derivatives with their corresponding prediction of penetration in the central nervous system (CNS). Compound Bibl.a Pe (10 − 6 cm s − 1)b Prediction Atenolol 0.8 1.0 ± 0.6 Caffeine 1.3 1.0 ± 0.8 Desipramine 12 12.9 ± 0.4  Enoxacin 0.9 0.2 ± 0.2 Hydrocortisone 1.9 0.4 ± 0.1 Ofloxacin 0.8 0.3 ± 0.3 Piroxicam 2.5 0.6 ± 0.2 Promazine 8.8 9.8 ± 0.5 Testosterone 17 25.0 ± 0.2  Verapamil 16 19.3 ± 0.7  1 13.4 ± 2.4  CNS + 4 19.0 ± 2.6  CNS+ 5 3.42 ± 1.26 CNS +/− 6 5.1 ± 0.1 CNS + 9 4.28 ± 3.45 CNS + 10 4.27 ± 2.7  CNS + aReference Di et al Eur. J. Med. Chem., 2003, 38 (3), 223-232. bAverage data ± standard deviation (SD) of at least 2 independent experiments.