S-substituted quinazolines and their therapeutic applications for the treatment of diseases mediated by PDE7

Abstract

The present invention relates to a family of S-substituted quinazoline derivatives that inhibitors of the enzyme phosphodiesterase 7 (PDE7), useful for the treatment or prevention of diseases mediated by said enzyme, especially inflammatory, neurodegenerative, neurological, psychiatric and/or autoimmune diseases.

Claims

1. A pharmaceutical composition comprising a compound selected from the group consisting of: (i) 2-Cyclohexylmethylthio-3-phenyl-4-oxo-3,4-dihydroquinazolin; (ii) 3-(2-Bromophenyl)-2-cyclohexylmethylthio-4-oxo-3,4-dihydroquinazoline; (iii) 3-Phenyl-2-neopentylthio-4-oxo-3,4-dihydroquinazoline; (iv) 3-(2,6-Difluorophenyl)-8-methyl-2-neopentylthio-4-oxo-3,4-dihydroquinazoline; (v) 8-Chloro-3-phenyl-2-neopentylthio-4-oxo-3,4-dihydroquinazoline; (vi) 3-(2-Bromophenyl)-2-cyclopropylmethylthio-4-oxo-3,4-dihydroquinazoline; (vii) 2-Cyclopropylmethylthio-3-(2,6-difluorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazoline; and (viii) 3-Phenyl-2-(2-naphthylmethylthio)-4-oxo-3,4-dihydroquinazoline; or a salt or an isomer thereof.

2. The pharmaceutical composition according to claim 1, wherein the composition is in solid form or in aqueous suspension.

3. A pharmaceutical composition according to claim 1, comprising an acceptable solvate.

4. A compound of formula selected from the group consisting of: (i) 2-Cyclohexylmethylthio-3-phenyl-4-oxo-3,4-dihydroquinazolin; (ii) 3-(2-Bromophenyl)-2-cyclohexylmethylthio-4-oxo-3,4-dihydroquinazoline; (iii) 3-Phenyl-2-neopentylthio-4-oxo-3,4-dihydroquinazoline; (iv) 3-(2,6-Difluorophenyl)-8-methyl-2-neopentylthio-4-oxo-3,4-dihydroquinazoline; (v) 8-Chloro-3-phenyl-2-neopentylthio-4-oxo-3,4-dihydroquinazoline; (vi) 3-(2-Bromophenyl)-2-cyclopropylmethylthio-4-oxo-3,4-dihydroquinazoline; (vii) 2-Cyclopropylmethylthio-3-(2,6-difluorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazoline; and (viii) 3-Phenyl-2-(2-naphthylmethylthio)-4-oxo-3,4-dihydroquinazoline.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1A shows the elimination of compound 5 in plasma wherein 2 hours after intraperitoneal or oral administration there were still considerable levels of this compound.

(2) FIG. 1B shows the elimination of compound TC3.6 in plasma wherein 2 hours after administration the compound had been eliminated regardless of administration.

(3) FIG. 2A shows the elimination of compound 5 in brain wherein 2 hours after intraperitoneal or oral administration there were still considerable levels of this compound.

(4) FIG. 2B shows the elimination of compound TC3.6 in brain wherein 2 hours after administration the compound had been eliminated regardless of administration.

EXAMPLES

Example 1

General Method for Synthesising the Compounds of the Invention

(5) The starting point for obtaining the compounds of the present invention was the corresponding tetrahydroquinazoline of formula (III) (as described above), which can be synthesised by following the procedure described in the document by Redondo M. et al., “Neuroprotective efficacy of quinazoline type phosphodiesterase 7 inhibitors in cellular cultures and experimental stroke model”, Eur. J. Med. Chem. 47 (2012) 175-185. To a solution of the corresponding tetrahydroquinazoline in 5 mL of acetonitrile was added the alkylating agent in the presence of carbonate (0.5 M). The reaction mixture was agitated at the temperature and for the time indicated below for each case. Finally, the solvent was eliminated by evaporation at reduced pressure. After carrying out chromatographic purification of the residue by using the eluents indicated in each case, the compounds of the present invention indicated in each case were obtained.

(6) 2-Cyclohexylmethylthio-3-phenyl-4-oxo-3,4-dihydroquinazoline (compound 1): Obtained according to the general method described previously.

(7) Reagents: 3-Phenyl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline (0.59 mmol, 0.150 g), cyclohexylmethyl bromide (0.70 mmol, 0.099 mL), K.sub.2CO.sub.3 (0.0045 g).

(8) The reaction conditions were: 1 hour under microwave radiation at 150° C.

(9) Purification was carried out by means of silica gel column chromatography (hexane/ethyl acetate, in a ratio of 6:1 by volume).

(10) The yield obtained was: a white solid (96 mg, 47%). P.f.: 148.1-149.8° C. .sup.1H-RMN (300 MHz, CDCl.sub.3) δ: 8.23 (dd, 1H, J=7.9 Hz), 7.73 (td, 1H, J=8.2, 1.5 Hz), 7.61 (d, 1H, J=8.2 Hz), 7.50-7.52 (m, 3H), 7.36 (td, 1H, J=8.0, 1.2 Hz), 7.32-7.28 (m), 3.08 (d, 2H, J=6.7 Hz), 1.85-1.60 (m, 5H), 1.24-0.93 (m, 6H). .sup.13C-RMN (75 MHz, CDCl.sub.3) δ: 161.9, 157.9, 147.8, 136.1, 134.5, 129.8, 129.6, 129.2, 127.2, 126.2, 125.6, 119.8, 39.5, 37.2, 32.7, 26.2, 25.9, purity analysed by High Pressure Liquid Chromatography (HPLC) >99%. EM (m/z): 352 [M+H].sup.+. Elemental analysis (C.sub.21H.sub.22N.sub.2OS): theoretical % C, 71.97; % H, 6.33; % N, 7.99; % S, 9.15. observed % C, 71.88; % H, 6.28; % N, 8.03; % S, 8.99.

(11) 3-(2-Bromophenyl)-2-cyclohexylmethylthio-4-oxo-3,4-dihydroquinazoline (compound 2): Obtained according to the general method described previously.

(12) Reagents: 3-(2-Bromophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline (0.30 mmol, 0.100 g), cyclohexylmethyl bromide (0.90 mmol, 0.125 mL), K.sub.2CO.sub.3 (0.0045 g).

(13) The reaction conditions were: 12 hours at ambient temperature.

(14) Purification was carried out by means of silica gel column chromatography (hexane/ethyl acetate, in a ratio of 6:1 by volume).

(15) The yield obtained was: a white solid (100 mg, 77%). P.f. 129.5-132.0° C. .sup.1H-RMN (400 MHz, DMSO) δ: 8.05 (dd, 1H, J=7.7 Hz), 7.85-7.79 (m, 2H), 7.64-7.54 (m, 3H), 7.50-7.43 (m, 2H), 3.16-2.97 (m, 2H), 1.74-1.52 (m, 6H), 1.14-0.89 (m, 5H). .sup.13C-RMN (100 MHz, DMSO) δ: 160.6, 157.5, 147.9, 135.9, 135.7, 134.0, 132.6, 132.3, 129.7, 127.3, 126.7, 123.8, 119.8, 38.8, 37.5, 32.7, 32.6, 26.4, 26.1, purity analysed by HPLC 98%. EM (m/z): 429, 431 [M+H].sup.+.

(16) 3-Phenyl-2-neopentylthio-4-oxo-3,4-dihydroquinazoline (compound 5): Obtained according to the general method described previously.

(17) Reagents: 3-Phenyl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline (0.59 mmol, 0.150 g), neopentyl bromide (0.70 mmol, 0.092 mL), K.sub.2CO.sub.3 (0.0045 g).

(18) The reaction conditions were: 1 hour under microwave radiation at 150° C.

(19) Purification was carried out by means of silica gel column chromatography (hexane/ethyl acetate, in a ratio of 6:1 by volume).

(20) The yield obtained was: a white solid (84 mg, 44%). P.f.: 161.0-162.1° C. .sup.1H-RMN (300 MHz, CDCl.sub.3) δ: 8.23 (dd, 1H, J=7.9, 1.5 Hz), 7.75-7.30 (m, 13H), 3.24 (s, 2H), 1.06 (s, 9H). .sup.13C-RMN (75 MHz, CDCl.sub.3) δ: 162.4, 158.3, 148.1, 136.6, 134.9, 129.7, 129.6, 129.2, 127.2, 126.1, 125.6, 46.2, 32.3, 29.3, purity analysed by HPLC >99%. EM (m/z): 325 [M+H].sup.+. Elemental analysis (C.sub.19H.sub.20N.sub.2OS): theoretical % C, 70.34; % H, 6.21; % N, 8.63; % S, 9.88. observed % C, 70.12; % H, 6.50; % N, 8.66; % S, 9.69.

(21) 3-(2,6-Difluorophenyl)-8-methyl-2-neopentylthio-4-oxo-3,4-dihydroquinazoline (compound 6): Obtained according to the general method described previously.

(22) Reagents: 3-(2,6-Difluorophenyl)-8-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline (0.32 mmol, 0.097 g), neopentyl bromide (0.64 mmol, 0.080 mL), K.sub.2CO.sub.3 (0.0045 g).

(23) The reaction conditions were: 12 hours at ambient temperature.

(24) Purification was carried out by means of silica gel column chromatography (hexane/ethyl acetate, in a ratio of 6:1 by volume).

(25) The yield obtained was: a white solid (51 mg, 42%). P.f.: 152.3° C. .sup.1H-RMN (400 MHz, DMSO) δ: 7.94 (dd, 1H, J=7.9, 0.8 Hz), 7.81-7.73 (m, 2H), 7.49-7.40 (m, 3H), 3.34 (s, 2H), 2.60 (s, 3H), 0.95 (s, 9H). .sup.13C-RMN (100 MHz, DMSO) δ: 160.7, 158.8 (d, 2C, J=252.2 Hz), 156.0, 145.9, 136.9, 135.1, 134.1, 126.9, 125.1, 118.8, 113.5, 44.9, 32.6, 28.9, 17.6, purity analysed by HPLC >99%. EM (m/z): 375 [M+H].sup.+.

(26) 8-Chloro-3-phenyl-2-neopentylthio-4-oxo-3,4-dihydroquinazoline (compound 11): Obtained according to the general method described previously.

(27) Reagents: 8-Chloro-3-phenyl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline (0.173 mmol, 0.050 g), neopentyl bromide (0.312 mmol, 0.04 mL), Cs.sub.2CO.sub.3 (0.169 g).

(28) The reaction conditions were: 2 hours under microwave radiation at 150° C.

(29) Purification was carried out by means of centrifugal circular chromatography (hexane/ethyl acetate, in a ratio of 18:1 by volume).

(30) The yield obtained was: a yellow solid (18.4 mg, 30%). P.f.: 128.0-130.1° C. .sup.1H-RMN (400 MHz, CDCl.sub.3) δ: 8.14 (dd, 1H, J=8.0, 1.5 Hz), 7.80 (dd, 1H, J=7.8, 1.5 Hz), 7.60-7.49 (m, 3H), 7.35-7.26 (m, 3H), 3.34 (s, 2H), 1.00 (s, 9H). .sup.13C-RMN (100 MHz, CDCl.sub.3) δ: 161.7, 159.6, 144.4, 136.1, 135.0, 130.9, 130.2, 130.0, 129.2, 126.2, 125.7, 121.5, 46.1, 32.4, 29.0, purity analysed by HPLC >99%. EM (m/z): 359 [M+H].sup.+. Elemental analysis (C.sub.19H.sub.19ClN.sub.2OS): theoretical % C, 63.59; % H, 5.34; % N, 7.81; % S, 8.93. observed % C, 63.60; % H, 5.51; % N, 7.66; % S, 8.59.

(31) 3-(2-Methylphenyl)-2-neopentylthio-4-oxo-3,4-dihydroquinazoline (compound 13): Obtained according to the general method described previously.

(32) Reagents: 3-(2-Methylphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline (0.373 mmol, 0.100 g), neopentyl bromide (0.559 mmol, 0.07 mL), Cs.sub.2CO.sub.3 (0.364 g).

(33) The reaction conditions were: 3 hours under microwave radiation at 150° C.

(34) Purification was carried out by means of centrifugal circular chromatography (hexane/ethyl acetate, in a ratio of 10:1 by volume).

(35) The yield obtained was: a yellow solid (55.0 mg, 44%). P.f.: 116.5-117.5° C. .sup.1H-RMN (400 MHz, CDCl.sub.3) δ: 8.25 (dd, 1H, J=8.0, 1.3 Hz), 7.77-7.6 (m, 1H), 7.63 (d, 1H, J=8.0 Hz), 7.50-7.33 (m, 4H), 7.20 (dd, 1H, J=7.2, 1.3 Hz), 3.32 (d, 1H, J=13.1 Hz), 3.17 (d, 1H, J=13.1 Hz), 2.17 (s, 2H), 0.98 (s, 9H). .sup.13C-BMN (100 MHz, CDCl.sub.3) δ: 161.6, 158.1, 148.0, 137.0, 135.3, 134.7, 131.5, 130.3, 129.3, 127.5, 126.2, 125.8, 119.9, 45.5, 32.2, 29.1, 17.6. Purity analysed by HPLC >99%. EM (m/z): 339 [M+H].sup.+. Elemental analysis (C.sub.20H.sub.22N.sub.2OS): theoretical % C, 70.97; % H, 6.55; % N, 8.28; % S, 9.47. observed % C, 70.95; % H, 6.49; % N, 8.24; % S, 9.28.

(36) 3-(2-Bromophenyl)-2-cyclopropylmethylthio-4-oxo-3,4-dihydroquinazoline (compound 14): Obtained according to the general method described previously.

(37) Reagents: 3-(2-Bromophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline (0.42 mmol, 0.150 g).sub.r cyclopropylmethyl bromide (0.85 mmol, 0.083 mL), K.sub.2CO.sub.3 (0.0045 g).

(38) The reaction conditions were: 12 hours at ambient temperature.

(39) Purification was carried out by means of silica gel column chromatography (hexane/ethyl acetate, in a ratio of 6:1 by volume).

(40) The yield obtained was: a white solid (161 mg, 98%). P.f.: 110.8-113.5° C. .sup.1H-RMN (400 MHz, DMSO) δ: 8.06 (dd, 1H, J=7.9 Hz), 7.86-7.80 (m, 2H), 7.65-7.56 (m, 3H), 7.51-7.43 (m, 2H), 3.10 (d, 2H, J=7.4 Hz), 1.13-1.05 (m, 1H), 0.48 (dd, 2H, J=8.1 Hz), 0.25 (dd, 2H, J=6.7 Hz). .sup.13C-RMN (100 MHz, DMSO) δ: 160.6, 157.6, 147.9, 136.9, 135.9, 135.7, 134.0, 132.3, 129.7, 127.3, 126.7, 123.8, 119.8, 117.3, 38.1, 10.5, 6.3, purity analysed by HPLC 98%. EM (m/z): 389 [M+Na].sup.+. Elemental analysis (C.sub.18H.sub.15BrN.sub.2OS): theoretical % C, 56.86; % H, 4.27; % N, 6.98; % S, 7.99. observed % C, 56.48; % H, 3.89; % N, 7.21; % S, 8.05.

(41) 2-Cyclopropylmethylthio-3-(2,6-difluorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazoline (compound 15): Obtained according to the general method described previously.

(42) Reagents: 3-(2.6-Difluorophenyl)-8-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline (0.32 mmol, 0.097 g), cyclopropylmethyl bromide (0.96 mmol, 0.096 mL), K.sub.2CO.sub.3 (0.0045 g).

(43) The reaction conditions were: 12 hours at ambient temperature.

(44) Purification was carried out by means of silica gel column chromatography (hexane/ethyl acetate, in a ratio of 6:1 by volume).

(45) The yield obtained was: a white solid (145 mg, 99%). P.f.: 143.6-146.3° C. .sup.1H-RMN (400 MHz, DMSO) δ: 7.94 (d, 1H, J=7.9 Hz), 7.80-7.73 (m, 2H), 7.48-7.40 (m, 3H), 3.21 (d, 2H, J=7.3 Hz), 2.58 (s, 3H), 1.29-1.19 (m, 1H), 0.56-0.29 (m, 4H). .sup.13C-RMN (100 MHz, DMSO) δ: 160.3, 158.8 (d, 2C, J=252.5 Hz), 156.2, 146.2, 136.8, 135.2, 134.0, 126.5, 125.0, 118.8, 113.6, 38.3, 17.6, 10.5, 6.4, purity analysed by HPLC >99%. EM (m/z): 359 [M+H].sup.+.

(46) 2-Ethylthio-3-phenyl-4-oxo-3,4-dihydroquinazoline (compound 16): Obtained according to the general method described previously.

(47) Reagents: 3-Phenyl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline (0.78 mmol, 0.200 g), diethyl sulphate (0.94 mmol, 0.122 mL), K.sub.2CO.sub.3 (0.3450 g).

(48) The reaction conditions were: 1 hour under microwave radiation at 150° C.

(49) Purification was carried out by means of silica gel column chromatography (hexane/ethyl acetate, in a ratio of 6:1 by volume).

(50) The yield obtained was: a white solid (94 mg, 43%). P.f.: 117.5-119.6° C. .sup.1H-RMN (300 MHz, CDCl.sub.3) δ: 8.28 (dd, 1H, J=7.9, 1.5 Hz), 8.25 (m, 1H), 7.80-7.34 (m, 7H), 3.21 (d, 2H, J=7.4 Hz), 1.39 (t, J=7.4 Hz, 3H), .sup.13C-RMN (75 MHz, CDCl.sub.3) δ: 162.3, 157.8, 148.4, 136.5, 134.9, 130.3, 130.0, 129.6, 127.6, 126.6, 126.6, 27.4, 14.2, purity analysed by HPLC 99%. EM (m/z): 283 [M+H].sup.+. Elemental analysis (C.sub.16H.sub.14N.sub.2OS): theoretical % C, 68.06; % H, 5.00; % N, 9.92; % S, 11.36. observed % C, 68.33; % H, 4.98; % N, 10.05; % S, 11.21.

(51) 2-Ethylthio-3-(2,6-difluorophenyl)-4-oxo-3,4-dihydroquinazoline (compound 17): Obtained according to the general method described previously.

(52) Reagents: 3-(2,6-Difluorophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline (0.28 mmol, 0.088 g), diethyl sulfate (0.86 mmol, 0.115 mL), K.sub.2CO.sub.3 (0.0045 g).

(53) The reaction conditions were: 1 hour under microwave radiation at 150° C.

(54) Purification was carried out by means of silica gel column chromatography (hexane/ethyl acetate, in a ratio of 6:1 by volume).

(55) The yield obtained was: a white solid (53 mg, 58%). P.f.: 154.1-155.2° C. .sup.1H-RMN (400 MHz, DMSO) δ: 8.10 (dd, 1H, J=7.9, 1.5 Hz), 7.89 (td, 1H, J=7.2, 1.5 Hz), 7.75 (m, 1H), 7.65 (dd, 1H, J=7.1, 1.5 Hz), 7.53 (td, 1H, J=7.2, 1.5 Hz), 7.44 (t, 2H, J=7.4 Hz), 3.18 (c, 2H, J=7.3 Hz), 1.29 (t, 3H, J=14.6 Hz). .sup.13C-RMN (100 MHz, DMSO) δ: 160.4 (d, 2C, J=246.8 Hz), 160.1, 157.5, 147.8, 136.6, 134.1, 127.4, 127.1, 118.9, 113.6, 113.4, 26.6, 14.6, purity analysed by HPLC >99%. MS (ES, m/z): 319 [M+H].sup.+. Elemental analysis (C.sub.16H.sub.12F.sub.2N.sub.2OS): theoretical % C, 60.37; % H, 3.80; % N, 8.80; % S, 10.07. observed % C, 60.42; % H, 3.93; % N, 8.84; % S, 9.98.

(56) 8-Chloro-2-ethylthio-3-(2,6-difluorophenyl)-4-oxo-3,4-dihydroquinazoline (compound 18): Obtained according to the general method described previously.

(57) Reagents: 8-Chloro-3-(2,6-difluorophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline (0.45 mmol, 0.160 g), diethyl sulphate (1.35 mmol, 0.178 mL), K.sub.2CO.sub.3 (0.0045 g).

(58) The reaction conditions were: 1 hour under microwave radiation at 150° C.

(59) Purification was carried out by means of silica gel column chromatography (hexane/ethyl acetate, in a ratio of 6:1 by volume).

(60) The yield obtained was: a white solid (52 mg, 33%). P.f.: 165.4-166.7° C. .sup.1H-RMN (400 MHz, DMSO) δ: 8.05 (dd, 2H, J=7.8, 1.6 Hz), 7.76 (m, 1H), 7.47 (m, 3H), 3.23 (c, 2H, J=7.3 Hz), 1.34 (t, 3H, J=7.3 Hz). .sup.13C-RMN (100 MHz, DMSO) δ: 163.1 (d, 2C, J=246.8 Hz), 161.5, 159.8, 144.4, 136.6, 132.5, 127.2, 125.7, 120.7, 116.1, 114.1, 113.9, 27.2, 14.7, purity analysed by HPLC 97%. MS (ES) m/z: 353 [M+H].sup.+. Elemental analysis (C.sub.16H.sub.11ClF.sub.2N.sub.2OS): theoretical % C, 54.47; % H, 3.14; % N, 7.94; % S, 9.09. observed % C, 54.19; % H, 2.89; % N, 8.06; % S, 8.79.

(61) 2-Ethylthio-3-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazoline (compound 19): Obtained according to the general method described previously.

(62) Reagents: 3-(4-Fluorophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline (0.38 mmol, 0.104 g), diethyl sulphate (1.14 mmol, 0.151 mL), K.sub.2CO.sub.3 (0.0045 g).

(63) The reaction conditions were: 1 hour under microwave radiation at 150° C.

(64) Purification was carried out by means of silica gel column chromatography (hexane/ethyl acetate, in a ratio of 6:1 by volume).

(65) The yield obtained was: a white solid (70 mg, 61%). P.f.: 130.7-131.8° C. .sup.1H-RMN (400 MHz, DMSO) δ: 8.04 (dd, 1H, J=7.9, 1.2 Hz), 7.80 (td, 2H, J=8.3, 1.5 Hz), 7.60-7.36 (m, 5H), 3.10 (c, 2H, J=14.7, 7.3 Hz), 1.36 (t, 3H, J=7.3 Hz). .sup.13C-RMN (100 MHz, DMSO) δ: 163.1 (d, 2C, J=246.8 Hz), 161.5, 158.0, 148.0, 135.5, 132.5, 127.2, 125.7, 126.5, 120.2, 117.1, 116.9, 26.9, 14.5, purity analysed by HPLC >99%. MS (ES) m/z: 301 [M+H].sup.+. Elemental analysis (C.sub.16H.sub.13FN.sub.2OS): theoretical % C, 63.98; % H, 4.36; % N, 9.33; % S, 10.68. observed % C, 63.75; % H, 4.26; % N, 9.29; % S, 10.47.

(66) 2-Benzylthio-3-phenyl-4-oxo-3,4-dihydroquinazoline (compound 21): Obtained according to the general method described previously.

(67) Reagents: 3-Phenyl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline (0.59 mmol, 0.150 g), benzyl bromide (0.71 mmol, 0.084 mL), K.sub.2CO.sub.3 (0.3450 g).

(68) The reaction conditions were: 1 hour under microwave radiation at 150° C.

(69) Purification was carried out by means of silica gel column chromatography (hexane/ethyl acetate, in a ratio of 8:1 by volume).

(70) The yield obtained was: a white solid (61 mg, 30%). P.f.: 175.0-176.0° C. .sup.1H-RMN (300 MHz, CDCl.sub.3) δ: 8.28 (dd, 1H, J=7.9, 1.5 Hz), 7.80 (td, 1H, J=8.2, 1.5 Hz), 7.72 (d, 1H, J=8.2 Hz), 7.57-7.33 (m, 11H), 4.42 (s, 2H). .sup.13C-RMN (75 MHz, CDCl.sub.3) δ: 162.2, 157.5, 148.2, 136.8, 136.2, 135.0, 130.3, 130.1, 129.8, 129.6, 128.9, 127.9, 127.7, 126.6, 126.3, 120.4, 37.5, purity analysed by HPLC 99%. EM (m/z): 345 [M+H].sup.+. Elemental analysis (C.sub.21H.sub.16N.sub.2OS): theoretical % C, 72.70; % H, 4.27; % N, 8.48; % S, 9.70. observed % C, 73.00; % H, 4.27; % N, 8.26; % S, 9.58.

(71) 3-Phenyl-2-(2-pyridylmethylthio)-4-oxo-3,4-dihydroquinazoline (compound 23): Obtained according to the general method described previously.

(72) Reagents: 3-Phenyl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline (0.80 mmol, 0.200 g), 2-bromomethylpyridine hydrobromide (1.2 mmol, 303.5 mg), Cs.sub.2CO.sub.3 (0.8145 g).

(73) The reaction conditions were: 3 hours under microwave radiation at 150° C.

(74) Purification was carried out by means of silica gel column chromatography (hexane/ethyl acetate, in a ratio of 4:1 by volume).

(75) The yield obtained was: a white solid (157 mg, 57%). P.f.: 173.0-174.0° C. .sup.1H-RMN (400 MHz, CDCl.sub.3) δ: 8.45 (ddd, 1H, J=4.8, 1.9, 1.0 Hz), 8.06 (dd, 1H, J=8.0, 1.5 Hz), 7.83 (ddd, 1H, J=8.6, 7.2, 1.6 Hz), 7.72 (td, 1H, J=7.6, 1.8 Hz), 7.65 (dd, 1H, J=7.6, 1.1 Hz), 7.60-7.49 (m, 3H), 7.43-7.39 (m, 4H), 7.24 (ddd, 1H, J=7.6, 4.8, 1.1 Hz), 4.50 (s, 2H). .sup.13C-RMN (100 MHz, CDCl.sub.3) δ: 162.0, 156.8, 156.6, 148.3, 147.9, 135.8, 135.6, 135.0, 130.3, 130.0, 129.4, 127.5, 126.4, 126.2, 124.5, 122.9, 120.2, 38.8, purity analysed by HPLC 99%. EM (m/z): 346 [M+H].sup.+. Elemental analysis (C.sub.20H.sub.15N.sub.3OS): theoretical % C, 69.54; % H, 4.38; % N, 12.17; % S, 9.28. observed % C, 69.81; % H, 4.65; % N, 12.32; % S, 9.00.

(76) 3-Phenyl-2-(3-pyridylmethylthio)-4-oxo-3,4-dihydroquinazoline (compound 24): Obtained according to the general method described previously.

(77) Reagents: 3-Phenyl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline (0.80 mmol, 0.200 g), 3-bromomethylpyridine hydrobromide (1.2 mmol, 303.5 mg), Cs.sub.2CO.sub.3 (0.8145 g).

(78) The reaction conditions were: 2 hours under microwave radiation at 150° C.

(79) Purification was carried out by means of silica gel column chromatography (hexane/ethyl acetate, in a ratio of 4:1 by volume).

(80) The yield obtained was: a white solid (127 mg, 46%). P.f.: 154.0-155.0° C. .sup.1H RMN (400 MHz, CDCl.sub.3) δ: 8.71 (d, 1H, J=2.5 Hz), 8.49 (d, 1H, J=4.4 Hz), 8.24 (d, 1H, J=8.0 Hz), 7.80-7.77 (m, 1H), 7.75 (d, 1H, J=6.9 Hz), 7.67 (d, 1H, J=8.2 Hz), 7.57-7.50 (m, 3H), 7.42 (t, 1H, J=7.5 Hz), 7.33-7.25 (m, 3H), 4.38 (s, 2H). .sup.13C RMN (100 MHz, CDCl.sub.3) δ: 161.9, 156.3, 150.0, 148.0, 147.8, 135.8, 135.1, 133.8, 130.4, 130.0, 129.4, 127.6, 126.4, 126.2, 123.8, 123.7, 120.2, 34.0, purity analysed by HPLC 98%. EM (m/z): 346 [M+H].sup.+. Elemental analysis (C.sub.20H.sub.15N.sub.3OS): theoretical % C, 69.54; % H, 4.38; % N, 12.17; % S, 9.28. observed % C, 69.75; % H, 4.61; % N, 12.02; % S, 9.05.

(81) 8-Chloro-2-(3-pyridylmethylthio)-4-oxo-3,4-dihydroquinazoline (compound 25): Obtained according to the general method described previously.

(82) Reagents: 8-Chloro-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline (0.173 mmol, 0.050 g), 3-pyridylmethyl bromide (0.311 mmol, 0.788 g), Cs.sub.2CO.sub.3 (0.203 g).

(83) The reaction conditions were: 2 hours 30 minutes under microwave radiation at 150° C.

(84) Purification was carried out by means of centrifugal circular chromatography (hexane/ethyl acetate, in a ratio of 5:1 by volume).

(85) The yield obtained was: a white solid (14.3 mg, 22%). P.f.: 191.5-192.5° C. .sup.1H-RMN (400 MHz, CDCl.sub.3) δ: 8.76 (d, 1H, J=2.4 Hz), 8.50 (s, 1H), 8.16 (dd, 1H, J=8.0, 1.5 Hz), 7.94 (d, 1H, J=7.9 Hz), 7.84 (dd, 1H, J=7.9, 1.5 Hz), 7.59-7.51 (m, 3H), 7.37-7.27 (m, 4H), 4.48 (s, 2H). .sup.13C-RMN (100 MHz, CDCl.sub.3) δ: 161.4, 158.0, 149.9, 148.0, 144.3, 137.9, 135.5, 135.3, 133.9, 131.0, 130.6, 130.1, 129.2, 126.3, 123.9, 121.7, 34.0, purity analysed by HPLC 98%. MS (ES) m/z: 360 [M+H].sup.+. Elemental analysis: (C.sub.20H.sub.14ClN.sub.3OS): theoretical % C, 63.24; % H, 3.71; % N, 11.06; % S, 8.44. observed % C, 62.40; % H, 3.99; % N, 11.65; % S, 8.01.

(86) 3-(2-Methylphenyl)-2-(3-pyridylmethylthio)-4-oxo-3,4-dihydroquinazoline (compound 26): Obtained according to the general method described previously.

(87) Reagents: 3-(2-Methylphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline (0.3730 mmol, 0.100 g), 3-pyridylmethyl bromide (0.559 mmol, 0.141 g), Cs.sub.2CO.sub.3 (0.364 g).

(88) The reaction conditions were: 3 hours under microwave radiation at 150° C.

(89) Purification was carried out by means of centrifugal circular chromatography (hexane/ethyl acetate, in a ratio of 6:1 by volume).

(90) The yield obtained was: a white solid (16.3 mg, 12%). P.f.: 150.0-151.8° C. .sup.1H-RMN (400 MHz, CDCl.sub.3) δ 8.71 (s, 1H), 8.48 (s, 1H), 8.26 (dd, 1H, J=8.2, 1.3 Hz), 7.81-7.75 (m, 2H), 7.72 (d, 1H, J=7.6 Hz), 7.48-7.40 (m, 2H), 7.40-7.31 (m, 2H), 7.28-7.26 (m, 1H), 7.18 (dd, J=7.6, 1.3 Hz, 1H), 4.40 (d, 1H, J=14.1 Hz), 4.35 (d, 1H, J=14.1 Hz), 2.10 (s, 3H). .sup.13C-RMN (100 MHz, CDCl.sub.3) δ: 161.3, 156.3, 150.1, 148.1, 147.9, 137.5, 137.0, 135.0, 134.8, 133.8, 131.6, 130.6, 129.3, 127.6, 126.4, 126.3, 123.8, 120.0, 33.7, 17.6, purity analysed by HPLC >99%. MS (ES) m/z: 360 [M+H].sup.+. Elemental analysis: (C.sub.21H.sub.17N.sub.3OS): theoretical % C, 70.17; % H, 4.77; % N, 11.63; % S, 8.92. observed % C, 69.87; % H, 5.02; % N, 11.82; % S, 8.87.

(91) 3-Phenyl-2-(4-pyridylmethylthio)-4-oxo-3,4-dihydroquinazoline (compound 27): Obtained according to the general method described previously.

(92) Reagents: 3-Phenyl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline (0.80 mmol, 0.200 g), 4-bromomethylpyridine hydrobromide (1.2 mmol, 303.5 mg), Cs.sub.2CO.sub.3 (0.8145 g).

(93) The reaction conditions were: 3 hours under microwave radiation at 150° C.

(94) Purification was carried out by means of silica gel column chromatography (hexane/ethyl acetate, in a ratio of 10:1 by volume).

(95) The yield obtained was: a white solid (130 mg, 47%). P.f.: 178.0-179.0° C. .sup.1H-RMN (400 MHz, CDCl.sub.3) δ: 8.53 (d, 2H, J=6.1 Hz), 8.24 (dd, 1H, J=7.9, 1.5 Hz), 7.81-7.71 (m, 1H), 7.65-7.58 (m, 1H), 7.57-7.39 (m, 4H), 7.38 (d, 2H, J=6.1 Hz), 7.33-7.28 (m, 2H), 4.37 (s, 2H). .sup.13C-RMN (100 MHz, CDCl.sub.3) δ: 161.6, 155.8, 149.5, 147.5, 147.2, 135.5, 134.8, 130.2, 129.8, 129.1, 127.4, 126.2, 126.1, 124.4, 119.9, 35.2, purity analysed by HPLC 99%. EM (m/z): 346 [M+H].sup.+. Elemental analysis (C.sub.20H.sub.15N.sub.3OS): theoretical % C, 69.54; % H, 4.38; % N, 12.17; % S, 9.28. observed % C, 69.38; % H, 4.45; % N, 12.06; % S, 9.30.

(96) 3-Phenyl-2-(2-naphthylmethylthio)-4-oxo-3,4-dihydroquinazoline (compound 28): Obtained according to the general method described previously.

(97) Reagents: 3-Phenyl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline (0.40 mmol, 0.100 g), 2-naphthylmethyl bromide (0.60 mmol, 132.7 mg), Cs.sub.2CO.sub.3 (0.8145 g).

(98) The reaction conditions were: 3 hours under microwave radiation at 150° C.

(99) Purification was carried out by means of silica gel column chromatography (hexane/ethyl acetate, in a ratio of 10:1 by volume).

(100) The yield obtained was: a white solid (30 mg, 19%). P.f.: 223.0-224.0° C. .sup.1H-RMN (400 MHz, DMSO) δ: 7.99 (dd, 1H, J=8.0, 1.5 Hz), 7.94-7.90 (m, 1H), 7.82-7.68 (m, 5H), 7.50-7.32 (m, 9H), 4.56 (s, 2H). .sup.13C-RMN (100 MHz, DMSO) δ: 161.4, 157.5, 147.9, 136.5, 135.7, 135.0, 133.4, 132.8, 130.5, 130.2, 130.1, 128.8, 128.7, 128.3, 128.2, 128.1, 127.3, 127.0, 126.8, 126.7, 120.3, 39.5, purity analysed by HPLC 98%. EM (m/z): 395 [M+H].sup.+. Elemental analysis (C.sub.25H.sub.18N.sub.2OS): theoretical % C, 76.12; % H, 4.60; % N, 7.10; % S, 8.13. observed % C, 75.86; % H, 5.04; % N, 7.25; % S, 7.96.

Example 2

Measurement of the PDE7 Inhibition of the Compounds of the Invention

(101) Measurement of PDE7 inhibition was carried out using a commercial phosphodiesterase activity measurement kit.

(102) Some of the compounds of the present invention (including those synthesised in Example 1) were evaluated. For this purpose, said compounds were incubated (in a range of concentrations from 0.1 nM to 100 μM) in the presence of 0.02 U/well of PDE7A1 and 0.05 μCi of [.sup.3H] cAMP, for 20 minutes at 30° C. in the assay buffer supplied with the kit (total volume per well=100 μL). Once this time had elapsed, 50 μL of a 20 mg/mL suspension of SPA glass silicate microspheres were added and kept in agitation at ambient temperature for 60 minutes. After allowing the plate to rest for 20 minutes, the radioactivity was tested in a scintillation detector. All the assays included two points in the absence of PDE7A1 (blank/negative control) and two points with PDE7A1 in the absence of inhibitors (positive control).

(103) Analysis of the data: All the compounds were initially evaluated at a concentration of 10 μM and the percentage inhibition of PDE7A1 was calculated according to the following formula:
% inhibition=((cpm control−cpm sample)×100)/(cpm control−cpm blank)

(104) For those compounds with % inhibition values above 45%, their inhibitory power (IC.sub.50) was calculated by constructing a concentration-response curve, following the protocol explained previously (concentration of analysed compound from 0.1 nM to 100 μM). The data were adjusted with a software program using non-linear adjustment.

(105) TABLE-US-00001 TABLE 1 PDE inhibition data of the compounds of the present invention. Compound PDE7A IC.sub.50 (μM) PDE4D3 PDE4B2  1 0.20 49% @10 μM 18% @10 μM  2 2.11  5 0.10 37% @10 μM 29% @10 μM  6 8.67 11 1.2 13 1.85 14 9.44 15 4.56 16 6.90 17 6.99 18 2.44 21 0.60 38% @10 μM 28% @10 μM 23 0.80 24 0.70 25 0.54 26 0.12 27 2.6 28 0.09

Example 3

Assay of Permeability in the Central Nervous System (CNS), Using the Parallel Artificial Membrane Permeability Assay (PAMPA), of the Compounds of the Present Invention

(106) The prediction of the permeability of the various compounds in the central nervous system (CNS), i.e. their passage across the blood-brain barrier, was determined using the parallel artificial membrane permeability assay (PAMPA) (Di, L. et al., “High throughput artificial membrane permeability assay for blood-brain barrier”, Eur. J. Med. Chem., 2003, 38 (3), 223-232). PDVF membrane filters were used for filtering the samples (diameter 30 mm, pore size 0.45 μm).

(107) Ten reference compounds were selected whose passage across the blood-brain barrier is known and in the public domain, in order to validate the experiment. Different quantities of these compounds were taken, namely: 3-5 mg of caffeine, enoxacin, hydrocortisone, desipramine, ofloxacin, piroxicam and testosterone, 12 mg of promazine, and 25 mg of verapamil and atenolol, which were dissolved in ethanol (1000 μL). 100 μL of these solutions were taken, and 1400 μL of ethanol and 3500 μL of PBS (pH=7.4) were added in order to achieve a final ethanol concentration of 30% in the solution. The solutions were filtered. Afterwards, 180 μL of a solution of PBS/ethanol (70/30) were added to each well of the acceptor plate. The donor plate was impregnated with 4 μL of a solution of porcine brain lipid dissolved in dodecane (20 mg mL-1).

(108) After 5 minutes, 180 μL of solution of each compound were added to this plate.

(109) For the compounds to be evaluated for their penetration in the central nervous system (namely compounds 13, 14, 15, 16, 17, 23, 24, 25, 26 and 27), 1-2 mg of the compound were taken and dissolved in 1500 μL of ethanol and 3500 μL of PBS (pH=7.4), they were filtered and added to the 96-well donor plate.

(110) The donor plate was then placed on the acceptor plate, forming a kind of sandwich, and left to incubate for 2 h and 30 min at 25° C. The compounds passed by passive transport from the donor plate, through the porcine brain lipid, to the acceptor plate. After 2 h and 30 min, the donor plate was carefully removed.

(111) The concentration and absorbance, both of the commercial compounds and of the compounds of the present invention that were evaluated in the acceptor and donor plates, were determined using a UV absorbance reader. Each sample was analysed at different wavelengths (between 3 and 5 absorbance minima and maxima were chosen for each compound at wavelength valves of between 220 nm and 450 nm), in 3 wells and in a minimum of 2 independent experiments. The results are the average of the averages [±standard deviation] of the different experiments performed. The measurements were carried out on the acceptor plate.

(112) In relation to the ten reference commercial compounds used in each experiment in order to validate the method, a good correlation was found between the experimental permeability (Pe) values and those described in the available bibliography (bibliographic permeability, Pb), Pe=(1.1512×Pb)−0.8973 (R.sup.2=0.977). Based on this equation and following the model described in the literature (Crivori, P.; Cruciani, G.; Testa, B. “Predicting Blood-Brain Barrier Permeation from Molecular Three-Dimensional 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 >3.71×10.sup.−6 cm s.sup.−1, and are classified as non-permeable to the CNS when they have a permeability of less than 1.40×10.sup.−6 cm s.sup.−1 (between these two values there is an area of uncertainty). The results are given in Table 2, where it can be seen that the majority of the assayed compounds are classified as capable of penetrating the blood-brain barrier.

(113) TABLE-US-00002 TABLE 2 Permeability data (bibliographic and experimental) of the commercial or bibliographic compounds and experimental permeability data for the assayed compounds of the present invention. Pb (10.sup.−6 Pe (10.sup.−6 Permeability Compound cm s.sup.−1) cm s.sup.−1) prediction Atenolol 0.8 0.2 ± 0.1 Caffeine 1.3 0.8 ± 0.1 Desipramine 12 8.0 ± 1.0 Enoxacin 0.9 0.7 ± 0.2 Hydrocortisone 1.9 0.3 ± 0.3 Ofloxacin 0.8 0.2 ± 0.1 Piroxicam 2.5 0.2 ± 0.1 Promazine 8.8 8.5 ± 0.1 Testosterone 17 17.2 ± 0.6  Verapamil 16 14.7 ± 1.1  16 7.9 ± 1.2 SNC+ 17 4.8 ± 0.6 SNC+ 14 1.9 ± 0.3 SNC+/− 15 1.3 ± 0.9 SNC+/− 23 12.4 ± 2.2  SNC+ 24 18.6 ± 1.7  SNC+ 27 15.9 ± 1.3  SNC+ 26 20.1 ± 0.1  SNC+ 25 12.1 ± 3.9  SNC+ 13 3.9 ± 0.7 SNC+

Example 4

Study of Toxicity on the Cardiac hERG Channel

(114) The hERG potassium channel contributes in the final phase of the action potential, bringing the cell to its resting state. If a drug suppresses the activity of the channel, it can produce a prolongation of the action of the channel, known as “long QT syndrome”, resulting in a fatal ventricular arrhythmia.

(115) To characterise the behaviour of the hERG potassium channel in the presence of the compounds of the present invention, use was made of an assay based on a fluorescent probe (FluxOR®, Life Technologies) with high affinity for thallium, an indicator of the activity of the potassium ion channel. When the potassium channels open in response to a stimulus, the influx of thallium from the external environment is detected by the probe. The fluorescent signal is therefore proportional to the number of open potassium channels in the cell. The FluxOR® is added in ester form without fluorescent emission capacity, thus preventing the emission of fluorescence outside the cell. When it enters the cell, the cytosol esterases activate the FluxOR®, so that it is capable of binding the thallium that passes into the cytoplasm through the hERG channel and of emitting fluorescence.

(116) This example shows the results obtained for compound 5 of the present invention (3-Phenyl-2-neopentylthio-4-oxo-3,4-dihydroquinazoline), synthesised as indicated in Example 1, and the PDE7 and PDE4 dual inhibitor compound TC3.6 (3-Phenyl-2,4-dithioxo-1,2,3,4-tetrahydroquinazoline).

(117) Black plates containing 96 wells treated with poly-D-lysine were seeded with HEK293 cells (deposit number ATCC CRL-1573) modified to stably express the hERG channel. After 24 hours, the plates were washed with assay buffer (NaCl 165 mM, KCl 4.5 mM, CaCl.sub.2 2 mM, MgCl.sub.2 1 mM, Hepes 10 mM and glucose 10 mM, pH 7.4), and 20 μL of FluxOR™ dissolved in assay buffer were added. After one hour of incubation of the fluorochrome with the cells at ambient temperature, the plates were washed with 50 μL of assay buffer. Subsequently, 20 μL of the compounds to be studied were added at a dilution of 1:200 (2 μL of compound/400 μL of assay buffer), in triplicate, on 12-point curves (1:2 dilutions of the compound in DMSO). The highest assayed concentration was 150 μM (initial concentration of the analysed compounds). After 30 minutes of incubation, the plates were read in a FLIPR TETRA®, which added 5 μL of stimulus buffer (Tl.sub.2SO.sub.4+K.sub.2SO.sub.4). The fluorescence reading was carried out for 120 seconds, allowing analysis of the kinetics of the channel. 1 μM of astemizol (which has an IC.sub.50 of approximately 2.6 μM), bepridil (IC.sub.50 of 1.4 μM), haloperidol (IC.sub.50 of 1.16 μM) and terfenadine (IC.sub.50 of 1.2 μM) were used as positive controls, while DMSO at 0.5% was used as a negative control.

(118) Compound 5 showed very low activity, with an IC.sub.50 of over μM (>30 μM). Compound TC3.6, on the other hand, stimulated the opening of the potassium channel, with an IC.sub.50 (concentration required to produce 50% of the response) of 5.19 μM. From these data, it is deduced that compound 5 did not have any cardiotoxic potential.

Example 5

Pharmacokinetic Studies in Mice: Exposure in Plasma and Brain

(119) This example shows the results of the pharmacokinetic studies carried out in mice for compound 5 of the present invention (3-Phenyl-2-neopentylthio-4-oxo-3,4-dihydroquinazoline), synthesised as indicated in Example 1, in comparison with the PDE7 and PDE4 dual inhibitor compound TC3.6 (3-Phenyl-2,4-dithioxo-1,2,3,4-tetrahydroquinazoline). In this case it was found that compound 5 can be quantified in plasma and brain (and is therefore capable of crossing the blood-brain barrier) at levels that prove its biological activity.

(120) In a first step, the study was carried out by means of intraperitoneal administration of the compounds to be studied (compound 5 and TC3.6). For this study, healthy C57BL/6 mice were used (8-12 weeks old, with a weight of between 20-35 g), which were kept at 22±3° C. and a humidity of 40-70%, with water and food ad libitum in 12-hour cycles of light and dark. The study was carried out in accordance with the guidelines and with the approval of the Institutional Animal Ethics Committee (IAEC). 15 mice were injected intraperitoneally with a solution of the compound to be studied (2% v/v DMSO in water: Tocrisolve® (95:5)) at a dosage of 10 mg/kg. The administration volume was 10 mL/kg. Blood samples (of approximately 120 μL) were taken from the retro-orbital plexus of 3 mice for each point studied (0, 0.25, 0.5, 1, and 2 h after injection of the dose), and these were placed in microcentrifuge tubes containing 10 μL of K.sub.2EDTA 20% w/v as anticoagulant. The plasma was obtained after centrifugation of the blood at 4000 rpm for 10 min at 4° C., and then stored at −70° C. until its analysis.

(121) After the blood extraction, the mice of each group were sacrificed by asphyxia with CO.sub.2, in order to obtain the brain. The brains were washed in a cold solution, dried in filter paper, weighed and placed in polypropylene tubes. The brains were homogenised with a buffered solution of phosphate pH 7.4, so that the total volume of the homogenate was three times the weight of the brain. The samples were stored at −70° C. until their analysis.

(122) The extraction procedure for the plasma/brain homogenate or plasma calibration standard/doped brain samples was the same: 100 μL of the internal standard (imipramine, 500 ng/mL) were added, prepared in acetonitrile, to 25 μL of sample (plasma/brain) or doped calibration standard, and agitated with a vortex agitator for 5 minutes. As a blank (negative control), only acetonitrile was added. The samples were centrifugated for 10 min at 15000 rpm (20600 g) at 4° C. 100 μL of each supernatant were transferred to 96-well plates for its analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The calibration standards were prepared by doping 10 μL of analyte (compound to be studied, 1 mg/mL) in 190 μL of virgin plasma/brain homogenate (and subsequent serial dilutions).

(123) The pharmacokinetic study was performed based on the time-concentration data obtained for the plasma and brain, by means of non-compartmental analysis using version 5.2 of WinNonlin®. The areas under the concentration-time curve (AUClast and AUCinf) were calculated using the linear trapezoidal rule.

(124) In a second step, it was tested whether compound 5 of the present invention (3-Phenyl-2-neopentylthio-4-oxo-3,4-dihydroquinazoline) synthesised as indicated in Example 1 and the dual PDE7 and PDE4 inhibitor compound TC3.6 (3-Phenyl-2,4-dithioxo-1,2,3,4-tetrahydroquinazoline) could be administered via the oral route in such a way that they could be quantified in plasma and brain (and therefore to see whether they were capable of crossing the blood-brain barrier) at levels that would prove their biological activity.

(125) For this purpose, a pharmacokinetic study similar to that described for the intraperitoneal administration was performed. The only difference lay in the administration of the compounds, which was via the oral route, in a suspension consisting of Tween 80 0.1% v/v and sodium carboxymethyl cellulose (NaCMC) 0.5% w/v in water. The compounds were administered at a dosage of 10 mg/kg, by gastric intubation using a 22-gauge oral feeding needle. The administration volume was 10 mL/kg.

(126) As can be seen in Table 3, after both intraperitoneal and oral administration, the concentration of compound 5 in brain was higher than that of TC3.6, indicating that compound 5 was better at crossing the blood-brain barrier (brain/plasma exposure ratio of >1 for compound 5, compared with <1 for compound TC3.6—see Table 3). This provides an additional advantage when using the compounds of the present invention in treatments for diseases related to the central nervous system, such as the neurodegenerative, inflammatory or autoimmune diseases mentioned previously.

(127) The clearest differences between the two compounds were observed after oral administration, where, having administered the same dose, the concentration of compound 5 was higher than that of TC3.6 in both plasma and brain. The concentration of compound 5 in plasma and brain was above its IC.sub.50 for PDE7 (13.8× and 16.4× respectively—see Table 4), supporting its biological activity, whereas that of TC3.6 was found below its IC.sub.50 for PDE7 (0.83× and 0.36× respectively—see Table 4). These data indicate a greater efficacy of the compounds of the present invention for use in the development of drugs.

(128) As can be seen in FIGS. 1 and 2, the elimination of compound 5 in plasma and brain was slower, and 2 hours after intraperitoneal or oral administration there were still considerable levels of this compound in plasma and brain (see FIGS. 1A and 2A). In contrast, compound TC3.6 had been almost eliminated after two hours, regardless of the route of administration used (see FIGS. 1B and 2B). These data demonstrated the potential of the compounds of the present invention to be more effective at lower doses and, therefore, to avoid possible toxic effects by increasing the therapeutic effect.

(129) The comparison of results relating to compound 5 and compound TC3.6 is summarised below in Tables 3 and 4.

(130) TABLE-US-00003 TABLE 3 Comparison of the inhibitory activity of PDE7 in vitro and of concentration in plasma and brain after intraperitoneal and oral administration in mice of compound 5 and compound TC3.6. Intraperitoneal PDE administration Oral administration inhibitory (Tmax 0.25 h) (Tmax 0.5 h) activity Plasma Brain Brain/ Plasma Brain Brain/ PDE7A Cmax Cmax plasma Cmax Cmax plasma Comp. CI.sub.50 (μM) (μM) (μM) ratio (μM) (μM) ratio 5 0.1 2.31 5.65 2.45 1.38 1.64 1.19 TC3.6 1.04 6.79 3.46 0.51 0.86 0.37 0.43

(131) TABLE-US-00004 TABLE 4 Comparison of PDE7 Cmax/IC.sub.50 ratios of compounds 5 and TC3.6 after intraperitoneal or oral administration in mice. Intraperitoneal administration Oral administration Cmax/PDE7 IC.sub.50 ratio Cmax/PDE7 IC.sub.50 ratio Comp. Plasma Brain Plasma Brain 5 23.1 56.5 13.8 16.4 TC3.6 6.53 3.33 0.83 0.36