INDOLE DERIVATIVES FOR THE PREVENTION AND/OR TREATMENT OF DIABETES AND ASSOCIATED METABOLIC DISORDERS

Abstract

The invention relates to substituted heterocyclic indole derivatives of Formula (I), which act as activators of the AMP-activated protein kinase (AMPK) and to the use of them for the treatment and prevention of diseases or disorders regulated by AMPK. As a result, these compounds can be used for the treatment of inflammatory, autoimmune, cardiovascular, neurological diseases and cancer.

Claims

1. A method for the treatment and/or prevention of a disease, disorder, or prophylaxis mediated by the AMPK enzyme comprising administering to a person in need thereof a compound of formula (I), ##STR00008## its pharmaceutically acceptable salts, solvates.sub.., and hydrates where, A is selected from between 5- or 6-membered phenyl or heteroaryl containing a heteroatom selected from between nitrogen and oxygen, R.sub.1 is selected from among hydrogen, benzyl and 2-(3-hydroxypyridyl)methyl; R.sub.2, R.sub.3 and R.sub.4 are independently selected from among hydrogen, C.sub.1-C.sub.18 alkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.2-C.sub.10 heterocycloalkyl, C.sub.2-C.sub.18 alkenyl, hydroxyl, C.sub.1-C.sub.6-O-alkyl, optionally substituted C.sub.7-C.sub.12-O-aralkyl, —NR.sub.aR.sub.b, —NCOR.sub.a, —CO.sub.2R.sub.a, —CONR.sub.aR.sub.b, halogen, —CN, —NO.sub.2, —COR.sub.a, C.sub.6-C.sub.18 aryl and optionally substituted C.sub.4-C.sub.18 heteroaryl, with the condition that at least one of R.sub.2, R.sub.3 or R.sub.4 is different from hydrogen when A is phenyl; and R.sub.a and R.sub.b are independently selected from among hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.2-C.sub.7 heterocycloalkyl, C.sub.2-C.sub.18 alkenyl, C.sub.5-C.sub.18 aryl and optionally substituted C.sub.4-C.sub.18 heteroaryl, R.sub.a and R.sub.b can form a C.sub.3-C.sub.7 carbocycle.

2. The method, according to claim 1, where A is selected from between phenyl and pyridinvl.

3. The method, according to claim 1, where A is phenyl and R.sub.4 is selected from among C.sub.1-C.sub.6-O-alkyl, optionally substituted C.sub.7-C.sub.12-O-aralkyl, —NR.sub.aR.sub.b, —NR.sub.aR.sub.b, —NCOR.sub.a, C.sub.2-C.sub.10 heterocycloalkyl, C.sub.6-C.sub.18 aryl and optionally substituted C.sub.4-C.sub.18 heteroaryl.

4. The method, according to claim 3, where R.sub.4 is selected from among —OMe, —OEt, —OBn, —NH.sub.2, —NCOMe, piperidinyl, morpholinyl and optionally substituted phenyl.

5. The method according to claim 1, where the compound of formula (I) is selected from 1-benzyl-3-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-indole-2-carboxylic acid (7); 1-benzyl-3-(4-methoxypyridine-3-yl)-1H-indole-2-carboxylic acid (8); 1-benzyl-3-(4-fluoro-3-methoxyphenyl)-1H-indole-2-carboxylic acid (9); 3-(2′-hydroxy-[1,1′-biphenyl]-4-O-1H-indole-2-carboxylic acid (16); 3-(3-(hydroxycarbonyl)phenyl)-1H-indole-2-carboxylic acid (17); 3-(3-benzyloxyphenyl)-1H-indole-2-carboxylic acid (18); 3-(4-fluoro-3-methoxyphenyl)-1H-indole-2-carboxylic acid (19); 3-(furan-2-yl)-1H-indole-2-carboxylic acid (20); 3-(4-methoxypyridine-3-yl)-1H-indole-2-carboxylic acid (21); and 3-(pyridine-4-yl)-1H-indole-2-carboxylic acid (22).

6. The method, according to claim 1, where the AMPK enzyme-mediated disease is selected from among type 2 diabetes, obesity, dyslipidemia, hypertension, hyperglycemia, hypertriglycerimidemia, and insulin resistance.

7. The method, according to claim 1, where the AMPK enzyme-mediated disease is selected from among Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease.

8. The method, according to claim 1, where the AMPK enzyme-mediated disease is prostate cancer and breast cancer.

9. The method, according to claim 1, where the AMPK enzyme-mediated disease is epilepsy.

10. A compound of formula (II), ##STR00009## its pharmaceutically acceptable salts, hydrates and solvates where, R.sub.1 is selected from among hydrogen, benzyl and 2-(3-hydroxypyridyl)methyl; R.sub.5, R.sub.6 and R.sub.7 are independently selected from among hydrogen, C.sub.3-C.sub.10 cycloalkyl, C.sub.2-C.sub.10 heterocyclolkyl, hydroxyl, optionally substituted C.sub.7-C.sub.12-O-aralkyl, —NR.sub.aR.sub.b, —NCOR.sub.a, —CO.sub.2R.sub.a, —CONR.sub.aR.sub.b, —CN, —NO.sub.2, C.sub.5-C.sub.18 aryl and optionally substituted C.sub.4-C.sub.18 heteroaryl, with the condition that at least one of R.sub.5, R.sub.6 or R.sub.7 is different from hydrogen; R.sub.a and R.sub.b are independently selected from among hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.2-C.sub.7 heterocycloalkyl, C.sub.2-C.sub.18 alkenyl, C.sub.5-C.sub.18 aryl and optionally substituted C.sub.4-C.sub.18 heteroaryl; and R.sub.a and R.sub.b can form a C.sub.3-C.sub.7 carbocycle.

11. A compound, according to claim 10, where R.sub.7 is selected from among C.sub.3-C.sub.10-cycloalkyl, C.sub.2-C.sub.10 heterocycloalkyl, optionally substituted C.sub.7-C.sub.12-O-aralkyl, —NR.sub.aR.sub.b, —NCOR.sub.a, —CO.sub.2R.sub.a, —CONR.sub.aR.sub.b, —CN and —NO.sub.2.

12. The compound, according to claim 10, which is selected from: 1-benzyl-3-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-indole-2-carboxylic acid (7); 3-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-indole-2-carboxylic acid (16); 3-(3-(hydroxycarbonyl)phenyl)-1H-indole-2-carboxylic acid (17); and 3-(3-benzyloxyphenyl)-1H-indole-2-carboxylic acid (18).

13. The compound of formula (III), according to claim 10, ##STR00010## its pharmaceutically acceptable salts, hydrates and solvates where, R.sub.1 is selected from among hydrogen, benzyl and 2-(3-hydroxypyridyl)methyl; R.sub.8 and R.sub.9 are independently selected from among hydrogen, halogen, hydroxyl, optionally substituted C.sub.7-C.sub.12-O-aralkyl, —NR.sub.cR.sub.d, —NCOR.sub.c, —CO.sub.2R.sub.c, —CONR.sub.cR.sub.d, —CN and —NO.sub.2, with the condition that R.sub.9 is not hydrogen; R.sub.c and R.sub.d are independently selected from among hydrogen, C.sub.1-C.sub.6 alkyl and C.sub.3-C.sub.7 cycloalkyl; and R.sub.c and R.sub.d can form a C.sub.3-C.sub.7 carbocycle.

14. The compound, according to claim 13, where R.sub.9 is selected from among hydroxyl, —NR.sub.cR.sub.d, —NCOR.sub.c, —CO.sub.2R.sub.c, —CONR.sub.cR.sub.d, —CN and —NO.sub.2; R.sub.c and R.sub.d are independently selected from among hydrogen, C.sub.1-C.sub.6 alkyl and C.sub.3-C.sub.7cycloalkyl; and R.sub.c and R.sub.d can form a C.sub.3-C.sub.7 carbocycle.

15. The compound, according to claim 13, which is selected from: 1-benzyl-3-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-indole-2-carboxylic acid (7) and 3-(2′-hydroxy-[1,1′-biphenyl]-4-11)-1H-indole-2-carboxylic acid (16).

16. A pharmaceutical composition comprising a compound, as defined in claim 10, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable adjuvant, carrier, or excipient.

17. (canceled)

Description

DESCRIPTION OF THE FIGURES

[0129] FIG. 1 Shows the activation of the AMPK of compound 7. Example of the Western Blot analysis that shows that compound 7 activates AMPK in a dose-dependent manner, this effect is confirmed by the increase in phosphorylation, which is also dependent upon the dose, of its ACC substrate, in a range of concentrations comprised between 12.5 and 50 μM. The HEK293 cells are treated with the amounts of compound indicated in the figure for 1 hour. The lysed cells are analysed by Western Blott using anti-phosphoThr172 AMPK alpha, anti-AMPKb1 (used as a loading control), anti-phosphoSer79ACC and anti-ACC (used as a loading control). The molecular weight markers are indicated on the right of the figure.

[0130] FIG. 2 Shows the effect of AMPK activation of compound 16. Example of the Western Blot analysis that shows that compound 16 activates AMPK in a dose-dependent manner, this effect is confirmed by the increase in phosphorylation, which is also dose-dependent, on its ACC substrate, in a range of concentrations comprised between 12.5 and 100 μM. The HEK293 cells are treated with the amounts of compound indicated in the figure for 1 hour. The lysed cells are analysed by Western Blot using anti-phosphoThr172 AMPK alpha, anti-AMPKb1 (used as a loading control), anti-phosphoSer79ACC and anti-ACC (used as a loading control). The molecular weight markers are indicated on the right of the figure.

EXAMPLES AND EMBODIMENT OF THE INVENTION

[0131] The invention is illustrated below by the assays conducted by the inventors, which demonstrate the effectiveness of the compounds of the invention.

Example 1

1.1. Synthesis of Compounds 7-9 and 16-22

[0132] ##STR00007##

3-iodo-1H-indole-2-ethyl carboxylate (2)

[0133] A solution of 1H-indole 2-ethyl carboxylate (1.89 g, 10 mmol) in DMF (15 ml) is slowly added to a solution containing NIS (2.25 g, 12 mmol) in DMF (20 ml) at 0° C. The mixture is stirred at room temperature for 1 hour. Next, a solution of sodium thiosulfate at 10% (5 ml) and water (10 ml) are added. stirring at room temperature for another hour. During that time, a precipitate appears that is collected by filtration. 2.9 g (96%) of a white solid are obtained. MS (ES, positive mode): m/z 315 (96%) (M+1).sup.+. .sup.1H NMR (DMSO-d.sub.6) δ 12.25 (s, 1H), 7.78-6.88 (m, 4H), 4.38 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H).

1-benzyl-3-iodo-1H-indole-2-ethyl carboxylate (3)

[0134] NaH (26.4 mg, 1.1 mmol) is added to a solution of iodised derivative 2 (315 mg, 1 mmol) in DMF (3 ml) at 0° C. Next, benzyl bromide (223 mg, 1.3 mmol) is slowly added. The reaction mixture is stirred at room temperature for 2 hours Next, water (10 ml) is added to the mixture and is extracted with AcOEt (2×15 ml). The organic layer is dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude obtained is purified by column chromatography (AcOEt:Hex 1:10). 315 mg (78%) of a white solid are obtained. MS (ES, positive mode): m/z 405 (95%) (M+1).sup.+. .sup.1H NMR (CDCl.sub.3) δ 7.53 (d, J=8.0 Hz, 1H), 7.36-7.10 (m, 5H), 6.94 (dd, J=6.8, 1.5 Hz, 2H), 5.73 (s, 3H), 4.30 (q, J=7.1 Hz, 3H), 1.31 (t, J=7.1 Hz, 5H). .sup.13C NMR (CDCl.sub.3) δ 13.2, 48.0, 60.3, 66.8, 109.9, 120.7, 123.0, 125.1, 125.3, 126.2, 127.4, 127.6, 129.4, 136.8, 137.8, 160.1.

1-benzyl-3-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-indole-2-ethyl carboxylate (4)

[0135] 4′-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) biphenyl-2-ol (255 mg, 0.86 mmol), Pd(dppf)Cl.sub.2 (26 mg, 0.036 mmol) and, lastly, an aqueous solution (5 ml) of K.sub.2CO.sub.3 (398 mg, 2.88 mmol) are added to a solution of the iodised benzyl derivative 3 (290 mg, 0.72 mmol) in a solvent mixture of 1,4-dioxane:toluene:ethanol:water 10:1:3:6 (20 ml). The mixture is stirred at 85° C. for 3 hours in a nitrogen atmosphere. Once the reaction has concluded, the solvent is evaporated at reduced pressure. The residue is dissolved in water (10 ml) and extracted with AcOEt (3×10 ml). The organic layer is dried over anhydrous sodium sulfate, filtered and evaporated. The crude is purified by column chromatography (CH.sub.2Cl.sub.2:MeOH 50:1). 305 mg (95%) are obtained as a beige solid. MS (ES, positive mode): m/z 447 (95%) (M+1).sup.+. .sup.1H NMR (DMSO-d.sub.6) δ 9.59 (s, 1H), 8.05-6.45 (m, 17H), 5.79 (s, 2H), 4.12 (q, J=6.5 Hz, 2H), 1.00 (t, J=7.1, 6.5 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ 13.8, 47.8, 55.3, 61.0, 111.7, 116.5, 119.9, 121.3, 121.5, 123.8, 125.0, 125.7, 126.2, 126.7, 127.5, 127.8, 128.8, 128.9, 129.0, 130.0, 130.6, 132.3, 137.5, 138.1, 138.7, 154.8, 162.2.

1-benzyl-3-(4-methoxypyridine-3-yl)-1H-indole-2-ethyl carboxylate (5)

[0136] (4-methoxypyridine-3-yl)boronic acid (136 mg, 0.9 mmol), Pd(dppf)Cl.sub.2 (28 mg, 0.04 mmol) and, lastly, an aqueous solution (5 ml) of K.sub.2CO.sub.3 (409 mg, 2.96 mmol) are added to a solution of iodised derivative 3 (300 mg, 0.74 mmol) in a solvent mixture of 1,4-dioxane:toluene:ethanol:water 10:1:3:6 (20 ml). The mixture is stirred at 85° C. for 2 hours in a nitrogen atmosphere. Once the reaction has concluded, the solvent is evaporated under reduced pressure. The crude obtained is purified by column chromatography (Hexane:Ethyl Acetate 1:1). 40 mg (14%) are obtained as a white solid. MS (ES, positive mode): m/z 386 (97%) (M+1).sup.+..sup.1H NMR (DMSO-d.sub.6) δ 8.23-6.92 (m, 12H), 5.86 (s, 2H), 4.11 (c, J=7.1 Hz, 2H), 3.92 (s, 3H), 1.15 (t, J=7.1 Hz, 3H).

1-benzyl-3-(4-fluoro-3-methoxyphenyl)-1H-indole-2-ethyl carboxylate (6)

[0137] (4-fluoro-3-methoxyphenyl)boronic acid (204 mg, 1.2 mmol), Pd(dppf)Cl.sub.2 (36 mg, 0.05 mmol) and, lastly, an aqueous solution (5 ml) of K.sub.2CO.sub.3 (553 mg, 4 mmol) are added to a solution of iodised derivative 3 (405 mg, 1 mmol) in a solvent mixture of 1,4-dioxane:toluene:ethanol:water 10:1:3:6 (20 ml). The mixture is stirred at 85° C. for 2 hours in a nitrogen atmosphere. Once the reaction has concluded, the solvent is evaporated under reduced pressure. The crude obtained is purified by column chromatography (Hexane:Ethyl Acetate 4:1). 145 mg (36%) are obtained as a white solid. MS (ES, positive mode): m/z 403 (94%) (M+1).sup.+..sup.1H NMR (DMSO-d.sub.6) δ 7.36 (m, 12H), 5.88 (s, 2H), 4.16 (c, J=7.1 Hz, 2H), 3.93 (s, 3H), 1.05 (t, J=7.1 Hz, 3H).

1-benzyl-3-(2′-hydroxy-[1,1′-biphenyl]-4-il)-1H-indole-2-carboxylic acid (7)

[0138] KOH (75 mg, 1.34 mmol) is added to a solution of indole 4 (200 mg, 0.45 mmol) in a solvent mixture of ethanol:water 4:1 (20 ml). The reaction mixture is heated at 100° C. for 3 hours. The reaction is treated with 1 M of HCl solution (20 ml) and the precipitate is collected by filtration. 125 mg (66%) of a white solid are obtained. MS (ES, positive mode): m/z 419 (95%) (M+1).sup.+. .sup.1H NMR (DMSO-d.sub.6) δ 13.11 (s, 1H), 9.64 (s, 1H), 8.27-6.53 (m, 16H), 5.86 (s, 2H). .sup.13C NMR (DMSO-d.sub.6) δ 47.6, 111.6, 116.5, 119.8, 121.3, 122.9, 125.3, 126.4, 126.8, 127.4, 127.7, 128.9, 130.0, 130.6, 132.7, 137.3, 137.9, 149.4, 154.8, 163.8.

1-benzyl-3-(4-methoxypyridine-3-yl)-1H-indole-2-carboxylic acid (8)

[0139] KOH (103 mg, 1.55 mmol) is added to a solution of indole 5 (200 mg, 0.52 mmol) in a solvent mixture of ethanol:water 3:2 (20 ml). The reaction mixture is heated at 100° C. for 2 hours. The reaction volume is reduced to half and is treated with 1 M of HCl solution (20 ml). The precipitate is collected by filtration. 70 mg (37%) of a white solid are obtained. MS (ES, positive mode): m/z 358 (90%) (M+1).sup.+.

[0140] .sup.1H NMR (DMSO-d.sub.6) δ 8.24-6.95 (m, 12H), 5.89 (s, 2H), 3.93 (s, 3H).

1-benzyl-3-(4-fluoro-3-methoxyphenyl)-1H-indole-2-carboxylic acid (9)

[0141] KOH (49 mg, 0.74 mmol) is added to a solution of indole 6 (100 mg, 0.25 mmol) in a solvent mixture of ethanol:water 3:2 (20 ml). The reaction mixture is heated at 100° C. for 2 hours. The reaction volume is reduced by half and is treated with 1 M of HClsolution (20 ml). The precipitate is collected by filtration. 70 mg (74%) of a white solid are obtained. MS (ES, positive mode): m/z 375 (93%) (M+1).sup.+.

[0142] .sup.1H NMR (DMSO-d.sub.6) δ 7.32 (m, 12H), 5.84 (s, 2H), 3.91 (s, 3H).

3-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-indole-2-ethyl carboxylate (10)

[0143] 4′-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) biphenyl-2-ol (98 mg, 0.33 mmol), Pd(dppf)Cl.sub.2 (10 mg, 0.01 mmol) and, lastly, an aqueous solution (5 ml) of K.sub.2CO.sub.3 (150 mg, 1.08 mmol) are added to a solution of iodised derivative 2 (87 mg, 0.27 mmol) in a solvent mixture of 1,4-dioxane:toluene:ethanol:water 10:1:3:6 (20 ml). The mixture is stirred at 85° C. all night in a nitrogen atmosphere. Once the reaction has concluded, the solvent is evaporated at reduce pressure. The residue is dissolved in water (10 ml) and extracted with AcOEt (3×10 ml). The organic layer is dried over anhydrous sodium sulfate, filtered and evaporated under reduce pressure. The crude obtained is purified by column chromatography (CH.sub.2Cl.sub.2:MeOH 20:1). 56 mg (60%) are obtained as a beige solid. MS (ES, positive mode): m/z 357 (96%) (M+1).sup.+. .sup.1H NMR (DMSO-d.sub.6) δ 11.96 (s, 1H), 9.63 (s, 1H), 8.18-6.05 (m, 12H), 4.30 (d, J=7.1 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ 14.4, 60.7, 113.1, 116.5, 119.9, 120.9, 121.1, 122.8, 123.1, 125.5, 127.2, 127.9, 128.8, 130.4, 130.7, 132.1, 136.6, 137.5, 154.8, 161.7.

3-(3-(ethoxicarbonyl)phenyl)-1H-indole-2-ethyl carboxylate (11)

[0144] 3-(methoxycarbonyl)phenyl-boronic acid (108 mg, 0.6 mmol), Pd(dppf)Cl.sub.2 (19 mg, 0.025 mmol) and, lastly, an aqueous solution (5 ml) of K.sub.2CO.sub.3 (275 mg, 2 mmol) are added to a solution of iodised derivative 2 (157 mg, 0.5 mmol) in a solvent mixture of 1,4-dioxane:toluene:ethanol:water 10:1:3:6 (20 ml). The mixture is stirred at 85° C. for 2 hours in a nitrogen atmosphere. Once the reaction has concluded, the solvent is evaporated under reduced pressure. The crude obtained is purified by column chromatography (Hexane:Ethyl Acetate 1:1). 120 mg (70%) are obtained as a white solid. MS (ES, positive mode): m/z 323 (98%) (M+1).sup.+..sup.1H NMR (DMSO-d.sub.6) δ 12.04 (s, 1H), 8.08-7.12 (m, 8H), 4.22 (q, J=7.1 Hz, 2H), 3.90 (s, 3H), 1.16 (t, J=7.1 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ 166.6, 161.5, 136.5, 135.6, 134.4, 131.4, 129.6, 128.7, 127.9, 126.9, 125.6, 123.4, 121.4, 121.1, 120.5, 113.1, 60.8, 52.5, 14.2.

3-(3-benzyloxyphenyl)-1H-indole-2-ethyl carboxylate (12)

[0145] (3-benzyloxyphenyl)boronic acid (102 mg, 0.57 mmol), Pd(dppf)Cl.sub.2 (18 mg, 0.02 mmol) and, lastly, an aqueous solution (5 ml) of K.sub.2CO.sub.3 (265 mg, 1.92 mmol) are added to a solution of iodised derivative 2 (150 mg, 0.48 mmol) in the solvent mixture of 1,4-dioxane:toluene:ethanol:water 10:1:3:6 (20 ml). The mixture is stirred at 85° C. for 2 hours in a nitrogen atmosphere. Once the reaction has concluded, the crude obtained is purified by column chromatography (CH.sub.2Cl.sub.2:MeOH 50:1). 135 mg (77%) are obtained as a white solid. MS (ES, positive mode): m/z 371 (94%) (M+1).sup.+.

[0146] .sup.1H NMR (DMSO-d.sub.6) δ 11.91 (s, 1H), 7.55-6.97 (m, 13H), 5.16 (s, 2H), 4.23 (q, J=7.1 Hz, 3H), 1.19 (t, J=7.1 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ 161.75, 157.91, 137.32, 136.27, 134.91, 129.41, 128.90, 128.23, 127.74, 126.84, 125.73, 123.42, 122.87, 122.60, 121.12, 120.79, 117.01, 113.98, 112.92, 69.48, 60.96, 14.14.

3-(4-methoxypyridine-3-yl)-1H-indole-2-ethyl carboxylate (13)

[0147] (4-fluoro-3-methoxyphenyl)boronic acid (204 mg, 1.2 mmol), Pd(dppf)Cl2 (36 mg, 0.05 mmol) and, lastly, an aqueous solution (5 ml) of K.sub.2CO.sub.3 (553 mg, 4 mmol) are added to a solution of iodised derivative 2 (315 mg, 1 mmol) in the solvent mixture of 1,4-dioxane:toluene:ethanol:water 10:1:3:6 (20 ml). The mixture is stirred at 85° C. for 12 hours in a nitrogen atmosphere. Once the reaction has concluded, the solvent is evaporated under reduced pressure. The crude obtained is purified by column chromatography (DCM: MeOH 50:1). 300 mg (95%) are obtained as a white solid. MS (ES, positive mode): m/z 313 (93%) (M+1).sup.+. .sup.1H NMR (DMSO-d.sub.6) δ 11.91 (s, 1H), 7.61-7.24 (m, 7H), 4.26 (c, J=6.9 Hz, 2H), 3.90 (s, 3H), 1.23 (t, J=7.1, 6.6 Hz, 3H).

3-(furan-2-yl)-1H-indole-2-ethyl carboxylate (14)

[0148] 3-(methoxycarbonyl)phenyl-boronic acid (135 mg, 1.2 mmol), Pd(dppf)Cl.sub.2 (37 mg, 0.05 mmol) and, lastly, an aqueous solution (5 ml) of K.sub.2CO.sub.3 (552 mg, 4 mmol) are added to a solution of iodised derivative 2 (315 mg, 1 mmol) in the solvent mixture of 1,4-dioxane:toluene:ethanol:water 10:1:3:6 (20 ml). The mixture is stirred at 85° C. for 2 hours in a nitrogen atmosphere. Once the reaction has concluded, the solvent is evaporated at low pressure. The crude obtained is purified by column chromatography (Hexane:Ethyl Acetate 3:2). 240 mg (94%) are obtained as a white solid. MS (ES, positive mode): m/z 255 (99%) (M+1).sup.+..sup.1H NMR (DMSO-d.sub.6) δ 8.24-6.50 (m, 7H), 4.35 (c, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).

3-(4-methoxypyridine-3-yl)-1H-indole-2-ethyl carboxylate (15)

[0149] (4-methoxypyridine-3-yl)boronic acid (183 mg, 1.2 mmol), Pd(dppf)Cl2 (36 mg, 0.05 mmol) and, lastly, an aqueous solution (5 ml) of K.sub.2CO.sub.3 (553 mg, 4 mmol) are added to a solution of iodised derivative 2 (315 mg, 1 mmol) in the solvent mixture of 1,4-dioxane:toluene:ethanol:water 10:1:3:6 (20 ml). The mixture is stirred at 85° C. for 2 hours in a nitrogen atmosphere. Once the reaction has concluded, the solvent is evaporated under reduced pressure. The crude obtained is purified by column chromatography (Hexane:Ethyl Acetate 5:1). 245 mg (83%) are obtained as a white solid. MS (ES, positive mode): m/z 296 (98%) (M+1).sup.+..sup.1H NMR (DMSO-d.sub.6) 11.98 (s, 1H), 8.28-6.91 (m, 7H), 4.25 (c, J=7.1 Hz, 2H), 3.92 (s, 3H), 1.21 (t, J=7.1 Hz, 3H).

3-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-indole-2-carboxylic acid (16)

[0150] KOH (94 mg, 1.68 mmol) is added to a solution of indole 10 (200 mg, 0.56 mmol) in the solvent mixture ethanol:water 2:1 (20 ml). The reaction mixture is heated at 100° C. for 1 hour. The reaction is treated with 1 M of HCl solution (20 ml) and the precipitate is collected by filtration. 90 mg (50%) are obtained of a white solid. MS (ES, positive mode): m/z 329 (99%) (M+1).sup.+. .sup.1H NMR (DMSO-d.sub.6) δ 11.82 (s, 1H), 8.05-6.48 (m, 12H). .sup.13C NMR (DMSO-d.sub.6) δ 112.9, 116.5, 119.8, 120.6, 120.9, 122.2, 123.9, 125.1, 127.4, 127.9, 128.8, 130.4, 130.6, 132.4, 136.4, 137.2, 154.8, 163.2.

3-(3-(hydroxycarbonyl)phenyl)-1H-indole-2-carboxylic acid (17)

[0151] KOH (59 mg, 0.90 mmol) is added to a solution of indole 11 (100 mg, 0.30 mmol) in the solvent mixture of ethanol:water 2:1 (20 ml). The reaction mixture is heated at 100° C. for 2 hours. The reaction volume is reduced by half and treated with 1 M of HClsolution (20 ml). The precipitate is collected by filtration. 24 mg (99%) of a white solid are obtained. MS (ES, positive mode): m/z 281 (100%) (M+1).sup.+. .sup.1H NMR (DMSO-d.sub.6) δ 12.95 (s, 1H), 11.91 (s, 1H), 7.68-7.09 (m, 8H). .sup.13C NMR (DMSO-d.sub.6) δ 167.75, 163.00, 136.31, 135.24, 134.55, 131.57, 130.72, 128.48, 127.94, 127.13, 125.23, 124.19, 121.12, 120.90, 120.46, 113.05.

3-(3-benzyloxyphenyl)-1H-indols-2-carboxylic acid (18)

[0152] KOH (51 mg, 0.77 mmol) dissolved in water is slowly added to a solution of indole 12 (95 mg, 0.26 mmol) in ethanol (20 ml). The reaction mixture is heated at 100° C. for 3 hours. The reaction mixture is evaporated until dry, treated with 1 M of HCl solution (20 ml) and the precipitate is collected by filtration. After washing with ethyl ether, 18 mg (21%) of a white solid are obtained. MS (ES, positive mode): m/z 343 (98%) (M+1).sup.+. .sup.1H NMR (DMSO-d.sub.6) δ 12.87 (s, 1H), 11.81 (s, 1H), 7.49-6.95 (m, 13H), 5.15 (s, 2H). .sup.13C NMR (DMSO-d.sub.6) δ 163.12, 158.15, 137.61, 136.25, 135.52, 129.09, 128.81, 128.11, 127.94, 127.26, 125.06, 123.92, 123.51, 121.98, 120.86, 120.64, 117.18, 113.66, 112.88, 69.53.

3-(4-fluoro-3-methoxyphenyl)-1H-indole-2-carboxylic acid (19)

[0153] KOH (97 mg, 1.72 mmol) is added to a solution of indole 13 (180 mg, 0.57 mmol) in a solvent mixture of ethanol:water 6:4 (20 ml). The reaction mixture is heated at 100° C. for 1 hour. The reaction volume is reduced by half and treated with 1 M of HCl solution (20 ml), and removed with CH.sub.2Cl.sub.2 (50 ml). The organic layer is dried with Na.sub.2SO.sub.4, filtered and the solvent removed at low pressure. 130 mg (80%) of a white solid are obtained. MS (ES, positive mode): m/z 285 (95%) (M+1).sup.+. .sup.1H NMR (DMSO-d.sub.6) δ 12.90 (s, 1H), 11.81 (s, 1H), 7.60-7.02 (m, 7H), 3.90 (s, 3H).

3-(furan-2-yl)-1H-indole-2-carboxylic acid (20)

[0154] KOH (138 mg, 2.05 mmol) is added to a solution of indole 14 (175 mg, 0.68 mmol) in a solvent mixture of ethanol:water 3:1 (20 ml). The reaction mixture is heated at 100° C. for 2 hours. The reaction volume is reduced by half and treated with 1 M of HCl solution (20 ml). The precipitate is collected by filtration. 70 mg (45%) of a white solid are obtained. MS (ES, positive mode): m/z 227 (98%) (M+1).sup.+. .sup.1H NMR (DMSO-d.sub.6) δ 13.18 (s, 1H), 11.91 (s, 1H), 8.08-6.92 (m, 7H).

3-(4-methoxypyridine-3-yl)-1H-indole-2-carboxylic acid (21)

[0155] KOH (127 mg, 1.92 mmol) is added to a solution of indole 15 (190 mg, 0.64 mmol) in a solvent mixture of ethanol:water 15:3 (20 ml). The reaction mixture is heated at 100° C. for 3 hours. The reaction volume is reduced by half and treated with 1 M of HCl solution (20 ml). The precipitate is collected by filtration. 120 mg (68%) of a white solid are obtained. MS (ES, positive mode): m/z 268 (97%) (M+1).sup.+. .sup.1H NMR (DMSO-d.sub.6) δ 11.91 (s, 1H), 8.30 (s, 1 H), 7.49-6.93 (m, 7H), 3.87 (s, 3H).

3-(pyridine-4-yl)-1H-indole-2-carboxylic acid (22)

[0156] (4pyridinyl)boronic acid (141 mg, 1.1 mmol), Pd(dppf)Cl.sub.2 (35 mg, 0.05 mmol) and, lastly, an aqueous solution (5 ml) of K.sub.2CO.sub.3 (525 mg, 3.8 mmol) are added to a solution of iodised derivative 2 (300 mg, 0.95 mmol) in a solvent mixture of 1,4-dioxane:toluene:ethanol 10:1:3 (20 ml). The mixture is stirred at 85° C. for 16 hours in a nitrogen atmosphere. Once the reaction has concluded, the solvent is evaporated at low pressure and removed with AcOEt/H.sub.2O (2×20 ml). The aqueous layer is acidulated with 1 M of HClsolution (20 ml), giving rise to a precipitate that is isolated by filtration. 200 mg (88%) are obtained as a beige solid. MS (ES, positive mode): m/z 238 (99%) (M+1).sup.+..sup.1H NMR (DMSO-d.sub.6) δ 12.57 (s, 1 H), 9.10-8.73 (m, 2H), 8.37-8.05 (m, 2H), 7.75-7.15 (m, 4H).

Example 2

[0157] AMPK activation measurements in cultured cells by means of compounds 7 and 16.

[0158] Cell line and treatments. The cell line that was used in the treatments with the different assayed reagents was HEK293T (human embryonic kidney cells). Cells were grown in DMEM (Dulbecco's Modified Eagle's Medium) with 25 mM of glucose supplemented with 10% of inactivated fetal bovine serum, 2 mM glutamine, 100 units/ml of penicillin and 100 μg/ml of streptomycin, in a humid atmosphere at 37° C. with 5% of CO.sub.2. Cells were grown on 60 mm (p. 60) plates to obtain 70-80% of confluence. Cells were washed in Krebs Ringer buffer (KRB: NaCI 12.5 mM, CaCl.sub.2 15 mM, KH.sub.2PO.sub.4 0.5 mM, KCl 3 mM, NaHCO.sub.3 2.5 mM, MgSO.sub.40.5 mM, HEPES 10 mM pH 7.4, 95:5 O.sub.2/CO.sub.2) tempered at 37° C. and subsequently treated for 1 hour at 37° C. in a culture oven, adding the adequate quantities of 7 and 16 (5 mM stock in DMSO) dissolved in KRB/25 mM glucose to reach the final concentrations indicated in the figures. Phenformin 5 mM was used as an activation control.

[0159] Preparation of HEK293T cell extracts. After the corresponding treatments, the supernatant was removed and cells were quickly-frozen in liquid N.sub.2. The plates were processed one by one and kept in ice , firstly adding the cold lysis buffer. The composition of the buffer was as follows: Tris 10 mM pH 7.4, EDTA 15 mM pH 8.0, NaF 50 mM, Na.sub.4P.sub.2O.sub.7 15 mM, sacarose 0.6 M, 2-Mercaptoethanol 15 mM, a mixture of protease inhibitors without EDTA (Roche) and 1 mM PMSF. Cells were collected in a lysis buffer with the help of a scraper and were lysed, passing each sample through 24 G×⅝″ syringes four times. A small amount was reserved to measure the quantity of protein using the Bradford protein assay and loading buffer for electrophoresis was added to the rest and boiled for 5 min maintaining the samples at −20° C. until their use. The concentration of proteins was determined through the Bradford method using the Bio-Rad Bradford Protein Assay Reagent (BioRad).

[0160] Protein analysis by Western Blot. The protein extracts were analysed using SDS-PAGE in gels with 8% or 10% acrylamide and 1.5 mm thick. 30 pg of protein were loaded and transferred to a PVDF (Millipore) membrane for 1.5 hours at 100 V. Blockage was performed using 5% of skimmed milk in TBS-T for 1 hour at room temperature. Immunodetection was performed by incubating the primary antibody all night at 4° C. After three 10-minute washes at room temperature using TBS-T, they were incubated with their corresponding secondary antibody conjugated to HRP. After the three 10-minute washes at room temperature using TBS-T, the membranes were developed using ECL plus (Pierce) and processed using a FUJI LAS 3000 (Fujifilm) unit. The antibodies used were: anti-pAMPKαThr172, anti-AMPKβ1/β2, anti-ACC and anti-pACCser79 from the company Cell Signaling Technology (Danvers, Mass., USA) diluted 1:1000, and the HRP goat anti-rabbit secondary antibody from the company Santa Cruz Technology at a dilution of 1:5000 or 1:10000. The detection of bands with the anti-pAMPKαThr172 and anti-pACCser79 antibodies (AMPK substrate) with respect to their respective loading controls (anti-AMPKβ1/β2 and anti-ACC) was taken as an indicative of AMPK activation.

[0161] Results. Description of the Dose-Response Effect of Compounds 7 and 16.

[0162] The activation status of the AMPK complex is correlated with the levels of the phosphorylated form of the AMPKα pT172 catalytic subunit. As can be observed in the first panel of the corresponding figures, the treatment of the HEK293 cells with increasing doses of products 7 or 16 produced an increase in endogenous levels of AMPKα pT172, being an indication of the increased state of activation of the AMPK complex. The activation reached in some cases was similar to that achieved with phenformin, a compound with renowned AMPK activation capacity.

[0163] The second panel shows the analysis of the endogenous levels of AMPKβ1 that were included as a loading control to demonstrate that the increase in AMPKα pT172 levels were not due to an increase in the total levels of the enzyme complex.

[0164] The third panel shows the state of phosphorylation of the acetyl CoA carboxylase (ACC) enzyme. This enzyme is a substrate of the AMPK kinase protein, due to which an increase in AMPK activity produces an increase in the state of phosphorylation of this substrate (ACC pS79). As can be observed, the state of phosphorylation of ACC increases in parallel to the AMPKα pT172 levels.

[0165] The fourth panel indicates the total levels of ACC as a loading control, to validate that the change in ACC pS79 levels are due to the phosphorylation of the protein and not to an increase in the total levels thereof.

[0166] All these data indicate that compounds 7 and 16 are capable of inducing the activation of the AMPK complex in vivo at the indicated doses.