New heteroaryl amide derivatives as selective inhibitors of histone deacetylases 1 and 2 (hdac1-2)

Abstract

The present invention relates to novel heteroaryl amide derivatives of formula (I), as selective inhibitors of histone deacetylase 1 and 2 (hdac1-2), to methods for the production of same, to pharmaceutical compositions comprising these compounds, and to the use of said compounds for the production of a medicament for the treatment of pathological conditions or diseases that can be improved by means of the inhibition of the activity of histone deacetylase class I, particularly HDAC1 and HDAC2, such as cancer, neurodegenerative diseases, infectious diseases, inflammatory diseases, heart failureand cardiac hypertrophy, diabetes, polycystic kidney disease, sickle cell disease and beta-thalassemia disease, and to methods for the treatment of the diseases mentioned above.

Description

technical field

[0001] The present invention relates to novel heteroarylamide derivatives as selective inhibitors of class I histone deacetylases of at least one enzyme selected from HDAC1 and HDAC2.

[0002] Other objects of the present invention are to provide methods for the preparation of these compounds; pharmaceutical compositions comprising an effective amount of these compounds; compounds for the treatment of pathological conditions, disorders or diseases which can be achieved by inhibiting at least one member selected from HDAC1 and HDAC2 The activity of the enzyme histone deacetylase class I is improved, such as cancer, neurodegenerative diseases, infectious diseases, inflammatory diseases, heart failure and cardiac hypertrophy, diabetes, polycystic kidney disease, sickle cell disease and beta - Thalassemia disease. Background technique

[0003] Histone deacetylases (HDACs) catalyze the removal of acetyl groups from histones (proteins that organize and regulate ch...

Examples

Embodiment 1

[0225] To a solution of Intermediate 5 (310 mg) in ethanol (20 ml) and ethyl acetate (35 ml) was added Pd / C (10%) (46 mg, 15% (w / w)) and the reaction was stirred under hydrogen overnight. After completion of the reaction as monitored by TLC, the reaction mixture was filtered through celite and evaporated to a residue. The residue was purified by preparative HPLC to obtain Example 1 as an off-white solid (20 mg, 10% yield).

[0226] 1 H-NMR (400MHz, DMSO-d 6 ):δ=10.25(br,s,1H),8.80(d,J=4.4Hz,1H),8.15(d,J=11.6Hz,1H),7.955(d,J=7.2Hz,2H),7.68 (d, J=8.0Hz, 1H), 7.42(t, J=7.6Hz, 2H), 7.31(m, 2H), 6.92(d, J=9.2Hz, 1H), 5.14(br,s, 2H) , 3.65 (t, J = 4.8Hz, 4H), 2.40 (t, J = 4.8Hz, 4H), 2.22 (s, 3H).

[0227] HPLC-MS: Rt 11.120m / z 389.6 (MH + ).

[0228] The following examples were synthesized using the procedure described in Scheme 6, starting from the corresponding pyridin-2-amine and nicotinic acid derivatives.

Embodiment 2

[0229] Example 2: N-(3-amino-6-phenylpyridin-2-yl)nicotinamide

[0230] 1 H-NMR (400MHz, DMSO-d 6 ):δ=10.60(s,1H),9.18(s,1H),8.77(dd,J=6.0,1.2Hz,1H),8.37(d,J=8.0Hz,1H),7.94(d,J= 7.6Hz, 2H), 7.71(d, J=8.4Hz, 1H), 7.58(m, 1H), 7.42(t, J=7.6Hz, H), 7.31(m, 2H), 5.29(br s, 2H ).

[0231] HPLC-MS: Rt 9.891m / z 291.0 (MH + ).

Embodiment 3

[0232] Example 3: N-(3-amino-6-(4-fluorophenyl)pyridin-2-yl)nicotinamide

[0233] 1 H-NMR (400MHz, DMSO-d 6)δ=10.59(s,1H),9.17(d,J=2.0Hz,1H),8.77(dd,J=6.8,1.6Hz,1H),8.37(m,1H),7.98(m,2H), 7.69 (d, J=8.4Hz, 1H), 7.58 (m, 1H), 7.26 (m, 3H), 5.29 (br, s, 2H).

[0234] HPLC-MS: Rt 10.590m / z 309.0 (MH + ).

technical field

[0001] The present invention relates to novel heteroarylamide derivatives as selective inhibitors of class I histone deacetylases of at least one enzyme selected from HDAC1 and HDAC2.

[0002] Other objects of the present invention are to provide methods for the preparation of these compounds; pharmaceutical compositions comprising an effective amount of these compounds; compounds for the treatment of pathological conditions, disorders or diseases which can be achieved by inhibiting at least one member selected from HDAC1 and HDAC2 The activity of the enzyme histone deacetylase class I is improved, such as cancer, neurodegenerative diseases, infectious diseases, inflammatory diseases, heart failure and cardiac hypertrophy, diabetes, polycystic kidney disease, sickle cell disease and beta - Thalassemia disease. Background technique

[0003] Histone deacetylases (HDACs) catalyze the removal of acetyl groups from histones (proteins that organize and regulate ch...

Examples

Embodiment 1

[0225] To a solution of Intermediate 5 (310 mg) in ethanol (20 ml) and ethyl acetate (35 ml) was added Pd / C (10%) (46 mg, 15% (w / w)) and the reaction was stirred under hydrogen overnight. After completion of the reaction as monitored by TLC, the reaction mixture was filtered through celite and evaporated to a residue. The residue was purified by preparative HPLC to obtain Example 1 as an off-white solid (20 mg, 10% yield).

[0226] 1 H-NMR (400MHz, DMSO-d 6 ):δ=10.25(br,s,1H),8.80(d,J=4.4Hz,1H),8.15(d,J=11.6Hz,1H),7.955(d,J=7.2Hz,2H),7.68 (d, J=8.0Hz, 1H), 7.42(t, J=7.6Hz, 2H), 7.31(m, 2H), 6.92(d, J=9.2Hz, 1H), 5.14(br,s, 2H) , 3.65 (t, J = 4.8Hz, 4H), 2.40 (t, J = 4.8Hz, 4H), 2.22 (s, 3H).

[0227] HPLC-MS: Rt 11.120m / z 389.6 (MH + ).

[0228] The following examples were synthesized using the procedure described in Scheme 6, starting from the corresponding pyridin-2-amine and nicotinic acid derivatives.

Embodiment 2

[0229] Example 2: N-(3-amino-6-phenylpyridin-2-yl)nicotinamide

[0230] 1 H-NMR (400MHz, DMSO-d 6 ):δ=10.60(s,1H),9.18(s,1H),8.77(dd,J=6.0,1.2Hz,1H),8.37(d,J=8.0Hz,1H),7.94(d,J= 7.6Hz, 2H), 7.71(d, J=8.4Hz, 1H), 7.58(m, 1H), 7.42(t, J=7.6Hz, H), 7.31(m, 2H), 5.29(br s, 2H ).

[0231] HPLC-MS: Rt 9.891m / z 291.0 (MH + ).

Embodiment 3

[0232] Example 3: N-(3-amino-6-(4-fluorophenyl)pyridin-2-yl)nicotinamide

[0233] 1 H-NMR (400MHz, DMSO-d 6)δ=10.59(s,1H),9.17(d,J=2.0Hz,1H),8.77(dd,J=6.8,1.6Hz,1H),8.37(m,1H),7.98(m,2H), 7.69 (d, J=8.4Hz, 1H), 7.58 (m, 1H), 7.26 (m, 3H), 5.29 (br, s, 2H).

[0234] HPLC-MS: Rt 10.590m / z 309.0 (MH + ).

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