US 11,628,159 B2 · Cell-protective compounds and their use

Abstract

The present invention is directed to cell-protective, in particular, cardio- and renal-protective organic compounds, preferably to organic compounds that inhibit substrate phosphorylation by the G-protein-coupled receptor kinase 2 (GRK2, ADRBK1). Preferably, the organic compounds inhibit the GRK2-mediated phosphorylation of serine/arginine-rich splicing factor 1 (SRSF1, ASF-1, SF2) and/or phosducin for treating hypertension, heart diseases, heart dysfunction or failure and heart disease-associated pathologies, e.g. cardiomyocyte necrosis, ischemic cardiac disease and/or ischemic heart damage or ageing. Furthermore, the present invention is directed to a method for the identification of inhibitors of the (GRK2)-mediated phosphorylation of (SRSF1) and/or phosducin.

A method for treatment of heart failure in a patient, the method comprising:

administering to the patient in need of such treatment a therapeutically effective amount of a compound according to Formula (Ia):
wherein:
X is N;
a is an integer between 0 and 15;
R1 is selected from the group consisting of
(i) hydroxyl, F, Cl, Br and oxo;
(ii) linear or branched, substituted or non-substituted (C1-10)alkyl ether, (C2-10)alkenyl ether, (C2-10)alkynyl ether and (C4-10)carbocyclic ether;
(iii) linear or branched, substituted or non-substituted (C2-10)alkenyl and (C2-10)alkynyl;
(iv) substituted or non-substituted (C3-10)carbocycle;
and
(v) non-substituted indazolyl, substituted or non-substituted benzimidazolyl, and substituted or non-substituted benzodioxolyl, (C7-C10)carbo-bicycle, and substituted or non-substituted (C3-6)heterocycle having 1 to 3 heteroatoms each independently selected from N, O and S;
R2 is selected from the group consisting of
(i) hydrogen, hydroxyl, O—R14, —O—C(═O)—R14, F, C1, Br and oxo wherein R14 is selected from the group consisting of
(aa) linear or branched, substituted or non-substituted (C1-10)alkyl, (C2-10)alkenyl, and (C2-10)alkynyl;
(bb) substituted or non-substituted aromatic or non-aromatic (C3-10)carbocycle;
and
(cc) substituted or non-substituted aromatic or non-aromatic (C3-6)heterocycle having 1 to 3 heteroatoms each independently selected from N, O and S;
(ii) linear or branched, substituted or non-substituted (C1-10)alkyl, (C2-10)alkenyl, (C2-10)alkynyl, and (C3-10)carbocycle;
(iii) linear or branched, substituted or non-substituted (C1-10)alkyl ether, (C2-10)alkenyl ether, (C2-10)alkynyl ether and (C4-10)carbocyclic ether;
and
(iv) substituted or non-substituted (C3-6)heterocycle and (C7-C10)carbo- or heterobicycle having 1 to 3 heteroatoms each independently selected from N, O and S;
R3 is selected from the group consisting of
(i) hydroxyl, —O—R14, —O—C(═O)—R14, F, C1, Br and oxo, wherein R14 is selected from the group consisting of
(aa) linear or branched, substituted or non-substituted (C1-10)alkyl, (C2-10)alkenyl, and (C2-10)alkynyl;
(bb) substituted or non-substituted aromatic or non-aromatic (C3-10)-carbocycle;
and
(cc) substituted or non-substituted aromatic or non-aromatic (C3-6)heterocycle having 1 to 3 heteroatoms each independently selected from N, O and S;
(ii) linear or branched, substituted or non-substituted (C1-10)alkyl, (C2-10)alkenyl, (C2-10)alkynyl, (C3-10)carbocycle, and (C3-6)heterocycle having 1 to 3 heteroatoms each independently selected from N, O and S;
(iii) linear or branched, substituted or non-substituted (C1-10)alkyl ether, (C2-10)alkenyl ether, (C2-10)alkynyl ether and (C4-10)carbocyclic ether;
(iv)
wherein R12 is selected from the group consisting of
(aa) hydrogen, hydroxyl, non-substituted N, F, Cl and Br;
(bb) linear or branched, substituted or non-substituted (C1-10)alkyl, (C2-10)alkenyl, and (C2-10)alkynyl;
(cc) substituted or non-substituted aromatic or non-aromatic (C3-10)carbocycle;
and
(dd) substituted or non-substituted aromatic or non-aromatic (C3-6) heterocycle having 1 to 3 heteroatoms each independently selected from N, O and S;
and
(v)
wherein X is N or C, a is an integer between 0 and 15, and R13 is selected from the group consisting of
(aa) hydrogen, hydroxyl, F, Cl and Br;
(bb) linear or branched, substituted or non-substituted (C1-10)alkyl, (C2-10)alkenyl and (C2-10)alkynyl;
(cc) substituted or non-substituted (C3-6)cycloalkyl, (C7-C10)carbo- or heterobicycle and (C3-6)heterocycle having 1 to 3 heteroatoms each independently selected from N, O and S,
optionally, for R3, R13 is (C7)heterobicycle having 2 heteroatoms selected from N and S, substituted or non-substituted indazolyl, benzimidazolyl and benzodioxolyl, and indazolyl, benzimidazolyl and benzodioxolyl connected via position (5) or (6), via position (5) of the indazolyl and benzodioxolyl or position (6) of the benzimidazolyl;
and
(dd) linear or branched, substituted or non-substituted (C1-10)alkyl ether, (C2-10)alkenyl ether, (C2-10)alkynyl ether and (C4-10)carbocyclic ether;
wherein, if position (2) is sp3-hybridized, R2 is optionally (R)- or (S)-configured;
R4 is hydroxyl;
R5 is selected from the group consisting of
(i) hydrogen, hydroxyl, F, C1, and Br;
(ii) linear or branched, substituted or non-substituted (C1-10)alkyl ether, (C2-10)alkenyl ether, (C2-10)alkynyl ether and (C4-10)carbocyclic ether;
(iii) linear or branched, substituted or non-substituted (C1-10)alkyl, (C2-10)alkenyl and (C2-10)alkynyl;
(iv) substituted or non-substituted (C3-10)carbocycle;
and
(v) (C3-6)heterocycle having 1 to 3 heteroatoms each independently selected from N, O and S, substituted or non-substituted imidazolyl and pyrazolyl, and imidazolyl and pyrazolyl connected via imidazolyl-/pyrazolyl-position-(1)-nitrogen to the rings of Formula (Ia);
wherein, if position (5) of the ring of Formula (Ia) is sp3-hybridized, R5 is optionally (S)- or (R)-configured;
wherein one or more of R2, R3, R4, and R5 are either directly attached to the rings of Formulas (Ia) or are attached to a linker between R2, R3, R4, and R5 and the rings of Formulas (Ia), wherein the linker is selected from the group consisting of linear or branched, substituted or non-substituted (C1-10)alkyl ether, (C2-10) alkenyl ether, (C2-10)alkynyl ether, (C4-10)carbocyclic ether, linear or branched, substituted or non-substituted (C1-10)alkyl, (C2-10)alkenyl and (C2-10)alkynyl;
and pharmaceutically acceptable salts.

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Cell-protective compounds and their use

Life of this patent

Cell-protective compounds and their use

Life of this patent

Abstract

Claims17