NOVEL COMPOUNDS AS DUAL INHIBITORS OF PHOSPHODIESTERASES AND HISTONE DEACETYLASES

摘要

It relates to certain compounds having a polycyclic structure and a hydroxamic acid moiety, wherein the polycyclic structure comprises at least three ring systems, wherein one ring system is a polycyclic ring system comprising from 2 to 4 rings; at least one ring is an aromatic ring; and wherein the structure comprises at least 3 nitrogen atoms and 1 oxygen atom. It also relates to a process for their preparation, as well as to pharmaceutical compositions containing them, and to their use in medicine, in particular in the treatment and/or prevention of neurological disorders coursing with a cognition deficit or impairment, or neurodegenerative diseases. wherein B1 is a radical selected from the group consisting of formula (A″), formula (B″), formula (C″), and formula (D″):;

主权项

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or any stereoisomer or mixtures thereof, either of the compound of formula (I) or of any of its pharmaceutically acceptable salts, wherein B1 is a radical selected from the group consisting of formula (A″), formula (B″), formula (C″), and formula (D″): p, n and r are independently 0 or 1; R1 and R2 are independently selected from the group consisting of H; saturated or unsaturated (C1-C7)alkyl optionally substituted with one or more halogen atoms; and a 3- to 7-membered carbocyclic or heterocyclic monocyclic ring, which is saturated or partially unsaturated or aromatic, and which is optionally substituted with one or more substituents selected from halogen and (C1-C3)alkyl; Z1 is a biradical selected from the group consisting of a formula (E), formula (F″), formula (G′), formula (H′), formula (J′), and formula (K): Z2 is selected from the group consisting of —Z5—; —Z5-Cy4-; —Z5—Cy4-Z5—; and -Cy4-; Z3 and each Z5 are independently a biradical of a saturated or unsaturated (C1-C6)alkyl optionally substituted with one or more halogen atoms; Z4 is a biradical of a saturated or unsaturated (C1-C6)alkyl optionally substituted with one or more substituents selected from halogen, OH, and —O(C1-C3)alkyl optionally substituted with one or more halogen atoms; or alternatively Z4 is —CR11R12—, wherein R11 and R12 taken together with the carbon they are attached to form C═O or a 3- to 7-membered carbocyclic or heterocyclic monocyclic ring, which is saturated or partially unsaturated, and which is optionally substituted with one or more halogen atoms or (C1-C3)alkyl optionally substituted with one or more halogen atoms; q and m are independently 0 or 1; Cy1, Cy3 and Cy4 are independently phenyl or a 3- to 7-membered carbocyclic or heterocyclic monocyclic ring, which is saturated or partially unsaturated or aromatic, and which is optionally substituted with one or more R3 groups; or alternatively Cy1 is a 3- to 7-membered saturated or partially unsaturated heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, wherein Cy1 is optionally substituted with one or more R3 groups; Cy2 is a N-attached 3- to 7-membered saturated or partially unsaturated heterocyclic monocyclic ring, which is optionally fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, wherein Cy2 is optionally substituted with one or more R3 groups; R3 is selected from halogen; saturated or unsaturated (C1-C7)alkyl optionally substituted with one or more halogen atoms; saturated or unsaturated —O(C1-C7)alkyl optionally substituted with one or more halogen atoms; and a 3- to 7-membered carbocyclic or heterocyclic monocyclic ring, which is saturated or partially unsaturated or aromatic, and which is optionally substituted with one or more substituents selected from the group consisting of halogen and (C1-C6)alkyl optionally substituted with one or more halogen atoms; R4 and R10 are independently H or (C1-C6)alkyl optionally substituted with one or more halogen atoms; and wherein in any heterocyclic ring one or more of the ring members are selected from NH, N, O, and S; wherein in all saturated or partially unsaturated rings one or two members of the rings are optionally C(═O) and/or C(═NH) and/or C[═N(C1-C4)alkyl], wherein saturated alkyl refers to a linear or branched hydrocarbon chain which contains only single bonds; and unsaturated alkyl refers to a linear or branched hydrocarbon chain which contains one or two double bonds and/or one or two triple bonds; wherein in any alkyl group one or two chain members selected from CH2 or CH are optionally replaced by chain members independently selected from N, NR4, O, C(═O), C(═O)NR4, NR4C(═O), and S; and with the condition that the moiety (L1) of the formula (A″), formula (B″), and formula (C″), and the moiety (L2) of the formula (D″) have a chain length comprised from 1 to 20 atoms.