Piperazine thiazole derivatives useful in the treatment of tauopathies such as Alzheimer's disease

Inventors

Griffioen, Gerard • Cecere, Giuseppe • Nettekoven, Matthias • Princen, Katrien • Ratni, Hasane • Rogers-Evans, Mark • Vifian, Walter

Assignees

reMYND NV

Abstract

The present invention relates to a compound of formula (IA), wherein G1 is lower alkyl; lower alkyl substituted by one or more halogens; cycloalkyl; tetrahydropyran-4-yl; phenethyl; phenethyl substituted by one or more halogens; phenoxymethyl; phenoxymethyl substituted by one or more halogens; benzyloxyethyl; benzyloxy-ethyl substituted by one or more halogens; or is —NR2R3; R2 is hydrogen or lower alkyl; R3 is lower alkyl; tetrahydropyran-4-yl; —CH2-cycloalkyl; or cycloalkyl optionally substituted by lower alkyl substituted by one or more halogens; or R2 and R3 form together with the N-atom to which they are attached a heterocycloalkyl group with 4 or 5 carbon atoms, which is optionally substituted by one or more substituents selected from halogen; or lower alkyl substituted by one or more halogens; X is —CH2— or —(CH2)2—; Ar is phenyl or pyridinyl; R4 is halogen; lower alkyl; lower alkyl substituted by one or more halogens; or lower alkoxy; n is 1 or 2; or to a pharmaceutically active salt thereof, to a stereoisomeric form, including an individual diastereoisomer or enantiomer of the compound of formula (IA) as well as to a racemic or non-racemic mixture thereof. The present invention also relates to the use of a compound of formula (IA) for treating certain neurodegenerative disorders characterized by cytotoxic TAU misfolding and/or aggregation.

Core Innovation

The invention relates to piperazine thiazole derivatives defined as compounds of formula IA and formula I, including stereoisomeric forms, pharmaceutically active salts, and racemic or non-racemic mixtures. The compounds are characterized by structural variables G1, R2, R3, X, Ar, R4, and n, with explicit substituent and connectivity constraints defining permitted structures, and a proviso excluding named thiadiazole-piperazine compounds.

The invention addresses tauopathies by targeting TAU misfolding and/or aggregation, and thereby cytotoxicity associated with TAU. The document frames a therapeutic approach for Alzheimer's disease and related tau-related neurodegenerative disorders through administration of an effective amount of a compound of formula IA or a pharmaceutically active salt thereof, with the chemical definition tied to the intended biological effects described in the treatment-related claims.

A stated motivation in the document is a pharmacokinetic improvement compared to WO2007/090617, where compounds show markedly reduced human microsomal intrinsic clearance and reduced lipophilicity. The document indicates that these properties are used to aim for improved oral bioavailability and safety, and example compound lists and comparative metabolic stability and lipophilicity data are used to support this motivation.

Claims Coverage

The document contains three independent claims, covering treatment of Alzheimer's disease, reduction of TAU-induced cytotoxicity, and reduction of human neuronal cell death and/or degeneration. All independent claims share the same core chemical scope defined by formula IA with stereoisomeric forms and a proviso excluding two named thiadiazole-piperazine compounds, with the claims differing in biological endpoint and cellular context.

Across the three independent claims, the central claim coverage is administration or contact of formula IA piperazine thiazole derivatives, including stereoisomeric forms and pharmaceutically active salts, with a shared structural framework and shared exclusion of two named thiadiazole-piperazine compounds.

Stated Advantages

Documented Applications