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
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Publication Number
US-9187440-B2
Publication Date
2015-11-17
Expiration Date
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 compounds of formula IA and pharmaceutically active salt thereof, including individual diastereoisomers or enantiomers and racemic or non-racemic mixtures. The compounds are defined by variable substituents G1, R2, R3, X, Ar, R4 and n, with a proviso excluding specific thiadiazole/piperazine compounds.
The invention also relates to synthetic schemes for preparing thiadiazole-containing piperazine and related derivatives, including conversion of amidine II into chloro-thiadiazole III, reaction of chloro-thiadiazole III with substituted piperazines or Boc-protected piperazines to produce final thiadiazole derivatives I or protected intermediates IV, and deprotection of protected piperazine intermediates followed by coupling with electrophiles of the form hal-X—Ar—(R4)n.
The resulting compounds are identified as final compounds and may be converted into pharmaceutically acceptable acid addition salts. The document also describes exemplified thiadiazole/piperazine derivatives prepared by analogous coupling from substituted thiadiazole/piperazine precursors and reports biological screening in TAU-P301L overexpressing BE-M17-derived stable cells using dose-response EC50 values.
Claims Coverage
The provided independent claims cover three inventive features: a broad structural chemical space for compounds of formula IA with stereoisomeric forms and a negative proviso, a selected group of specifically named thiadiazole/piperazine compounds, and a process for preparing compounds of formula IA by coupling and optional protection/deprotection and salt formation.
Compounds of formula IA with defined substituent variables and stereoisomer coverage
A compound of formula IA or a pharmaceutically active salt thereof, including an individual diastereoisomer or enantiomer and a racemic or non-racemic mixture thereof, wherein G1, R2, R3, X, Ar, R4, and n are defined with a proviso excluding 5-(4-(3-fuorobenzyl)piperazin-1-yl)-3-methyl-1,2,4-thiadiazole and 3-isopropyl-5-(4-(3-(trifluoromethyl)benzyl)piperazin-1-yl)-1,2,4-thiadiazole.
Selected set of specifically named thiadiazole/piperazine compounds
A compound selected from the group consisting of specifically listed thiadiazole/piperazine compounds having detailed structural substituents including piperidinyl, pyrrolidinyl, tetrahydro-pyran-4-yl, cyclohexyl, cyclopropylmethyl, alkyl, and substituted phenyl/piperazinyl components, as enumerated in the claim.
Coupling to prepare compounds of formula IA with optional protection/deprotection and optional salt formation
A process for preparing compounds of formula IA by coupling a compound of the depicted formula IV with a compound of the depicted formula containing X, Ar, and (R4)n to yield a compound of formula IA, where PG is hydrogen or a protecting group with optional deprotection before coupling, and where the resulting compounds may be converted into pharmaceutically acceptable acid addition salts.
Overall, the claim set emphasizes formula IA scaffolds with explicitly defined substituent variables and stereoisomer coverage while excluding two specific thiadiazole/piperazine compounds, a selected group of explicitly enumerated thiadiazole/piperazine derivatives, and a coupling-based process concept with optional protecting-group handling and conversion into pharmaceutically acceptable acid addition salts.
Stated Advantages
Improved metabolic stability indicated by reduced human and rat microsomal clearance (Clint) and lower lipophilicity (clogP) versus WO2007/090617.
Improved metabolic stability may increase oral bioavailability and reduce daily dose and safety risk.
Documented Applications
Generation of TAU-P301L overexpressing BE-M17-derived stable cells for use in measuring increased TAU(P301L) cytotoxicity upon retinoic acid differentiation.
Use of the BE-M17-derived TAU-P301L overexpressing stable cell model for screening inhibitors, with dose-response EC50 values reported in Table III.
Treating tauopathies characterized by cytotoxic TAU misfolding and/or aggregation.
Medicaments and therapeutic methods for Alzheimer’s disease (AD), Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, and parkinsonism linked to chromosome 17 (FTDP-17).
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