Compounds for the treatment or alleviation of disorders associated with Tau aggregates

Patent metadata

Field	Value
Publication number	US-12202840-B2
Application number	US-201917056270-A
Country	US
Kind code	B2
Filing date	May 20, 2019
Priority date	Jun 4, 2018
Publication date	Jan 21, 2025
Grant date	Jan 21, 2025

Abstract

The present invention relates to novel compounds that can be employed in the treatment, alleviation or prevention of a group of disorders and abnormalities associated with Tau (Tubulin associated unit) protein aggregates including, but not limited to, Neurofibrillary Tangles (NFTs), such as Alzheimer's disease (AD).

First claim

The invention claimed is:

1. A compound of formula (I):

and all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof;
wherein
B is selected from the group consisting of O and NR a ;
E is N and V is S, E is S and V is N, E is N and V is O, or E is O and V is N;
X is selected from the group consisting of N—R 6 and HC—N(Me) 2 ;
R is independently selected from the group consisting of

and

R a is selected from the group consisting of H and alkyl; and
R 6 is alkyl.

2. The compound according to claim 1 , which is a compound of formula (Ia):

wherein B, R, and X are as defined in claim 1 .

3. The compound according to claim 2 , which is a compound of formula (Ib):

wherein B is selected from the group consisting of O and NR a ;
R is independently selected from the group consisting of

and

and
R 6 is alkyl.

4. The compound according to claim 2 , which is a compound of formula (Ic):

wherein B is selected from the group consisting of O and NR a ; and
R is independently selected from the group consisting of

and

5. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier or excipient.

6. A method of treating or alleviating a disorder caused by Tau protein aggregates, the method comprising administering an effective amount of a compound as defined in claim 1 to a patient in need thereof.

7. The method according to claim 6 , wherein the disorder is selected from Alzheimer's disease (AD), familial AD, Primary Age-Related Tauopathy (PART), Creutzfeldt-Jacob disease, dementia pugilistica, Down's Syndrome, Gerstmann-Sträussler-Scheinker disease (GSS), inclusion-body myositis, prion protein cerebral amyloid angiopathy, Parkinsonism-dementia complex of Guam, non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain disease, diffuse neurofibrillary tangles with calcification, Hallervorden-Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallido-ponto-nigral degeneration, progressive subcortical gliosis, subacute sclerosing panencephalitis, tangle predominant dementia, postencephalitic Parkinsonism, myotonic dystrophy, subacute sclerosis panencephalopathy, mutations in LRRK2, familial British dementia, familial Danish dementia, frontotemporal lobar degenerations, Guadeloupean Parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy, Lewy body dementia (LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, HIV-related dementia, adult onset diabetes, senile cardiac amyloidosis, glaucoma, ischemic stroke, psychosis in AD and Huntington's disease.

8. The method according to claim 7 , wherein the disorder is selected from the group consisting of Alzheimer's disease (AD), corticobasal degeneration (CBD), Pick's disease (PiD), and progressive supranuclear palsy (PSP).

9. The method according to claim 7 , wherein the frontotemporal lobar degeneration is selected from the group consisting of traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), corticobasal degeneration (CBD), frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Pick's disease (PiD), progressive supranuclear palsy (PSP), and chronic traumatic encephalopathy (CTE).

10. A mixture comprising a compound as defined in claim 1 and at least one further biologically active compound selected from a therapeutic agent different from the compound as defined in claim 1 , a pharmaceutically acceptable carrier, a diluent and an excipient.

11. The mixture according to claim 10 , wherein the further biologically active compound is a compound used in the treatment of amyloidosis.

12. The mixture according to claim 10 , wherein the further biologically active compound is selected from the group consisting of compounds against oxidative stress, anti-apoptotic compounds, metal chelators, inhibitors of DNA repair, α-secretase activators, β- and γ-secretase inhibitors, Tau proteins, neurotransmitters, β-sheet breakers, attractants for amyloid beta clearing/depleting cellular components, inhibitors of N-terminal truncated amyloid beta, anti-inflammatory molecules, cholinesterase inhibitors (ChEIs), M1 agonists, an antibody, any functionally equivalent antibody or functional parts thereof of an antibody, and a vaccine.

13. The mixture according to claim 12 ,
wherein the inhibitor of DNA repair is selected from the group consisting of pirenzepine and metabolites, 3-amino-1-propanesulfonic acid (3APS), and 1,3-propanedisulfonate (1,3PDS);
wherein the inhibitor of N-terminal truncated amyloid beta is pyroglutamated amyloid beta 3-42; and
wherein the cholinesterase inhibitor is selected from the group consisting of tacrine, rivastigmine, donepezil, and galantamine.

Assignees

• Ac Immune Sa

Inventors

• Nampally Sreenivasachary
• Gabellieri Emanuele
• Molette Jerome
• Kroth Heiko
• Boudou Cedric

Classifications

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D491/147

  the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title