Compound suitable for the treatment of synucleopathies
Inventors
Masliah, Eliezer • Rockenstein, Edward M. • Wrasidlo, Wolfgang • Tsigelny, Igor Flint
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-8846682-B2
Publication Date
2014-09-30
Expiration Date
Abstract
The present invention relates to a compound of formula (I): Wherein R1 is a substituted or unsubstituted aromatic hetero- or homocyclic or a substituted or unsubstituted alicyclic hetero- or homocyclic group; R2 is an alkyl group with 1 to 18 carbon atoms or a substituted or unsubstituted cycloalkyl or aryl group; R3 is a substituted or unsubstituted aromatic hetero- or homocyclic or a substituted or unsubstituted alicyclic hetero- or homocyclic group; L is a single bond, an alkyl group having 1 to 6 carbon atoms, NHCO, O, S, NHCONH or NHCOO; X, Y and Z are independently O, N, NH, S or CH; W is a single bond or an alkyl group having from 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of said compound or salt.
Core Innovation
The invention relates to compounds of formula (I) and formula (Ia), as well as pharmaceutically acceptable salts and pharmaceutically acceptable solvates of said compounds. The compounds are defined by structural options for R1, R2, R3, L, X, Y, Z, and W, where L can be NHCO, O, S, NHCONH or NHCOO, and where X, Y and Z are independently O, N, NH, S or CH. The selection of substituent groups and linkage options specifies the chemical space covered by the invention.
The invention relates to therapeutic compounds for synucleopathies, including Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, Parkinson’s disease dementia, multiple system atrophy, Lewy body disease, Pick’s disease, Down’s syndrome, Hallervorden-Spatz syndrome, and amylotrophic lateral sclerosis. The compounds are based on a heteroaromatic–urea/amide scaffold and are designed to selectively bind misfolded alpha-synuclein. The disclosure includes pharmaceutical preparations comprising the compounds, together with pharmaceutically acceptable excipients and optional salt/solvate forms.
The compounds are described as inhibiting the formation of propagating dimers and toxic SYN oligomers, including pentamers and heptamers. The scaffold design specifies a central —NH—CO— motif together with a 5-membered heteroaromatic ring, and the preferred urea linker (L=NHCONH) is selected for stability. The document also identifies preferred compound sets including compound A, compound B, compound C, compound D, and compound E/F.
Claims Coverage
The provided independent claims define a family of compounds by a general Formula (I) specifying the allowed structural options for R1, R2, R3, L, X, Y, Z, and W, and explicitly include pharmaceutically acceptable salts and solvates. A further independent claim covers selecting a compound from a defined group and includes characterization by reference to a specific chemical structure shown in accompanying images/files.
Compound of formula (I)
A compound of formula (I) in which R1 is selected from a group consisting of defined R1 options; R2 is selected as an alkyl group with 1 to 18 carbon atoms or a substituted or unsubstituted cycloalkyl or aryl group; R3 is defined in the claim; L is NHCO, O, S, NHCONH or NHCOO; X, Y and Z are independently O, N, NH, S or CH; and W is a single bond or an alkyl group having from 1 to 6 carbon atoms.
Pharmaceutically acceptable salt or solvate
The compound of formula (I) is provided as a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate of said compound or salt.
Compound selected from a defined group
A compound selected from a defined group, with the selected compound further characterized by reference to a specific chemical structure shown in accompanying images/files.
The claim coverage centers on a Formula (I) chemical scaffold with defined substituent options for R1, R2, R3, L, X, Y, Z, and W, together with pharmaceutically acceptable salts and solvates. It also includes a selection-type claim that characterizes a compound by the specific chemical structure shown in accompanying embedded images/files.
Stated Advantages
Selectively binds misfolded alpha-synuclein.
Blocks formation of propagating dimers.
Inhibits formation of toxic SYN oligomers, including pentamers and heptamers.
The preferred urea linker (L=NHCONH) is selected for stability.
Documented Applications
Therapeutic treatment for synucleopathies, including Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, Parkinson’s disease dementia, multiple system atrophy, Lewy body disease, Pick’s disease, Down’s syndrome, Hallervorden-Spatz syndrome, and amylotrophic lateral sclerosis.
Treating synucleopathies, including alpha-synucleopathies.
Treating Parkinson's Disease.
Treating Parkinson's Disease with Dementia.
Treating Dementia with Lewy bodies.
Treating Pick's Disease.
Treating Down's Syndrome.
Treating Multiple System Atrophy.
Treating Hallervorden-Spatz Syndrome.
Treating Amylotrophic Lateral Sclerosis (ALS).
Interested in licensing this patent?