Bicyclic compounds for diagnosis and therapy
Inventors
MOLETTE, Jérôme • Gabellieri, Emanuele • Darmency, Vincent
Assignees
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Publication Number
US-11623931-B2
Publication Date
2023-04-11
Expiration Date
Abstract
The present invention relates to novel compounds that can be employed in the diagnosis, monitoring of disease progression or monitoring of drug activity, of a group of disorders and abnormalities associated with alpha-synuclein (α-synuclein, A-synuclein, aSynuclein, A-syn, α-syn, aSyn) aggregates including, but not limited to, Lewy bodies and/or Lewy neurites, such as Parkinson's disease. The instant compounds are particularly useful in determining a predisposition to such a disorder, monitoring residual disorder, or predicting the responsiveness of a patient who is suffering from such a disorder to the treatment with a certain medicament. The present compounds can also be used to treat, alleviate or prevent a disorder or abnormality associated with alpha-synuclein aggregates.
Core Innovation
The patent provides a compound of formula (IIa) and all derivatives, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof. The compounds can be optionally detectably labeled by replacing any atom at any position with a label, where the label is a radionuclide, a positron emitter, or a gamma emitter. The labeling capability is described as being enabled by substituent selections and by optionally substituting the compound with a leaving group (LG) that is capable of being replaced with the radionuclide, positron emitter, or gamma emitter.
The chemical scope includes variable groups R_D and R_E, together with related substituent variables such as R_f, R_10, R_11, n, and in some descriptions D, V2, Z2, and E. R_D is independently selected from halogen, —OH, —O-alkyl, and hydrogen, while R_E is independently selected from hydrogen, —(CH2CH2O)n—R_f, —(CH2CH2O)n—(CH2CH2)n—R_d, alkyl, carbocyclyl, heterocyclyl, and other listed functional groups, with optional substitution and adjacent R_E groups optionally taken together to form a 5- to 8-membered ring containing carbon atoms and optionally one or more heteroatoms selected from O, S, or N.
The disclosed scope further includes optional leaving-group substitution at any available position, such that the compound is capable of being detectably labeled upon replacement of the LG with a radionuclide, a positron emitter, or a gamma emitter. The described material frames these labeled compounds in diagnostic and imaging contexts, including PET imaging and diagnostic imaging data collection, and it includes characterization of example compounds by 1H NMR and MS.
Claims Coverage
The consolidated claim coverage centers on one broad independent claim family for formula (IIa) compounds with optional detectable labeling by radionuclides, positron emitters, or gamma emitters, including leaving-group-enabled radiolabeling. Across the inputs, the claim scope is defined by four main inventive features: formula (IIa) labeling, optional LG replacement, defined substituent variability, and dependent isotope/composition/mixture refinements.
Formula (IIa) with optional detectable labeling
A compound of formula (IIa) and related forms, including derivatives, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs, wherein the compound can be optionally detectably labeled by replacing any atom at any position with a radionuclide, a positron emitter, or a gamma emitter.
Leaving-group enabled radiolabeling
The compound is optionally substituted by a leaving group (LG) at any available position, wherein the compound is capable of being detectably labeled upon replacement of the LG with a radionuclide, a positron emitter, or a gamma emitter.
Defined substituent scope for R_D and R_E
For each occurrence, R_D is independently selected from halogen, —OH, —O-alkyl, and hydrogen; R_E is independently selected from hydrogen, —(CH2CH2O)n—R_f, —(CH2CH2O)n—(CH2CH2)n—R_d, alkyl, carbocyclyl, heterocyclyl, and other listed functional groups, with optional substitution and optional formation of a 5- to 8-membered ring from adjacent R_E groups containing carbon atoms and optionally one or more heteroatoms selected from O, S, or N.
Dependent label, composition, and mixture refinements
Dependent claims narrow the leaving-group options, enumerate detectable label isotopes including 2H, 3H, 18F, 123I, 124I, 125I, 131I, 11C, 13N, 15O, and 77Br, and add diagnostic composition and mixture embodiments, including a diagnostic composition with pharmaceutically acceptable carrier, diluent, adjuvant, and/or excipient, and a mixture containing the detectably labeled compound and at least one additional beta or tau imaging agent.
The claims cover formula (IIa) compounds that are optionally detectably labeled through direct atom replacement or LG replacement, with the chemical scope controlled by defined substituent classes and ring-forming options. Dependent claims further specify label isotopes, diagnostic compositions, and mixtures with additional beta or tau imaging agents.
Stated Advantages
Provides a compound that can be optionally detectably labeled with a radionuclide, a positron emitter, or a gamma emitter.
Enables detectably labeling upon replacement of a leaving group (LG) with a radionuclide, a positron emitter, or a gamma emitter.
Documented Applications
Diagnostic composition comprising a detectably labeled compound together with pharmaceutically acceptable carrier, diluent, adjuvant, and/or excipient.
Mixtures containing a detectably labeled compound and at least one additional beta or tau imaging agent different from the detectably labeled compound.
PET imaging of alpha-synuclein aggregates (Lewy bodies, Lewy neurites) and diagnostic use for synucleinopathies such as Parkinson’s disease.
Diagnostic imaging and diagnostic composition use, including mixtures with an additional beta or tau imaging agent.
Imaging and diagnostic/imaging data collection for disorders associated with alpha-synuclein aggregates.
PET imaging using detectably labeled compounds with radionuclides or positron emitters including fluorine-18 (18F).
Diagnosis of synucleinopathies by imaging alpha-synuclein aggregates including Lewy bodies and Lewy neurites.
Monitoring disease progression.
Drug activity monitoring.
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