Gamma-carboline compounds for the detection of Tau aggregates

Patent metadata

Field	Value
Publication number	US-11306089-B2
Application number	US-201916964952-A
Country	US
Kind code	B2
Filing date	Jan 22, 2019
Priority date	Jan 24, 2018
Publication date	Apr 19, 2022
Grant date	Apr 19, 2022

Abstract

The present invention relates to novel compounds of the formula (II) and formula (III)that can be employed in the selective Tau detection of disorders and abnormalities associated with Tau aggregates such as Alzheimer's disease and other tauopathies using Positron Emission Tomography (PET) Imaging.

First claim

The invention claimed is:

1. A compound of the formula (II)

as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof;
wherein R 1 is selected from the group consisting of 18 F, F and LG;
R 2 is H or PG;
PG is a protecting group;
LG is a leaving group,
wherein the hydrogen in formula II are independently selected from 1 H, 2 H and 3 H.

2. The compound according to claim 1 , which is

3. A compound of the formula (III)

as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof;
wherein
R 1 is selected from the group consisting of 18 F, F and LG;
R 2 is H or PG;
PG is a protecting group;
LG is a leaving group,
wherein the hydrogen in the formula III are independently selected from 1 H, 2 H and 3 H.

4. The compound according to claim 3 , which is

5. The compound according to claim 1 , wherein R 1 is 18 F and R 2 is H, R 1 is F and R 2 is H, or R 1 is LG and R 2 is H or PG.

6. The compound according to claim 1 , wherein LG is nitro, halogen or trimethyl ammonium.

7. The compound according to claim 1 , wherein PG is tert-butyloxycarbonyl (BOC), triphenylmethyl (Trityl) or dimethoxytrityl (DMT).

8. The compound according to claim 1 , wherein R 1 is 18 F and/or the compound contains at least one 3 H.

9. A diagnostic composition comprising a compound as defined in claim 8 and optionally a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

10. A method of imaging Tau aggregates by positron emission tomography, comprising administering a diagnostically effective amount of a compound as defined in claim 8 to a patient and imaging Tau aggregates in the patient.

11. A method of diagnosing a disorder associated with Tau aggregates or a tauopathy by positron emission tomography, comprising administering a diagnostically effective amount of a compound as defined in claim 8 to a patient and imaging Tau aggregates in the patient.

12. The method according to claim 11 , wherein the disorder is selected from Alzheimer's disease (AD), familial AD, Creutzfeldt-Jacob disease, dementia pugilistica, Down's Syndrome, Gerstmann-Sträussler-Scheinker disease, inclusion-body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis, Parkinsonism-dementia complex of Guam, non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain disease, corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with Parkinsonism linked to chromosome 17, Hallervorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, pallido-ponto-nigral degeneration, Pick's disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle only dementia, postencephalitic Parkinsonism, myotonic dystrophy, Tau panencephalopathy, AD-like with astrocytes, GSS with Tau, mutations in LRRK2, chronic traumatic encephalopathy, familial British dementia, familial Danish dementia, frontotemporal lobar degeneration, Guadeloupean Parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, traumatic stress syndrome, epilepsy, Lewy body dementia (LBD), hereditary cerebral hemorrhage with amyloidosis of the Dutch type, mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, atypical parkinsonism, HIV-related dementia, adult onset diabetes, senile cardiac amyloidosis, endocrine tumors, glaucoma, ocular amyloidosis, primary retinal degeneration, macular degeneration, optic nerve drusen, optic neuropathy, optic neuritis, lattice dystrophy, Huntington's disease, ischemic stroke and psychosis in AD.

13. An in vitro screening tool, which comprises a compound according to claim 5 wherein R 1 is F and R 2 is H.

14. A method of preparing a compound as defined in claim 5 wherein R 1 is 18 F and R 2 is H, the method comprising reacting a compound as defined in claim 5 wherein R 1 is LG and R 2 is H or PG with a [ 18 F]fluorinating agent, wherein the method further comprises cleaving of the protecting group PG, if present.

15. A kit for preparing a radiopharmaceutical preparation, said kit comprising a sealed vial containing a predetermined quantity of a compound as defined in claim 5 , wherein R 1 is LG and R 2 is H or PG.

16. A method of collecting data for the diagnosis of a disorder associated with tau aggregates in a sample or a patient comprising:
(a) bringing a sample or a specific body part or body area suspected to contain a tau aggregate into contact with a compound as defined in claim 8 ;
(b) allowing the compound to bind to the tau aggregate;
(c) detecting the compound bound to the tau aggregate; and
(d) optionally correlating the presence or absence of compound binding with the tau aggregate with the presence or absence of tau aggregate in the sample or specific body part or body area.

17. A method which comprises the steps of:
(a) bringing a sample or a specific body part or body area suspected to contain a tau aggregate into contact with the compound as defined in claim 8 , which compound specifically binds to the tau aggregate;
(b) allowing the compound to bind to the tau aggregate to form a compound/tau aggregate complex;
(c) detecting the formation of the compound/tau aggregate complex;
(d) optionally correlating the presence or absence of the compound/tau aggregate complex with the presence or absence of tau aggregate in the sample or specific body part or body area; and
(e) optionally comparing the amount of the compound/tau aggregate to a normal control value
wherein the method is
a method of collecting data for determining a predisposition to a disorder associated with tau aggregates in a patient comprising detecting the specific binding of a compound as defined in claim 8 to a tau aggregate in a sample or in situ, or
a method of collecting data for predicting responsiveness of a patient suffering from a disorder associated with tau aggregates and being treated with a medicament.

18. The compound according to claim 3 , wherein R 1 is 18 F and/or the compound contains at least one 3 H.

19. The compound according to claim 18 , wherein R 1 is 18 F.

20. A diagnostic composition comprising a compound as defined in claim 18 and optionally a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

21. A method of imaging Tau aggregates, which comprises administering a diagnostically effective amount of a compound as defined in claim 18 to a patient and the imaging the Tau aggregates in the patient.

22. A method of diagnosing a disorder associated with Tau aggregates or a tauopathy, which comprises administering a diagnostically effective amount of a compound as defined in claim 18 to a patient and imaging the Tau aggregates in the patient.

Assignees

• Ac Immune Sa
• Life Molecular Imaging Sa
• Life Molecular Imaging Ltd

Inventors

• Berndt Mathias
• Müller Andre
• Oden Felix
• Schieferstein Hanno
• Schmitt-Willich Heribert
• Kroth Heiko
• Molette Jérôme

Classifications

• C07B59/002

  Heterocyclic compounds · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K51/0455

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• C07D513/14

  Ortho-condensed systems · CPC title