Granted Patent B2

US 10,865,207 · App. 16/319,808 · Granted Dec 15, 2020

Inventors: Heiko Kroth (Ecublens, CH); Jérôme Molette (Prevessin Moens, FR); Hanno Schieferstein (Berlin, DE); Andre Müller (Berlin, DE); Heribert Schmitt-Willich (Berlin, DE); Mathias Berndt (Berlin, DE); Felix Oden (Berlin, DE)

Assignees: AC IMMUNE S.A.; LIFE MOLECULAR IMAGING SA

C07D471/14A61K51/0455C07B59/002G01N33/60G01N33/6896G01N2800/2821G01N2800/2835G01N2800/7047

Abstract

Claims (91)

1. A compound of the formula (I)

as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof;

wherein R 1 is 18 F and R 2 is H.

2. A compound of the formula (I)

as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof; wherein R 1 is F and R 2 is H.

3. A compound of the formula (I)

as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof;

R 1 is LG, wherein LG is nitro, halogen or trimethyl ammonium;

R 2 is H or PG;

PG is a protecting group;

LG is a leaving group.

4. The compound according to claim 3 , wherein PG is tert-butyloxycarbonyl (BOC), triphenylmethyl (Trityl) or dimethoxytrityl (DMT).

5. The compound according to claim 2 , wherein the compound is detectably labeled with 2 H, 3 H.

6. A diagnostic composition comprising a compound as defined in claim 1 and optionally a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

7. A method of preparing a compound as defined in claim 1 comprising reacting a compound of the formula (I)

wherein R 1 is a leaving group (LG) and R 2 is H or protecting group (PG), with a [ 18 F]fluorinating agent, wherein the method further comprises cleaving of the protecting group PG, if present.

8. A kit for preparing a radiopharmaceutical preparation, said kit comprising a sealed vial containing a predetermined quantity of a compound as defined in claim 3 .

9. 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 5 ;

(b) allowing the compound to bind to the tau aggregate;

(c) detecting the compound bound to the tau aggregate; and

(d) collecting data for the diagnosis of the disorder associated with tau aggregates in the sample or the specific body part or body area;

(e) 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.

10. A method of determining the amount of tau aggregate in a tissue and/or a body fluid comprising:

(a) providing a sample representative of the tissue and/or body fluid under investigation;

(b) bringing the sample into contact with a compound as defined in claim 5 ;

(c) testing the sample for the presence of tau aggregate with the compound;

(d) determining the amount of compound bound to the tau aggregate; and

(e) calculating the amount of tau aggregate in the tissue and/or body fluid.

11. 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 5 to a tau aggregate in a sample or in situ which comprises the steps of:

(a) bringing the sample or a specific body part or body area suspected to contain the tau aggregate into contact with the compound as defined in claim 5 , 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) collecting data for determining the predisposition to the disorder associated with tau aggregates in the patient;

(e) 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

(f) optionally comparing the amount of the compound/tau aggregate to a normal control value.

12. A method of collecting data for monitoring residual disorder in a patient suffering from a disorder associated with tau aggregates who has been treated with a medicament, wherein the method comprises:

(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 5 , 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) collecting data for monitoring residual disorder in the patient suffering from the disorder associated with tau aggregates who has been treated with the medicament;

(e) 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

(f) optionally comparing the amount of the compound/tau aggregate to a normal control value.

13. 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 comprising:

(a) bringing a sample or a specific body part or body area suspected to contain an tau aggregate into contact with a compound as defined in claim 5 , 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) collecting data for predicting responsiveness of the patient suffering from the disorder associated with tau aggregates and being treated with the medicament;

(e) 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

(f) optionally comparing the amount of the compound/tau aggregate to a normal control value.

14. The method of claim 9 , wherein the disorder associated with tau aggregates is a tauopathy, 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, 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, progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle only dementia, postencephalitic Parkinsonism, myotonic dystrophy, Tau panencephalopathy, AD-like with astrocytes, certain prion diseases (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 (Dutch type), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, 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, and lattice dystrophy, or atypical parkinsonism.

15. The method of claim 14 , wherein the tauopathy is a 3R tauopathy or a 4R tauopathy.

16. The method of claim 9 , wherein the body part or body area comprises the brain or the eye.

17. The method of claim 9 , wherein the detecting comprises positron emission tomography imaging.

18. 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 1 ;

(b) allowing the compound to bind to the tau aggregate;

(c) detecting the compound bound to the tau aggregate; and

(d) collecting data for the diagnosis of the disorder associated with tau aggregates in the sample or the specific body part or body area;

(e) 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.

19. A method of determining the amount of tau aggregate in a tissue and/or a body fluid comprising:

(a) providing a sample representative of the tissue and/or body fluid under investigation;

(b) bringing the sample into contact with a compound as defined in claim 1 ;

(c) testing the sample for the presence of tau aggregate with the compound;

(d) determining the amount of compound bound to the tau aggregate; and

(e) calculating the amount of tau aggregate in the tissue and/or body fluid.

20. 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 1 to a tau aggregate in a sample or in situ which comprises the steps of:

(a) bringing the sample or a specific body part or body area suspected to contain the tau aggregate into contact with the compound as defined in claim 1 , 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) collecting data for determining the predisposition to the disorder associated with tau aggregates in the patient;

(e) 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

(f) optionally comparing the amount of the compound/tau aggregate to a normal control value.

21. A method of collecting data for monitoring residual disorder in a patient suffering from a disorder associated with tau aggregates who has been treated with a medicament, wherein the method comprises:

(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 1 , 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) collecting data for monitoring residual disorder in the patient suffering from the disorder associated with tau aggregates who has been treated with the medicament;

(e) 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

(f) optionally comparing the amount of the compound/tau aggregate to a normal control value.

22. 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 comprising:

(a) bringing a sample or a specific body part or body area suspected to contain an tau aggregate into contact with a compound as defined in claim 1 , 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) collecting data for predicting responsiveness of the patient suffering from the disorder associated with tau aggregates and being treated with the medicament;

(e) 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

(f) optionally comparing the amount of the compound/tau aggregate to a normal control value.

23. The method of claim 22 , wherein the disorder associated with tau aggregates is a tauopathy, 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, 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, progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle only dementia, postencephalitic Parkinsonism, myotonic dystrophy, Tau panencephalopathy, AD-like with astrocytes, certain prion diseases (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 (Dutch type), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, 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, and lattice dystrophy, or atypical parkinsonism.

24. The method of claim 23 , wherein the tauopathy is a 3R tauopathy or a 4R tauopathy.

25. The method of claim 18 , wherein the body part or body area comprises the brain or the eye.

26. The method of claim 18 , wherein the detecting comprises positron emission tomography imaging.

Assignments (12)

Priority Claims (1)

Continuity (1)