HK1220201B - Imidazo[1,2-a]pyridin-7-amines as imaging tools - Google Patents

Description

Imidazo [1, 2-a ] pyridin-7-amines as imaging tools

The invention relates to compounds of the general formula

Wherein

R¹Is lower alkyl or lower alkyl substituted by halogen;

R²、R³is hydrogen or tritium;

or to pharmaceutically acceptable acid addition salts.

Similar compounds are described, for example, in WO2011/117264 as modulators of phosphodiesterase 10A (PDE10A) for the treatment of central nervous system diseases and in WO2010/068453 and WO2010/068452 as modulators of fatty acid amide hydrolases. 2-aryl-3- (heteroaryl) -imidazo (1, 2-a) pyrimidines are described in WO0134605 for the treatment of conditions alleviated by the reduction of inflammatory cytokines.

It has been shown that the present compounds may be used for binding and imaging tau aggregates (tau aggregates) and related beta (beta) sheet aggregates, including especially beta-amyloid aggregates or alpha (alpha) -synuclein aggregates, in particular for binding and imaging tau aggregates in alzheimer's patients.

Alzheimer's Disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline, irreversible memory loss, disorientation and language loss (Arch. neurol.1985, 42(11), 1097-. Post-mortem AD brain sections showed a large number of Senile Plaques (SPs) consisting of beta amyloid (a β) peptides, and a number of Neuronal Fibrillar Tangles (NFTs) formed from filaments of highly phosphorylated tau protein.

Tau belongs to the microtubule-associated protein family and is mainly expressed in neurons, where it plays an important role in the assembly of tubulin monomers into microtubules to form a neuronal microtubule network that serves as an axon transport track (brain res. rev.2000, 33(1), 95-130). Tau is translated from a single gene located on chromosome 17 and expression is developmentally regulated by a selective splicing mechanism, producing six different subtypes in the adult brain, which can be distinguished by the number of their binding domains. The underlying mechanisms leading to tau hyperphosphorylation, misfolding and aggregation are not well understood, but deposits of tau aggregates follow a patterned spatiotemporal pathway both at the intracellular level and at the brain topographic level (stereotypopicatographic pathway).

Recently, the discovery that mutations in the tau gene leading to frontotemporal dementia (FTD) in parkinson's disease are associated with chromosome 17 has strengthened the significant role in the pathogenesis of neurodegenerative diseases due to tau and underscores the fact that different groups of tau subtypes expressed in different neuronal populations may lead to different pathologies (biochim. biophys. acta 2005, 1739(2) 240-. Neurodegenerative diseases characterized by pathological tau accumulation are referred to as 'tauopathies' (Ann. Rev. Neurosci.2001, 24, 1121-. In addition to AD and FTD, other tauopathies include Progressive Supranuclear Palsy (PSP), dominant-tangle dementia (tangliosis), Pick's disease, frontotemporal lobar degeneration (FTLD), Down's syndrome, and the like.

A direct link has been established between progressive involvement of neocortical regions and increased dementia severity, revealing that pathological tau aggregates such as NFTs are reliable markers of the neurodegenerative process. The extent of NFT involvement in AD is defined by the Braak phase (Acta Neuropathol.1991, 82, 239-259). NFT is defined as Braak stages I and II when it is implicated mainly in the transverse olfactory region of the brain, stages III and IV when it is implicated in the limbic region such as the hippocampus, and stages V and VI when a large number of neocortical involvement is found.

Currently, detection of tau aggregates is only possible by histological analysis of biopsy or autopsy material. In vivo imaging of tau pathology would provide a new insight into tau aggregate deposits in the human brain and allow non-invasive examination of the extent of tau pathology, quantification of changes in tau deposits over time, assessment of their association with cognition and analysis of the efficacy of anti-tau therapy. A possible ligand for the detection of tau aggregates in the living brain must cross the blood brain barrier and have high affinity and specificity for tau aggregates. For this reason, successful neuroimaging radiotracers must have appropriate lipophilicity (logD 1-3) and low molecular weight (< 450), exhibit rapid clearance from blood and low non-specific binding.

The aim of the present application is to find an imaging tool that will improve the diagnosis by identifying potential patients with excess tau aggregates in the brain that may develop into alzheimer's disease. It would also be useful to monitor the progression of the disease. Imaging tau tangles in the brain can provide an important tool for monitoring therapy when anti-tau aggregate drugs become available.

A further object of the invention is a method of imaging tau aggregate deposits, the method comprising

-introducing a detectable amount of the composition into the mammal

-allowing sufficient time for the compound of formula I to associate with the tau-aggregate deposits, and

-detecting compounds associated with more than one tau-aggregate deposit.

A further object of the invention is a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, which can be used to identify potential patients.

The following definitions of general terms used in this specification apply regardless of whether the terms in question appear alone or in combination.

As used herein, the term "lower alkyl" denotes a saturated, i.e. aliphatic hydrocarbon group, including straight or branched carbon chains having 1-7 carbon atoms. Examples of "alkyl" are methyl, ethyl, n-propyl and isopropyl.

The term "halogen" denotes chlorine, bromine, fluorine or iodine.

The term "lower alkyl substituted by halogen" denotes an alkyl group as defined above, wherein at least one hydrogen atom is replaced by a halogen atom.

³H represents a tritium atom.

The term "leaving group" denotes halogen or sulfonate. Examples of sulfonates are tosylate, mesylate, triflate, nitrobenzenesulfonate (nosylate) or brosylate.

The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable acid addition salts" include salts of inorganic and organic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.

It has been found that compounds of formula I can be used for binding and imaging tau aggregates and related beta-sheet aggregates, including especially beta-amyloid aggregates or alpha-synuclein aggregates.

An embodiment of the invention are compounds of formula I, wherein R¹Is lower alkyl, e.g. the following compounds

2- (4-methoxyphenyl) imidazo [1, 2-a ] pyridin-7-amine

[³H]-2- (4-methoxyphenyl) imidazo [1, 2-a]Pyridin-7-amine.

An embodiment of the invention is further a compound of formula I, wherein R is¹Is lower alkyl substituted by halogen, e.g. the following compounds

2- (4- (fluoromethoxy) phenyl) imidazo [1, 2-a ] pyridin-7-amine

2- [4- (3-Fluoropropoxy) phenyl ] imidazo [1, 2-a ] pyridin-7-amine

2- [4- (2-fluoroethoxy) phenyl ] imidazo [1, 2-a ] pyridin-7-amine

[³H]-2- [4- (2-fluoroethoxy) phenyl]Imidazo [1, 2-a ]]Pyridin-7-amine.

An embodiment of the invention is further a compound of formula I, wherein R is²And R³Is tritium, e.g. the following compounds

[³H]-2- (4-methoxyphenyl) imidazo [1, 2-a]Pyridin-7-amines

[³H]-2- [4- (2-fluoroethoxy) phenyl]Imidazo [1, 2-a ]]Pyridin-7-amine.

The compounds of formula I may be used for binding and imaging tau aggregates, beta-amyloid aggregates, alpha-synuclein aggregates or huntingtin aggregates.

A preferred use of the compounds of formula I is for binding and imaging tau aggregates in alzheimer's patients.

Furthermore, the compounds of formula I may be used in tau binding studies.

The compounds of formula I are suitable for diagnostic imaging of tau-aggregates in the brain of mammals.

The invention is also useful for diagnostic imaging of tau-aggregate deposits in the brain of mammals.

The compounds of formula I of the present invention,

and pharmaceutically acceptable salts thereof can be prepared by a process comprising

a) NH for compound of formula 2 (X ═ Cl, Br)₄Amination of OH

Thereby providing a compound of formula I

Wherein R is¹Is as defined above, and R²And R³Is hydrogen and, if desired, the resulting compound is converted into a pharmaceutically acceptable acid addition salt, or

b) Reacting a compound of formula 4

Coupling with the corresponding alpha-activated ketone of formula 3 (X is a leaving group, e.g. Br)

Thereby providing a compound of formula I

Wherein R is¹Is as defined above, and R²And R³Is hydrogen and, if desired, the resulting compound is converted into a pharmaceutically acceptable acid addition salt, or

c) Reacting a compound of formula 5 with a suitable alkylating agent R¹-X (X is halogen or sulfonate) reaction

Thereby providing a compound of formula I

Wherein R is¹Is as defined above, and R²And R³Is hydrogen and, if desired, converting the resulting compound into a pharmaceutically acceptable acid addition salt, and

d) reacting a compound of formula I with tritium gas in the presence of a catalyst such as an iridium-, ruthenium-, rhodium-or palladium-containing complex in a suitable solvent such as dichloromethane, chlorobenzene, DMF, DMSO or mixtures thereof at ambient or elevated temperature

Wherein R is²And R³Is a hydrogen atom, and is,

thereby providing a compound of formula I

Wherein R is¹Is as defined above and R²And R³Is tritium, and, if desired, the resulting compound is converted to a pharmaceutically acceptable acid addition salt.

The following schemes 1-3 describe in more detail the processes for preparing the compounds of formula I. The starting materials are known compounds or can be prepared according to methods known in the art.

The preparation of the compounds of formula I of the present invention may be carried out in a sequential or convergent route. The techniques required to carry out this reaction and to purify the product produced are known to those skilled in the art. Substituents and indices used in the following process descriptions have the meanings given herein, unless indicated to the contrary.

In more detail, the compounds of formula I can be manufactured by the methods given below, by the methods given in the examples, or by analogous methods. Suitable reaction conditions for each reaction step are known to those skilled in the art. The reaction sequence is not limited to the sequence shown in schemes 1 to 3, but the order of the reaction steps may be varied at will depending on the starting materials and their respective reactivities. The starting materials are commercially available or can be prepared by methods analogous to those given below, by the methods described in the references cited in the description or in the examples, or by methods known in the art.

Scheme 1

According to scheme 1, derivatives of imidazopyridines are prepared via amination of a compound of formula 2 with a suitable ammonia reagent, such as ammonium hydroxide, in the presence of a suitable catalyst, such as copper (I) oxide, in a suitable solvent, such as N-methyl-2-pyrrolidone, at elevated or ambient temperatureI, wherein the substituent R¹Is as defined above and R²And R³Is hydrogen.

Scheme 2

According to scheme 2, activated ketone 3 (wherein the substituent R¹Is as defined above, R²And R³Is hydrogen and X is halogen) with amino-pyridine 4 in a suitable solvent such as acetone or ethanol, in an oil bath or in a microwave reactor at elevated temperature to provide the derivative of compound I.

Scheme 3

According to scheme 3, by using a suitable alkylating agent R¹-X, e.g. an alkyl halide such as 1-fluoroethyl bromide or an alkyl tosylate such as fluoromethyl tosylate, alkylating phenol 5 in the presence of a suitable base such as cesium carbonate or sodium hydride in a suitable solvent such as DMF at ambient or elevated temperature to synthesize further derivatives I of imidazopyridine wherein the substituent R is¹As defined above.

Isolation and purification of Compounds

If desired, isolation and purification of the compounds and intermediates described herein can be accomplished by any suitable separation or purification method such as, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, preparative low or high pressure liquid chromatography or a combination of these methods. Specific illustrations of suitable separation and isolation procedures can be found by reference to the preparations and examples below. However, it is of course also possible to use other equivalent separation or isolation methods.

Salts of compounds of formula I

The compounds of formula I are basic and can be converted into the corresponding acid addition salts. The conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or an organic acid, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid is added to a similar solvent. The temperature was maintained between 0 ℃ and 50 ℃. The resulting salt precipitates spontaneously or can be precipitated by addition of a less polar solvent.

The acid addition salts of the basic compounds of formula I can be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.

The compounds were studied according to the tests given below.

TAU radioligand in vitro displacement assay

This in vitro binding assay assesses the affinity of compounds for native tau aggregates. Reacting the compound with a well-established tau-specific radioligand [ alpha ], [ beta ] -a tau-specific radioligand³H]T808 co-incubation and determination of the compound by in vitro autoradiography using human Alzheimer's Disease (AD) brain slices³H]Replacement potency of T808 binding (see figure 3).

Material

AD human brains were purchased from Banner Sun Health Research Institute (Sun City, AZ, USA). Pathological diagnosis of AD is based on neuropathological data according to the standard NIA-Reagan Institute standard. Radioactive ligand [ alpha ], [³H]T808 internal synthetic [ 2 ]³H]-2- [4- (2-fluoro-ethyl) -piperidin-1-yl]-benzo [4, 5 ]]Imidazo [1, 2-a ]]Pyrimidine, radiochemical purity 99.0%). Cold T808 was used as reference (2- [4- (2-fluoro-ethyl) -piperidin-1-yl)]-benzo [4, 5 ]]Imidazo [1, 2-a ]]Pyrimidine). For autoradiography, FujiFilm Imaging Plates (BAS-IP TR 2025) were exposed to the sections and read using a FujiFilm IP reader (BAS-5000).

Method of producing a composite material

Transfer the sections to a Histobond + microscope slide (Marienfeld Laboratory Glas) after drying at room temperature for 3 hours, store the sections at-20 ℃. incubate the sections with radioligand (10nM) and respective cold compounds (at different concentrations) in 50mM Tris buffer, pH 7.4 at room temperature for 30min, wash at 4 ℃ in 50mM Tris buffer, pH 7.4 for 3 × 10min and at distilled H for 3 8910 min₂After 3 rapid dips in O at 4 ℃, the sections were dried for 3h at 4 ℃. The sections were placed in a FujiFilm Cassette (BAS 2025), exposed for five days with an imaging plate and then scanned at a resolution of 25 μ M/pixel.

Data analysis

The signal intensity in the region of interest (ROI) of the autoradiogram (Dens-PSL/mm2) was quantified using software MCID analysis (version 7.0, Imaging Research Inc.). In the absence or presence of a compound³H]Specific Binding (SB) for T808 binding was calculated by subtracting non-specific binding signals in the white matter, thus generating SB_{Only [3H]T808}And SB_{Compound (I)}. The% displacement of the different compounds was calculated as follows:

% substitution ═ 100- (SB)_{Compound (I)}/SB_{Only [3H]T808})*100。

Validating data

In each experiment, cold T808 was used as a positive internal control. Co-incubation of equimolar amounts of hot and cold T808 was expected to reduce specific binding by about 50%.

Reference to the literature

Szardenings et al 'Imaging agents for detecting neurological disorders'. US patent application No. US20110182812

W, Zhang et al, ' A highlylly selective and specific PET trap for imaging of oft & pathologies (highly selective and specific PET tracers for imaging tau pathology) '. Journal of Alzheimer's Disease 31(2012)601- & 612.

TABLE 1

FIGS. 1 and 2 respectively show [ 2 ] incubated with a human cortical brain slice obtained from an AD patient in the Braak V stage³H]-2- (4-methoxyphenyl) imidazo [1, 2-a]Pyridine-7-amine (example 5) and [ 2 ]³H]-2- [4- (2-fluoroethoxy) phenyl]Imidazo [1, 2-a ]]Autoradiogram of pyridin-7-amine (example 6). Radioligand concentrations were 2.6 and 2.5nM, respectively. Both radioligands showed punctate staining of tau aggregates in lamellar distribution in white matter and varying degrees of nonspecific binding.

The compounds of formula I and their pharmaceutically acceptable salts can be used in the form of pharmaceutical preparations. The pharmaceutical preparation may be administered in the form of an injection.

The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers for the preparation of pharmaceutical preparations. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, may be used in aqueous injection solutions of water-soluble salts of compounds of formula I, but are generally not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. It may also contain other therapeutically valuable substances.

The dosage may vary within wide limits and will of course be adapted to the individual requirements in each particular case.

Examples

Abbreviations used:

h-hour

min-min

Example 1

2- (4-methoxyphenyl) imidazo [1, 2-a ] pyridin-7-amine

A microwave vial was charged with pyridine-2, 4-diamine (400mg, 3.67mmol), 2-bromo-1- (4-methoxyphenyl) ethanone (882mg, 3.85mmol), sodium bicarbonate (329mg, 3.92mmol) and methanol (3.5 mL). The reaction mixture was stirred at reflux for 4 h. The reaction mixture was cooled to room temperature, diluted with water and ethyl acetate, sonicated and stirred at room temperature for-15 min. The suspension was filtered and washed with water and ethyl acetate. Will be provided withThe resulting pale yellow solid was placed under high vacuum to provide 2- (4-methoxyphenyl) imidazo [1, 2-a]Pyridine-7-amine hydrobromide. It was suspended in-5 mL saturated NaHCO₃In aqueous solution, sonicated, filtered and washed with water. The residue was suspended in-5 mL of 2M aqueous NaOH, sonicated, filtered and washed with water. The resulting residue was placed under high vacuum to afford the title compound as a light brown solid (310mg, 1.3mmol, 35% yield). MS m/z:240.1[M+H]⁺。

example 2

2- (4- (fluoromethoxy) phenyl) imidazo [1, 2-a ] pyridin-7-amine

a) 7-bromo-2- (4- (hydroxyphenyl) imidazo [1, 2-a)]Pyridine compound

In analogy to example 1, 4-bromopyridin-2-amine instead of pyridine-2, 4-diamine and 2-bromo-1- (4-hydroxyphenyl) ethanone instead of bromo-1- (4-methoxyphenyl) ethanone were converted into the title compound (2.34g, 80%) which was obtained as a grey solid. MS m/z: 289.3[ M ]]⁺。

b) 7-bromo-2- (4- (fluoromethoxy) phenyl) imidazo [1, 2-a]Pyridine compound

To 4- (7-bromoimidazo [1, 2-a ]]Solution of pyridin-2-yl) phenol (2.37g, 6.56mmol) and fluoromethyl 4-methylbenzenesulfonate (1.34g, 6.56mmol) in DMF (10.00mL) was added cesium carbonate (2.78g, 8.52mmol) and heated to 70 ℃ for 18h and then irradiated in a microwave at 100 ℃ for 30 min. It was poured into water and extracted twice with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. Toluene (200 mL) was added to the resulting oil and the solvent was evaporated to remove residual DMF. Some aqueous NaOH 1N was added and stirring was continued for 15 minutes. It was filtered and dried under high vacuum to give the title compound (1.69g, purity-60%) as a light brown oilThe product was used without further purification. MS m/z: 321.3[ M + H]⁺。

c)2- (4- (fluoromethoxy) phenyl) imidazo [1, 2-a]Pyridin-7-amines

To the 7-bromo-2- (4- (fluoromethoxy) phenyl) imidazo [1, 2-a]A solution of pyridine (112mg, 349. mu. mol) in N-methyl-2-pyrrolidone (2mL) was added copper (I) oxide (9.98mg, 69.8. mu. mol) and ammonium hydroxide (733mg, 5.23 mmol). The vial was then closed and the reaction mixture was stirred at 110 ℃ for 3 h. It was diluted with dichloromethane (15mL) and washed twice with water (15 mL). The aqueous layer was extracted with dichloromethane (15 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. Flash chromatography using a gradient of dichloromethane: methanol: ammonia (90: 9: 1 vol%) 85: 15 to 50: 50 provided the title compound (17mg, 19% yield) as a light brown solid. MS m/z: 258.6[ M + H]⁺。

Example 3

2- [4- (3-Fluoropropoxy) phenyl ] imidazo [1, 2-a ] pyridin-7-amine

a)4- (7-Aminoimidazo [1, 2-a) pyridin-2-yl) phenol hydrobromide

In a 5mL microwave vial, pyridine-2, 4-diamine (500mg, 4.58mmol) and 2-bromo-1- (4-hydroxyphenyl) ethanone (1.03g, 4.81mmol) were combined with acetone (8.0mL) to yieldAn off-white suspension was generated. The vial was purged with argon and sealed. The reaction mixture was stirred at 65 ℃ (oil bath temperature) overnight. The off-white suspension was filtered and washed with acetone. The resulting off-white solid was dried under high vacuum overnight to provide the title compound (363mg, 18% yield) as an off-white solid. MS m/z: 226.1[ M + H]⁺。

b)2- [4- (3-Fluoropropoxy) phenyl]Imidazo [1, 2-a ]]Pyridin-7-amines

In a 5mL microwave vial, 4- (7-aminoimidazo [1, 2-a)]Pyridin-2-yl) phenol hydrobromide (150mg, 343 μmol) was combined with DMF (2.5mL) to give a colorless solution. Cesium carbonate (335mg, 1.03mmol) was added. The reaction mixture was stirred at room temperature for 1h (gas evolution was observed; the reaction mixture turned into a dark brown suspension). 1-bromo-3-fluoropropane (48.4mg, 343. mu. mol) dissolved in DMF (0.5mL) was added. The vial was purged with argon and sealed. The reaction mixture was stirred at 90 ℃ (oil bath temperature) overnight. The reaction mixture was cooled to ambient temperature and extracted with dichloromethane and water. The aqueous layer (pH 9) was extracted with dichloromethane. The organic layer was washed three times with water and once with brine. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The residue (brown oil) was dried in high vacuum for 4 h. The brown solid was triturated with ethyl acetate to provide the title compound (53mg, 48% yield) as a brown solid. MS m/z: 286.1[ M + H]⁺。

Example 4

2- [4- (2-fluoroethoxy) phenyl ] imidazo [1, 2-a ] pyridin-7-amine

To 4- (7-aminoimidazo [1, 2-a ] at 0 ℃ under nitrogen atmosphere]Pyridin-2-yl) phenol hydrobromide (156mg, 510. mu. mol) in DMF (2mL) was added sodium hydride 60% (81.5mg, 2.04 mmol). After stirring at ambient temperature for 30min, 1-bromo-2-fluoroethane (71.2mg, 560. mu. mol) was added over a period of 1 min. The reaction mixture was then stirred at ambient temperature for 2 h. It was poured onto water (15mL) and extracted twice with ethyl acetate (15 mL). The organic layer was washed with water (15mL) and brine (10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. Flash chromatography using a gradient of dichloromethane: methanol: ammonia (90: 9: 1 vol%) 80: 20 to 40: 60 provided the title compound (80mg, 58% yield) as an off-white solid. MS m/z: 272.5[ M + H]⁺。

Example 5

[³H]-2- (4-methoxyphenyl) imidazo [1, 2-a]Pyridin-7-amines

In a 2mL tritiated flask, 2- (4-methoxyphenyl) imidazo [1, 2-a ] was placed]Pyridine-7-amine (2.0mg, 8.4 μmol) and Crabtree catalyst (10.1mg, 15.5 μmol) were dissolved in dichloromethane (1.0 mL.) the flask was connected to a tritium manifold (RC-TRITEC) and degassed by freeze-pump-thaw, tritium gas was introduced and the light orange solution was vigorously stirred at 1050 mbar for 4 hours under a tritium atmosphere, the solution was cooled by liquid nitrogen and excess tritium gas in the reaction vessel was reabsorbed in a uranium trap for spent tritium (uranium-trap), the solvent was lyophilized off and the unstable tritium was removed by lyophilization with a 9: 1-mixture of ethanol and water (3 × 1mL) and toluene (2 × 1mL), the remaining oil was dissolved in dichloromethane (25mL) and transferred to a SCX-3 cation exchange column, the remaining catalyst was eluted with dichloromethane (15mL) and discarded, the product was used with NH in MeOH₃(1N, 25mL), collected separately and concentrated under reduced pressureConcentration the crude product was purified by preparative HPLC (xbridge c-18Prep, 5 μ M, 10 × 250mm) using acetonitrile, water and pH 9 buffer as eluent to obtain 833MBq (22.5mCi) the title compound, with a radiochemical purity of 99% and a specific activity of 1.02TBq/mmol (27.6Ci/mmol) (determined by MS spectrometry) which was stored as an ethanol solution MS M/z 240.2[ M + H ] M/z]⁺(48％)，242.2[M(T)+H]⁺(10％)，244.2[M(T₂)+H]⁺(40％)，246.2[M(T₃)+H]⁺(2％)。

Example 6

[³H]-2- [4- (2-fluoroethoxy) phenyl]Imidazo [1, 2-a ]]Pyridin-7-amines

In a 2ml tritiated flask, 2- [4- (2-fluoroethoxy) phenyl group]Imidazo [1, 2-a ]]Pyridine-7-amine (2.0mg, 7.4. mu. mol) and Crabtree catalyst (5.9mg, 7.4. mu. mol) were dissolved in DMF (1.0 mL.) the flask was connected to a tritium manifold (RC-TRITEC) and degassed by freeze-pump-thaw, tritium gas was introduced and the light orange solution was vigorously stirred at 550 mbar for 4 hours under a tritium atmosphere, the solution was cooled by liquid nitrogen and excess tritium gas in the reaction vessel was reabsorbed in a uranium trap for spent tritium, the solvent was lyophilized off and the unstable tritium was removed by lyophilization with a 9: 1-mixture of ethanol and water (3 × 1mL) and toluene (2 × 1 mL). the remaining brown oil was dissolved in dichloromethane (10mL) and transferred to a SCX-3 cation exchange column, the remaining catalyst was eluted with MeOH (5mL) and discarded, the product was treated with NH in MeOH₃The crude product was purified by preparative HPLC (Xbridge C-18Prep, 5 μm, 10 × 250mm) using acetonitrile, water and pH 7 buffer as eluents to afford the title compound at 833MBq (22.5mCi) with a radiochemical purity of 98% and a specific activity of 1.58TBq/mmol (42).6Ci/mmol) (determined by MS spectrometry). The compound was stored as a methanol solution. MS m/z: 272.2[ M + H]⁺(7％)，274.2[M(T)+H]⁺(39％)，276.2[M(T₂)+H]⁺(54％)。

Claims (13)

1. A compound of formula I

Wherein

R¹Is C_1-7Alkyl or C substituted by halogen_1-7An alkyl group;

R²、R³is hydrogen or tritium;

or a pharmaceutically acceptable acid addition salt.

2. A compound of formula I according to claim 1, wherein R¹Is C_1-7Alkyl and R²And R³As claimed in claim 1.

3. A compound of formula I according to claim 1 or 2, which is

2- (4-methoxyphenyl) imidazo [1, 2-a ] pyridin-7-amine

[³H]-2- (4-methoxyphenyl) imidazo [1, 2-a]Pyridin-7-amine.

4. A compound of formula I according to claim 1, wherein R¹Is C substituted by halogen_1-7Alkyl and R²And R³As claimed in claim 1.

5. A compound of formula I according to claim 1 or 4, which is

2- (4- (fluoromethoxy) phenyl) imidazo [1, 2-a ] pyridin-7-amine

2- [4- (3-Fluoropropoxy) phenyl ] imidazo [1, 2-a ] pyridin-7-amine

2- [4- (2-fluoroethoxy) phenyl ] imidazo [1, 2-a ] pyridin-7-amine

[³H]-2- [4- (2-fluoroethoxy) phenyl]Imidazo [1, 2-a ]]Pyridin-7-amine.

6. A compound of formula I according to claim 1, wherein R²And R³Is tritium and R¹As claimed in claim 1.

7. A compound of formula I according to claim 1 or 6, which is

[³H]-2- (4-methoxyphenyl) imidazo [1, 2-a]Pyridin-7-amines

[³H]-2- [4- (2-fluoroethoxy) phenyl]Imidazo [1, 2-a ]]Pyridin-7-amine.

8. A process for the preparation of a compound of formula I as defined in any one of claims 1 to 5, which process comprises

a) NH for the compound of formula 2₄Amination of OH, X ═ Cl, Br in formula 2,

thereby providing a compound of formula I

Wherein R is¹Is as defined above, and R²And R³Is hydrogen and, if desired, the resulting compound is converted into a pharmaceutically acceptable acid addition salt, or

b) Reacting a compound of formula 4

Coupled with a corresponding alpha-activated ketone of formula 3, wherein X in formula 3 is a leaving group,

thereby providing a compound of formula I

Wherein R is¹Is as defined above, and R²And R³Is hydrogen and, if desired, the resulting compound is converted into a pharmaceutically acceptable acid addition salt, or

c) Reacting a compound of formula 5 with a suitable alkylating agent R¹-X, wherein X is halogen or sulfonate,

thereby providing a compound of formula I

Wherein R is¹Is as defined above, and R²And R³Is hydrogen and, if desired, converting the resulting compound into a pharmaceutically acceptable acid addition salt, and

d) reacting a compound of formula I with tritium gas in the presence of a catalyst selected from complexes containing iridium, ruthenium, rhodium or palladium, in a suitable solvent selected from dichloromethane, chlorobenzene, DMF, DMSO or mixtures thereof, at ambient or elevated temperature

Wherein R is²And R³Is a hydrogen atom, and is,

thereby providing a compound of formula I

Wherein R is¹Is as defined above and R²And R³Is tritium, and, if desired, the resulting compound is converted to a pharmaceutically acceptable acid addition salt.

9. Use of a compound of formula I according to any one of claims 1-7 for the preparation of a medicament for binding and imaging tau aggregates, beta-amyloid aggregates or alpha-synuclein aggregates.

10. Use of a compound of formula I according to any one of claims 1-7 for the preparation of a medicament for binding and imaging tau aggregates in alzheimer's patients.

11. Use of a compound of formula I according to any one of claims 1-7 for the preparation of a medicament for use in tau binding studies.

12. Use of a compound of formula I according to any one of claims 1-7 for the preparation of a medicament for the diagnostic imaging of tau-aggregates in the brain of a mammal.

13. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1-7 and a pharmaceutically acceptable carrier.