Compounds binding to neuropathological aggregates
10328163 · 2019-06-25
Assignee
Inventors
Cpc classification
G01N2333/47
PHYSICS
A61K51/0453
HUMAN NECESSITIES
International classification
Abstract
The present invention provides compounds binding to neuropathological aggregates of peptides or proteins, including aggregates such as neurofibrillary tangles (NFTs), osynuclein aggregates and other amyloid aggregates. The compounds of the present invention are useful for the detection and/or diagnosis of disorders associated with such neuropathological aggregates. In further aspects, the invention provides diagnostic compositions comprising these compounds, and methods for the preparation of radiolabeled compound from non-radiolabeled precursors.
Claims
1. A method of imaging a patient, the method comprising administering to the patient an amount of a compound of the following formula (I) or a pharmaceutically acceptable salt thereof ##STR00040## wherein: X.sup.1 and X.sup.4 are independently selected from CH and N; X.sup.2 and X.sup.3 are independently selected from CH.sub.2, S and O; R.sup.1 and R.sup.2 are independently selected from F, I, Br, and At, m and n are integers independently selected from 0 or 1; Ar.sup.1 and Ar.sup.2 are independently aryl, heteroaryl, or a substituted version of either of these groups, wherein one or more hydrogen atom is replaced independently for each occurrence with a halogen, hydroxy, nitro, cyano, alkyl, haloalkyl, alkenyl, alkynyl, amino, alkylaryl, alkylamino, alkylamine, alkoxy, aryloxy; (OCH.sub.2CH.sub.2).sub.oR.sup.10, wherein R.sup.10 is selected from H, OH, OSO.sub.2alkyl, OSO.sub.2aryl, and F, and o is an integer from 1 to 4; NR.sup.11COOalkyl, NR.sup.11COOarylCOalkyl, NR.sup.11COaryl; COOalkyl, COOaryl, COalkyl, COaryl, aryl, cycloalkyl; cycloalkylamino-, -cycloalkylamine, heterocycle, a fluorescent label; or ZR.sup.12 substitutions wherein Z is selected from O, NR.sup.13, NH and S; and wherein R.sup.11, R.sup.12 and R.sup.13 are independently selected from H, C.sub.nH.sub.2n+1, C.sub.nH.sub.2n-hal, with n being an integer of 1 to 3, CH.sub.2CHCH-hal, and [CH.sub.2CH.sub.2O].sub.p[CH.sub.2CH.sub.2].sub.q-hal, wherein hal is selected from F, Cl, I, Br, and At, p is an integer of 1 to 3 and q is 1 or 2; wherein suitable pairs of substituents attached to adjacent ring members of Ar.sup.1 or Ar.sup.2, respectively, can be combined to form a ring fused with Ar.sup.1 or Ar.sup.2; wherein the compound of formula (I) or the pharmaceutically acceptable salt thereof is a radiolabeled compound, wherein one or more groups selected from R.sup.1, R.sup.2, a substituent attached to Ar.sup.1 and a substituent attached to Ar.sup.2 contain a radioisotope of an element which is present therein.
2. The method of claim 1, wherein X.sup.1 and X.sup.4 are both N, and X.sup.2 and X.sup.3 are independently selected from S and O.
3. The method of claim 1, wherein the compound corresponds to formula (II) or a pharmaceutically acceptable salt thereof: ##STR00041## wherein R.sup.1 and R.sup.2 are independently selected from F, I, Br, and At, m and n are integers independently selected from 0 and 1; Ar.sup.1 and Ar.sup.2 are independently aryl, heteroaryl, or a substituted version of either of these groups, wherein one or more hydrogen atom is replaced independently for each occurrence with a halogen, hydroxy, nitro, cyano, alkyl, haloalkyl, alkenyl, alkynyl, amino, alkylaryl, alkylamino, alkylamine, alkoxy, aryloxy; (OCH.sub.2CH.sub.2).sub.oR.sup.10, wherein R.sup.10 is selected from H, OH, OSO.sub.2alkyl, OSO.sub.2aryl, and F, and o is an integer from 1 to 4; NR.sup.11COOalkyl, NR.sup.11COOarylCOalkyl, NR.sup.11COaryl; COOalkyl, COOaryl, COalkyl, COaryl, aryl, cycloalkyl; cycloalkylamino-, -cycloalkylamine, heterocycle, a fluorescent label; or ZR.sup.12 substitutions wherein Z is selected from O, NR.sup.13, NH and S; and wherein R.sup.11, R.sup.12 and R.sup.13 are independently selected from H, C.sub.nH.sub.2n+1, C.sub.nH.sub.2n-hal, with n being an integer of 1 to 3, CH.sub.2CHCH-hal, and [CH.sub.2CH.sub.2O].sub.p[CH.sub.2CH.sub.2].sub.q-hal, wherein hal is selected from F, Cl, I, Br, and At, p is an integer of 1 to 3 and q is 1 or 2; wherein suitable pairs of substituents attached to adjacent ring members of Ar.sup.1 or Ar.sup.2, respectively, can be combined to form a ring fused with Ar.sup.1 or Ar.sup.2; wherein the compound of formula (II) or the pharmaceutically acceptable salt thereof is a radiolabeled compound, wherein one or more groups selected from R.sup.1, R.sup.2, a substituent attached to Ar.sup.1 and a substituent attached to or Ar.sup.2 contain a radioisotope of an element which is present therein.
4. The method of claim 1, wherein R.sup.1 and R.sup.2 are absent.
5. The method of claim 1, wherein the compound corresponds to formula (III) or a pharmaceutically acceptable salt thereof: ##STR00042## wherein R.sup.1a and R.sup.2a are independently selected from H, F, I, Br, and At, Ar.sup.1a and Ar.sup.2a are independently aryl, heteroaryl, or a substituted version of either of these groups, wherein one or more hydrogen atom is replaced independently for each occurrence with a halogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, alkylamino, alkylamine, alkoxy, (OCH.sub.2CH.sub.2).sub.oR.sup.10, wherein R.sup.10 is selected from H, OH, OSO.sub.2alkyl, OSO.sub.2aryl, and F, and o is an integer from 1 to 4; or ZR.sup.12 substitutions where Z is selected from O, NR.sup.13, NH and S, and wherein R.sup.12 and R.sup.13 are independently selected from H, C.sub.nH.sub.2n+1, C.sub.nH.sub.2n-hal, with n being an integer of 1 to 3, CH.sub.2CHCH-hal, and [CH.sub.2CH.sub.2O].sub.p[CH.sub.2CH.sub.2].sub.q-hal, wherein hal is selected from F, Cl, I, Br, and At, p is an integer of 1 to 3 and q is 1 or 2; wherein suitable pairs of substituents attached to adjacent ring members of Ar.sup.1a or Ar.sup.2a, respectively, can be combined to form a ring fused with Ar.sup.1a or Ar.sup.2a; wherein the compound of formula (III) or the pharmaceutically acceptable salt thereof is a radiolabeled compound, wherein one or more groups selected from R.sup.1a, R.sup.2a, a substituent attached to Ar.sup.1a and a substituent attached to or Ar.sup.2a contain a radioisotope of an element which is present therein.
6. The method of claim 5, wherein R.sup.1a and R.sup.2a are H.
7. The method of claim 1, further comprising obtaining results indicating the presence or absence of a pathological condition in the patient associated with the formation of a neuropathological aggregate of peptides or proteins.
8. The method of claim 7, wherein the neuropathological aggregate of peptides or proteins is -amyloid aggregates, neurofibrillary tangles of tau, or -synuclein aggregates.
9. The method of claim 7, wherein the pathological condition is selected from Alzheimer's disease (AD) and Alzheimer's disease related dementia, Parkinson's disease (PD) and Parkinson's disease related dementia, frontotemporal dementias (FTDP), Creutzfeldt-Jakob disease (CJD) and Creutzfeldt-Jakob disease related dementia, Huntington's disease (HD) and Huntington's disease related dementia, and Lewy body disease (DLB) and Lewy body disease related dementia.
10. An in vitro method for the detection and/or quantification of neuropathological aggregates in a tissue sample obtained from a human or animal body, involving the steps of (i) contacting the tissue sample with compounds of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1, and (ii) detecting and/or quantifying the compounds of formula (I) or a pharmaceutically acceptable salt thereof which have bound to the sample.
11. A diagnostic composition comprising a radiolabeled compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1.
12. The diagnostic composition in accordance with claim 11, wherein X.sup.1 and X.sup.4 are both N, and X.sup.2 and X.sup.3 are independently selected from S and O.
13. The diagnostic composition of claim 11, wherein the compound is a compound of formula (II) or a pharmaceutically acceptable salt thereof: ##STR00043## wherein R.sup.1 and R.sup.2 are independently selected from F, I, Br, and At, m and n are integers independently selected from 0 or 1; Ar.sup.1 and Ar.sup.2 are independently aryl, heteroaryl, or a substituted version of either of these groups, wherein one or more hydrogen atom is replaced independently for each occurrence with a halogen, hydroxy, nitro, cyano, alkyl, haloalkyl, alkenyl, alkynyl, amino, alkylaryl, alkylamino, alkylamine, alkoxy, aryloxy; (OCH.sub.2CH.sub.2).sub.oR.sup.10, wherein R.sup.10 is selected from H, OH, OSO.sub.2alkyl, OSO.sub.2aryl, and F, and o is an integer from 1 to 4; NR.sup.11COOalkyl, NR.sup.11COOarylCOalkyl, NR.sup.11COaryl; COOalkyl, COOaryl, COalkyl, COaryl, aryl, cycloalkyl; cycloalkylamino-, -cycloalkylamine, heterocycle, a fluorescent label; or ZR.sup.12 substitutions wherein Z is selected from O, NR.sup.13, NH and S; and wherein R.sup.11, R.sup.12 and R.sup.13 are independently selected from H, C.sub.nH.sub.2n+1, C.sub.nH.sub.2n-hal, with n being an integer of 1 to 3, CH.sub.2CHCH-hal, and [CH.sub.2CH.sub.2O].sub.p[CH.sub.2CH.sub.2].sub.q-hal, wherein hal is selected from F, Cl, I, Br, and At, p is an integer of 1 to 3 and q is 1 or 2; wherein suitable pairs of substituents attached to adjacent ring members of Ar.sup.1 or Ar.sup.2, respectively, can be combined to form a ring fused with Ar.sup.1 or Ar.sup.2; and wherein one or more groups selected from R.sup.1, R.sup.2, a substituent attached to Ar.sup.1 and a substituent attached to or Ar.sup.2 contain a radioisotope of an element which is present therein.
14. The diagnostic composition of claim 11, wherein Ar.sup.1 and Ar.sup.2 are independently selected from phenyl, 5- or 6-membered heteroaryl, or substituted versions thereof.
15. The diagnostic composition of claim 11, wherein Ar.sup.1 and Ar.sup.2 each carry 1 or 2 substituents.
16. The diagnostic composition of claim 11, wherein R.sup.1 and R.sup.2 are absent.
17. The diagnostic composition in accordance with claim 11, wherein the compound is a compound of formula (III) or a pharmaceutically acceptable salt thereof: ##STR00044## wherein R.sup.1a and R.sup.2a are independently selected from H, F, I, Br, and At, Ar.sup.1a and Ar.sup.2a are independently aryl, heteroaryl, or a substituted version of either of these groups, wherein one or more hydrogen atom is replaced independently for each occurrence with a halogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, alkylamino, alkylamine, alkoxy, (OCH.sub.2CH.sub.2).sub.oR.sup.10, wherein R.sup.10 is selected from H, OH, OSO.sub.2alkyl, OSO.sub.2aryl, and F, and o is an integer from 1 to 4; or ZR.sup.12 substitutions where Z is selected from O, NR.sup.13, NH and S, and wherein R.sup.12 and R.sup.13 are independently selected from H, C.sub.nH.sub.2n+1, C.sub.nH.sub.2n-hal, with n being an integer of 1 to 3, CH.sub.2CHCH-hal, and [CH.sub.2CH.sub.2O].sub.p[CH.sub.2CH.sub.2]-hal, wherein hal is selected from F, Cl, I, Br, and At, p is an integer of 1 to 3 and q is 1 or 2; wherein suitable pairs of substituents attached to adjacent ring members of Ar.sup.1a or Ar.sup.2a, respectively, can be combined to form a ring fused with Ar.sup.1a or Ar.sup.2a; and wherein one or more groups selected from R.sup.1a, R.sup.2a, a substituent attached to Ar.sup.1a and a substituent attached to or Ar.sup.2a contain a radioisotope of an element which is present therein.
18. The diagnostic composition in accordance with claim 15, wherein R.sup.1a and R.sup.2a are H.
19. The diagnostic composition of claim 11, wherein 20 mol % or more of the total amount of the compound of formula (I) or a pharmaceutically acceptable salt form thereof contain a radioisotope.
Description
EXAMPLES
(1) A library of bithiazoles was prepared using available building blocks (e.g. acyl bromides or acyl chlorides) using one step or two-step synthesis. Two-step synthesis of the bisthiazoles was carried out in DMF at room temperature (Mikhailenko et al., Mol. Cryst. Liq. Cryst., Vol. 542: pp. 115/[637]-122/[644], 2011):
(2) ##STR00007##
(3) For the preparation of asymmetric bithiazoles, the resulting product may be reacted with a different acyl bromide in line with the following scheme:
(4) ##STR00008##
(5) A one-step combinatorial approach for synthesis of the bithiazoles was performed in ethanol at reflux temperature:
(6) ##STR00009##
(7) The mixture of three possible products was purified by means of flash chromatography or preparative HPLC. Exemplary compounds obtained following these routes are listed in the following:
(8) ##STR00010## ##STR00011##
(9) Symmetric bithiazoles were synthesized by a one step reaction of two equivalents of acylbromide building blocks with one equivalent of the dithiooxamide in EtOH at reflux temperature.
(10) ##STR00012##
(11) All isolated intermediates and products were confirmed by mass spectrometry, .sup.1H-NMR and selected compound also confirmed by .sup.13C-NMR spectroscopy.
(12) Saturation and competition binding assays of compounds in this invention towards synthetic amyloid peptides, human tau-441 recombinant and human -synuclein recombinant aggregate (fibrils) were performed similar to previously reported assays (Manook et al. 2012 and Yousefi et al. 2011) and adapted to the change of peptides and label. Aggregates sample was deployed on 96-well cell culture plates (Greiner Bio-One, Germany) to a final reaction volume of 280 mL per well using 8-channel electronic pipettes (Mettler Toledo, Germany) giving 12-24 octuples of data points per sample. Bound and free fractions were separated by vacuum filtration through polyethyleneimine-pretreated GF/B glass filtermats using a semi-automated Harvester 96 Mach II M (Tomtec, USA). Filters were cut and retained radioactivity determined using an automatic NaI(TI) well-type -detector (Wallac 1480-011 Automatic Gamma Counter, PerkinElmer, USA). Data were processed and analyzed using GraphPad Prism 6.0 (GraphPad Software, USA). The results are shown in the following tables:
(13) TABLE-US-00001 TABLE 1 Data on selected example compounds' A.sub.1-40, A.sub.1-42 , -Syn affinities % Inhibition of Potential [.sup.3H]PiB at Use: 100 nM Affinity Ki (nM) Targeting Compound ClogP A.sub.1-40 A.sub.1-42 T -syn A.sub.1-40 A.sub.1-42 of 1
(14) Example compound 2 binds to -amyloids, NFT and synuclein aggregates with in vitro affinity of 7-12 nM (Ki, see table 1). Specificity studies with ex vivo and in vitro validation on APP/PS1 (Willuweit et al., 2009, Manook et al., 2012) and a APP/PS1-tau triple tg mouse model of AD brain confirmed specific binding of compound 2 to A and NFT (
(15) In vitro staining experiments of compound 2 on APP/PS1 tg mouse brain showed specific binding to -amyloids (
(16) The biodistribution study (following the procedure previously described (Yousefi et al., 2011)) results confirmed that compound [.sup.11C]2 as a representative compound for the brain uptake behaviour of the compounds of formula (I), crosses the blood brain barrier and clears from brain in 30 min p.i. fast (in wt Balb-C mice) which is a very important property of a CNS tracer.
(17) These results suggest by further modification of functional groups and introduction of F-18 with physical half life of 110 min even superior compounds could be prepared (Table 2).
(18) TABLE-US-00002 TABLE 2 Library of the compounds based of bithiazole were synthesized, the table indicates their logP (octanol/PBS), mass spectrometry and in vitro selectivity. log P MS (Octanol/ [M + 1] Potential Use: Compound PBS) amu Targeting of 7
(19) TABLE-US-00003 TABLE 3 Data on compounds 20-23 affinities % Inhibition Potential of [.sup.3H]PiB at Use: 100 nM Affinity Ki (nM) Targeting Compound logP A.sub.1-40 A.sub.1-42 -syn A.sub.1-40 A.sub.1-42 of 20
(20) Lipophilicity of CNS tracers plays an important role on blood brain barrier (BBB) and neuronal cells uptake. Therefore a library of .sup.18F-bithiazoles with high binding affinity towards A.sub.1-40, A.sub.1-42 , -Syn were synthesized and log P (octanol/PBS) of these compounds measured (Table 2). The log P values were between 1.1-3.2. This suggests that all compounds are crossing BBB and compounds with log P 1.9-2.6 penetrate cell membrane and reach intercellular targets.
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