Pharmaceutical Compositions Comprising Diphenyldiazole Derivatives and Methods of Use - Patent application

Abstract

Provided herein are compounds of general formula (A) or (A * ) and methods of using same for the treatment of neurodegenerative diseases, particularly alpha-synucleinopathies.

Description

[Technical field]

[0001] In the present specification, the general formula (A) or (A * ) and methods of using same for the treatment of neurodegenerative diseases, particularly α-synucleinopathies. [Background technology]

[0002] Numerous neurological and neurodegenerative diseases are known, many of which are currently incurable. Neurodegenerative diseases include Huntington's disease (HD), Hallervorden-Spatz syndrome, Alzheimer's disease (AD), senile dementia, Creutzfeldt-Jakob disease (CJD), arteriosclerotic dementia, Parkinson's disease (PD), cerebral thromboangiitis obliterans (Buerger's disease), and many others.

[0003] Alpha-synucleinopathies, a class of neurodegenerative diseases, are characterized by the intracellular accumulation of protein aggregates, oligomers, prefibrils and fibrils that contain primarily alpha-synuclein. Examples of alpha-synucleinopathies are Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA).

[0004] The disease phenotype depends on the localization of pathological changes and may primarily affect the autonomic, nigrostriatal, pontocerebellar and cortical systems. MSA patients present with autonomic dysfunction combined with either prominent parkinsonism (MSA-P) or cerebellar ataxia (MSA-C) (Gilman, 2008). PD patients display a prominent hypokinetic-rigid phenotype (Berg, 2018), while patients with DLB show mixed cognitive and motor impairments (McKeith, 2017). No effective treatment is available to slow disease progression (Levin, 2016). Inhibition of α-synuclein aggregation is a rational therapeutic intervention that targets the main pathophysiological process of α-synucleinopathies (Wong, 2017; Meissner, 2019).

[0005] The pathological effects on neurons in α-synucleinopathies are believed to be induced by the formation of small aggregates (oligomers) of α-synuclein and subsequent formation of membrane pores. α-synuclein oligomers have been shown to be the most relevant neurotoxic species and are targeted by compounds disclosed in International Patent Application PCT / EP2009 / 004144. One particular compound, anle138b, is a small molecule compound that shows strong disease-modifying effects in animal models of α-synucleinopathies. In these studies, anle138b showed high oral bioavailability and blood-brain barrier penetration, with anle138b levels in the brain five-fold higher than in plasma (Wagner, 2013). In a series of different mouse models, anle138b potently inhibited oligomer accumulation, neurodegeneration, and disease progression in vivo ( Wagner, 2013 ; Martinez Hernandez, 2018 ; Wagner, 2015 ; Brendel, 2019 ; Levin, 2014 ; Heras-Garvin, 2019 ; Wegrzynowicz, 2019 ).

[0006] Anle138b is a highly lipophilic molecule, which may explain its ability to cross the blood-brain barrier and enter target cells, but which represents a challenge for formulation development. An oral pharmaceutical composition useful for human administration would be beneficial, with reduced feeding / fasting effects. Summary of the Invention

[0007] In this specification, General formula (A) or (A * At least one compound having [ka] or a stereoisomer, racemate, hydrate or solvate thereof (In the formula, R is hydrogen, C 1~4 Alkyl, and -C 1~4 alkylene-halogen; Hal is selected from F, Cl, Br and I; RE7 and R E8 are independently H or F). and a pharma- ceutical composition comprising at least one monoester of a fatty acid and polyethylene glycol and / or at least one diester of a fatty acid and polyethylene glycol; Fatty acids are C8 to C 22 independently selected from fatty acids, The polyethylene glycol is independently selected from polyethylene glycols containing from about 20 to about 40 ethylene oxide units. Pharmaceutical compositions are provided. In some embodiments, the PEG contains about 32 ethylene oxide units. In some embodiments, the fatty acids are independently C8 to C 18 The fatty acids are selected from the group consisting of aryl, aryl, phenyl ...

[0008] In certain embodiments, the pharmaceutical composition comprises R, R E7 and R E8 are H, Hal is Br, and the general formula (B), (B * ) [ka] or mixtures thereof.

[0009] The excipient may further comprise a monoglyceride of a fatty acid, a diglyceride of a fatty acid, and / or a triglyceride of a fatty acid, the fatty acids being independently selected from the group consisting of C8 to C6 22 The excipient may further comprise a polyethylene glycol (PEG) containing from about 20 to about 40 ethylene oxide units, and in certain embodiments, about 32 ethylene oxide units. In some embodiments, the fatty acids are independently selected from C8 to C 18 The fatty acids are selected from the group consisting of aryl, aryl, phenyl ...

[0010] In some embodiments, the excipient comprises a mixture of monoesters of fatty acids and polyethylene glycol and / or diesters of fatty acids and polyethylene glycol, where the fatty acids may be derived from natural sources, such as vegetable sources including coconut oil and / or hydrogenated coconut oil. In certain embodiments, the excipient comprises a mixture of monoesters of fatty acids and polyethylene glycol and / or diesters of fatty acids and polyethylene glycol, where the fatty acids comprise up to 15% by weight caprylic acid (C8), up to 12% by weight capric acid (C10), 30-50% by weight lauric acid (C12), 5-25% by weight myristic acid (C14), 4-25% by weight palmitic acid (C16), and 5-35% by weight stearic acid (C18).

[0011] In some embodiments, the excipient comprises about 50% to about 80% by weight, preferably about 60% to about 75% by weight, more preferably about 72% by weight of at least one monoester of a fatty acid and a polyethylene glycol and / or at least one diester of a fatty acid and a polyethylene glycol. In some embodiments, the excipient further comprises about 10% to about 30% by weight, preferably about 15% to about 25% by weight, more preferably about 20% by weight of a monoglyceride of a fatty acid, a diglyceride of a fatty acid, and / or a triglyceride of a fatty acid. In some embodiments, the excipient further comprises about 5% to about 20% by weight, preferably about 5% to about 10% by weight, more preferably about 8% by weight of a polyethylene glycol containing about 20 to about 40 ethylene oxide units, or about 32 ethylene oxide units.

[0012] The excipient may have a melting range of about 33° C. to about 64° C., preferably about 35° C. to about 55° C., more preferably about 42.5° C. to about 47.5° C., and even more preferably about 44° C. In some embodiments, the excipient has a hydrophilic lipophilic balance (HLB) of about 1 to about 16, preferably about 7 to about 14, about 11 or about 14.

[0013] The method of obtaining the excipient is not limited.The excipient can be obtained, for example, by alcoholysis reaction between polyethylene glycol and triglyceride of fatty acid, or by polyglycolysis of hydrogenated vegetable oil and PEG, for example, hydrogenated coconut oil or palm kernel oil and PEG, for example, PEG-32.

[0014] In some embodiments, the pharmaceutical composition comprises about 3% to about 5% by weight of a compound represented by formula (A) or (A * ) or a mixture thereof, and about 95% to about 97% by weight of an excipient. In certain embodiments, the pharmaceutical composition comprises about 3% to about 5% by weight of a compound having the general formula (B) or (B * ) or a mixture thereof, and about 95% to about 97% by weight of an excipient.

[0015] Further provided is an oral dosage form comprising the medicament described herein. The oral dosage form may be in the form of a capsule, such as an HPMC capsule or a gelatin capsule. In some embodiments, the oral dosage form contains about 1 mg to about 100 mg of a compound, i.e., a compound of formula (A), (A * ) or a mixture thereof, or a compound of formula (B), (B * ), or a mixture thereof, about 5 mg to about 50 mg of the compound, or about 10 mg to about 30 mg of the compound.

[0016] Further provided herein is a method for treating or preventing a disease associated with protein aggregation and / or a neurodegenerative disease, such as an α-synucleinopathies, wherein a therapeutically effective amount of a pharmaceutical composition or oral dosage form disclosed herein is administered to a patient in need thereof. Further provided is a pharmaceutical composition or oral dosage form for use in the treatment or prevention of a disease associated with protein aggregation and / or a neurodegenerative disease, such as the treatment or prevention of an α-synucleinopathies. Additionally provided is a compound of formula (A), (A), (B), (C), (D), (E), (F), (G), (H), (I ... * ), or a mixture thereof, or (B), (B * ), or mixtures thereof, and a pharma- ceutically acceptable excipient, wherein the excipient comprises at least one monoester of a fatty acid and polyethylene glycol, and / or at least one diester of a fatty acid and polyethylene glycol; Fatty acids are C8 to C 22 independently selected from fatty acids, The polyethylene glycol is independently selected from polyethylene glycols containing about 20 to about 40 ethylene oxide units. The α-synucleinopathies may be selected from multiple system atrophy (MSA), Parkinson's disease (PD), or dementia with Lewy bodies (DLB), preferably multiple system atrophy (MSA). The pharmaceutical composition or medicament may be administered orally and is administered to the subject without regard to food intake.

[0017] Further provided are pharmaceutical compositions, unit dosage forms, and methods described in any of the following sections. 1. Formula (A), (A * ) or a mixture thereof and an excipient comprising lauroyl polyoxyl-32 glyceride, wherein the lauroyl polyoxyl-32 glyceride comprises a mixture of mono-, di- and triglycerides, PEG fatty acid mono- and / or diesters, and free PEG. 2.Formula (B), (B * Item 2. The pharmaceutical composition according to item 1, comprising a compound of formula (I) or a mixture thereof and lauroyl polyoxyl-32 glyceride, wherein the lauroyl polyoxyl-32 glyceride comprises a mixture of monoglycerides, diglycerides and triglycerides, PEG fatty acid monoesters and / or diesters, and free PEG. 3. About 50 mg to about 300 mg of formula (B), (B * Item 3. The pharmaceutical composition according to item 2, comprising a compound of formula (I) or a mixture thereof. 4. An oral dosage form comprising the pharmaceutical composition according to any one of items 1 to 3, in particular item 2 or 3. 5. The oral dosage form of paragraph 4, wherein, when administered as a single dose to fasted healthy subjects, an oral dosage form containing 50 mg of the compound provides a geometric mean plasma Cmax of anle138b of about 54.3 ng / mL, an oral dosage form containing 100 mg of the compound provides a geometric mean plasma Cmax of anle138b of about 156 ng / mL, an oral dosage form containing 200 mg of the compound provides a geometric mean plasma Cmax of anle138b of about 458 ng / mL, or an oral dosage form containing 300 mg of the compound provides a geometric mean plasma Cmax of anle138b of about 704 ng / mL. 6. When administered as a single dose to fasted healthy subjects, an oral dosage form containing 50 mg of compound provides approximately 113 ng * h / mL, resulting in a geometric mean plasma AUC(0-24) of anle138b of approximately 366 ng / mL for an oral dosage form containing 100 mg of the compound. * h / mL, resulting in a geometric mean plasma AUC(0-24) of anle138b of approximately 1090 ng / mL for an oral dosage form containing 200 mg of the compound. * h / mL, or an oral dosage form containing 300 mg of the compound provides a geometric mean plasma AUC(0-24) of approximately 1650 ng * The oral dosage form of claim 4 or 5, which provides a geometric mean plasma AUC(0-24) of anle138b in h / mL. 7. The oral dosage form according to any one of paragraphs 4 to 6, wherein, when administered as a single dose to fasted healthy subjects, an oral dosage form containing 50 mg of the compound provides a geometric mean plasma T1 / 2 of anle138b of about 3.94 hr, a composition containing a 100 mg oral dosage form provides a geometric mean plasma T1 / 2 of anle138b of about 10.79 hr, an oral dosage form containing 200 mg of the compound provides a geometric mean plasma T1 / 2 of anle138b of about 12.76 hr, or an oral dosage form containing 300 mg of the compound provides a geometric mean plasma T1 / 2 of anle138b of about 16.22 hr. 8. The oral dosage form of paragraph 4, wherein when administered once daily for at least 7 days to fasted healthy subjects, an oral dosage form containing 100 mg of the compound provides a geometric mean plasma Cmax of anle138b of about 135 ng / mL on day 1 and about 70.9 ng / mL on day 7, an oral dosage form containing 200 mg of the compound provides a geometric mean plasma Cmax of anle138b of about 447 ng / mL on day 1 and about 128 ng / mL on day 7, or an oral dosage form containing 300 mg of the compound provides a geometric mean plasma Cmax of anle138b of about 910 ng / mL on day 1 and about 307 ng / mL on day 7. 9. When administered once daily for at least 7 days to fasted healthy subjects, an oral dosage form containing 100 mg of compound delivers approximately 261 ng of * h / mL and approximately 141 ng on day 7 * h / mL, an oral dosage form containing 200 mg of the compound provided a geometric mean plasma AUC(0-tau) of approximately 905 ng / mL on Day 1. * h / mL and approximately 308 ng on day 7 * h / mL, or an oral dosage form containing 300 mg of the compound provides a geometric mean plasma AUC(0-tau) of approximately 2210 ng on Day 1. * h / mL and approximately 633 ng on day 7 * The oral dosage form of item 4 or 8, which provides a geometric mean plasma AUC(0-tau) of anle138b in h / mL. 10. The oral dosage form of any one of paragraphs 4, or 8-9, wherein when administered once daily for at least 7 days to fasted healthy subjects, an oral dosage form containing 100 mg of the compound provides a geometric mean plasma T1 / 2 of anle138b of about 4.23 hr on day 7, an oral dosage form containing 200 mg of the compound provides a geometric mean plasma T1 / 2 of anle138b of about 9.48 hr on day 7, or an oral dosage form containing 300 mg of the compound provides a geometric mean plasma T1 / 2 of anle138b of about 6.07 hr on day 7. 11. When administered as a single dose to healthy subjects in the fasted state, an oral dosage form containing 150 mg of the compound has a geometric mean plasma Cmax of about 442 ng / mL of anle138b, and / or a Cmax of about 896 ng / mL of anle138b. * h / mL, and / or a geometric mean plasma T1 / 2 of about 11.3 hr. 12. When administered as a single dose to healthy subjects in the fed state, an oral dosage form containing 150 mg of the compound has a geometric mean plasma Cmax of about 196 ng / mL of anle138b, and / or a Cmax of about 641 ng / mL of anle138b. * h / mL, and / or a geometric mean plasma T1 / 2 of about 15.22 hr. 13. When a composition containing 150 mg of the compound is administered once daily for 7 consecutive days to patients in a fed state, a geometric mean plasma Cmax of anle138b of about 462 ng / mL on day 1, and / or a Cmax of about 1040 ng / mL on day 1. * The oral dosage form according to item 4, which provides an AUC(0-24) of anle138b in h / mL. 14. When administered to patients in a fed state an oral dosage form containing 150 mg of the compound once daily for 7 consecutive days, a geometric mean plasma Cmax of anle138b of about 160 ng / mL on day 7, and / or a Cmax of about 388 ng / mL on day 7 * h / mL, and / or a T1 / 2 of anle138b of about 11.7 h. 15. When a composition containing 300 mg of the compound is administered once daily for 7 consecutive days to patients in a fed state, the geometric mean plasma Cmax of anle138b of about 933 ng / mL on Day 1, and / or * The oral dosage form according to item 4, which provides an AUC(0-24) of anle138b in h / mL. 16. When a composition containing 300 mg of the compound is administered once daily for 7 consecutive days to patients in a fed state, the geometric mean plasma Cmax of anle138b of about 365 ng / mL on day 7, and / or * 5. The oral dosage form of claim 4, which provides an AUC(0-24) of anle138b of about 1.0 h / mL, and / or a T1 / 2 of anle138b of about 12.1 h. 17. When a composition containing 150 mg of the compound is administered twice daily for 7 consecutive days to patients in a fasted state, the geometric mean plasma Cmax of anle138b of about 546 ng / mL on day 1, and / or * The oral dosage form according to item 4, which provides an AUC(0-24) of anle138b in h / mL. 18. When a composition containing 150 mg of the compound is administered twice daily for 7 consecutive days to patients in a fasted state, the geometric mean plasma Cmax of anle138b of about 182 ng / mL on day 7, and / or * h / mL, and / or a T1 / 2 of anle138b of about 14.2 hr. 19. The pharmaceutical composition according to any one of items 1 to 3 or the oral dosage form according to any one of items 4 to 18 for use in the treatment or prevention of a disease associated with protein aggregation and / or a neurodegenerative disease. 20. The pharmaceutical composition or oral dosage form for use according to item 19, wherein the disease is an alpha-synucleinopathy, for example the synucleinopathy is multiple system atrophy (MSA), Parkinson's disease (PD), or dementia with Lewy bodies (DLB), preferably multiple system atrophy (MSA). 21. A method for treating or preventing a disease associated with protein aggregation and / or a neurodegenerative disease, comprising the step of administering a therapeutically effective amount of the pharmaceutical composition according to any one of items 1 to 3 or the oral dosage form according to any one of items 4 to 18 to a subject in need thereof. 22. The method according to clause 21, wherein the disease is an alpha-synucleinopathy, for example the synucleinopathy is multiple system atrophy (MSA), Parkinson's disease (PD), or dementia with Lewy bodies (DLB), preferably multiple system atrophy (MSA).

[0018] The oral dosage form may be administered in one or more units, each unit containing from about 10 mg to about 50 mg, or about 10 mg, or about 30 mg of the compound of formula (B), (B * ) compounds or mixtures thereof. [Brief description of the drawings]

[0019] [Figure 1] Figure 1 is a graph showing the particle size distribution of nanomilled anle138b. The y-axis is volume (%) and the x-axis is particle size (μm) on a log scale. [Figure 2A] 2A-2D are graphs showing the PK Cmax profile for each of the three rats in each group in the rat formulation study described in Example 1.2. [Figure 2B] 2A-2D are graphs showing the PK Cmax profile for each of the three rats in each group in the rat formulation study described in Example 1.2. [Figure 2C] 2A-2D are graphs showing the PK Cmax profile for each of the three rats in each group in the rat formulation study described in Example 1.2. [Figure 2D] 2A-2D are graphs showing the PK Cmax profile for each of the three rats in each group in the rat formulation study described in Example 1.2. [Diagram 3] FIG. 3 is a log plot of the plasma concentration of anle138b following a single dose of DP in healthy volunteers. [Figure 4A]4A and 4B are log plots of repeat dose plasma concentrations of anle138b DP on day 1 (4A) and day 7 (4B) in healthy volunteers. [Figure 4B] 4A and 4B are log plots of repeat dose plasma concentrations of anle138b DP on day 1 (4A) and day 7 (4B) in healthy volunteers. [Diagram 5] FIG. 5 is a logarithmic plot of the effect of food on single dose plasma concentrations of anle138b DP. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The present disclosure relates to a compound represented by the general formula (A) or (A * At least one compound having and a pharma- ceutical composition comprising at least one monoester of a fatty acid and polyethylene glycol and / or at least one diester of a fatty acid and polyethylene glycol; It relates to pharmaceutical compositions.

[0021] Compositions according to the present disclosure have advantageous properties including safety, good bioavailability and / or little or no effect of food intake on bioavailability, particularly as measured by AUC.

[0022] The pharmaceutical compositions disclosed herein comprise, as an active ingredient (API), a compound represented by the general formula (A) or (A * ) [ka] A bicyclic compound having the formula or a stereoisomer, racemate, hydrate or solvate thereof (In the formula, R is hydrogen, C 1~4 Alkyl, or C 1~4 alkylene-halogen; Hal is F, Cl, I or Br; R E7 and R E8 each of which is independently H or F. In some embodiments, R E7 , R E8 and each R is hydrogen (H). In some embodiments, Hal is Br.

[0023] In some embodiments, the API is anle138b. As used herein, "anle138b" refers to a compound represented by the general formula (A) and (A * Its chemical name is 3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole, which has the following formulas (B) and (B * ) [ka] It exists as a tautomer having the following structure:

[0024] anle138b is a first-in-class compound that modulates toxic oligomers based on high affinity binding to a structural epitope associated with misfolding along the amyloidogenic pathway, which has been shown to destabilize toxic oligomers, prevent the formation of oligomeric pores in membranes, and block prion-like propagation of α-synuclein aggregates (Wagner, 2013; Martinez Hernandez, 2018; Camilleri, 2020; Ghio, 2019). anle138b exhibited structure-dependent binding to pathological aggregates in vitro and in vivo against α-synuclein and other disease-related amyloidogenic proteins such as prion protein, Aβ (amyloid beta, Aβ), and tau, and potently inhibited the formation of pathological oligomers (Wagner, 2013; Martinez Hernandez, 2018; Camilleri, 2020; Ghio, 2019; Deeg, 2015; Reiner, 2018; Wagner, 2015). The molecular mode of action of anle138b was also studied on multi-microsecond timescales by means of all-atom molecular dynamics simulations. This study provides insight into the binding mechanism of anle138b. It shows its ability to bind small oligomers and directly modulate their structure during peptide aggregate formation. Importantly, anle138b does not bind to monomers and therefore does not interfere with their physiological function. Without wishing to be bound by theory, anle138b has been shown to reduce the overall number of intermolecular hydrogen bonds in oligomers, disfavoring the sampling of aggregation states and remodeling the conformational distribution within small oligomeric peptide aggregates (Matthes, 2017).

[0025] In principle, the general formula (A) or (A * ) or any stereoisomer, racemate, hydrate or solvate thereof may be used in the preparation of the pharmaceutical compositions disclosed herein.

[0026] In preparing the pharmaceutical compositions disclosed herein, a compound represented by general formula (A) or (A* It is understood that any tautomer, crystalline or amorphous form of at least one compound having the formula (I) may be used.

[0027] In a preferred embodiment, in the preparation of the pharmaceutical compositions disclosed herein, anle138b (formula (B), (B * ) or a mixture) is utilized.

[0028] In accordance with the present invention, the terms "formulation" and "pharmaceutical composition" may be used interchangeably and refer to a composition for administration to a subject, preferably a human patient. By "pharmaceutical acceptable excipient" is meant a non-toxic solid, semi-solid or liquid carrier or diluent. In some embodiments, the excipient confers enhanced bioavailability to the composition compared to the unformulated compound. The pharmaceutical compositions disclosed herein are of the general formula (A), (A * ), or a mixture thereof, and a pharma- ceutically acceptable excipient, wherein the excipient comprises at least one monoester of a fatty acid and polyethylene glycol (PEG) and / or at least one diester of a fatty acid and polyethylene glycol (PEG). In addition, the excipient may further comprise a glyceride, such as a monoglyceride of a fatty acid, a diglyceride of a fatty acid, a triglyceride of a fatty acid, or a mixture thereof. Furthermore, the excipient may further comprise polyethylene glycol (PEG) that does not react with a fatty acid (i.e., "free polyethylene glycol" or "free PEG").

[0029] In one embodiment, the excipient comprises polyethylene glycol (PEG) fatty acid esters (particularly at least one monoester of a fatty acid and polyethylene glycol and at least one diester of a fatty acid and polyethylene glycol), glycerides (particularly monoglycerides of fatty acids, diglycerides of fatty acids, and triglycerides of fatty acids) and free polyethylene glycol.

[0030] The polyethylene glycol and fatty acid, glyceride and free polyethylene glycol present in the monoester and / or diester of fatty acid and polyethylene glycol may be the same or different. For ease of manufacture, the polyethylene glycol and fatty acid, glyceride and free polyethylene glycol present in the PEG fatty acid ester are the same.

[0031] The amount of at least one monoester and / or diester of fatty acid and PEG in the excipient is not particularly limited, and is preferably in the range of about 50% by weight to about 80% by weight, more preferably about 60% by weight to about 75% by weight, and even more preferably about 72% by weight. In a preferred embodiment, the excipient contains about 10% by weight to about 30% by weight, more preferably about 15% by weight to about 25% by weight, and even more preferably about 20% by weight of glyceride. Preferably, the excipient contains about 5% by weight to about 20% by weight, more preferably about 5% by weight to about 10% by weight, and even more preferably about 8% by weight of free polyethylene glycol, such as PEG1500. In some embodiments, the excipient contains about 72% by weight of at least one monoester and / or diester of fatty acid and PEG, about 20% by weight of glyceride, and about 8% by weight of free PEG.

[0032] The at least one mono- and / or diester of a fatty acid with PEG, glycerides, and free polyethylene glycol in the pharmaceutical composition of the present invention are all considered to be part of the excipient and are taken into consideration when determining the above amounts. A fatty acid is a monocarboxylic acid having an aliphatic chain. The aliphatic chain may be branched or linear, typically linear. In one embodiment, the aliphatic chain may include a hydroxyl group substituent. A single fatty acid or a mixture of fatty acids may be utilized as the fatty acid in the present invention. A mixture of fatty acids may be selected due to their ready availability.

[0033] The fatty acids may be unsaturated (i.e., containing a carbon-carbon double bond) or saturated, and are typically saturated. If a mixture of fatty acids is used, the fatty acids are preferably predominantly saturated, e.g., the mixture contains at least 75% by weight saturated fatty acids, more preferably at least 80% by weight saturated fatty acids.

[0034] The composition of a fatty acid is specified, among other things, by the length of its aliphatic chain. Fatty acids typically contain 8 to 22 carbons (C8 to C 22 ) in length, and in certain embodiments, 8 to 18 carbons (C 18 ) aliphatic chain length. Examples of suitable fatty acids include caprylic acid (C8:0), capric acid (C10:0), lauric acid (C12:0), myristic acid (C14:0), palmitic acid (C16:0), stearic acid (C18:0), oleic acid (C18:1), linoleic acid (C18:2), gamma-linolenic acid (C18:3), ricinoleic acid (C18:1, (OH)), arachidonic acid (C20:0), and / or behenic acid (C22:0). Preferably, the fatty acid comprises lauric acid (C12:0). More preferably, the fatty acids comprise lauric acid (C12:0), in combination with myristic acid (C14:0), palmitic acid (C16:0), and / or stearic acid (C18:0), and optionally in combination with caprylic acid (C8:0) and / or capric acid (C10:0). Even more preferably, the fatty acids comprise lauric acid (C12:0), myristic acid (C14:0), palmitic acid (C16:0), and stearic acid (C18:0), and optionally caprylic acid (C8:0) and / or capric acid (C10:0). More preferably, the fatty acids include caprylic acid (C8:0), capric acid (C10:0), lauric acid (C12:0), myristic acid (C14:0), palmitic acid (C16:0), and stearic acid (C18:0). (Cx:y) is the designation used for fatty acids, where x refers to the number of carbon atoms in the fatty acid chain and y refers to the number of unsaturated carbon bonds in the fatty acid chain.

[0035] Below, the weight percentages are based on the total weight of fatty acids.

[0036] Caprylic acid may be absent. In a preferred embodiment, the fatty acid contains caprylic acid in an amount of preferably at least 0.5% by weight, more preferably at least 1% by weight, even more preferably at least 3% by weight. Preferably, the fatty acid contains caprylic acid in an amount of up to 20% by weight, more preferably at most 15% by weight, even more preferably at most 10% by weight. Preferably, the fatty acid contains caprylic acid in an amount of up to 15% by weight.

[0037] Capric acid may be absent. In a preferred embodiment, the fatty acid contains capric acid in an amount of preferably at least 0.5% by weight, more preferably at least 1% by weight, even more preferably at least 3% by weight. Preferably, the fatty acid contains capric acid in an amount of up to 20% by weight, more preferably at most 15% by weight, even more preferably at most 10% by weight. Preferably, the fatty acid contains capric acid in an amount of up to 12% by weight.

[0038] In a preferred embodiment, the fatty acid contains lauric acid, preferably in an amount of at least 20% by weight, more preferably at least 30% by weight, even more preferably at least 40% by weight. Preferably, the fatty acid contains up to 60% by weight of lauric acid, more preferably up to 50% by weight of lauric acid. The fatty acid preferably comprises 30-50% by weight of lauric acid.

[0039] In a preferred embodiment, the fatty acid contains myristic acid in an amount of at least 1 wt%, more preferably at least 5 wt%, even more preferably at least 10 wt%. Preferably, the fatty acid contains myristic acid in an amount of up to 40 wt%, more preferably up to 30 wt%, even more preferably up to 25 wt%. The fatty acid preferably contains 5-25 wt% myristic acid.

[0040] In a preferred embodiment, the fatty acid contains palmitic acid in an amount of preferably at least 1 wt%, more preferably at least 4 wt%, even more preferably at least 5 wt%, even more preferably at least 10 wt%. Preferably, the fatty acid contains palmitic acid in an amount of up to 40 wt%, more preferably up to 30 wt%, even more preferably up to 25 wt%. The fatty acid preferably contains 4-25 wt% palmitic acid. In a preferred embodiment, the fatty acid contains stearic acid in an amount of preferably at least 1 wt%, more preferably at least 5 wt%, even more preferably at least 10 wt%. Preferably, the fatty acid contains stearic acid in an amount of up to 40 wt%, more preferably up to 35 wt%, even more preferably up to 30 wt%, even more preferably up to 25 wt%. The fatty acid preferably contains 5-35 wt% stearic acid.

[0041] Mixtures of one or more of the above listed fatty acids are also contemplated.

[0042] The mixture of fatty acids in a typical composition can be illustrated as follows (weight percent based on the total weight of fatty acids, wt%): up to 15% by weight of caprylic acid, up to 12% by weight of capric acid, 30 to 50% by weight of lauric acid, 5 to 25% by weight of myristic acid, 4 to 25% by weight of palmitic acid, and 5-35% by weight of stearic acid.

[0043] The fatty acid may be of natural or synthetic origin, preferably of natural origin.Some fatty acids are abundant in vegetable and animal fats.Non-limiting examples include coconut oil, palm kernel oil, sunflower oil, rice bran oil, safflower oil, sesame oil, peanut oil, palm oil, olive oil, soybean oil, grapeseed oil, linseed oil, soybean oil, tallow, tall oil, legume oil, cocoa butter, shea butter and mixtures thereof.Preferably, the fatty acid is coconut oil, palm kernel oil or mixtures thereof, more preferably coconut oil.It is also possible to use hydrogenated fatty acids, such as hydrogenated coconut oil or hydrogenated palm kernel oil, preferably hydrogenated coconut oil.

[0044] Polyethylene glycol (PEG) has the formula H-(O-CH2CH2) n It is a compound having -OH. It is also known as polyethylene oxide or macrogol. The average number of ethylene oxide repeat units (n) can vary and range, for example, from about 6 to about 200, preferably from about 6 to about 100, more preferably from about 6 to about 40, and even more preferably from about 20 to 40. In some embodiments, the PEG has an average of about 32 ethylene glycol units (i.e., PEG-32). The PEG of the monoester and / or diester of fatty acid and PEG can have PEG chains of different lengths, i.e., different amounts of ethylene glycol (ethylene oxide, EO) units. The monoester and / or diester of fatty acid and PEG disclosed herein can have PEG with a molecular weight of about 300 to about 2000 g / mol (Da). In some embodiments, the PEG has a molecular weight of about 260 to about 10,000 g / mol, preferably about 260 to about 4,400 g / mol, more preferably about 260 to about 1,800 g / mol, and even more preferably about 880 to 1,800 g / mol. In some embodiments, the PEG has a molecular weight of about 1500 g / mol.

[0045] In some embodiments, the excipient comprises mono- and diesters of fatty acids and PEG, each having a PEG with about 32 ethylene glycol units and a fatty acid as defined above. The fatty acids include caprylic acid (C8), capric acid (C 10 ), lauric acid (C 12 ), myristic acid (C 14 ), palmitic acid (C 16 ), and / or stearic acid (C 18 In some embodiments, the preferred fatty acid may be lauric acid (C 12 In some embodiments, the mono-, di- and triglycerides include glycerol and caprylic acid (C8), capric acid (C 10 ), lauric acid (C 12 ), myristic acid (C 14 ), palmitic acid (C 16 ), and / or stearic acid (C 18 ), preferably lauric acid (C 12 ) containing fatty acid components.

[0046] The excipients are generally non-aqueous. They may be in the form of semi-solid waxy substances that are amphiphilic in nature. Due to their structure, the excipients are surface active.

[0047] An excipient is typically a mixture such that it has a range over which it melts, rather than a specific melting point. The melting range of an excipient may range from about 33°C to about 64°C, preferably from about 35°C to about 55°C, more preferably from about 42.5°C to about 47.5°C, and even more preferably about 44°C. When an excipient contains a mixture of compounds, the excipient typically exhibits a melting range rather than a defined melting point. In some embodiments, the excipients disclosed herein contain a mixture, such as mono-, di- and triglycerides and PEG fatty acid esters, and exhibit a melting range with an onset of melting at about 38°C and a peak melting temperature of about 43°C.

[0048] An excipient can also be characterized by its HLB value (hydrophilic-lipophilic balance), which can be, for example, in the range of about 1 to about 16, preferably about 7 to about 14, and more preferably about 11 to 14, or 11 or 14.

[0049] The delivery profile (e.g., immediate release, sustained release) can be modified by one of skill in the art by selecting the appropriate melting point and HLB. In certain embodiments, the excipients and API exist as an emulsion at body temperature.

[0050] A preferred class of excipients are polyoxylglycerides. Polyoxylglycerides are, for example, Gelucire® 43 / 01 (mono-, di- and triglyceride esters of fatty acids (C8-C 18 These excipients are available under the trade name Gelucire®, such as Gelucire® 44 / 14 (lauroyl polyoxyl-32 glyceride), Gelucire® 48 / 16 (polyethylene glycol monostearate), Gelucire® 50 / 13 (stearoyl polyoxyl-32 glyceride) and Gelucire® 59 / 14 (a mixture of lauroyl polyoxyl-32 glyceride and PEG 6000). In a preferred embodiment, the excipient is Gelucire® 44 / 14.

[0051] Information about lauroyl polyoxylglycerides and other related polymers can be found, for example, in Panigrahi, 2017, Jannin, 2009 and Strickley, 2004.

[0052] The excipients may be synthesized by any suitable method. In one embodiment, the excipients may be prepared by partial alcoholysis between glycerides of fatty acids and polyethylene glycol, for example between optionally hydrogenated coconut oil and / or optionally hydrogenated palm kernel oil and polyethylene glycol such as PEG-32. The possible reactions are shown in the following scheme: [ka] "PEG monoester" Monoester of fatty acid and polyethylene glycol "PEG diester" A diester of fatty acid and polyethylene glycol "Triglyceride" Triglyceride of fatty acids "Diglyceride" Diglyceride of fatty acids "Monoglyceride" Monoglyceride of fatty acid "PEG" Polyethylene glycol

[0053] In the scheme, R represents at least one fatty acid (i.e., -C(O)-R * R * is the aliphatic chain of a fatty acid, optionally substituted with a hydroxy group, and n is the number of ethylene oxide repeat units in the PEG. * is as defined above.

[0054] In certain embodiments, the excipient is obtained by polyglycolysis of hydrogenated vegetable oil with PEG, for example, optionally hydrogenated coconut oil or optionally hydrogenated palm kernel oil with polyethylene glycol, such as PEG-32. In another embodiment, the excipient can be obtained by esterification of polyol with fatty acid, such as esterification of glycerol with fatty acid, esterification of polyethylene glycol (PEG) with fatty acid and mixture. Free PEG can be present in the excipient. If desired, additional free polyethylene glycol can be added.

[0055] In the pharmaceutical composition, * The amount of the compound having the general formula (A) and / or the excipient is not particularly limited. The pharmaceutical composition may contain, for example, about 2% by weight to about 10% by weight, preferably about 3% by weight to 5% by weight of the compound having the general formula (A) and / or the excipient. *The pharmaceutical composition may contain about 90% by weight to about 98% by weight (preferably about 95% by weight to about 97% by weight) of an excipient, based on 100% by weight of the total pharmaceutical composition.

[0056] In some embodiments, the pharmaceutical composition comprises about 90% to about 98% by weight, preferably about 95% to about 97% by weight, of an excipient which is lauroyl polyoxyl-32 glyceride, and about 2% to about 10% by weight, preferably about 3% to about 5% by weight, of a compound of the general formula (A) and / or (A * In certain embodiments, the pharmaceutical composition contains about 90% to about 98% by weight, preferably about 95% to about 97% by weight, of an excipient which is lauroyl polyoxyl-32 glyceride, and about 2% to about 10% by weight, preferably about 3% to about 5% by weight, of a compound having the general formula (B) and / or (B * ) is contained.

[0057] The pharmaceutical compositions are formulated and administered in a manner consistent with good medical practice, taking into consideration the clinical condition of the individual patient, the site of delivery of the pharmaceutical composition, the method of administration, administration scheduling, and other factors known to physicians. Thus, the "effective amount" of the pharmaceutical composition for purposes herein is determined by such considerations.

[0058] The pharmaceutical compositions disclosed herein are preferably formulated for oral administration and may be in unit dose form of a tablet, capsule, caplet, etc., preferably a capsule.

[0059] In one embodiment, the unit dosage form comprises a compound represented by the general formula (A), (A * In certain embodiments, the unit dosage form contains 5 mg to 100 mg, or 10 mg to 75 mg, or 10 mg to 50 mg, or 10 mg, or 30 mg of a compound having the general formula (B), (B * ) or mixtures thereof, containing 5 mg to 100 mg, or 10 mg to 75 mg, or 10 mg to 50 mg, or 10 mg, or 30 mg of a compound having the formula:

[0060] The pharmaceutical composition of the present invention is for use in medicine, in particular for use in the treatment or prevention of diseases associated with protein aggregation and / or neurodegenerative diseases.

[0061] General formula (A) and / or (A * ) may be used for the preparation of a pharmaceutical composition of the present invention, the pharmaceutical composition being for treating or preventing a disease associated with protein aggregation and / or a neurodegenerative disease. In certain embodiments, a compound having the general formula (B) and / or (B * ) are used for the preparation of pharmaceutical compositions of the present invention.

[0062] In a further embodiment, the present invention is directed to a method for treating or preventing a disease associated with protein aggregation and / or a neurodegenerative disease, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention. In a particular embodiment, the method comprises administering to a patient in need thereof a compound represented by the general formula (B) and / or (B * The method includes administering a pharmaceutical composition containing a compound having the formula:

[0063] Diseases associated with protein aggregation are characterized by the presence of aggregated forms of at least one protein or a fragment or derivative thereof, where the protein is selected from the group consisting of α-synuclein, prion protein, Abeta (amyloid beta, Aβ), tau, amyloid precursor protein (APP), superoxide dismutase, immunoglobulins, amyloid-A, transthyretin, beta2-microglobulin, cystatin C, apolipoprotein A1, TDP-43, islet amyloid polypeptide, ANF, gelsolin, insulin, lysozyme, fibrinogen, huntingtin and ataxin, and other proteins with polyglutamine expansions.Preferably, α-synuclein, prion protein, Abeta (amyloid beta, Aβ), and tau, more preferably α-synuclein.

[0064] Examples of disease include, but are not limited to, Parkinson's disease, multiple system atrophy, dementia with Lewy bodies (DLB), prion disease, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia and other polyglutamine diseases, hereditary cerebral amyloid angiopathy, familial amyloid polyneuropathy, primary systemic amyloidosis (AL amyloidosis), reactive systemic amyloidosis (AA amyloidosis), type 2 diabetes, injection site localized amyloidosis, beta 2 microglobulin amyloidosis, hereditary non-neuropathic amyloidosis, Finnish hereditary systemic amyloidosis.Preferably, the disease is Parkinson's disease, multiple system atrophy (MSA), or dementia with Lewy bodies (DLB).

[0065] As used herein, the terms "treating" and "method of treatment" include preventative (e.g., prophylactic), curative, or palliative, as well as their different forms. As used herein, the term "treating" includes alleviating or reducing at least one of the harmful or negative effects or symptoms of a condition, disease, or disorder. The condition, disease, or disorder may be a neurodegenerative disease, including alpha-synucleinopathies, such as MSA, PD, DLB, etc.

[0066] The term "administering" means providing a pharmaceutical composition or unit dosage form of the present invention to a patient.

[0067] The term "therapeutically effective amount" refers to, for example, a compound of the general formula (A) and / or (A * ) or the general formula (B) and / or (B * ) refers to an amount of the compound sufficient to elicit the biological or medical response in a cell, tissue, organ, animal or human that is desired by a physician when administered.

[0068] The terms "subject" and "patient" are used interchangeably herein and refer to, for example, a mammalian subject, preferably a human or human patient.

[0069] The singular forms "a," "an," and "the" may refer to plural articles unless specifically stated otherwise.

[0070] The term "wt%" refers to the weight percentage of the total weight, e.g., the total weight of the pharmaceutical composition. In some embodiments, the unit dose contains about 2% to about 10% by weight of the compound disclosed herein, based on 100% by weight of the total pharmaceutical composition of the unit dose. In certain embodiments, the pharmaceutical composition contains about 3% to about 5% by weight of the compound disclosed herein, based on 100% by weight of the total pharmaceutical composition, and about 95% to about 97% by weight of the excipient.

[0071] As used herein, in the case of a capsule, references to the total weight of the dosage form refer to the total weight of the capsule contents, excluding the weight of the capsule itself. The type of capsule is not limited and may be made from natural or synthetic materials, including gelatin or hydroxypropylmethylcellulose (HPMC).

[0072] As used herein, the terms "once daily" and "QD" refer to administration of one dose per day, approximately every 24 hours. As used herein, the terms "twice daily" and "BID" refer to administration of two doses per day, typically one in the morning and one in the evening.

[0073] The term "about" as used herein is meant to qualify the numerical value it modifies and indicates that such value varies within an acceptable error. Where a specific error tolerance, such as a standard deviation to the average value given in a graph or table of data, is not indicated, the term "about" should be understood to mean a range that encompasses the indicated value and ranges included in that number by rounding up or down, taking into account significant digits.

[0074] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat the therapeutic disorders described herein. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, e.g., in a single dosage form with a fixed ratio of active ingredients, or in repeated, separate dosage forms for each active ingredient. In addition, such administration also encompasses the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will result in the beneficial effects of the drug combination in the treatment of the disorders described herein. A non-limiting example is in the treatment of Parkinson's disease, where the compounds of general formula (A) and / or (A * ) or the general formula (B) and / or (B * Compounds having the general formula (A) or (A) may be administered in combination with dopaminergic active ingredients (APIs) or anti-Parkinson's disease APIs that increase dopamine-related actions in the brain. Such APIs may be selected from, for example, dopamine precursors, dopamine agonists, inhibitors of dopamine degradation and / or dopamine agonists, dopa decarboxylase inhibitors, and other APIs (Cacabelos, 2017). * Therapeutic compounds that may be administered with a compound having the formula (I) include levodopa, carbidopa, opicapone, rasagiline, and the like.

[0075] Pharmacokinetic (PK) terms: "Tmax", "Cmax", "T1 / 2", "AUC 0-t ", "A.U.C. 0-24 " and "AUC 0-inf " are terms known to those of skill in the art. Tmax refers to the time of maximum observed concentration, Cmax refers to the maximum observed concentration, T1 / 2 refers to the time it takes for Cmax to decline by half, and AUC 0-t is the area under the plasma concentration versus time curve from time zero to a set time t, AUC 0-24 is the area under the plasma concentration versus time curve from time zero to 24 hours, AUC 0-inf is the area under the concentration-time curve from time zero to infinity. In certain embodiments, the general formula (B) and / or (B *) compound (i.e., anle138b) was measured in plasma and the PK parameters disclosed herein refer to measurements of anle138b.

[0076] The term "bioavailability" or abbreviated as "BA" refers to the ability of a drug, i.e., a compound represented by the general formula (A) or (A * For example, bioavailability can refer to the fraction of a drug in the systemic circulation following administration to a subject or patient in the fed or fasted state.

[0077] In the field of pharmaceutical formulations, it is well understood that the pharmacokinetic (PK) performance of some compositions is affected by the presence or absence of food in the gastrointestinal (GI) system. A "food effect study" is typically performed to observe the effect of food on the bioavailability (BA) of a drug between fed and fasted treatments. Thus, administration of an oral dosage form exhibiting a food effect may be preferably performed under "fasted" conditions, for example, 1 hour before or 2 hours after a meal. As used herein, the term "without food" or "without food" means that a human's exposure to a drug is substantially unaffected by food, and that the agent, i.e., the pharmaceutical composition of the present invention, may be administered regardless of the feeding state of a human subject. In some embodiments, the compound of formula (B), (B * When a single dose of a compound of formula (I) or a mixture thereof is administered to a healthy subject, the ratio of fasted AUC(0-24) to fed AUC(0-24) of anle138b is less than 1.5, preferably less than 1.4.

[0078] The US FDA requirements for food effect testing, and definitions of fasted and "fed" states, can be found at https: / / www.regulations.gov / document?D=FDA-2001-D-0040-0003 (July 22, 2020), which is incorporated by reference herein in its entirety.

[0079] With respect to the preceding embodiments, it is contemplated that each embodiment disclosed herein is applicable to each of the other embodiments disclosed, for example features described in composition embodiments described herein may be used in use embodiments, and vice versa.

[0080] Having described the disclosure with respect to certain preferred embodiments, other embodiments will become apparent to those skilled in the art from consideration of the present specification. The present disclosure is further illustrated by reference to the following examples, which describe in detail the methods of preparing and using the compositions of the present disclosure. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be made without departing from the scope of the present disclosure. EXAMPLES

[0081] Example 1.1: anle138b formulation study Anle138b is a lipophilic compound. Studies were conducted to evaluate approaches to increase the solubility of anle138b for formulation development. The formulations were prepared as gelatin capsules and tested for drug loading in biorelevant dissolution media 0.1 N HCl, simulated gastric fluid (SGF) and fasted state simulated intestinal fluid (FaSSIF) as well as in vivo (PK in rats).

[0082] In the initial excipient screening, three formulations were prepared in which anle138b was soluble. The formulation compositions and dissolution data from 0.1 N HCl solution are shown in Table 1.

[0083] [Table 1]

[0084] Vehicles 1, 2 and 3 were selected as having good solubility and were further tested for dissolution in 0.1N HCl media. The dissolution data shows that vehicle 1 exhibited slow dissolution at the 25mg dose and too rapid dissolution at the 50mg dose. Vehicle 2 exhibited slow dissolution at the 25mg dose and too rapid dissolution at the 50mg dose. Vehicle 3 exhibited a good dissolution profile at the 50mg dose and was further tested in simulated gastric fluid (SGF) and fasted state simulated intestinal fluid (FaSSIF). In both media, the samples began to exhibit large flakes, which increased over time and may be responsible for the rapid release profile observed after 60 minutes.

[0085] Tables 2A and 2B show the dissolution rates of formulations with Vehicle 3 as an average of three samples in SGF and FaSSIF, respectively.

[0086] [Table 2A]

[0087] [Table 2B]

[0088] Visual Observation in both media (SGF and FaSSIF): Samples began to change appearance from fine suspension to larger flakes / clumps that increased over time 45-60 minutes after the start of dissolution, consistent with the decrease in % values ​​observed after this time point.

[0089] In the second approach, the enhancement of solubility by nanomilling the API was tested. A vehicle was prepared by dissolving 1 w / v % HPMC Pharmacoat 603 (Shin-Etsu Chemical Co., Ltd.) and 0.25 w / v % sodium lauryl sulfate (SLS) in purified water, anle138b was added, and the suspension was subjected to three consecutive cycles (99 min each) of milling using a Retsch Mill MM200 with 0.6 mm diameter yttrium zirconium beads, after which the resulting suspension was collected and kept under constant magnetic stirring until dose administration. The mean particle size distribution (PSD) of the nanomilled samples is as follows: D(10) 0.07 um, D(50) 0.156 um, and D(90) 1.57 um. Figure 1 shows the particle size distribution graph of two batches of nanomilled formulation.

[0090] Tables 3A and 3B show the dissolution rates of the nanomilled formulations as an average of three samples in SGF and FaSSIF, respectively.

[0091] [Table 3A]

[0092] [Table 3B]

[0093] The nanomilled formulation exhibited a slow and steady release profile with less than 10% of the API released after 2 hours. This was considered an unacceptable release profile. The drug appeared as a fine suspension throughout the dissolution run. In a third approach, anle138b was formulated into the sole solubilizer, lauroyl polyoxyl-32 glyceride, also known under the trade name Gelucire® 44 / 14, which is a mixture of one mono- and / or diester of fatty acids, mono-, di- and triglycerides of fatty acids and free PEG.

[0094] Tables 4A and 4B show the dissolution rates of anle138b lauroyl polyoxyl-32 glyceride formulations in capsules as an average of three samples in SGF and FaSSIF, respectively.

[0095] [Table 4A]

[0096] [Table 4B]

[0097] Tables 4A and 4B show that the capsules dissolved approximately 15-30 minutes after the dissolution run and provided stable release profiles in biorelevant simulated fluids (simulated gastric fluid (SGF) and simulated fasted state intestinal fluid (FaSSIF)) and were deemed suitable for clinical use.

[0098] A formulation containing lauroyl polyoxyl-32 glyceride ("Gelucire® 44 / 14") was selected for further preclinical and clinical development. The study resulted in the identification of a semi-solid in capsule formulation in a 00 size capsule shell (two dosage strengths, 10 mg and 30 mg anle138b per capsule, respectively, and one placebo) containing lauroyl polyoxyl-32 glyceride (Gelucire® 44 / 14) as an excipient.

[0099] Example 1.2 Formulation testing in rats A rat study was conducted to evaluate the pharmacokinetics of anle138b following single oral administration of different formulations of anle138b in male Sprague Dawley rats (n=3 / group), as shown below in Table 5.

[0100] [Table 5]

[0101] Preparation of Formulation A: A vehicle was prepared by weighing out Kolliphor® RH40 (Sigma Aldrich, 45% of final volume), PEG400 (Sigma Aldrich, 35% of final volume) and Caprylol90 (Gattefosse, 20% of final volume). The mixture was stirred and warmed (using a thermostatically controlled bath) to approximately 50°C for about 15 minutes until a clear liquid was obtained. Anle138b was added to the vehicle, which was kept under continuous stirring at 50°C. The mixture was stirred for an additional 15 minutes and sonicated for 10 minutes until a visually clear solution was obtained.

[0102] Preparation of Dosage Formulation B: Vehicle was prepared by dissolving 1 w / v % HPMC Pharmacoat 603 (Shin-Etsu Chemical Co., Ltd.) and 0.25 w / v % sodium lauryl sulfate (SLS) in purified water, anle138b was added, and the suspension was subjected to three consecutive cycles (99 min each) of milling using a Retsch Mill MM200 with 0.6 mm diameter yttrium zirconium beads, after which the resulting suspension was collected and kept under constant magnetic stirring until dose administration. The mean particle size distribution (PSD) of the nanomilled sample is as follows: D(10) 0.07 um, D(50) 0.156 um, and D(90) 1.57 um.

[0103] Preparation of Dosage Formulation C: anle138b was added to PEG400 (Sigma Aldrich) under constant magnetic stirring until complete dissolution of the test substance was obtained.

[0104] Preparation of Dosage Formulation D: The vehicle (Gattefosse; lauroyl polyoxyl-32 glyceride) was warmed to at least 20° C. above its melting point and anle138b was added under constant magnetic stirring. The formulation was maintained at 40° C. in a thermostatically controlled water bath and the treatment room syringes and cannulas were also preassembled and warmed prior to administration.

[0105] Anle138b was formulated on the day of dosing, except for Formulation C, which was prepared one day earlier.

[0106] Male Sprague Dawley (SD) rats (n=3 / formulation) procured from Charles River Italia were housed for 5 days for acclimatization. The feeding regimen was ad libitum, with food provided 4 hours after dosing only on dosing days, and the evening portion removed beforehand. Animals were orally dosed with anle138b (10 mg / kg) formulated as above. Individual serial plasma profiles were obtained from each animal over a 24-hour period following dosing.

[0107] Actual body weights were recorded on the day of dose administration, and doses were adjusted to take into account the body weight of the animals at the time of dose administration.

[0108] Dosing formulations were administered orally via gavage (2 mL / kg) and any formulation remaining after dosing was discarded.

[0109] After oral dosing, blood samples were taken from the tail vein of each rat at detailed time points: pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post-dose.

[0110] Approximately 150 μL of blood was collected into tubes containing anticoagulant (K3 EDTA), placed on crushed wet ice, and then centrifuged (2000 g for 10 min at +4° C.) as soon as practicable, and in any case within 1 h. The resulting plasma was separated from the red blood cell pellet and then transferred to uniquely labeled clear polypropylene tubes and immediately frozen in solid carbon dioxide or in a freezer at nominal −20° C.

[0111] PK profiling was performed by noncompartmental analysis using Phoenix™ WinNonlin. Nominal sampling times were used for all calculations. When feasible, systemic exposure to anle138b was determined by calculating the area under the plasma concentration-time curve (AUC) from the start of dosing to the last quantifiable time point (AUC0-t, t=8h) using the linear-log trapezoidal method. The highest observed peak plasma concentration (Cmax) and the time at which it was observed (Tmax) were determined by inspection of the observed data.

[0112] Relative bioavailability (% free) between dosage formulations of anle138b was calculated by comparing systemic exposure (AUC0-t) and is reported rounded to at least two significant figures. All dose levels, plasma concentrations and pharmacokinetic parameters are shown for the parent compound anle138b.

[0113] Results: Following a single oral dose of 10 mg / kg anle138b to male rats, anle138b was quantifiable in plasma in all animals for up to 8 hours post-dose. Tmax occurred between 2 and 8 hours post-dose. Significant differences in systemic exposure to anle138b, as mean Cmax and AUC0-t, were observed among the four formulations evaluated. PK values ​​(mean and range) are shown in Table 6.

[0114] [Table 6]

[0115] Differences in systemic exposure to anle138b were observed among the four formulations as mean Cmax and AUC0-8h. Formulations A and D performed best in terms of AUC and Cmax, with administration of formulation D resulting in mean AUC0-8h of anle138 approximately 5.6, 3, and 1.4-fold higher than those obtained after administration of formulations B, C, and A, respectively.

[0116] Using formulation A as a reference point, the relative bioavailability (Frel%) of formulated anle138b as B vs. A (reference) was approximately 25%, C vs. A (reference) was approximately 49%, and D vs. A (reference) was approximately 140%. Rat PK data show that after a single dose, formulations A and D exhibited superior AUC and higher Cmax than nanomilled anle138b suspension or anle138b in PEG400. Formulation D (Gelucire44 / 14) exhibited better AUC and Tmax overall and was selected for further development and testing.

[0117] Figures 2A-2D are graphs showing the PK Cmax profiles for each of the three animals in each group. Figure 2A shows the PK results for Formulation A, Figure 2B shows the PK results for Formulation B, Figure 2C shows the PK results for Formulation C, and Figure 2D shows the PK results for Formulation D.

[0118] Example 1.3 Phase 1 Drug (DP) Table 7 shows the ingredients for the Phase 1 DP of anle138b.

[0119] [Table 7]

[0120] The DP was packaged in white high density polyethylene (HDPE) bottles closed with tamper evident caps.

[0121] Solubility evaluation in lauroyl polyoxyl-32 glycerides: The visible solubility of API in dissolved lauroyl polyoxyl-32 glycerides was evaluated at 55°C. Six solutions at different concentrations (up to saturation) were prepared and then cooled to room temperature. A concentration of 50 mg (API) / g lauroyl polyoxyl-32 glycerides was considered as the starting reference.

[0122] Preparation of capsules and stress stability study: Two API doses (10mg and 30mg) were selected and solutions of the corresponding API were prepared in dissolved lauroyl polyoxyl-32 glyceride and filled into capsules. These capsule prototypes were banded and stored at 40°C / 75%RH and 50°C / ambient RH conditions and tested for assay and impurities after 15 and 30 days to check for incompatibilities (RH: relative humidity).

[0123] Technical batch manufacturing scale-up: The manufacturing of the semi-solid in capsule formulation (two dosage strengths) was scaled up to batch sizes representative of clinical manufacturing (1000-3000 units). A placebo batch was also prepared.

[0124] Preparation of solutions: The vehicle was prepared by melting lauroyl polyoxyl-32 glyceride at 55° C. The API was then added and mixed until complete solubilization.

[0125] Capsule preparation: The solution (pure dissolution vehicle for placebo) was filled into capsules at the appropriate fill weight by a HIBAR-P0450 machine, and the capsules were then banded with the appropriate gelatin in water solution using a BONAPACE-BD3000 banding machine. After banding, visibly damaged and / or improperly sealed capsules were discarded.

[0126] The capsules were dried for at least 24 hours and then checked under vacuum (T=55° C. and P<100 mbar, Heraeus VT6130M) for shell and banding integrity and for possible leakage. Capsules showing leakage of material were discarded.

[0127] Formal stability study on technical batches: Stability studies of two active and one placebo batches packaged in typical primary packaging (i.e. HDPE bottle packs with desiccant) were performed as detailed in the schedule shown in Table 8 below.

[0128] [Table 8]

[0129] Anle138b capsules (DP test and placebo) were tested in an ICH compliant stability study under long-term conditions (25°C / 60%RH) for 36 months and accelerated conditions (40°C / 75%RH) for 6 months. Drug stability is tested using standard assays including content integrity, impurities, appearance, moisture content and dissolution.

[0130] The anle138b DP described herein is stable at 25° C. / 60% RH for at least 18 months, preferably at least 24 months, and more preferably at least 36 months.

[0131] For subsequent clinical trials, formulations using hydroxypropyl methylcellulose (HPMC) capsules were prepared as described above substituting gelatin capsules for the HPMC capsules.

[0132] Example 2: Human Studies Example 2.1 Phase 1: Safety, tolerability and pharmacokinetics of anle138b: A first-in-human (FIH), randomized, double-blind, placebo-controlled Phase 1 study.

[0133] anle138b was studied in healthy subjects in a single-center, double-blind, randomized, placebo-controlled single-ascending dose (SAD) and multiple-ascending dose (MAD) study. Eligible participants were randomly assigned (1:1 for sentinel subjects and 1:5 for primary group) to placebo or anle138b, respectively (doses ranging from 50 mg to 300 mg daily). In addition, the effect of food on the pharmacokinetics (PK) of anle138b in healthy subjects was investigated at a dose of 150 mg daily (FES, food effect study). Participants were randomized to treatment sequence (fed → fasted) or (fasted → fed). Treatments for the SAD, MAD, and FES arms of the study were administered orally in hard gelatin capsules containing either 10 mg or 30 mg of anle138b with excipient (i.e., lauroyl polyoxyl-32 glyceride) or excipient alone. The primary endpoints were safety and tolerability, and the secondary endpoint was pharmacokinetics.Data from all randomized individuals were evaluated [Clinicaltrials.gov-identifier:NCT04208152.EudraCT-number:2019-004218-33].

[0134] Findings: 196 healthy volunteers were screened and 68 participants were enrolled. Of these, all completed the study according to protocol. Adverse events in this healthy volunteer study were mostly mild, and all recovered or resolved completely. No abnormal trends were observed in any major organ system class. The study drug was safe and well tolerated at all dose levels, and in humans achieved plasma levels significantly higher than required for full therapeutic efficacy in MI2 mice, a recently established rodent model of α-synucleinopathy (Wegrzynowicz, 2019; Levin 2022).

[0135] method Study Design: Single-centre, double-blind, randomised, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD), study of anle138b at doses up to 300mg daily in healthy subjects. The effect of food (FES) on the PK of anle138b in healthy subjects was investigated using a dose of 150mg. Participants were recruited from the Quotient Sciences ("CRO", Nottingham, UK) volunteer database. Approval from the ethical review committee and the Medicines and Healthcare products Regulatory Agency (UK) was obtained. The study was conducted in accordance with the protocol and the following legislation: Good Clinical Practice (GCP) International Conference on Harmonisation, latest edition including Consolidated Supplement E6, and Medicines for Human Use (Clinical Trials) Regulations including amendments Nos. 1928, 2984 and 941. In addition the study was conducted in accordance with the ethical principles outlined in the World Medical Association Declaration of Helsinki and its amendments. Study data was monitored. Independent study monitors were appointed to verify that the study was conducted in accordance with current GCP, regulatory requirements and the protocol, and that the data was authentic, accurate and complete.

[0136] Participants were healthy volunteers between the ages of 18 and 55 years who were able to understand the nature of the study and any risks associated with their participation. Participants had to be prepared to cooperate and able and willing to give written informed consent in accordance with the regulations and requirements of the protocol. The study included healthy male volunteers and healthy female volunteers of non-childbearing potential. Eligible participants had a body weight between 18.5 and 30.0 kg / m2 at screening. 2 To participate in the dietary effects study, participants had to be able to eat 90% of a U.S. Food and Drug Administration (FDA)-approved high-fat breakfast, including bacon.

[0137] Randomization and Masking: Eight participants were enrolled per dosing cohort in the SAD and MAD parts of the study. Participants were randomly assigned to placebo (N=2) or anle138b (N=6). Sentinel subjects and primary groups were randomized 1:1 and 1:5 to placebo or anle138b, respectively. A computer-generated randomization schedule was used. All participants and study staff who had direct contact with participants were blinded to treatment allocation. Medicine kits were numbered consecutively.

[0138] In the FES, participants (N=12) were unblinded to treatment as this cohort did not include a placebo, but were randomized 1:1 to a series of treatments in a two-way crossover design, such that six volunteers were first in the fed then fasted dietary condition, and the remaining six volunteers were randomized to the fasted then fed treatment order.

[0139] Justification of safe starting dose and exposure limits: This study followed the recommendations of the EMA (EMEA / CHMP / SWP / 28367 / 07 Rev.1; July 20, 2017) and the FDA (Guidance for Industry: Evaluation of the Maximum Safe Starting Dose for Early Clinical Trials of Therapeutics in Healthy Adult Volunteers. U.S. Department of Health and Human Services, Center for Drug Evaluation and Research (CDER), July 2005) for dose findings in first-in-human studies. A safe starting dose was established based on toxicity studies in animals. In a 28-day toxicity study in rats, the no observed adverse effect level (NOAEL) was determined to be 50 mg / kg / day (human equivalent dose 8.1 mg / kg). The dose range for this study was designed to start at 50 mg. The escalation between doses was planned to be flexible depending on the results obtained, but not to exceed a 2-fold increase.

[0140] Procedure: The test drug was manufactured by Aptuit, Italy. Anle138b in capsules was prepared as described in Example 1.3 above.

[0141] Subjects were screened for enrollment in the study up to 28 days prior to dosing, entered the clinical site the morning before dosing (day -1) and remained at the site until 48 h after dosing. A post-study follow-up visit was conducted 5-7 days after the final dose to monitor safety and health. Volunteer screening included complete physical examination, medical history taking and review of medical reports, safety procedures such as weight and height check to calculate body mass index (BMI), blood safety (hematology, clinical chemistry and virology, serum pregnancy test), 12-lead electrocardiogram, vital signs (blood pressure, heart rate, and oral temperature), breath carbon monoxide test, drug screen for drugs of abuse, breath alcohol test, and urine test.

[0142] In the SAD, subjects received a single dose of anle138b or placebo after abstaining from all food and drink (except water) for at least 8 hours prior to dosing. Dosages in the four SAD cohorts were 50 mg, 100 mg, 200 mg, and 300 mg of free anle138b equivalents once daily for cohorts A, B, C, and D, respectively. In the MAD part, subjects received anle138b or placebo once daily (QD) for 7 days after abstaining from all food and drink (except water) for at least 8 hours prior to dosing. Dosages in the three MAD cohorts were 50 mg, 100 mg, 200 mg, and 300 mg of free anle138b equivalents once daily for cohorts A, B, C, and D, respectively. M , B M and C MThe doses were equivalent to 100 mg, 200 mg, and 300 mg free anle138b, respectively. Post-dose mouth and hand checks were performed to ensure that the capsules were swallowed. Intra-study decisions were made by a Safety Advisory Committee (SAC) including the principal investigator, sponsor's medical monitor, and PK experts. To proceed with dose escalation, data had to be available from at least 6 subjects per cohort who completed per-protocol safety and PK reviews through 48 hours post-dose to ensure that at least 4 subjects received active IMP. The decision to proceed to the next higher dose level was based on safety, tolerability, and available PK data through 48 hours post-dose. The following data were analyzed: adverse events, vital signs, safety labs, ECG, physical examination, plasma concentrations of anle138b, and interim PK parameter estimates (Tmax, Cmax, AUC 0-24 , AUC 0-tau , AUC 0-last and T1 / 2, if applicable). Data to the SAC were provided according to the CRO's standard operating procedures (SOPs) for interim dose titration and dose escalation.

[0143] In the food effect study (FES), the effect of food on the PK of anle138b was explored using a single 150mg dose of anle138b, a dose level previously deemed safe and well tolerated in the SAD and MAD cohorts. This dose was administered either i) after a standard FDA approved high-fat breakfast, or ii) in a fasting state, i.e. abstaining from all food and drink (except water) for at least 8 hours prior to dosing. Overall, a cohort of 12 subjects was randomized 1:1 to two treatment sequences (fed → fasted) or (fasted → fed). A minimum washout of at least 5 half-lives of anle138b was ensured between each dose.

[0144] Outcome Measures: The primary objective was to evaluate the safety and tolerability of single (SAD) and multiple (MAD) ascending doses of anle138b in healthy subjects in the fasted state, as well as to evaluate the safety and tolerability of a single dose of anle138b in both fasted and fed states (FES). For this purpose, adverse events (AEs), clinical laboratory tests, vital signs, electrocardiogram (ECG), QT interval corrected for heart rate (QTcF) using the Fridericia formula, and physical examination findings were recorded. Participants were instructed to immediately report all potential AEs to on-site staff and to undergo a physician evaluation before each administration of study drug. In addition, if a subject reported any new symptoms or AEs, a physical examination of the relevant body systems was performed. AEs were defined according to standard criteria described in the protocol. Details of PK parameters are shown in Tables 9-10 below. Any clinically significant abnormalities in these assessments, including changes from baseline, were required to be reported as AEs.

[0145] Secondary outcome measures were the oral PK of anle138b in the fasted state with single (SAD) and multiple (MAD) ascending doses, and the effect on PK of coadministration of anle138b with food. For this purpose, PK blood samples were taken pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16 and 20 h after dosing on day 1 (and day 7 for MAD), pre-dose only (MAD) on days 2-6, and 24, 30, 36 and 48 h after the last dose. Analysis of anle138b in plasma was performed by Aptuit. The last time point of quantifiable data showed an increase with increasing dose as follows: SAD: 50 mg dose (subjects ranging from 8 to 24 h) to 300 mg dose (subjects ranging from 36 to 48 h). MAD: dose 100mg (subjects in the range of 8-36h) to dose 300mg (subjects in the range of 20-48h). In FES, subjects were in the range of 24-48h.

[0146] Data management was performed by the CRO using a validated electronic case report form (eCRF) database system to ensure data consistency and validity. Data queries were performed by data management staff within the study's eCRF database and resolved with the assistance of clinical staff.

[0147] AEs and medicines were coded using the Medical Dictionary for Clinical Description of Events (MedDRA) (v22·1). An independent review of the codes was performed within the Data Science department. Clinical chemistry and haematology data (and other safety laboratory data) were collected by a central laboratory (The Doctors Laboratory) and transferred electronically to the CRO. All demographic details and sampling dates were cross-referenced with corresponding data on the study database. Data were monitored by an external entity (Wirral Clinical Consultancy Ltd, Heswall, UK). Monitoring included conducting an initial visit to the site, interim monitoring visits and a terminal visit. The database was closed once all queries had been resolved.

[0148] Statistical Analysis: The study was exploratory and no formal sample size calculation was performed. Based on experience from previous studies of similar design, 8 subjects per cohort were enrolled in Part 1 (SAD) and Part 2 (MAD) and a total of 12 subjects in Part 3 (FES). Populations and analysis sets for safety and PK data were determined after database lock using criteria defined in the reporting and analysis plan. Safety populations and safety analysis sets for SAD and MAD were defined after database lock but before unblinding of the study. Statistical analysis and generation of summary tables, figures and listings for all safety data (AEs, vital signs, ECG and safety laboratory assessments) including changes from baseline were performed using the statistical package SAS (v9·4) as required for this study. Additional statistics were provided for PK-related data including coefficient of change (CV%), geometric mean, geometric CV% and geometric n (i.e., number of subjects under observation included in natural log transformation). Dose proportionality was assessed in SAD and MAD. To assess dose proportionality, log-transformed PK parameters, AUC for SAD (day 1), 0-last , AUC 0-inf , and Cmax, and AUC for MAD (days 1 and 7) 0-tau Formal statistical analysis was performed for and Cmax using the following power model: log e (AUC or Cmax) = μ + β x log e (dose)

[0149] The relationship between the PK parameter (y) and dose is defined as follows: y=α * Dose β, where y is the AUC or Cmax. Dose proportionality requires that β=1 for the dose-dependent parameters, which, after logarithmic transformation, results in a linear relationship: Log(y)=μ+β * log(dose)

[0150] where μ=log(α) is the intercept and β is the slope from the linear model. Using this model, it is possible to estimate β (a measure of dose proportionality) and obtain a 90% confidence interval (CI) for β (Gough, 1995; Smith, 2000). The estimate of β and its 90% CI (βI, βu) were used to quantify the degree of non-proportionality. In the MAD, the PK parameter AUC 0-tau Formal statistical analysis was performed to assess dose accumulation for Cmax and Cmax. Log-transformed AUC 0-tau Cmax and Cmax were subjected to a mixed effects model with treatment (dose level), day (day 1 or day 7) and the interaction of treatment by day as fixed effects and subject as a random effect. Adjusted means obtained from the model including the differences and associated 90% CIs for each comparison of interest were back transformed to log scale to obtain adjusted geometric means, adjusted geometric mean ratios (GMRs) and 90% CIs for the ratios. GMRs and 90% CIs were given for each treatment and overall, i.e., day 7 / day 1. For FES, the PK parameters C max , AUC 0-last and AUC 0-24 Formal statistical analysis was performed to assess the effect of food on anle138b. PK parameters were natural log transformed and analyzed using a mixed-effects model with treatment condition (i.e., dietary condition) as fixed effects, period and sequence, and subjects stratified within sequence as a random effect. Adjusted GMR and 90% CIs for adjusted GMR are given for comparisons between fed and fasted states, with the ratio defined as fed / fasted.

[0151] Results: Of 196 individuals assessed for eligibility, 89 failed screening, 39 were reserve subjects, and 68 were included in the study. Of the included participants, 32 subjects (8 in 4 dose groups) were included in the SAD part, 24 subjects (8 in 3 dose groups) in the MAD part, and 12 subjects in the FES. In the SAD part, 8 participants received placebo. In the MAD part, 6 participants received placebo. All participants completed the study as planned according to the protocol. There were no dropouts or early discontinuations. The demographic characteristics of the study population at baseline were similar for all cohorts and groups. Of the 32 participants in the SAD part, 3 (9%) were female, and all other participants, including the MAD part and FES, were male. 100% of the study medication was taken as scheduled in all groups.

[0152] The primary readouts of this study were safety and tolerability. There were no serious adverse events (SAEs) or AEs leading to withdrawal of study drug in any part of the study. Treatment-emergent AEs were reported in comparable numbers in both treatment and placebo groups. There was no dose dependency in AE reporting. All AEs were fully resolved. In summary, daily oral administration of anle138b was shown to be safe and well tolerated when administered up to 7 consecutive days at a maximum dose of 300 mg per subject per day. The secondary readout was PK.

[0153] anle138b-P1-01 Exam Part 1 (SAD) Table 9 shows the geometric means (CV%) of the main pharmacokinetic parameters of anle138b in healthy volunteers following single-dose oral administration of anle138b DP. For Tmax, median values ​​(range) are shown. Abbreviations: T max : Time to maximum peak; C max :Maximum concentration;AUC:Area under the curve (=exposure);T 1 / 2 : plasma half-life; h: hour; ng: nanogram; ml: milliliter; NA: not applicable. Maximum concentrations were achieved between 0.5 and 2 hours after dosing (median Tmax was 1 to 1.5 hours after dosing).

[0154] [Table 9]

[0155] Overall, the PK data showed that the drug was systemically distributed following oral dosing with rapid absorption and biphasic elimination. The actual terminal elimination half-life was approximately 12 h. Potential therapeutic exposure (based on non-clinical in vivo models) was already achieved after a single 100 mg dose of anle138b. Increasing doses of 200 or 300 mg resulted in a corresponding increase in therapeutic exposure without any associated safety concerns.

[0156] Following oral administration of DP, plasma concentrations of anle138b were quantifiable 0.5 hours post-dose in all subjects and remained quantifiable up to 24 hours post-dose in the low-dose group and up to 48 hours post-dose in the high-dose group. Single-dose plasma concentrations of anle138b (Figure 3, log plot).

[0157] Cmax values ​​increased more than proportionally across the 50-200 mg dose range and proportionally from 200 to 300 mg. A two-fold dose increase from 50 mg to 100 mg resulted in an approximately 2.9-fold increase in Cmax and a 3.3-fold increase in AUC. A further two-fold dose increase from 100 mg to 200 mg resulted in an approximately 2.9-fold increase in Cmax and a 3.0-fold increase in AUC. A 1.5-fold dose increase from 200 mg to 300 mg resulted in an approximately 1.5-fold increase in Cmax and a 1.5-fold increase in AUC.

[0158] The elimination half-life of anle138b was variable. 1 / 2 was 3.9 hours in the 50 mg cohort, and 10.8 and 12.8 hours in the 100 and 200 mg cohorts, respectively. 1 / 2 The mean time to recovery increased to 16.2 hours in the 300 mg group. 1 / 2The variability in is suspected to be due to differences in the time of the last quantifiable concentration between subjects, leading to an inaccurate characterization of the true terminal elimination phase, especially in the 50 mg cohort. Dosage variation may also be due to autoinhibition of metabolic pathways of the drug, such as CYP1A2.

[0159] anle138b-P1-01 Exam Part 2 (MAD) Following oral administration of anle138b in capsule form, plasma concentrations of anle138b were quantifiable 0.5 hours post-dose in all subjects and remained quantifiable up to 24 hours post-dose in all dose groups, both on days 1 and 7 (Figures 4A and 4B, respectively).

[0160] T max appeared to be relatively unaffected by repeated dosing. Maximum concentrations were achieved between 1.0 and 2.0 hours after dosing (T max The median time was 1-1.5 hours after administration. On the first day, max The values ​​increased more than proportionally over the dose range of 100 to 300 mg. A doubling of the dose from 100 mg to 200 mg resulted in a C max A 3.3-fold increase in C and a 3.5-fold increase in AUC were observed. A 1.5-fold increase in dose from 200 mg to 300 mg resulted in a max The C was increased by 2.0-fold and the AUC was increased by 2.4-fold (Table 10). max and AUC exposure were reduced. For example, compared to day 1, max and AUC decreased by approximately 53% in the 100 mg group and C max and AUC were reduced by approximately 70%, and C max and AUC were reduced by 66% and 71%. Thus, the accumulation ratio was less than 0.54 per cohort. max and AUC values ​​increased almost dose-proportionally with increasing dose.

[0161] Repeated dosing also resulted in decreased half-life compared with single-dose escalation in Part 1 of the study, with the exception of T1 / 2 was approximately 10 h and was therefore broadly similar to those in MAD and SAD, which may be related to the autoinduction of the drug's metabolic pathway.

[0162] [Table 10]

[0163] Overall, repeated daily administration of anle138b C max and AUC were decreased by approximately 50 to 70%. These decreases with repeated dosing are consistent with those seen with repeated dosing in animal studies. The decreased exposure appears to be the result of induction of metabolic enzymes, e.g., CYP1A2 (oxidative metabolism). Decreased levels of anle138b were also observed relative to nadir (i.e., pre-dose) levels. Of note, a steady state of exposure relative to nadir levels appeared to be reached by day 5.

[0164] In summary, the PK data demonstrated that the study drug was safe and well tolerated at all dose levels. The actual elimination half-life was approximately 12 h. C max and AUC increased with dose. Potential therapeutic exposure levels (AUC (0-24) >300ng * h / ml) was obtained at a dose of 100 mg. Maximum concentrations were achieved between 0.5 and 2 hours after administration (T max The median elimination half-life was 1-1.5 hours after administration. The terminal elimination half-life was approximately 12 hours. max C following 7 days of daily dosing max and AUC values ​​were decreased by approximately 50% to 70%, which is thought to be due to induction of metabolizing CYP enzymes, especially CYP1A2.

[0165] Overall, based on non-clinical in vivo models, potential therapeutic exposure was achieved after a single 100 mg dose, with increased doses of 200 or 300 mg correspondingly increasing exposure levels without any safety concerns.

[0166] Study Part 3: Food Effects Following oral administration of anle138b in both fasted and fed states, plasma concentrations of anle138b became quantifiable between 0.5 and 1.0 hours post-dose and remained quantifiable for up to 24 to 48 hours post-dose (Figure 5).

[0167] The maximum concentration was achieved between 1 and 2 hours after administration in the fasting state (T max The median time was 1.25 hours after administration), and in the fed state, it was between 1.5 and 3 hours after administration (T max The median bioavailability was achieved 3.00 hours after dosing (Table 10). A change from fasted to fed food state resulted in approximately 74% (90% CI: 61%, 84%) of the dose being bioavailable in the fed state compared with the fasted state. max The mean Cmax decreased by about half when accompanied by food (mean Cmax was 196 ng / ml (range 110-479) when fed and 442 ng / ml (range 225-1420) when fasted), and T max Total exposure was less affected following dosing with food (fasted AUC 0-24 The average value was 896ng. * h / mL (range 433-2720), and 641 ng when fed. * h / mL (range 378-1920). Exposure (C max Within-subject variability associated with ΔP (ΔC and AUC) was moderate across both regimens. Overall, the ranges of exposure observed overlapped for fed and fasted dosing.

[0168] The elimination half-life of anle138b was only slightly higher in the fed state, with geometric means of 11.3 and 15.2 hours after administration in fasted and fed regimens, respectively.

[0169] [Table 11]

[0170] Overall, the PK data demonstrated that the study drug was safe and well tolerated following both fasted and fed conditions. Treatment under fed conditions led to a delay in time to maximum concentration, which is predictable based on the altered kinetics of IMP uptake in a full stomach compared to an empty stomach. Cmax was reduced by approximately half with food, and T max coincided with a delay in

[0171] Administration of anle138b with food led to a slight decrease in total exposure, however, as exposure levels were observed in largely overlapping ranges for fed and fasted dosing, the decrease is not considered clinically relevant for dosing.

[0172] Example 2.2 Phase 1 Clinical Trial in PD Patients Study Title: A single-part study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending oral doses of anle138b and to characterize the effect of food on the pharmacokinetics of anle138b in patients with mild to moderate Parkinson's disease.

[0173] This was a two-center, double-blind, randomized, placebo-controlled study that enrolled twenty-two (22) participants in cohorts (i.e., regimens) A through C. All completed the study according to protocol. After completion of cohorts A through C, it was decided to add 24 subjects in cohorts D and E. Cohort D was to expand the sample size of the previous dosing regimens of 150 mg and 300 mg QD, and cohort E was to receive 300 mg of anle138b in a non-fasted state for 28 days.

[0174] Medications used are described in section 1.3 above, with placebo being the vehicle in the capsule. Subjects were 50-80 years old and diagnosed with idiopathic PD as defined by Movement Disorder Society criteria (meeting either criteria for "clinically established PD" or for "clinically possible PD"). Subjects were required to demonstrate Horn-Yahr stage I-III (i.e., ambulatory without assistance) and expected stable medication for the month prior to participation and for the duration of the study. Subjects were randomly assigned to receive one of three drug regimens, A, B, or C, as follows:

[0175] Regimen A- 150 mg (5 × 30 mg) anle138b oral capsule or matching placebo QD for 7 consecutive days under fasted condition, followed by a single dose of 150 mg anle138b oral capsule or matching placebo under fed condition on day 9.

[0176] Regimen B- 300 mg (10 × 30 mg) anle138b oral capsules or matching placebo QD for 7 consecutive days in the fasted state, followed by a single dose of 300 mg anle138b oral capsules (10 × 30 mg capsules) or matching placebo in the fed state on day 9.

[0177] Regimen C-150 mg (5 × 30 mg) anle138b oral capsule or matching placebo BID (total 300 mg daily) for 7 consecutive days in fasting state.

[0178] Subjects in Regimen E were randomly assigned to receive either 300 mg (10 × 30 mg) anle138b oral capsules or matching placebo QD for 28 consecutive days in the non-fasting state.

[0179] The feeding state was considered moderate with a standard-sized breakfast of 570 kcal containing 24% fat.

[0180] The primary endpoint was to provide safety and tolerability information of the test product by assessing AEs, vital signs, ECGs, physical examination and laboratory safety tests, and to provide additional information on the safety and tolerability of the test product in the fed state by assessing AEs, vital signs, ECGs, physical examination and laboratory safety tests.

[0181] Secondary endpoints provided PK information in PD patients for the test product by assessing plasma exposure in fasted and fed states.

[0182] Pharmacodynamic assessment included the Movement Disorder Society-provided Revised Unified PD Rating Scale (MDS-UPDRS). Interim data reviews were conducted following each cohort to agree on progression and dose levels for the next cohort.

[0183] A dose of 150 mg of anle138b was selected for the first dosing cohort of the study to allow for an additional safety factor 2 compared to the maximum dose (i.e., 300 mg) tested in the first-in-human (FIH) study (see Example 2.1 above).

[0184] Results: The data show that doses of anle138b up to 300 mg were safe and well tolerated in the conditions tested. Furthermore, the PK data were similar to those obtained in the FIH healthy volunteer study. Table 12 shows the geometric means (CV%) of the main pharmacodynamic parameters of anle138b following repeated oral administration of anle138b in capsule form in patients in the fasted state on days 1 and 7.

[0185] The 300 mg dose of anle138b on day 28 will have similar PK trends to those observed following dosing on day 7. Concentrations are expected to be in a similar range; therefore, efficacy responses are not expected to be compromised, with an overall well-tolerated safety profile.

[0186] [Table 12]

[0187] Table 13 shows the geometric means (CV%) of the major pharmacokinetic parameters of anle138b following a single oral dose of anle138b in capsule form in patients in the fed state on Day 9.

[0188] [Table 13]

[0189] Following single oral doses of anle138b in capsule form at 150 mg (regimen A [QD] and regimen C [BID]) and 300 mg (regimen B (QD)) in the fasted state on day 1, peak plasma concentrations (Cmax) of anle138b occurred between 1.00 and 1.50 hours (h) post-dose, 1.00 to 4.00 h post-dose, and 1.00 to 2.00 h post-dose, respectively, and median Tmax occurred at 1.25 h, 1.50 h, and 1.00 h post-dose for regimens A, B, and C, respectively.

[0190] Following oral administration of anle138b in capsule form at 150 mg (regimen A [QD] and regimen C [BID]) and 300 mg (regimen B [QD]) once daily for 7 days, peak plasma concentrations of anle138b occurred between 1.00 and 2.00 h post-dose, 1.00 and 2.00 h post-dose, and 1.00 and 1.50 h post-dose, respectively, and median Tmax occurred at 1.00 h, 1.50 h, and 1.00 h post-dose for regimens A, B, and C, respectively.

[0191] Following oral dosing once and twice daily for 7 days, systemic exposure appeared to be reduced for all three regimens, with geometric mean accumulation ratios at day 7 of Cmax 0.346, 0.428, and 0.333, and AUC(0-tau) values ​​of 0.371, 0.351, and 0.299 for regimens A, B, and C, respectively. For regimens B and C, the geometric mean T 1 / 2The values ​​were 11.8 h and 14.1 h, respectively. Individual terminal half-lives following administration of 150 mg anle138b QD for 7 days (regimen A) were 16.25 h and 17.10 h.

[0192] Following single oral doses of DP on day 9 at 150 mg and 300 mg in the fed state, peak plasma concentrations (Cmax) of anle138b occurred between 1.50 and 4.00 h post-dose and between 3.00 and 4.00 h post-dose, respectively. Following administration of both regimens, the median Tmax occurred at 3.00 h post-dose. Geometric mean terminal T 1 / 2 were 15.9 h and 13.0 h at the 150 mg and 300 mg dose levels, respectively.

[0193] When administered in the presence of food, the geometric mean relative bioavailability of anle138b following a single dose on day 9 versus day 7, fasted, was 104% and 71.4% based on Cmax and 132% and 109% based on AUC(0-24) at the 150 mg and 300 mg dose levels, respectively.

[0194] Following a single oral dose of anle138b in capsule form at 150 mg (regimen A-QD and regimen C-BID) and 300 mg (regimen B-QD) in the fasted state on day 1, maximum individual Cmax and AUC(0-24) values ​​were approximately 24.9% and 6.19%, 75.8% and 8.4%, and 26.4% and 4.94% of the anle138b exposure limits outlined in the protocol for regimens A, B, and C, respectively (note that for regimen C, AUC(0-tau) for this dosing occasion was equivalent to AUC(0-12), with exposure limits based on AUC(0-24)).

[0195] Following repeated oral administration of 300 mg anle138b QD in the fasted state to male and female patients with mild to moderate PD, the geometric mean (geometric CV%) CSF anle138b concentration was 0.3186 ng / mL (108.1%) and the geometric mean (geometric CV%) plasma anle138b concentration was 132.593 ng / mL (58.5%) 3 h post-dose on day 5. The geometric mean (geometric CV%) CSF / plasma anle138b concentration ratio was 0.00240 (45.0%).

[0196] reference Berg D, et al. Movement disorder society criteria for clinically established early Parkinson's disease. Mov Disord 2018; 33(10): 1643-6. Brendel M, et al. Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer's disease tau. Alzheimers Res Ther 2019; 11(1): 67. Cacabelos R., Parkinson's Disease: From Pathogenesis to Pharmacogenomics. Int J Mol Sci. 2017, 18(3):551 Camilleri A, et al. Tau-induced mitochondrial membrane perturbation is dependent upon cardiolipin. Biochim Biophys Acta Biomembr 2020; 1862(2): 183064. Deeg AA, et al. Anle138b and related compounds are aggregation specific fluorescence markers and reveal high affinity binding to alpha-synuclein aggregates. Biochim Biophys Acta 2015; 1850(9): 1884-90. Ghio S, et al. Cardiolipin Promotes Pore-Forming Activity of Alpha-Synuclein Oligomers in Mitochondrial Membranes. ACS Chem Neurosci 2019; 10(8): 3815-29. Gilman S, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008; 71(9): 670-6. Gough et al., "Assessment of Dose Proportionality: Report from the Statisticians in the Pharmaceutical Industry / Pharmacokinetics UK Joint Working Party", Drug Information Journal, 1995, 29: 1039-1048. Heras-Garvin A, et al. Anle138b modulates alpha-synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy. Mov Disord 2019; 34(2): 255-63. Jannin, V. Lauroyl polyoxylglycerides, functionalized coconut oil, enhancing the bioavailability of poorly soluble active substances. OCL J. 2009. 16:4, 267-272. Levin J, et al. The oligomer modulator anle138b inhibits disease progression in a Parkinson mouse model even with treatment started after disease onset. Acta Neuropathol 2014; 127(5): 779-80. Levin J, et al. The Differential Diagnosis and Treatment of Atypical Parkinsonism. Dtsch Arztebl Int 2016; 113(5): 61-9. Levin J, et al. Safety, tolerability and pharmacokinetics of the oligomer modulator anle138b with exposure levels sufficient for therapeutic efficacy in a murine Parkinson model: A randomised, double-blind, placebo-controlled phase 1a trial. EBioMedicine. 2022; 80: 104021; doi: 10.1016 / j.ebiom.2022.104021. Martinez Hernandez A, et al. The diphenylpyrazole compound anle138b blocks Abeta channels and rescues disease phenotypes in a mouse model for amyloid pathology. EMBO Mol Med 2018; 10(1): 32-47. Matthes D, et al. Resolving the Atomistic Modes of Anle138b Inhibitory Action on Peptide Oligomer Formation. ACS Chem Neurosci 2017; 8(12): 2791-808. McKeith IG, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology 2017; 89(1): 88-100. Meissner WG, et al. Multiple System Atrophy: Recent Developments and Future Perspectives. Mov Disord 2019; 34(11): 1629-42. Panigrahi KC et al. Gelucire: a versatile polymer for modified release drug delivery system. Future J Pharma Sci 2018. 4:102-108. Reiner AM, et al. Photophysics of diphenyl-pyrazole compounds in solutions and a-synuclein aggregates. Biochim Biophys Acta Gen Subj 2018; 1862(4): 800-7. Smith, B. et al., "Confidence Interval Criteria for Assessment of Dose Proportionality", Pharmaceutical Research, 2000 17(10): 1278-1283. Strickley, RG. Solubilizing Excipients in Oral and Injectable Formulations. Pharma Res, 2004. 21(2):201-230. Wagner J, et al. Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies. Acta Neuropathol 2015; 130(5): 619-31. Wagner J, et al. Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease. Acta Neuropathol 2013; 125(6): 795-813. Wegrzynowicz M, et al. Depopulation of dense alpha-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson's disease model. Acta Neuropathol 2019; 138(4): 575-95. Wong YC, and D. Krainc. alpha-Synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat Med 2017; 23(2): 1-13. All patents and publications disclosed in this specification are herein incorporated by reference to the same extent as if each separate publication was specifically and individually indicated to be incorporated by reference. The invention illustratively described herein may suitably be practiced in the absence of any element not specifically disclosed herein. Thus, for example, in each instance herein, either of the terms "comprising" and "consisting of" may be replaced with the other of the two terms. With respect to the preceding embodiments, it is contemplated that each embodiment disclosed herein is applicable to each of the other embodiments disclosed. For example, features described in the composition embodiment described herein can be used in the use embodiment, and vice versa. The terms and expressions used are used as terms of description and not of limitation, and there is no intention in using such terms and expressions to exclude any equivalents of the features shown and described or their parts, and it is recognized that various modifications are possible within the scope of the invention as claimed. Thus, although the present invention is specifically disclosed by preferred embodiments and optional features, it should be understood that modifications and variations of the concept disclosed herein may be contemplated by those skilled in the art, and such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

Claims

1. General formula (A) or (A ＊ ) at least one compound having 【Chemistry 1】 or a stereoisomer, racemate, hydrate or solvate thereof (In the formula, R is hydrogen, C １～４ Alkyl, and —C １～４ alkylene-halogen; Hal is selected from F, Cl, Br and I; R Ｅ７ and R Ｅ８ are independently H or F. and a pharmaceutically acceptable excipient, wherein the excipient comprises at least one monoester of a fatty acid and polyethylene glycol and / or at least one diester of a fatty acid and polyethylene glycol; Fatty acids are C ８ ~C ２２ independently selected from fatty acids, The polyethylene glycols are independently selected from polyethylene glycols containing from about 20 to about 40 ethylene oxide units; Pharmaceutical compositions.

2. General formula (B), (B ＊ ) a compound having 【Chemistry 2】 or a mixture thereof.

3. The excipient further comprises a monoglyceride of a fatty acid, a diglyceride of a fatty acid, and / or a triglyceride of a fatty acid, wherein the fatty acid is C ８ ~C ２２ Fatty acids, preferably C ８ ~C １８ 2. The pharmaceutical composition of claim 1, wherein the hydroxybenzoates are independently selected from fatty acids.

4. 10. The pharmaceutical composition of claim 1, wherein the polyethylene glycol contains about 32 ethylene oxide units.

5. 10. The pharmaceutical composition of claim 1, wherein the excipient further comprises polyethylene glycol containing about 20 to about 40 ethylene oxide units, preferably about 32 ethylene oxide units.

6. 2. The pharmaceutical composition of claim 1, wherein the fatty acid comprises lauric acid, preferably the fatty acid comprises 30-50% by weight of lauric acid based on the total weight of the fatty acids.

7. 2. The pharmaceutical composition of claim 1, wherein the excipient comprises a mixture of monoesters of fatty acids and polyethylene glycol and / or diesters of fatty acids and polyethylene glycol, wherein the fatty acids are derived from coconut oil and / or hydrogenated coconut oil.

8. The excipient comprises a mixture of monoesters of fatty acids and polyethylene glycol and / or diesters of fatty acids and polyethylene glycol, wherein the fatty acids are up to 15% by weight of caprylic acid (C8), up to 12% by weight of capric acid (C10), 30 to 50% by weight of lauric acid (C12), 5 to 25% by weight of myristic acid (C14), 4 to 25% by weight of palmitic acid (C16), and 5 to 35% by weight of stearic acid (C18) 2. The pharmaceutical composition of claim 1, comprising:

9. 2. The pharmaceutical composition of claim 1, wherein the excipient comprises about 50% to about 80% by weight, preferably about 60% to about 75% by weight, more preferably about 72% by weight of at least one monoester of a fatty acid and polyethylene glycol and / or at least one diester of a fatty acid and polyethylene glycol.

10. 4. The pharmaceutical composition of claim 3, wherein the excipient comprises about 10% to about 30% by weight, preferably about 15% to about 25% by weight, more preferably about 20% by weight of a monoglyceride of a fatty acid, a diglyceride of a fatty acid, and / or a triglyceride of a fatty acid.

11. 6. The pharmaceutical composition of claim 5, wherein the excipient comprises about 5% to about 20%, preferably about 5% to about 10%, more preferably about 8% by weight of polyethylene glycol containing about 20 to about 40 ethylene oxide units.

12. 2. The pharmaceutical composition according to claim 1, wherein the excipient is obtained by alcoholysis reaction between polyethylene glycol and triglycerides of fatty acids.

13. 10. The pharmaceutical composition of claim 1, wherein the excipient has a melting range in the range of about 33°C to about 64°C, preferably about 35°C to about 55°C, more preferably about 42.5°C to about 47.5°C, and even more preferably about 44°C.

14. 2. The pharmaceutical composition of claim 1, wherein the excipient has a hydrophilic lipophilic balance (HLB) of about 1 to about 16, preferably about 7 to about 14, about 11 or about 14.

15. About 3% to about 5% by weight of the compound represented by formula (A) or (A ＊ 10. The pharmaceutical composition of claim 1, comprising a compound having the formula:

16. 16. An oral dosage form comprising the pharmaceutical composition of any one of claims 1 to 15, wherein the oral dosage form comprises from about 1 mg to about 100 mg of the compound, or from about 5 mg to about 50 mg of the compound, preferably about 10 mg or about 30 mg of the compound.

17. 17. The oral dosage form of claim 16 in the form of a capsule.

18. A pharmaceutical composition according to any one of claims 1 to 15 for use in the treatment or prevention of diseases associated with protein aggregation and / or neurodegenerative diseases.

19. The pharmaceutical composition for use according to claim 18, wherein the disease is an α-synucleinopathy.

20. The pharmaceutical composition for use according to claim 19, wherein the α-synucleinopathy is multiple system atrophy (MSA), Parkinson's disease (PD), or dementia with Lewy bodies (DLB), preferably multiple system atrophy (MSA).

21. 19. The pharmaceutical composition for use according to claim 18, which is administered orally and is administered to a subject without regard to food intake.

22. An oral dosage form as described in claim 16 for use in the treatment or prevention of diseases associated with protein aggregation and / or neurodegenerative diseases.

23. An oral dosage form for use as described in claim 22, wherein the disease is an alpha-synucleinopathy.

24. The oral dosage form for use according to claim 23, wherein the α-synucleinopathy is multiple system atrophy (MSA), Parkinson's disease (PD), or dementia with Lewy bodies (DLB), preferably multiple system atrophy (MSA).

25. The oral dosage form of claim 16, wherein when administered as a single dose to fasted healthy subjects, an oral dosage form containing 300 mg of the compound of formula (B), (B*) or a mixture thereof provides a geometric mean plasma Cmax of the compound of formula (B), (B*) or a mixture thereof of about 704 ng / mL.

26. The oral dosage form of claim 16, wherein when administered as a single dose to fasted healthy subjects, an oral dosage form containing 300 mg of the compound of formula (B), the compound of formula (B*) or a mixture thereof provides a geometric mean plasma AUC(0-24) of the compound of formula (B), the compound of formula (B*) or a mixture thereof of approximately 1650 ng*h / mL.

27. ​​The oral dosage form of claim 16, wherein when administered as a single dose to fasted healthy subjects, an oral dosage form containing 300 mg of the compound of formula (B), (B*) or a mixture thereof provides a geometric mean plasma T1 / 2 of the compound of formula (B), (B*) or a mixture thereof of approximately 16.22 hr.

28. The oral dosage form of claim 16, wherein when administered once daily for at least 7 days to fasted healthy subjects, an oral dosage form containing 300 mg of the compound of formula (B), (B*) or a mixture thereof provides a geometric mean plasma Cmax of the compound of formula (B), (B*) or a mixture thereof of about 910 ng / mL on day 1 and about 307 ng / mL on day 7.

29. An oral dosage form as described in claim 16, wherein when administered once daily for at least 7 days to fasted healthy subjects, an oral dosage form containing 300 mg of the compound of formula (B), the compound of formula (B*) or a mixture thereof provides a geometric mean plasma AUC(0-tau) of the compound of formula (B), the compound of formula (B*) or a mixture thereof of about 2210 ng*h / mL on day 1 and about 633 ng*h / mL on day 7.

30. The oral dosage form of claim 16, wherein when administered once daily for at least 7 days to fasted healthy subjects, an oral dosage form containing 300 mg of the compound of formula (B), (B*) or a mixture thereof provides a geometric mean plasma T1 / 2 of the compound of formula (B), (B*) or a mixture thereof of approximately 6.07 hr on day 7.

31. The oral dosage form of claim 16, wherein when a composition containing 300 mg of the compound is administered once daily for 7 consecutive days to a patient in a fed state, the oral dosage form provides a geometric mean plasma Cmax of anle138b of about 933 ng / mL on day 1 and / or an AUC(0-24) of anle138b of about 2500 ng*h / mL.

32. The oral dosage form of claim 16, wherein when a composition comprising 300 mg of the compound is administered once daily for 7 consecutive days to a patient in a fed state, the oral dosage form provides a geometric mean plasma Cmax of anle138b of about 365 ng / mL on day 7, and / or an AUC(0-24) of anle138b of about 722 ng*h / mL, and / or a T1 / 2 of anle138b of about 12.1 h.

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