Specific doses of phenothiazine compounds for use in the treatment or prevention of Alzheimer's disease

Abstract

In a first aspect, the present invention relates to a compound of formula (I) for use in the treatment and / or prevention of Alzheimer's dementia, wherein the compound of formula (I) is administered in a dosage of <20 mg. In a second aspect, the present invention relates to a pharmaceutical composition comprising a compound according to the first aspect.

Description

[Technical Field]

[0001] In a first embodiment, the present invention relates to a compound of formula (I) for use in the treatment and / or prevention of Alzheimer's disease, wherein the compound of formula (I) is administered in doses of ≤20 mg. In a second embodiment, the present invention relates to a pharmaceutical composition comprising a compound according to the first embodiment. [Background technology]

[0002] European Patent Registration No. 2 614 060 B1 (WO 2012 / 031941 A2) discloses thiethylperazine (IUPAC: 2-(ethylsulfanyl)-10-[3-(4-methylpiperazine-1-yl)propyl]-10H-phenothiazine, CAS: 1420-55-9) and its derivatives for the treatment of beta-amyloidopathy or alpha-synucleinopathy, which involves deposition in brain proteins and decreased activity of the brain ABCC1 transporter. Furthermore, as described by Krohn et al., thiethylperazine activates ABCC1, a transport protein that removes beta-amyloid from the mouse brain (Krohn, M., C. Lange, J. Hofrichter, K. Scheffler, J. Stenzel, J. Steffen, T. Schumacher, T. Bruning, AS Plath, F. Alfen, A. Schmidt, F. Winter, K. Rateitschak, A. Wree, J. Gsponer, LC Walker and J. Pahnke (2011). "Cerebral amyloid-beta proteostasis is regulated by the membrane transport protein ABCC1 in mice." J Clin Invest 2011, 121(10): 3924~3931). Therefore, thiethylperazine was proven effective in effluxing amyloid-beta (Abeta) from endothelial cells of the blood-brain barrier to the periphery in a mouse model of Alzheimer's disease (AD). Pharmacological activation of ABCC1 was also shown to reduce the deposition of amyloid plaques in the brain. Thiethylperazine was used in mice in this study at a concentration of 15 mg / kg body weight per day, which, considering the relative growth ratio between mice and humans is 7, would correspond to a human equivalent dose of 105 mg of thiethylperazine per day.

[0003] Jepsen, De Both, et al. showed that ABCC1 not only excretes Abeta from the cytoplasm of human cells, but its overexpression significantly reduces Abeta production and increases the alpha-to-beta-secretase-mediated amyloid precursor protein (APP) cleavage ratio, possibly through indirect modulation of alpha-, beta-, and gamma-secretase activity. When incubated with fluorescent Abeta-42, 79.7% of wild-type human BE(2)-m17 neuroblastoma cells and 68.4% of ABCC1-overexpressing BE(2)-m17 cells become fluorescent. Treatment with thiethylperazine reduced the number of wild-type cells efficiently taking up Abeta-42 by 29.6%. Co-overexpression of ABCC1 enhanced this effect to 44.4%. Therefore, ABCC1 effectively protects cells from Abeta entry, and thiethylperazine amplifies this effect (Jepsen, WM, M. De Both, AL Siniard, K. Ramsey, IS Piras, M. Naymik, A. Henderson and MJ Huentelman (2020). "Adenosine triphosphate Binding Cassette subfamily C member 1 (ABCC1) overexpression reduces APP processing and increases alpha-versus beta-secretase activity, in vitro." Biol Open: bio.054627). Furthermore, ABCC1-overexpressing BE(2)-m17 cells reduce the production of Abeta-42 and Abeta-40 by shifting APP processing to a non-amyloidogenic pathway (Jepsen, De Both et al.).

[0004] Regarding beta-amyloidopathy, such as Alzheimer's disease (and Parkinson's disease), it is considered that eticlopazine can potentially delay the progression of Alzheimer's dementia and Parkinson's disease for several years. This drug is in Phase II clinical trials under the EudraCT number: 2014-000870-20. These clinical trials were conducted using 26 mg of eticlopazine per person per day and 52 mg of eticlopazine per person per day, respectively, considering what was deemed necessary regarding efficiency. However, considering the increase in Alzheimer's disease, the extension of average life expectancy, and the increase in the proportion of the elderly in the total population, there is still a need for improved formulations for the treatment of Alzheimer's disease. Summary of the Invention

[0005] Therefore, the objective technical problem underlying the present invention was to provide an improved formulation for the treatment (for use in) and / or prevention of Alzheimer's disease. Modes for Carrying Out the Invention

[0006] First Aspect - Compound of Formula (I) for Use in the Treatment and / or Prevention of Alzheimer's Dementia In a first aspect, the present invention is a compound of formula (I) for use in the treatment and / or prevention of Alzheimer's dementia

[0007]

Chemical formula

[0008] Preferably, a compound of formula (I) for use in the treatment and / or prevention of Alzheimer's type dementia is administered at a dose in the range of 2-20 mg per day of administration date. "Per day of administration date" means that a dose of ≤20 mg is administered in the range of 1-7 days per week, preferably daily (7 days per week, i.e., every day) or every other day or every two days, more preferably a dose of ≤20 mg is given daily or every other day, and even more preferably a dose of ≤20 mg is given daily.

[0009] In some embodiments, the [CH3] m -group(s) is preferably present at a position selected from 6, 7, 8 and 9 of the phenothiazine structure, and the [CH3] p -group(s) is present at a position selected from 1, 3 and 4 of the phenothiazine structure. When R 2 is a methyl group, the carbon atom having R 2 preferably has an R configuration.

[0010] Normally, those skilled in the art strive to minimize drug dosages, but they can predict that the effectiveness of treatments using active agents (pharmaceutical active ingredients, APIs) will decrease as the amount of active agent administered decreases. Therefore, those skilled in the art predict that lower doses of drugs (cheaper and safer treatments) will be offered at the expense of lower therapeutic efficacy and potentially fewer responsive patients. Patient response is related to dose, and the maximum effect (E) max It is a generally accepted principle that increasing the dose leads to a greater response until a certain threshold is reached (see, for example, R. Lieberman et al., 1993). Surprisingly, however, in the context of the present invention, it has been found that the efficacy of treatment and the response to treatment in humans are improved at lower doses, rather than at higher doses, for the compound of formula (I) or pharmaceutically acceptable salts thereof, in particular thiethylperazine, and more particularly thiethylperazine maleate(plural). Thiethylperazine is 2-(ethylsulfanyl)-10-[3-(4-methylpiperazine-1-yl)propyl]-10H-phenothiazine (CAS: 1420-55-9), and thiethylperazine maleate (CAS: 1179-69-7, C 30 H 37 N3O8S2) is a salt of (positively charged) thiethylperazine and two (negatively charged) maleic acid molecules. Surprisingly, not only were more subjects, i.e., 30–117% more, found to respond to lower doses of thiethylperazine in the range of 2–20 mg, but the mean increase in plasma Abeta1–40 was also significantly higher, particularly ≥20%, compared to subjects treated with higher doses of thiethylperazine. Furthermore, the mean difference in plasma Abeta1–40 concentration between responders and non-responders was substantially increased by ≥10 pg / ml in subjects treated with lower doses of thiethylperazine in the range of 2–20 mg compared to subjects treated with higher doses of thiethylperazine.

[0011] Where used below, the terms “have,” “comprise,” or “include,” or any grammatical variations thereof, are used in a non-exclusive sense. Therefore, these terms may refer to both situations where, in the entity described in this context, there are no further features other than those introduced by these terms, and situations where there are one or more further features. For example, the expressions “A has B,” “A comprises B,” and “A includes B” may all refer to situations where, in A, there are no other elements other than B (i.e., A is exclusive only to B), as well as situations where, in entity A, there are one or more further elements other than B, such as one element C, multiple elements C and D, or even more elements. Furthermore, as will be understood by those skilled in the art, the expressions “comprising a” and “comprising an” preferably mean “comprising one or more,” that is, equivalent to “comprising at least one.”

[0012] Furthermore, where used below, the terms “preferably,” “more preferably,” “most preferably,” “especially,” “even more specifically,” “specifically,” and “more specifically” or similar terms are used with optional features without limiting further possibilities. Thus, features introduced by these terms are optional features and are not intended in any way to limit the scope of the claims. The present invention can be implemented by using alternative features, as will be recognized by those skilled in the art. Similarly, features introduced by “in one embodiment” or similar expressions are intended to be optional features without any limitation with respect to further embodiments of the invention, without any limitation with respect to the scope of the invention, and without any limitation with respect to the possibility of such introduced features being combined with other optional or non-optional features of the invention.

[0013] As used herein, the term “pharmaceutically acceptable” refers to a pharmaceutically acceptable salt in the sense that it is not harmful to its recipient and is preferably compatible with other optional components of the formulation. Preferably, a pharmaceutically acceptable salt is a salt of the compound of formula (I) that causes a moderately adverse drug reaction, preferably a mildly adverse drug reaction. As used herein, the term “mild” adverse reaction means an adverse reaction that does not require medical intervention, such as skin rash, headache, gastrointestinal disorder, fatigue, etc., while “moderate” adverse reaction means an adverse reaction that requires medical intervention but is not potentially life-threatening.

[0014] As used herein, the term "alkyl" refers to a linear or branched saturated hydrocarbon group that is covalently linked to the main chain by at least one of its at least one carbon atoms. Preferred alkyl groups are linear or branched alkyl groups. Thus, alkyl groups include primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups.

[0015] The terms “to treat” and “treatment” mean to alleviate to a significant degree a disease or disorder, or symptoms associated therewith, as used herein. When used herein, “to treat” also includes complete recovery of health with respect to a disease or disorder as used herein. It should be understood that, when the term “to treat” is used herein, it does not mean that it is effective in all subjects being treated. However, the term requires that a preferably statistically significant portion of subjects suffering from a disease or disorder as used herein can be successfully treated. Whether a portion is statistically significant can be determined without further difficulty by a person skilled in the art using various well-known statistical evaluation tools, such as confidence interval determination, p-value determination, Student's t-test, Mann-Whitney test, etc. Preferred confidence intervals are at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%. P-values ​​are preferably 0.1, 0.05, 0.01, 0.005, or 0.0001. Preferably, the treatment is effective for at least 10%, at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the subjects in a given cohort or group. Preferably, treating Alzheimer's disease involves improving one or more biomarkers of neurodegeneration known to those skilled in the art, such as Abeta-40, Abeta-42, or Abeta42 / 40 ratios in body fluids (blood, CSF), phosphorylated variants of tau protein (e.g., p-Tau181, p-Tau217, etc.), glial fibrillary acidic proteins (GFAP), neurofilamentous light chains (NfL), etc., and / or improving the brain load of Abeta and / or tau as determined using positron emission tomography (PET), and / or slowing, halting, or improving the decline in the subject's cognitive abilities as determined by one or more tests known to those skilled in the art, such as ADAS-Cog, FCSRT, ADCS-iADL, QoL-AD, CDR, MMSE, etc. As will be understood by those skilled in the art, the effectiveness of treating Alzheimer's disease depends on various factors, including, for example, the stage and severity of the disease."Improving one or more biomarkers" should be understood as the deviation of the values ​​of each biomarker in the subject after or during treatment from the reference value in healthy subjects compared to before treatment. "Slowing down or halting cognitive decline or improving cognitive ability" refers to the results from each test showing that, after or during treatment, the deviation from the reference value in healthy subjects or a known reference value compared to before treatment.

[0016] The terms “prevention” and “prevention” refer to maintaining health in a subject over a period of time with respect to Alzheimer’s disease. It will be understood that the said period may depend on the amount of the drug compound administered and individual factors of the subject as discussed elsewhere herein. It should be understood that prevention is not necessarily effective in all subjects treated with the compounds according to the present invention. However, this term requires that a cohort or population of subjects, preferably a statistically significant portion, is effectively prevented from developing the disease or disorder, or its associated symptoms, as described herein. Preferably, in this context, a cohort or population of subjects is assumed to be what would normally, i.e., without the preventive measures according to the present invention, develop the disease or disorder as described herein. Whether a portion is statistically significant can be determined without further difficulty by a person skilled in the art using the various well-known statistical evaluation tools discussed elsewhere herein.

[0017] When used herein, the term "subject" refers to multicellular animals, preferably vertebrates, more preferably mammals, and more preferably humans.

[0018] In some embodiments of its use in the treatment and / or prevention of Alzheimer's disease, the compound of formula (I) R 1 The group is selected from the group consisting of a hydrogen atom, a chlorine atom, a thiomethyl group, a thioethyl group, a methoxy group, an ethoxy group, and a trifluoromethyl group, preferably from the group consisting of a thiomethyl group, a thioethyl group, a methoxy group, an ethoxy group, and a trifluoromethyl group.

[0019] In some embodiments of its use in the treatment and / or prevention of Alzheimer's disease, R 1 This is selected from the group consisting of a hydrogen atom, a chlorine atom, a methoxy group, a trifluoromethyl group, and a thioethyl group. R 2 is a hydrogen atom or a methyl group, R 3 and R 4 These groups are independently methyl or ethyl groups, or together form a 6-membered alkyl ring containing at least one further nitrogen atom, where the at least one further nitrogen is a C1-C3 alkyl-R group. 5 It is substituted with R 5 is a hydrogen atom or a hydroxyl group, n is either 0 or 1. m and p are both 0.

[0020] In some embodiments of its use in the treatment and / or prevention of Alzheimer's disease, the compound of formula (I) is selected from the group consisting of levomepromazine, trifluoperazine, thiethylperazine, perphenazine, chlorpromazine, thioridazine, dietadine, and mixtures of two or more of these. Each of these compounds is known to activate the ABCC1 transporter, which removes beta-amyloid from the brain.

[0021] In some embodiments of its use in the treatment and / or prevention of Alzheimer's disease, R 3 and R 4 This forms a six-membered ring containing one additional nitrogen atom, where the additional nitrogen atom has either a methyl group or a -CH2-CH2-OH group.

[0022] In some embodiments of its use in the treatment and / or prevention of Alzheimer's disease, the compound has formula (Ia)

[0023] [ka] [In the formula, R 1 This is selected from the group consisting of a methoxy group, a trifluoromethyl group, and a thioethyl group. R 2 This is a hydrogen atom or a methyl group (preferably having an R stereoconfiguration), R 3 , R 4 They are both methyl groups, or together they form a 6-membered alkyl ring containing one additional nitrogen atom, where the additional nitrogen is substituted with a methyl group. n is either 0 or 1.

[0024] In some embodiments of its use in the treatment and / or prevention of Alzheimer's disease, the compound of formula (Ia) is used 3 , R 4 These are either both methyl groups or together form a piperazine ring, where the additional nitrogen atom is substituted with a methyl group (4-methylpiperazine-1-yl group).

[0025] The compound of formula (I) or formula (Ia) is used as an (uncharged) compound or in the form of a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt of the compound of formula (I) or formula (Ia) is administered such that the cationic moiety corresponding to the compound of formula (I) or formula (Ia) reaches preferably ≤20 mg, preferably 2 to 20 mg, per administration day.

[0026] Preferably, the pharmaceutically acceptable salt is sulfuric acid. ion , pyrosulfate ion , bicarbonate ion sulfurous acid ion , bisulfite ion ,phosphoric acid ion , monohydrogen phosphate ion , dihydrogen phosphate ion metaphosphate ion pyrophosphate ion , ion Compounds, bromides, iodides, acetic acid ion , propionic acid ion , decanoic acid ion Caprylic acid ionacrylic acid ion , formic acid ion isobutyric acid ion , capric acid ion heptanoic acid ion , propiolic acid ion oxalic acid ion , malonic acid ion succinic acid ion suberic acid ion , sebacinic acid ion fumaric acid ion malic acid ion maleic acid ion , butyne-1,4-dioxide ion , hexin-1,6-diacid ion , benzoic acid ion chlorobenzoic acid ion methylbenzoic acid ion , dinitrobenzoic acid ion , hydroxybenzoic acid ion Methoxybenzoic acid ion phthalates ion terephthalic acid ion sulfonic acid ion xylene sulfonic acid ion phenylacetic acid ion phenylpropionic acid ion phenylbutyric acid ion , citric acid ion lactic acid ion β-hydroxybutyrate ion Glycolic acid ion , tartaric acid ion methanesulfonic acid ion , propanesulfonic acid ion Naphthalene-1-sulfonic acid ion naphthalene-2-sulfonic acid ion almond acid ion adipic acid ion alginic acid ion mucinic acid ion , aspartic acid ion benzenesulfonic acid ion , butyric acid ion , camphor acid ion camphor sulfonic acid ion cyclopentanepropionic acid ion Digluconate ion, dodecyl sulfate ion , ethanesulfonic acid ion , glucoheptanoic acid ion glycerophosphate ion hemisulfate ion hexanoic acid ion , 2-hydroxyethanesulfonic acid ion , 2-naphthalene sulfonic acid ion nicotinic acid ion ,nitric acid ion palmitic acid ion pectin acid ion , persulfate ion picric acid ion pivalic acid ion salicylic acid ion thiocyanic acid ion tosylic acid ion , alginic acid ion , and undecanoic acid ion It contains one or more anions selected from the group consisting of the following. More preferably, the pharmaceutically acceptable salt is a chloride. ion , sulfuric acid ion mesylic acid ion , besilicic acid ion tosylic acid ion fumaric acid ion , malonic acid ion malic acid ion maleic acid ion succinic acid ion lactic acid ion Glycolic acid ion , citric acid ion , aspartic acid ion and mandelic acid ion One or more anions selected from the group consisting of, preferably malic acid ion and / or maleic acid ion , more preferably maleic acid ion Includes.

[0027] In some embodiments, the compound of formula (I) or formula (Ia) is selected from the group consisting of levomepromazine, trifluoperazine, and thiethylperazine and pharmaceutically acceptable salts of these compounds, preferably levomepromazine or thiethylperazine or a pharmaceutically acceptable salt of levomepromazine or a pharmaceutically acceptable salt of thiethylperazine, and more preferably thiethylperazine or a pharmaceutically acceptable salt of thiethylperazine.

[0028] Preferably, the compounds of formula (I) or formula (Ia) are used alone, as a mixture of two or more compounds of formula (I) or formula (Ia), as pharmaceutically acceptable salts of the compounds of formula (I) or formula (Ia), or as a mixture of two or more pharmaceutically acceptable salts of the compounds of formula (I) or formula (Ia). Similarly, a mixture of one or more compounds of formula (I) or formula (Ia) and one or more pharmaceutically acceptable salts of the compounds of formula (I) or formula (Ia) can be used. In some preferred embodiments, one or more compounds of formula (I) or formula (Ia) are used only in the form of their pharmaceutically acceptable salts, more preferably one or more compounds of formula (I) or formula (Ia) are used in the form of their maleate and / or malate salts, and more preferably one or more compounds of formula (I) or formula (Ia) are used in the form of their maleate salts. The salt forms have the advantage of improved solubility in aqueous solutions.

[0029] As indicated above, the compound of formula (I) is used in the treatment and / or prevention of Alzheimer's disease, preferably in a dose of ≤20 mg per day, preferably in the range of 2 to 20 mg. In some embodiments of its use in the treatment and / or prevention of Alzheimer's disease, the compound of formula (I) or formula (Ia) is administered in a dose of 5 to 15 mg per day, preferably in the range of 6 to 13.5 mg. More preferably, the compound of formula (I) or formula (Ia) is administered in a dose of 6 to 7 mg per day or in the range of 12.5 to 13.5 mg per day.

[0030] In the context of the present invention, when a salt of the compound of formula (I) or formula (Ia) is used, the weights shown above relate to the compound of formula (I) or formula (Ia), and that is, the amount of each salt to be used will be greater due to the higher molecular weight of the salt. However, as shown above, a pharmaceutically acceptable salt of the compound of formula (I) or formula (Ia) is used such that the cationic portion corresponding to the compound of formula (I) or formula (Ia) is preferably in the range of ≤20 mg, preferably 2 to 20 mg, per day of administration. For example, when thiethylperazine maleate is used, the range of 2 to 20 mg for thiethylperazine corresponds to the range of 3.16 to 31.62 mg of thiethylperazine maleate. Thiethylperazine malate (CAS: 52239-63-1, C), which is a salt of (positively charged) thiethylperazine and two (negatively charged) malic acid molecules, is used. 30 H 41 N3O 10 When S2) is used, the range of 2 to 20 mg for thiethylperazine corresponds to the range of 3.34 to 33.42 mg for thiethylperazine maleate. The same applies to preferred ranges and values. Therefore, in some embodiments, the compound of formula (I) or formula (Ia) is used as a pharmaceutically acceptable salt of formula (I) or formula (Ia), preferably as thiethylperazine maleate, in doses of preferably ≤31.62 mg per administration day, more preferably in the range of 3.16 to 31.62 mg, more preferably in the range of 7.9 to 23.72 mg, and more preferably in the range of 9.48 to 21.34 mg. More preferably, thiethylperazine maleate is administered in doses of 9.47 to 11.07 mg per administration day or in doses of 19.77 to 21.34 mg per administration day.

[0031] In some embodiments of its use in the treatment and / or prevention of Alzheimer's disease, a compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt of formula (I) or formula (Ia) is administered as a single dose once per day or twice per day.

[0032] In some embodiments of its use in the treatment and / or prevention of Alzheimer's disease, a compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt of formula (I) or formula (Ia) is administered orally or rectally.

[0033] Second aspect - Pharmaceutical composition In a second embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or formula (Ia) as defined above in the section relating to the first embodiment, in an amount of ≤20 mg, preferably in the range of 2 to 20 mg, more preferably in the range of 5 to 15 mg, and more preferably in the range of 6 to 13.5 mg. All given definitions and all preferred embodiments described in the section relating to the first embodiment also apply to pharmaceutical compositions according to the second embodiment.

[0034] A pharmaceutical composition may also contain, in addition to the active compound, at least one pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients include, but are not limited to, carriers, adjuvants, stabilizers, and / or other compounds deemed suitable by those skilled in the art for, for example, galenic formulation purposes. Where referred to herein, the compounds of formula (I), (Ia) or their respective pharmaceutically acceptable salts, as specified above in the section relating to the first aspect herein, are the “active compound” of the composition, although there may be “further active compounds” as referred to under this term. Preferably, the further active compounds are also pharmaceutically active compounds. A particular pharmaceutical composition is prepared in a manner well known in the field of compounding and contains, preferably, at least one pharmaceutically acceptable carrier or diluent mixed with, or otherwise associated with, at least one active compound as referred above herein. To prepare those particular pharmaceutical compositions, the active compound(s) are usually mixed with a carrier or diluent. The resulting formulations should be adapted to the method of administration, that is, to the form of tablets, capsules, suppositories, solutions, suspensions, etc., as will be outlined in more detail below for specific preferred embodiments.

[0035] In one embodiment, the pharmaceutical composition is a unit dose preparation comprising a compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt of formula (I) or formula (Ia) as defined above in the section relating to the first embodiment, and a pharmaceutically acceptable excipient. "Unit dose preparation," "unit dose," or "unit dose form" means a single dose of a compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt of a compound of formula (I) or formula (Ia) that can be administered to a subject and can be easily handled and packaged as a physically and chemically stable unit dose.

[0036] Each unit dose preparation contains ≤20 mg of the compound of formula (I) or formula (Ia), preferably 2 to 20 mg of the compound of formula (I) or formula (Ia), more preferably 5 to 15 mg of the compound of formula (I) or formula (Ia), and more preferably 6 to 13.5 mg of the compound of formula (I) or formula (Ia). More preferably, each unit dose preparation contains the compound of formula (I) or formula (Ia) in the range of 6 to 7 mg or 12.5 to 13.5 mg. In some embodiments, the compound of formula (I) or formula (Ia) is administered once per day as a single dose, and each unit dose preparation is designed to contain the entire amount of the compound of formula (I) or formula (Ia) in one unit dose preparation. In some embodiments, the compound of formula (I) or formula (Ia) is administered twice per day, and the unit dose preparation is designed to contain half the total amount of the compound of formula (I) or formula (Ia) per unit dose preparation.

[0037] In some embodiments, when a pharmaceutically acceptable salt of the compound of formula (I) or formula (Ia) is used, the cationic portion corresponding to the compound of formula (I) or formula (Ia) reaches a range of ≤20 mg, preferably 2 to 20 mg, in the unit dose preparation. In some embodiments, when thiethylperazine maleate is used, the unit dose preparation contains ≤31.62 mg, more preferably in the range of 3.16 to 31.62 mg, more preferably in the range of 7.9 to 23.72 mg, and more preferably in the range of 9.48 to 21.34 mg of thiethylperazine maleate. More preferably, the unit dose preparation contains thiethylperazine maleate in amounts ranging from 9.47 to 11.07 mg of thiethylperazine maleate or in the range of 19.77 to 21.34 mg of thiethylperazine maleate. In some embodiments, a pharmaceutically acceptable salt of the compound of formula (I) or formula (Ia) is administered once per day as a single dose, and the unit dose preparation is designed to contain the total amount of the pharmaceutically acceptable salt of the compound of formula (I) or formula (Ia) in one unit dose preparation. In some embodiments, a pharmaceutically acceptable salt of the compound of formula (I) or formula (Ia) is administered twice per day, and the unit dose preparation is designed to contain half the total amount of the pharmaceutically acceptable salt of the compound of formula (I) or formula (Ia) in one unit dose preparation.

[0038] In some embodiments, the pharmaceutical composition comprising a compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt of formula (I) or formula (Ia) is in the form of a tablet or suppository. The tablet preferably further comprises one or more excipients selected from the group consisting of gum arabic, gelatin, talc, stearic acid, corn starch, lactose, sucrose, β-carotene, and peanut oil. In some embodiments, the tablet comprises one or more coatings on its outer surface, wherein the coating material is selected from sugars, polymer materials, and mixtures of sugars and polymer materials. The sugar coating preferably comprises one or more sugars selected from the group consisting of sucrose, glucose, lactose, maltitol, mannitol, isomalt, sorbitol, xylitol, and starch. The polymer coating preferably comprises one or more polymers selected from the group consisting of cellulose ethers, vinyl polymers, glycols, and acrylic acid (co)polymers, wherein suitable polymers are known to those skilled in the art. The coating preferably comprises one or more further components selected from fillers, colorants, antiadhesives, lubricants, flow promoters, flavoring agents, suspension stabilizers, smoothing agents, and abrasives, where suitable substances are therefore known to those skilled in the art.

[0039] The suppositories preferably further contain one or more adjuvants selected from the group consisting of lactose, preferably lactose monohydrate, and semi-synthetic solid glycerides.

[0040] In some embodiments, the pharmaceutical composition comprising a compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt of formula (I) or formula (Ia) is in the form of a solution, preferably a solution suitable for injection.

[0041] A solution suitable for injection preferably comprises water and one or more components selected from the group consisting of sodium metabisulfite, ascorbic acid, and sorbitol. Furthermore, a solution suitable for injection preferably has a pH value of <5, preferably <4, and more preferably <3, the pH value of which is preferably determined by a pH-sensitive glass electrode according to DIN 19263:2007-05.

[0042] In some embodiments, the pharmaceutical composition comprising a compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt of formula (I) or formula (Ia) is in the form of an aerosol, preferably an aerosol suitable for spray application.

[0043] Treatment method The present invention also relates to a method for treating and / or preventing Alzheimer's disease, (a) Compound of formula (I)

[0044] [ka] [In the formula, R 1 This is selected from the group consisting of hydrogen atoms, halogen atoms, methoxy groups, perhalogenated alkyl groups, and -X-C1~C2 alkyl groups, where X is either a sulfur atom or an oxygen atom. R 2 is a hydrogen atom or a methyl group, R 3 , R 4 These atoms are, independently of each other, either hydrogen atoms or C1-C4 alkyl groups, or together form a 6-membered alkyl ring containing at least one further nitrogen atom, where the at least one further nitrogen is a C1-C3 alkyl-R 5 It is substituted with R 5 is a hydrogen atom or a hydroxyl group, n is either 0 or 1. m is either 0 or an integer selected from the range of 1 to 4. p is either 0 or an integer selected from the range 1 to 3. The step of administering, wherein the compound of formula (I) is administered in a dose preferably in the range of ≤20 mg, preferably 2 to 20 mg, per administration day. (b) thereby, steps to treat and / or prevent Alzheimer's disease, This includes methods.

[0045] In some embodiments, the present invention relates to a method for treating and / or preventing Alzheimer's disease, comprising the step of administering a pharmaceutical composition, for example, the pharmaceutical composition described above in the section relating to the second embodiment. Herein, all the details described in the sections relating to the first and second embodiments also apply to the method for treating and / or preventing the disease.

[0046] The method for treatment and / or prevention is preferably an in vivo method. Furthermore, the method may include several steps in addition to the steps explicitly mentioned above. For example, a further step may relate, prior to step (a), to diagnosing, for example, Alzheimer's disease and / or identifying a subject that would benefit from treatment with a compound of formula (I) according to the method specified above. Thus, the method preferably includes a further step of (i) determining or being determined to have Alzheimer's disease in a subject, and (ii) identifying or being identified a subject that would benefit from treatment with a compound of formula (I). A further step may also include, in step (b), a combined treatment of the subjects specified above herein. Furthermore, one or more of the steps may be carried out by an automated apparatus.

[0047] The present invention is further described by the following embodiments and combinations of embodiments, as indicated by their respective dependencies and backreferences. In particular, in each case in which a range of embodiments is referred to, the term, for example, “any one of Embodiments 1 to 4,” means that all embodiments within that range are expressly disclosed to those skilled in the art, i.e., the usage of this term should be understood by those skilled in the art as synonymous with “any one of Embodiments 1, 2, 3, and 4.”

[0048] According to one embodiment (1), the present invention relates to a compound of formula (I) for use in the treatment and / or prevention of Alzheimer's disease,

[0049] [ka] [In the formula, R 1 This is selected from the group consisting of hydrogen atoms, halogen atoms, methoxy groups, perhalogenated alkyl groups, and -X-C1~C2 alkyl groups, where X is either a sulfur atom or an oxygen atom. R 2 is a hydrogen atom or a methyl group, R 3 , R 4 These atoms are, independently of each other, either hydrogen atoms or C1-C4 alkyl groups, or together form a 6-membered alkyl ring containing at least one further nitrogen atom, where the at least one further nitrogen is a C1-C3 alkyl-R 5 It is substituted with R 5 is a hydrogen atom or a hydroxyl group, n is either 0 or 1. m is either 0 or an integer selected from the range of 1 to 4. p is either 0 or an integer selected from the range 1 to 3. This relates to a compound of formula (I) administered at a dose of ≤20 mg per day of administration.

[0050] A preferred embodiment (2) embodying embodiment (1) relates to a compound of formula (I) for use according to embodiment (1), administered in a dose ranging from 2 to 20 mg per administration day.

[0051] A preferred embodiment (3) that embodies embodiment (1) or (2) is R 1 The present invention relates to a compound of formula (I) for use according to embodiment (1) or (2), which is selected from the group consisting of a hydrogen atom, a chlorine atom, a thiomethyl group, a thioethyl group, a methoxy group, an ethoxy group, and a trifluoromethyl group, preferably selected from the group consisting of a thiomethyl group, a thioethyl group, a methoxy group, an ethoxy group, and a trifluoromethyl group.

[0052] A preferred embodiment (4) that embodies any one of embodiments (1) to (3) is: R 1 However, it is selected from the group consisting of a hydrogen atom, a chlorine atom, a methoxy group, a trifluoromethyl group, and a thioethyl group. R 2 However, it is a hydrogen atom or a methyl group, R 3 and R 4 However, they are either independently methyl or ethyl groups, or together form a 6-membered alkyl ring containing at least one further nitrogen atom, where at least one further nitrogen is a C1-C3 alkyl-R 5 It is substituted with R 5 is a hydrogen atom or a hydroxyl group, n is 0 or 1, m and p are both 0. This relates to a compound of formula (I) for use according to any one of embodiments (1) to (3).

[0053] A preferred embodiment (5) that embodies any one of embodiments (1) to (4) relates to a compound of formula (I) selected from the group consisting of levomepromazine, trifluoperazine, thiethylperazine, perphenazine, chlorpromazine, thioridazine, dietadine, and mixtures of two or more thereof.

[0054] A preferred embodiment (6) that embodies any one of embodiments (1) to (5) is R 3 and R 4 The present invention relates to a compound of formula (I) for use according to any one of embodiments (1) to (5), wherein it forms a six-membered ring containing one further nitrogen atom, where the further nitrogen atom has a methyl group or a -CH2-CH2-OH group.

[0055] A preferred embodiment (7) embodying any one of embodiments (1) to (6) relates to a compound of formula (I) for use according to any one of embodiments (1) to (6), wherein the compound has formula (Ia).

[0056] [ka] [In the formula, R 1 This is selected from the group consisting of a methoxy group, a trifluoromethyl group, and a thioethyl group. R 2 This is a hydrogen atom or a methyl group (preferably having an R stereoconfiguration), R 3 , R 4 They are both methyl groups, or together they form a 6-membered alkyl ring containing one additional nitrogen atom, where the additional nitrogen is substituted with a methyl group. n is either 0 or 1.

[0057] A preferred embodiment (8) that embodies any one of embodiments (1) to (7) is R 3 , R 4 The present invention relates to compounds of formula (Ia) for use according to embodiments (1) to (7), wherein both are methyl groups, or together form a piperazine ring, where the further nitrogen atom is substituted with a methyl group (4-methylpiperazine-1-yl group).

[0058] A preferred embodiment (9) embodying any one of embodiments (1) to (8) relates to a compound of formula (I) or formula (Ia) for use according to embodiments (1) to (8), wherein the compound of formula (I) or formula (Ia) is used as a pharmaceutically acceptable salt of the compound of formula (I) or formula (Ia), and the pharmaceutically acceptable salt of the compound of formula (I) or formula (Ia) is administered such that the cationic portion corresponding to the compound of formula (I) or formula (Ia) is preferably in the range of ≤20 mg, preferably 2 to 20 mg, per administration day.

[0059] A preferred embodiment (10) that embodies any one of embodiments (1) to (9) is a pharmaceutically acceptable salt of formula (I) or formula (Ia) that is sulfuric acid ion , pyrosulfate ion , bicarbonate ion sulfurous acid ion , bisulfite ion ,phosphoric acid ion , monohydrogen phosphate ion , dihydrogen phosphate ion metaphosphate ion pyrophosphate ion Chloride ion bromide ion iodide ion acetic acid ion , propionic acid ion , decanoic acid ion Caprylic acid ion acrylic acid ion , formic acid ion isobutyric acid ion , capric acid ion heptanoic acid ion , propiolic acid ion oxalic acid ion , malonic acid ion succinic acid ion suberic acid ion , sebacinic acid ion fumaric acid ion malic acid ion maleic acid ion , butyne-1,4-dioxide ion , hexin-1,6-diacid ion , benzoic acid ion chlorobenzoic acid ionmethylbenzoic acid ion , dinitrobenzoic acid ion , hydroxybenzoic acid ion Methoxybenzoic acid ion phthalates ion terephthalic acid ion sulfonic acid ion xylene sulfonic acid ion phenylacetic acid ion phenylpropionic acid ion phenylbutyric acid ion , citric acid ion lactic acid ion β-hydroxybutyrate ion Glycolic acid ion , tartaric acid ion methanesulfonic acid ion , propanesulfonic acid ion Naphthalene-1-sulfonic acid ion naphthalene-2-sulfonic acid ion almond acid ion adipic acid ion alginic acid ion mucinic acid ion , aspartic acid ion benzenesulfonic acid ion , butyric acid ion , camphor acid ion camphor sulfonic acid ion cyclopentanepropionic acid ion Digluconate ion , dodecyl sulfate ion , ethanesulfonic acid ion , glucoheptanoic acid ion glycerophosphate ion hemisulfate ion hexanoic acid ion , 2-hydroxyethanesulfonic acid ion , 2-naphthalene sulfonic acid ion nicotinic acid ion ,nitric acid ion palmitic acid ion pectin acid ion , persulfate ion picric acid ion pivalic acid ion salicylic acid ion thiocyanic acid ion tosylic acid ion , alginic acid ion , and undecanoic acid ion The present invention relates to a compound of formula (I) or formula (Ia) for use according to any one of embodiments (1) to (9), comprising one or more anions selected from the group consisting of the above.

[0060] A preferred embodiment (11) that embodies any one of embodiments (1) to (10) is a pharmaceutically acceptable salt of formula (I) or formula (Ia) that is a chloride ion , sulfuric acid ion mesylic acid ion , besilicic acid ion tosylic acid ion fumaric acid ion , malonic acid ion malic acid ion maleic acid ion succinic acid ion lactic acid ion Glycolic acid ion , citric acid ion , aspartic acid ion and mandelic acid ion One or more anions selected from the group consisting of, preferably malic acid ion and / or maleic acid ion , more preferably maleic acid ion The present invention relates to a compound of formula (I) or formula (Ia) for use according to any one of embodiments (1) to (10), including the above.

[0061] A preferred embodiment (12) embodying any one of embodiments (1) to (11) relates to a compound of formula (I) or formula (Ia) for use according to any one of embodiments (1) to (11), wherein the compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt of formula (I) or formula (Ia) is selected from the group consisting of levomepromazine, trifluoperazine, and thiethylperazine and pharmaceutically acceptable salts of these compounds, preferably levomepromazine or thiethylperazine or a pharmaceutically acceptable salt of levomepromazine or a pharmaceutically acceptable salt of thiethylperazine, and more preferably thiethylperazine or a pharmaceutically acceptable salt of thiethylperazine.

[0062] A preferred embodiment (13) embodying any one of embodiments (1) to (12) relates to a compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt of formula (I) or formula (Ia) for use according to any one of embodiments (1) to (12), wherein the compound of formula (I) or formula (Ia) is used alone, as a mixture of two or more compounds of formula (I) or formula (Ia), as a pharmaceutically acceptable salt of a compound of formula (I) or formula (Ia), or as a mixture of two or more pharmaceutically acceptable salts of a compound of formula (I) or formula (Ia).

[0063] A preferred embodiment (14) embodying any one of embodiments (1) to (13) relates to a compound of formula (I) or formula (Ia) for use according to any one of embodiments (1) to (13), administered in a dose in the range of 5 to 15 mg, preferably 6 to 13.5 mg, per administration day.

[0064] A preferred embodiment (15) embodying any one of embodiments (1) to (14) relates to a compound of formula (I) or formula (Ia) for use according to embodiment (1) or (14), administered in doses ranging from 6 to 7 mg per administration day or from 12.5 to 13.5 mg per administration day.

[0065] A preferred embodiment (16) embodying any one of embodiments (1) to (15) relates to a compound of formula (I) or formula (Ia) for use according to any one of embodiments (1) to (15), used as a pharmaceutically acceptable salt of formula (I) or formula (Ia), preferably as thiethylperazine maleate, and administered in doses of thiethylperazine maleate in the range of ≤31.62 mg per administration day, more preferably in the range of 3.16 to 31.62 mg, more preferably in the range of 7.9 to 23.72 mg, and more preferably in the range of 9.48 to 21.34 mg.

[0066] A preferred embodiment (17) embodying embodiment (16) relates to a compound of formula (I) or formula (Ia) for use according to embodiment (16), which is used as a pharmaceutically acceptable salt of formula (I) or formula (Ia), preferably as thiethylperazine maleate, and is administered preferably in doses ranging from 9.47 to 11.07 mg of thiethylperazine maleate or in doses ranging from 19.77 to 21.34 mg of thiethylperazine maleate per administration day.

[0067] A preferred embodiment (18) embodying any one of embodiments (1) to (17) relates to a compound of formula (I) or formula (Ia) for use according to any one of embodiments (1) to (17), wherein the compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt of formula (I) or formula (Ia) is administered as a single dose once per day or twice per day.

[0068] A preferred embodiment (19) embodying any one of embodiments (1) to (18) relates to a compound of formula (I) or formula (Ia) for use according to any one of embodiments (1) to (18), wherein the compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt of formula (I) or formula (Ia) is administered orally or rectally.

[0069] One embodiment of the present invention (20) relates to a pharmaceutical composition comprising a compound of formula (I) or formula (Ia) as defined in any one of embodiments (1) to (19) in an amount of ≤20 mg, preferably in the range of 2 to 20 mg, more preferably in the range of 5 to 15 mg, and more preferably in the range of 6 to 13.5 mg.

[0070] A preferred embodiment (21) embodying embodiment (20) relates to a pharmaceutical composition comprising a compound of formula (I) or formula (Ia) according to embodiment (20), wherein the compound of formula (I) or formula (Ia) is used as a pharmaceutically acceptable salt of formula (I) or formula (Ia), and the pharmaceutically acceptable salt of the compound of formula (I) or formula (Ia) is used such that the cationic portion corresponding to the compound of formula (I) or formula (Ia) is preferably in the range of ≤20 mg, preferably 2 to 20 mg, of thiethylperazine maleate, and the pharmaceutical composition comprises ≤31.62 mg, preferably in the range of 3.16 to 31.62 mg, more preferably in the range of 7.9 to 23.72 mg, more preferably in the range of 9.48 to 21.34 mg.

[0071] A preferred embodiment (22) that embodies embodiment (20) or (21) relates to the pharmaceutical composition according to embodiment (20) or (21), which is a preparation of a unit dose.

[0072] A preferred embodiment (23) embodying any one of embodiments (20) to (22) relates to the pharmaceutical composition according to any one of embodiments (20) to (22) in the form of a tablet or suppository, comprising a compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt of formula (I) or formula (Ia).

[0073] A preferred embodiment (24) embodying embodiment (23) relates to the pharmaceutical composition according to embodiment (23), wherein the tablet further comprises one or more excipients selected from the group consisting of preferably gum arabic, gelatin, talc, stearic acid, corn starch, lactose, sucrose, β-carotene, and peanut oil.

[0074] A preferred embodiment (25) embodying embodiment (23) relates to the pharmaceutical composition according to embodiment (23), wherein the suppository further comprises one or more excipients selected from the group consisting preferably of lactose, preferably lactose monohydrate, and semi-synthetic solid glycerides.

[0075] A preferred embodiment (26) embodying any one of embodiments (20) to (22) relates to a pharmaceutical composition according to any one of embodiments (20) to (22) in the form of a solution, preferably a solution suitable for injection, comprising a compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt of formula (I) or formula (Ia).

[0076] A preferred embodiment (27) embodying embodiment (26) relates to the pharmaceutical composition according to embodiment (26), wherein the solution suitable for injection further comprises water and one or more components selected from the group consisting of sodium metabisulfite, ascorbic acid, and sorbitol.

[0077] A preferred embodiment (28) embodying embodiment (26) or (27) relates to the pharmaceutical composition according to embodiment (26) or (27), wherein the solution suitable for injection has a pH value of <5, preferably <4, more preferably <3, and the pH value is preferably determined by a pH-sensitive glass electrode according to DIN 19263:2007-05.

[0078] A preferred embodiment (29) embodying embodiment (28) relates to an embodiment (28) of the pharmaceutical composition according to an embodiment (28) in the form of an aerosol, preferably an aerosol suitable for spray application, comprising a compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt of formula (I) or formula (Ia).

[0079] The present invention is further illustrated by the following reference examples, comparative examples, and embodiments. [Examples]

[0080] The following examples are merely illustrative of the present invention. They are not to be construed as limiting the scope of the present invention in any way.

[0081] "Abeta1-40" represents the human amyloid beta (1-40) protein fragment (CAS number 131438-79-4, peptide sequence DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVV).

[0082] "Abeta1-42" represents the human amyloid beta (1-42) protein fragment (CAS number 107761-42-2), with the peptide sequence DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA.

[0083] I method I.1 Blood Sampling A 10 ml sample of venous blood was collected in a standardized test tube containing ethylenediaminetetraacetic acid (EDTA) and gently shaken once or twice. The sample was centrifuged at 1600 g at room temperature for 10 minutes as quickly as possible (within a maximum of 30 minutes). The plasma was divided into six equal 0.5 ml portions. All portions were frozen in a deep freezer (-80°C) within 10 minutes of centrifugation and stored until use.

[0084] I.2 Determination of Plasma Abeta Abeta was measured using an immunoassay with bead-based INNO-BIA plasma Abeta form (Innogenetics / Fujirebio Europe, Gent, Belgium) according to the manufacturer's protocol. Plasma samples and all other kit reagents were prepared according to the manufacturer's protocol. Briefly, plasma samples were thawed at room temperature, centrifuged at 4000g for 10 minutes to remove any debris, vortexed, and then diluted 3-fold with plasma diluent. After transferring to a filter plate, the diluted samples, control, and standard were washed, the first conjugate was added, and the plate was incubated overnight with shaking at 4°C. The following day, all wells were washed three times and incubated with the detection conjugate at room temperature for 1 hour. After three further washes, reading solution was added to all wells, shaken for 2 minutes, and then measured on a Luminex IS 100 (Luminex Corporation, Austin, TX, USA) platform. The Luminex instrument settings used were a gate of 7500-15000, a sample volume of 50 μL, and a count of 100 beads per region. Standard curve calculations were performed using a 4-parameter logistic fit (nl log4 command) with Stata 14.2 (StataCorp, College Station, TX, USA).

[0085] All standard, control, and patient samples were analyzed in pairs, and all samples from a given individual were assayed with a single analyte. The average concentrations (pg / ml) of the pairs of two biomarkers (Abeta1-40 and Abeta1-42) were calculated. In all eight standard curve-fitting models (4 units × 2 biomarkers), the adjusted R-squared statistic was greater than 0.995, indicating excellent curve-fitting quality.

[0086] II. Experiments and Results In this specification, thiethylperazine is used as thiethylperazine maleate, and the amount of thiethylperazine is given in weight-based units [mg], with the weight-based amount of thiethylperazine maleate [mg] indicated in parentheses. Based on preclinical results (Wesolowska, Molnar et al. 2009, Bateman 2010, Mawuenyega, Sigurdson et al. 2010, Krohn, Lange et al. 2011, Hofrichter, Krohn et al. 2013, Roberts, Elbert et al. 2014, Krohn, Bracke et al. 2015, Jepsen, De Both et al.), 15 human subjects were treated with different doses of thiethylperazine. Blood samples were collected from all subjects on day 1 (t=0 hours). Immediately thereafter, on day 1, the subjects received a first dose of 6.5 mg of thiethylperazine (10.28 mg of thiethylperazine maleate), and a blood sample was taken 4 hours after administration. Immediately after blood sampling, a second dose of 6.5 mg of thiethylperazine (10.28 mg of thiethylperazine maleate) was administered, and a second blood sample was taken 4 hours later. After the second blood sampling, two further doses of 6.5 mg of thiethylperazine (10.28 mg of thiethylperazine maleate) were administered 4 hours later, with a nighttime interruption between the fourth dose of the day and the first dose the following morning, 12 hours later. Thus, in total, 26 mg of thiethylperazine (41.12 mg of thiethylperazine maleate) was administered per day for three consecutive days. A steady state was reached between the end of day 2 (48 hours, four times the half-life of thiethylperazine) and the beginning of day 3 (52 hours, five times the half-life of thiethylperazine). On day 4, when a steady state was achieved, blood samples were taken four hours after the administration of the second dose to analyze the steady-state thiethylperazine concentration, etc. Thiethylperazine was always administered orally in the form of one tablet containing 6.5 mg of thiethylperazine (10.28 mg of thiethylperazine maleate).

[0087] Plasma Abeta is considered an indicator of brain Abeta content and Abeta efflux, with higher plasma Abeta concentrations indicating higher Abeta clearance from the brain (Ferrero, Williams et al. 2016; Sevigny, Chiao et al. 2016). Plasma Abeta was determined after subjects were treated with thiethylperazine at doses of 6.5 mg (10.28 mg thiethylperazine maleate) and 13 mg (20.56 mg thiethylperazine maleate), as well as after ingesting 26 mg / day of thiethylperazine (for comparison) (41.12 mg thiethylperazine maleate) for 3 days.

[0088] After ingesting an initial dose of 6.5 mg of thiethylperazine (10.28 mg of thiethylperazine maleate) on day 1, an increase in plasma Abeta1-40 was observed in 53% of subjects (8 out of 15). After the second dose on day 1, i.e., a dose of 13 mg of thiethylperazine (20.56 mg of thiethylperazine maleate), plasma Abeta1-40 was elevated in 87% of subjects (13 out of 15). Both doses resulted in a similar mean increase of 7.8% in plasma Abeta1-40.

[0089] With 26 mg of thiethylperazine per day for three consecutive days (41.12 mg of thiethylperazine maleate), only 40% of the study participants (6 out of 15) showed an increase in plasma Abeta1-40 at steady state, with a mean change of 6.5%.

[0090] In other words, significantly more subjects, ranging from 30% to 117%, responded to lower doses of thiethylperazine in the range of 2 to 20 mg, specifically 6.5 mg (10.28 mg of thiethylperazine maleate) and 13 mg of thiethylperazine (20.56 mg of thiethylperazine maleate), respectively, compared to only 40% (6 out of 15) of the study subjects who showed elevated plasma Abeta1-40 levels.

[0091] Furthermore, compared to subjects treated with a larger dose of 26 mg of thiethylperazine (41.12 mg of thiethylperazine maleate), the mean increase in plasma Abeta1-40 was significantly higher, particularly by ≥20%.

[0092] The mean difference in plasma Abeta1-40 concentrations between responders and non-responders was 33.04 pg / ml, 28.07 pg / ml, and 16.53 pg / ml for 6.5 mg, 13 mg, and 26 mg of thiethylperazine (10.28 mg, 20.56 mg, and 41.12 mg of thiethylperazine maleate), respectively. In other words, the mean difference in plasma Abeta1-40 concentrations between responders and non-responders was substantially increased by ≥10 pg / ml (or ≥60%) in steady-state mode in subjects treated with lower doses of thiethylperazine in the range of 2–20 mg, particularly 6.5 mg (10.28 mg of thiethylperazine maleate) and 13 mg of thiethylperazine (20.56 mg of thiethylperazine maleate), respectively, compared to subjects treated with a higher dose of 26 mg of thiethylperazine (41.12 mg of thiethylperazine maleate). Both the difference in Abeta1-40 and the thiethylperazine dose were highly correlated with plasma thiethylperazine levels (R of Abeta1-40). 2 =-0.999, R of dose 2 (=0.998).

[0093] Therefore, surprisingly, the efficacy of thiethylperazine treatment and the response to thiethylperazine treatment in humans were shown to be improved with lower doses of thiethylperazine rather than higher doses.

[0094] The results of determining the Abeta plasma concentration after treatment are shown in Figure 1.

[0095] Interassay precision was estimated based on four replicates of two quality control (QC) samples (A+B), and the coefficient of variation (CV) is shown in Table 1 below.

[0096] [Table 1]

[0097] Inter-assay precision was estimated based on four replicates of two types of QC samples, and the coefficient of variation (CV) for A or B is shown in Tables 2 and 3 below.

[0098] [Table 2]

[0099] [Table 3]

[0100] Inter-assay precision was estimated as the median and interquartile range (p25-p75) of the difference between pairs of measurements obtained by dividing them by their mean across all samples ("range vs. mean"), and is presented in Table 4 below.

[0101] [Table 4] The following are examples of the forms of this disclosure: [1] A compound of formula (I) for use in the treatment and / or prevention of human Alzheimer's disease, [ka] [In the formula, R 1 This is selected from the group consisting of hydrogen atoms, halogen atoms, methoxy groups, perhalogenated alkyl groups, and -X-C1~C2 alkyl groups, where X is either a sulfur atom or an oxygen atom. R 2 is a hydrogen atom or a methyl group, R 3 , R 4These atoms are, independently of each other, either hydrogen atoms or C1-C4 alkyl groups, or together form a 6-membered alkyl ring containing at least one further nitrogen atom, where the at least one further nitrogen is a C1-C3 alkyl-R 5 It is substituted with R 5 is a hydrogen atom or a hydroxyl group, n is either 0 or 1. m is either 0 or an integer selected from the range of 1 to 4. p is either 0 or an integer selected from the range 1 to 3. A compound of formula (I) administered at a dose of ≤20 mg per day of administration. [2] A compound of formula (I) for use as described in Embodiment 1, administered in a dose ranging from 2 to 20 mg per day of administration. [3] A compound of formula (I) having formula (Ia) for use as described in embodiment 1 or 2. [ka] [In the formula, R 1 This is selected from the group consisting of a methoxy group, a trifluoromethyl group, and a thioethyl group. R 2 is a hydrogen atom or a methyl group, R 3 , R 4 They are both methyl groups, or together they form a 6-membered alkyl ring containing one additional nitrogen atom, where the additional nitrogen is substituted with a methyl group. n is either 0 or 1. [4] The drug is administered in a dose of 5 to 15 mg per day, preferably in the range of 6 to 13.5 mg. More preferably, the drug is administered in a dose ranging from 6 to 7 mg per day or from 12.5 to 13.5 mg per day. A compound of formula (I) or formula (Ia) for use as described in any one of embodiments 1 to 3. [5] A compound of formula (I) or formula (Ia) is used as a pharmaceutically acceptable salt of formula (I) or formula (Ia), and the pharmaceutically acceptable salt is a chloride. ion , sulfuric acid ion mesylic acid ion , besilicic acid ion tosylic acid ion fumaric acid ion , malonic acid ion malic acid ion maleic acid ion succinic acid ion lactic acid ion Glycolic acid ion , citric acid ion , aspartic acid ion and mandelic acid ion One or more anions selected from the group consisting of, preferably malic acid ion and / or maleic acid ion , more preferably maleic acid ion A compound of formula (I) or formula (Ia) for use according to any one of embodiments 1 to 4, including the above. [6] A compound of formula (I) or formula (Ia) for use according to any one of embodiments 1 to 5, wherein the compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt of formula (I) or formula (Ia) is selected from the group consisting of levomepromazine, trifluoperazine, and thiethylperazine and pharmaceutically acceptable salts of these compounds, preferably levomepromazine or thiethylperazine or a pharmaceutically acceptable salt of levomepromazine or a pharmaceutically acceptable salt of thiethylperazine, and more preferably thiethylperazine or a pharmaceutically acceptable salt of thiethylperazine. [7] The compound of formula (I) or formula (Ia) for use according to any one of embodiments 1 to 6, wherein the compound of formula (I) or formula (Ia) is used as thiethylperazine maleate, and the thiethylperazine maleate is administered in a dose of ≤31.62 mg per administration day, more preferably in the range of 3.16 to 31.62 mg, more preferably in the range of 7.9 to 23.72 mg, and more preferably in the range of 9.48 to 21.34 mg. [8] A compound of formula (I) or formula (Ia) for use according to any one of embodiments 1 to 7, wherein the compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt of formula (I) or formula (Ia) is administered orally or rectally. [9] A pharmaceutical composition comprising a compound of formula (I) or formula (Ia) as defined in any one of embodiments 1 to 8, or a pharmaceutically acceptable salt of formula (I) or formula (Ia), and a pharmaceutically acceptable excipient, wherein the preparation contains, in solution form, 2 to 20 mg of the compound of formula (I) or formula (Ia), preferably 5 to 15 mg of the compound of formula (I) or formula (Ia), and more preferably 6 to 13.5 mg of the compound of formula (I) or formula (Ia).

[10] The pharmaceutical composition according to embodiment 9, in the form of a solution suitable for injection, comprising a compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt of formula (I) or formula (Ia). [Brief explanation of the drawing]

[0102] [Figure 1] The table shows individual plasma Abeta concentrations in treatment responders before (pre) and after (post) administration of different doses of thiethylperazine. Asterisks indicate the significance level of the mean before versus mean after administration (*p≦0.05, **p≦0.01, ***p≦0.001). [Prior art documents] [Non-patent literature]

[0103] [Non-Patent Document 1] Bateman, RJ (2010). "O2-03-05: Amyloid-beta production and clearance rates in Alzheimer's disease." Alzheimer's & Dementia 6(4): S101-S101. [Non-Patent Document 2] Ferrero, J., L. Williams, H. Stella, K. Leitermann, A. Mikulskis, J. O'Gorman and J. Sevigny (2016). "First-in-human, double-blind, placebo-controlled, single-dose escalation study of aducanumab (BIIB037) in mild-to-moderate Alzheimer's disease." Alzheimer's & Dementia: Translational Research & Clinical Interventions 2(3): 169-176. [Non-Patent Document 3] Hofrichter, J., M. Krohn, T. Schumacher, C. Lange, B. Feistel, B. Walbroel, H. J. Heinze, S. Crockett, T. F. Sharbel and J. Pahnke (2013). "Reduced Alzheimer's disease pathology by St. John's Wort treatment is independent of hyperforin and facilitated by ABCC1 and microglia activation in mice." Curr. Alzheimer Res. 10(10): 1057-1069. [Non-Patent Document 4] Jepsen, W. M., M. De Both, A. L. Siniard, K. Ramsey, I. S. Piras, M. Naymik, A. Henderson and M. J. Huentelman (2020). "Adenosine triphosphate Binding Cassette subfamily C member 1 (ABCC1) overexpression reduces APP processing and increases alpha- versus beta-secretase activity, in vitro." Biol Open: bio.054627. Non-Patent Document 5 Krohn, M., A. Bracke, Y. Avchalumov, T. Schumacher, J. Hofrichter, K. Paarmann, C. Froehlich, C. Lange, T. Bruening, O. von Bohlen Und Halbach and J. Pahnke (2015). "Accumulation of murine amyloid-beta mimics early Alzheimer's disease." Brain 138(Pt 8): 2370-2382. Non-Patent Document 6 Krohn, M., C. Lange, J. Hofrichter, K. Scheffler, J. Stenzel, J. Steffen, T. Schumacher, T. Bruning, A. S. Plath, F. Alfen, A. Schmidt, F. Winter, K. Rateitschak, A. Wree, J. Gsponer, L. C. Walker and J. Pahnke (2011). "Cerebral amyloid-beta proteostasis is regulated by the membrane transport protein ABCC1 in mice." J Clin Invest 121(10): 3924-3931.

Direct Environment 7

Outdoor Track 8

Outdoor Tools9

Outdoor Tools 10

Outdoor Content11

Claims

1. A composition for use in the treatment and / or prevention of human Alzheimer's disease, wherein the composition comprises thiethylperazine maleate, A composition in which the composition is administered such that the thiethylperazine maleate portion corresponding to thiethylperazine is administered in an amount of ≤20 mg per administration day.

2. The composition for use according to claim 1, wherein the composition is administered such that the cation portion corresponding to thiethylperazine maleate is 2 to 20 mg per administration day.

3. The composition for use according to claim 1 or 2, wherein the composition is administered such that the cation portion corresponding to thiethylperazine maleate is 5 to 15 mg per administration day.

4. The composition for use according to claim 1 or 2, wherein the composition is administered such that thiethylperazine maleate is administered in a dose of ≤31.62 mg per administration day.

5. The composition for use according to claim 1 or 2, wherein the composition is administered orally or rectally.

6. A pharmaceutical composition comprising thiethylperazine maleate as defined in claim 1 or 2 and a pharmaceutically acceptable excipient, wherein the preparation contains thiethylperazine maleate in solution form such that the cation portion corresponding to thiethylperazine is 2 to 20 mg.

7. The pharmaceutical composition according to claim 6 in the form of a solution suitable for injection.

Images