Specific Dosages of Phenothiazine Compounds for Use in Treating or Preventing Alzheimer's Dementia - Patent application

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 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. [Background technology]

[0002] European Patent Registration No. 2 614 060 B1 (WO 2012 / 031941 A2) discloses thiethylperazine (IUPAC: 2-(ethylsulfanyl)-10-[3-(4-methylpiperazin-1-yl)propyl]-10H-phenothiazine, CAS: 1420-55-9) and its derivatives for the treatment of beta-amyloidopathies or alpha-synucleinopathies accompanied by deposition of brain proteins and reduced activity of the brain ABCC1 transporter. As described by Krohn et al., thiethylperazine also activates the transport protein ABCC1, which removes beta-amyloid from 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). Thus, thiethylperazine proved to be effective in expelling amyloid beta (Abeta) from the endothelial cells of the blood-brain barrier and through it to the periphery in a mouse model of Alzheimer's disease (AD). It was also shown that pharmaceutical activation of ABCC1 can reduce the deposition of amyloid plaques in the brain. Thiethylperazine was used in this study at a concentration of 15 mg / kg body weight per day for mice, which, considering the allometric fold difference between mice and humans of 7, would result in a human equivalent dose of 105 mg of thiethylperazine per day.

[0003] Jepsen, De Both et al. showed that ABCC1 can not only export Abeta from the cytoplasm of human cells, but that its overexpression significantly reduces Abeta production and increases the ratio of alpha- to beta-secretase-mediated cleavage of amyloid precursor protein (APP), 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 wild-type cells that efficiently took up Abeta-42 by 29.6%. Concomitant overexpression of ABCC1 enhanced this effect to 44.4%. Thus, 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 produce less Abeta-42 and Abeta-40 by shifting APP processing to a non-amyloidogenic pathway (Jepsen, De Both et al.).

[0004] With regard to beta amyloidopathy, such as Alzheimer's disease (and Parkinson's disease), it is believed that thiethylperazine 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 EudraCT number: 2014-000870-20. This clinical trial was carried out with 26 mg thiethylperazine per person per day and 52 mg thiethylperazine per person per day, respectively, considering what is considered necessary in terms of efficiency. However, considering the increase in Alzheimer's disease and the increase in life expectancy and the increasing proportion of elderly people in the total population, there is still a need for improved formulations for the treatment of Alzheimer's disease. Summary of the Invention

[0005] Thus, the objective technical problem underlying the present invention was to provide improved formulations for (use in) the treatment of Alzheimer's disease and / or in the prevention of Alzheimer's disease. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[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 relates to a compound of formula (I) for use in the treatment and / or prevention of Alzheimer's dementia

[0007] [ka] [In the formula, R 1 is selected from the group consisting of a hydrogen atom, a halogen atom, a methoxy group, a perhalogenated alkyl group, and an -X-C1-C2 alkyl group, where X is either a sulfur atom or an oxygen atom; R 2 is a hydrogen atom or a methyl group, R 3 , R 4are each independently either a hydrogen atom or a C1-C4 alkyl group, or taken together form a 6-membered alkyl ring containing at least one additional nitrogen atom, where the at least one additional nitrogen is a C1-C3 alkyl-R 5 is substituted with an R 5 is a hydrogen atom or a hydroxyl group, n is 0 or 1, m is 0 or an integer selected from the range of 1 to 4; p is 0 or an integer selected from the range of 1 to 3; The compound of formula (I) is administered in a dosage of ≦20 mg per day.

[0008] Preferably, the compound of formula (I) for use in the treatment and / or prevention of Alzheimer's dementia is administered at a dosage in the range of 2-20 mg per day of administration. By "per day of administration" is meant a dosage of ≦20 mg administered in the range of 1-7 days per week, preferably either daily (7 days per week, i.e. daily) or every other day or every third day, more preferably a dosage of ≦20 mg given daily or every other day, more preferably a dosage of ≦20 mg given daily.

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

[0010] Usually, those skilled in the art strive to reduce the dosage of drugs as much as possible, but it is expected by those skilled in the art that the efficacy of treatments, especially with active agents (active pharmaceutical ingredients, APIs), decreases with decreasing amounts of the administered active agent. Thus, those skilled in the art expect to offer lower dosages of drugs (cheaper and safer treatments) at the expense of lower therapeutic efficacy and potentially fewer responsive patients. Responses in patients are dose-related, with the maximum efficacy (E max It is a generally accepted principle that increasing the dose produces a greater response until a dose of 100 mg / kg / day is reached (see, for example, R. Lieberman et al., 1993). However, it has surprisingly been found in the context of the present invention that for the compounds of formula (I) or pharma- ceutically acceptable salts thereof, in particular thiethylperazine, and more particularly the maleate salt(s) of thiethylperazine, the efficacy of and response to treatment in humans improves at lower doses, but not at higher doses. Thiethylperazine is 2-(ethylsulfanyl)-10-[3-(4-methylpiperazin-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 found to respond to lower doses of thiethylperazine in the range of 2-20 mg, i.e., 30-117% more subjects, but the mean increase in plasma Abeta1-40 was also significantly higher, especially ≧20% higher, compared to subjects treated with higher doses of thiethylperazine. Furthermore, the mean difference in plasma Abeta1-40 between responders and non-responders was also substantially increased, ≧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] When used below, the terms "having", "comprise" or "include" or any grammatical variants thereof are used in a non-exclusive sense. Thus, these terms may refer both to the situation in which, in the entity described in this context, there are no further features apart from the features introduced by these terms, and to the situation in which there are one or more further features. As an example, the expressions "A has B", "A comprises B" and "A includes B" may all refer to the situation in which there are no other elements apart from B in A (i.e., the situation in which A is exclusive only from B), as well as to the situation in which, in the entity A, there are one or more further elements apart from B, such as an element C, multiple elements C and D, or even more elements. Also, as will be understood by those skilled in the art, the expressions "comprising a" and "comprising an" preferably refer to "comprising one or more", i.e. are equivalent to "comprising at least one".

[0012] Furthermore, when used below, the terms "preferably", "more preferably", "most preferably", "particularly", "more particularly", "particularly", "more particularly" or similar terms are used with optional features without further limiting the possibilities. Features introduced by these terms are therefore optional features and are not intended to limit the scope of the claims in any way. The invention can be implemented by using alternative features, as 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 limitations with respect to further embodiments of the invention, without any limitations with respect to the scope of the invention, and without any limitations with respect to the possibility that the features so introduced may be combined with other optional or non-optional features of the invention.

[0013] The term "pharmaceutically acceptable" as used herein relates to a pharmaceutically acceptable salt in the sense that it is not harmful to the recipient and is preferably compatible with any other components of the formulation. Preferably, the pharmaceutically acceptable salt is a salt of a compound of formula (I) that causes only moderate adverse drug reactions, preferably only mild adverse drug reactions. As used herein, the term "mild" adverse reactions relates to adverse reactions that do not require medical intervention, such as skin rash, headache, gastrointestinal disorders, fatigue, etc., and "moderate" adverse reactions are adverse reactions that require medical intervention but are not potentially life-threatening.

[0014] The term "alkyl" as used herein refers to a straight or branched chain saturated hydrocarbon group connected to the backbone by a covalent bond to at least one of its at least one carbon atoms. Preferred alkyl groups are straight or branched chain alkyl groups. Thus, alkyl groups include primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups.

[0015] The terms "treating" and "treatment" refer to alleviating to a significant extent the disease or disorder referred to herein, or symptoms associated therewith. Said treating, as used herein, also includes complete restoration of health with respect to the disease or disorder referred to herein. It should be understood that treating, as the term is used herein, may not be effective in all subjects treated. However, the term requires that a preferably statistically significant portion of subjects suffering from the disease or disorder referred to herein can be successfully treated. Whether a portion is statistically significant can be determined by the skilled artisan without further ado using various well-known statistical evaluation tools, such as determining confidence intervals, determining p-values, Student's t-test, Mann-Whitney test, and the like. Preferred confidence intervals are at least 90%, at least 95%, at least 97%, at least 98% or at least 99%. The p-value is preferably 0.1, 0.05, 0.01, 0.005, or 0.0001. Preferably, the treatment will be effective in 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 population. Preferably, treating Alzheimer's disease is improving one or more biomarkers of neurodegeneration known to those skilled in the art, such as Abeta-40, Abeta-42 or Abeta42 / 40 ratio in body fluids (blood, CSF), phosphorylated variants of tau protein (e.g., p-Tau181, p-Tau217, etc.), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), etc., and / or improving the brain burden of Abeta and / or tau as determined using positron emission tomography (PET) methods, and / or slowing or halting or improving the decline in cognitive ability of a subject 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 appreciated 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 value of the respective biomarker after or during treatment of the subject deviating less from the reference value for healthy subjects than before treatment. "Slowing or halting cognitive decline or improving cognitive performance" relates to results from the respective test in which after or during treatment, the value deviates less from the reference value for healthy subjects or a known reference value than before treatment.

[0016] The terms "preventing" and "prevention" refer to maintaining health in a subject for a certain period of time with respect to Alzheimer's disease. It will be understood that said period may depend on the amount of drug compound administered and the individual factors of the subject discussed elsewhere herein. It should be understood that prevention is not effective in all subjects treated with a compound according to the present invention. However, the term requires that a preferably statistically significant portion of the subjects of a cohort or population is effectively prevented from suffering from the disease or disorder referred to herein, or its associated symptoms. Preferably, in this context, a cohort or population of subjects is envisaged that would normally, i.e., develop the disease or disorder referred to herein, without the preventive measures according to the present invention. Whether a portion is statistically significant can be determined by the skilled artisan without further ado using various well-known statistical evaluation tools discussed elsewhere herein.

[0017] The term "subject", as used herein, relates to a multicellular animal, preferably a vertebrate, more preferably a mammal, more preferably a human.

[0018] In some embodiments of the use in the treatment and / or prevention of Alzheimer's dementia, R 1 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.

[0019] In some embodiments of the use in the treatment and / or prevention of Alzheimer's dementia, R 1 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 are, independently of each other, a methyl or ethyl group, or taken together form a six-membered alkyl ring containing at least one additional nitrogen atom, where the at least one additional nitrogen is a C1-C3 alkyl-R 5 is substituted with an R 5 is a hydrogen atom or a hydroxyl group, n is 0 or 1, m and p are each 0.

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

[0021] In some embodiments of the use in the treatment and / or prevention of Alzheimer's dementia, R 3 and R 4 forms a six-membered ring with one further nitrogen atom, where the further nitrogen atom bears a methyl group or a -CH2-CH2-OH group.

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

[0023] [ka] [In the formula, R 1 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 (preferably having the R configuration); R 3 , R 4 are both methyl groups or taken together to form a six-membered alkyl ring containing one additional nitrogen atom, where the one additional nitrogen is replaced with a methyl group; n is 0 or 1.

[0024] In some embodiments of the use in the treatment and / or prevention of Alzheimer's dementia, R 3 , R 4 are both methyl groups or taken together to form a piperazine ring in which the additional nitrogen atom is substituted with a methyl group (4-methylpiperazin-1-yl group).

[0025] The compounds of formula (I) or formula (Ia) are used as (uncharged) compounds or in the form of their pharma- ceutically acceptable salts. The compounds of formula (I) or the pharma- ceutically acceptable salts of the compounds of formula (I) or formula (Ia) are administered so that the cationic moiety corresponding to the compounds of formula (I) or formula (Ia) reaches preferably ≦20 mg, preferably 2-20 mg, per day of administration.

[0026] Preferably, the pharma- ceutically acceptable salt is selected from the group consisting of sulfate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydrogenbenzoate, benzoic acid salt ... The anion may comprise one or more anions selected from the group consisting of hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, almondate, adipate, alginate, mucate, aspartate, benzenesulfonate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, hexanoate, 2-hydroxyethanesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmitate, pectinate, persulfate, picrate, pivalate, salicylate, thiocyanate, tosylate, arginate, and undecanoate. More preferably, the pharma- ceutically acceptable salt comprises one or more anions selected from the group consisting of chloride, sulfate, mesylate, besylate, tosylate, fumarate, malonate, malate, maleate, succinate, lactate, glycolate, citrate, aspartate and mandelate, preferably malate and / or maleate, more preferably maleate.

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

[0028] Preferably, the compound of formula (I) or formula (Ia) is used alone or as a mixture of two or more compounds of formula (I) or formula (Ia), or as a pharma- ceutically acceptable salt of the compound of formula (I) or formula (Ia), or as a mixture of two or more pharma- ceutically acceptable salts of the compound of formula (I) or formula (Ia). Similarly, a mixture of one or more compounds of formula (I) or formula (Ia) and one or more pharma- ceutically acceptable salts of the compound 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 pharma- ceutical 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, 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 systems.

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

[0030] In the context of the present invention, when a salt of a compound of formula (I) or formula (Ia) is used, the weights indicated above relate to the compound of formula (I) or formula (Ia), i.e. the amount of the respective salt to be used will be greater due to the higher molecular weight of the salt. However, as indicated above, the pharma- ceutically acceptable salt of the compound of formula (I) or formula (Ia) is used such that the cationic moiety corresponding to the compound of formula (I) or formula (Ia) is preferably in an amount of ≦20 mg, preferably in the range of 2-20 mg, per day of administration. For example, when thiethylperazine maleate is used, the range of 2-20 mg for thiethylperazine corresponds to a range of 3.16-31.62 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 preferably in an amount of ≦20 mg, preferably in the range of 2-20 mg, per day of administration. 30 H 41 N3O 10 When S2) is used, the range of 2-20 mg for thiethylperazine corresponds to a range of 3.34-33.42 mg of thiethylperazine maleate. The same applies to the preferred ranges and values. Thus, in some embodiments, the compound of formula (I) or formula (Ia) is used as a pharma- ceutically acceptable salt of formula (I) or formula (Ia), preferably as thiethylperazine maleate, at a dose of preferably ≦31.62 mg, more preferably in the range of 3.16-31.62 mg, more preferably in the range of 7.9-23.72 mg, more preferably in the range of 9.48-21.34 mg of thiethylperazine maleate per day of administration. More preferably, thiethylperazine maleate is administered at a dose of 9.47-11.07 mg of thiethylperazine maleate per day of administration or at a dose of 19.77-21.34 mg of thiethylperazine maleate per day of administration.

[0031] In some embodiments of the use in the treatment and / or prevention of Alzheimer's dementia, the compound of Formula (I) or Formula (Ia) or a pharma- ceutically 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 the use in the treatment and / or prevention of Alzheimer's dementia, the compound of Formula (I) or Formula (Ia) or a pharma- ceutically acceptable salt of Formula (I) or Formula (Ia) is administered orally or rectally.

[0033] Second Aspect-Pharmaceutical Compositions In a second aspect, 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 aspect 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, more preferably in the range of 6 to 13.5 mg. All the definitions given and all the preferred embodiments described in the section relating to the first aspect also apply to the pharmaceutical composition according to the second aspect.

[0034] The pharmaceutical composition may also contain at least one pharma- ceutically acceptable excipient in addition to the active compound. Pharmaceutically acceptable excipients include, but are not limited to, carriers, adjuvants, stabilizers and / or other compounds deemed appropriate by the skilled artisan, for example for galenic purposes. As referred to herein, the compounds of formula (I), (Ia) or their respective pharma- ceutically acceptable salts as specified herein above in the section on the first aspect are the "active compounds" of the composition, although "further active compounds" as referred to under this term may be present. Preferably, the further active compounds are also pharma- ceutically active compounds. Certain pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound as referred to herein above, preferably in admixture or otherwise in association with at least one pharma- ceutically acceptable carrier or diluent. To make those particular pharmaceutical compositions, the active compound(s) are usually mixed with a carrier or diluent. The resulting formulation should be adapted to the method of administration, i.e., in the form of tablets, capsules, suppositories, solutions, suspensions, etc., as outlined in more detail below for certain 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 pharma- ceutically acceptable salt of Formula (I) or Formula (Ia) as defined above in the section relating to the first aspect and a pharma- ceutically acceptable excipient. By "unit dose preparation", "unit dose" or "unit dose form" is meant a single dose of a compound of Formula (I) or Formula (Ia) or a pharma- ceutically acceptable salt of a compound of Formula (I) or Formula (Ia) that can be administered to a subject and that can be easily handled and packaged as a physically and chemically stable unit dose.

[0036] The unit dose preparation contains ≦20 mg of the compound of formula (I) or formula (Ia), preferably 2-20 mg of the compound of formula (I) or formula (Ia), more preferably 5-15 mg of the compound of formula (I) or formula (Ia), more preferably 6-13.5 mg of the compound of formula (I) or formula (Ia). More preferably, the unit dose preparation contains the compound of formula (I) or formula (Ia) in the range of 6-7 mg or in the range of 12.5-13.5 mg. In some embodiments, the compound of formula (I) or formula (Ia) is administered once per day on the administration day as a single dose, and the 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 preparations are designed to contain half of the total amount of the compound of Formula (I) or Formula (Ia) per unit dose preparation.

[0037] In some embodiments, when a pharma- ceutically acceptable salt of the compound of formula (I) or formula (Ia) is used, the cationic moiety corresponding to the compound of formula (I) or the compound of formula (Ia) amounts to ≦20 mg, preferably in the range of 2-20 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 3.16-31.62 mg, more preferably in the range of 7.9-23.72 mg, more preferably in the range of 9.48-21.34 mg of thiethylperazine maleate. More preferably, the unit dose preparation contains thiethylperazine maleate in the range of 9.47-11.07 mg of thiethylperazine maleate or in an amount in the range of 19.77-21.34 mg of thiethylperazine maleate. In some embodiments, the pharma- ceutically 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 entire amount of the pharma- ceutically acceptable salt of the compound of formula (I) or formula (Ia) in one unit dose preparation. In some embodiments, the pharma- ceutically 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 of the entire amount of the pharma- ceutically acceptable salt of the compound of formula (I) or formula (Ia) per unit dose preparation.

[0038] In some embodiments, the pharmaceutical composition comprising a compound of Formula (I) or Formula (Ia) or a pharma- ceutically 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 auxiliary agents, preferably 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 sugar, polymeric material, and mixtures of sugar and polymeric material. The sugar coating comprises one or more sugars, preferably selected from the group consisting of sucrose, glucose, lactose, maltitol, mannitol, isomalt, sorbitol, xylitol, and starch. The polymer coating comprises one or more polymers, preferably 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 optionally comprises one or more further components, preferably selected from fillers, colorants, antiadhesives, lubricants, glidants, flavorings, suspension stabilizers, smoothing agents, and abrasives, where suitable substances are therefore known to those skilled in the art.

[0039] The suppositories preferably further comprise one or more auxiliaries, preferably 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 pharma- ceutically acceptable salt of Formula (I) or Formula (Ia) is in the form of a solution, preferably a solution suitable for injection.

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

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

[0043] Treatment The present invention also provides a method for treating and / or preventing Alzheimer's dementia, comprising: (a) A compound of formula (I)

[0044] [ka] [In the formula, R 1 is selected from the group consisting of a hydrogen atom, a halogen atom, a methoxy group, a perhalogenated alkyl group, and an -X-C1-C2 alkyl group, 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 are each independently either a hydrogen atom or a C1-C4 alkyl group, or taken together form a 6-membered alkyl ring containing at least one additional nitrogen atom, where the at least one additional nitrogen is a C1-C3 alkyl-R 5 is substituted with an R 5 is a hydrogen atom or a hydroxyl group, n is 0 or 1, m is 0 or an integer selected from the range of 1 to 4; p is 0 or an integer selected from the range of 1 to 3. wherein the compound of formula (I) is preferably administered at a dose of ≦20 mg, preferably in the range of 2-20 mg per day of administration; (b) thereby treating and / or preventing Alzheimer's dementia; The present invention relates to a method comprising the steps of:

[0045] In some embodiments, the present invention relates to a method for treating and / or preventing Alzheimer's dementia comprising administering a pharmaceutical composition, such as the pharmaceutical composition described above in the section relating to the second aspect, wherein all details described in the sections relating to the first and second aspects also apply to the treatment and / or prevention method.

[0046] The method for treating and / or preventing is preferably an in vivo method. Moreover, the method may comprise multiple steps in addition to the steps explicitly mentioned above. For example, the further step may relate to diagnosing, for example, Alzheimer's dementia before step (a) and / or identifying the subject as benefiting from treatment with a compound of formula (I), preferably according to the method specified above. Thus, preferably, the method comprises the further step of (i) determining or having determined the Alzheimer's dementia of the subject, and (ii) identifying or having identified the subject as benefiting from treatment with a compound of formula (I). The further step may also comprise, in step (b), co-treating the subject as specified herein above. Moreover, one or more of the steps may be carried out by an automated device.

[0047] The present invention is further described by the following embodiments and combinations of embodiments, as indicated by the respective dependencies and back references. In particular, in each case where a range of embodiments is mentioned, it is noted that in the context of a term, such as "the method of any one of embodiments 1 to 4", all embodiments in this range are expressly disclosed for those skilled in the art, i.e., the wording of this term should be understood by those skilled in the art as being equivalent to "the method of 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 dementia,

[0049] [ka] [In the formula, R 1 is selected from the group consisting of a hydrogen atom, a halogen atom, a methoxy group, a perhalogenated alkyl group, and an -X-C1-C2 alkyl group, 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 are each independently either a hydrogen atom or a C1-C4 alkyl group, or taken together form a 6-membered alkyl ring containing at least one additional nitrogen atom, where the at least one additional nitrogen is a C1-C3 alkyl-R 5 is substituted with an R 5 is a hydrogen atom or a hydroxyl group, n is 0 or 1, m is 0 or an integer selected from the range of 1 to 4; p is 0 or an integer selected from the range of 1 to 3; The compound of formula (I) is administered in a dosage of ≦20 mg per day.

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

[0051] A preferred embodiment (3) embodying embodiment (1) or (2) is R 1 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) which embodies any one of the embodiments (1) to (3) is as follows: R 1 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 are each independently a methyl or ethyl group, or together form a six-membered alkyl ring containing at least one additional nitrogen atom, where the at least one additional nitrogen is a C1-C3 alkyl-R 5 is substituted with an R 5 is a hydrogen atom or a hydroxyl group, n is 0 or 1; m and p are each 0. It relates to a compound of formula (I) as defined above for use according to any one of embodiments (1) to (3).

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

[0054] A preferred embodiment (6) embodying any one of the embodiments (1) to (5) is R 3 and R 4 forms a 6-membered ring with one further nitrogen atom, wherein the further nitrogen atom carries a methyl group or a -CH2-CH2-OH group,

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

[0056] [ka] [In the formula, R 1 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 (preferably having the R configuration); R 3 , R 4 are both methyl groups or taken together to form a six-membered alkyl ring containing one additional nitrogen atom, where the one additional nitrogen is replaced with a methyl group; n is 0 or 1.

[0057] A preferred embodiment (8) embodying any one of the embodiments (1) to (7) is R 3 , R 4 are both methyl groups or together form a piperazine ring, in which the further nitrogen atom is substituted with a methyl group (a 4-methylpiperazin-1-yl group).

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

[0059] A preferred embodiment (10) embodying any one of the embodiments (1) to (9) is a pharma- ceutically acceptable salt of formula (I) or formula (Ia) that is a sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, Oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β- The compound of formula (I) or formula (Ia) for use according to any one of embodiments (1) to (9) comprises one or more anions selected from the group consisting of hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, almondate, adipate, alginate, mucate, aspartate, benzenesulfonate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, hexanoate, 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectinate, persulfate, picrate, pivalate, salicylate, thiocyanate, tosylate, arginate, and undecanoate.

[0060] A preferred embodiment (11), embodying any one of the embodiments (1) to (10), relates to a compound of formula (I) or formula (Ia) for use according to any one of the embodiments (1) to (10), wherein the pharma- ceutically acceptable salt of formula (I) or formula (Ia) comprises one or more anions selected from the group consisting of chloride, sulfate, mesylate, besylate, tosylate, fumarate, malonate, malate, maleate, succinate, lactate, glycolate, citrate, aspartate and mandelate, preferably malate and / or maleate, more preferably maleate.

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

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

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

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

[0065] A preferred embodiment (16) embodying any one of the embodiments (1) to (15) relates to a compound of formula (I) or formula (Ia) for use according to any one of the embodiments (1) to (15), used as a pharma- ceutically acceptable salt of formula (I) or formula (Ia), preferably as thiethylperazine maleate, preferably administered at a dose of ≦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, more preferably in the range of 9.48 to 21.34 mg of thiethylperazine maleate per day of administration.

[0066] A preferred embodiment (17) embodying embodiment (16) relates to a compound of formula (I) or formula (Ia) for use according to embodiment (16) used as a pharma- ceutically acceptable salt of formula (I) or formula (Ia), preferably as thiethylperazine maleate, preferably administered in a dose range of 9.47 to 11.07 mg of thiethylperazine maleate per day of administration or in a dose range of 19.77 to 21.34 mg of thiethylperazine maleate per day of administration.

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

[0068] A preferred embodiment (19), embodying any one of the embodiments (1) to (18), relates to a compound of formula (I) or formula (Ia) for use according to any one of the embodiments (1) to (18), wherein said compound of formula (I) or formula (Ia) or a pharma- ceutically 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 the 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, more preferably in the range of 6 to 13.5 mg.

[0070] A preferred embodiment (21) embodying embodiment (20) relates to said 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 pharma- ceutically acceptable salt of formula (I) or formula (Ia), and wherein the compound of formula (I) or a pharma- ceutically acceptable salt of the compound of formula (I) or formula (Ia) is used such that the cationic moiety corresponding to the compound of formula (I) or the compound of formula (Ia) is preferably in an amount of ≦20 mg, preferably in the range of 2 to 20 mg, as thiethylperazine maleate, and wherein the pharmaceutical composition comprises an amount of ≦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, of thiethylperazine maleate.

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

[0072] A preferred embodiment (23), embodying any one of the embodiments (20) to (22), relates to the pharmaceutical composition according to any one of the embodiments (20) to (22) in the form of a tablet or suppository, comprising a compound of formula (I) or formula (Ia) or a pharma- ceutically 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, preferably selected from the group consisting of 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 auxiliaries, preferably selected from the group consisting of lactose, preferably lactose monohydrate and semi-synthetic solid glycerides.

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

[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 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, the pH value being preferably determined by a pH-sensitive glass electrode according to DIN 19263:2007-05.

[0078] A preferred embodiment (29), embodying embodiment (28), relates to said pharmaceutical composition according to 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 pharma- ceutically acceptable salt of formula (I) or formula (Ia).

[0079] The present invention is further illustrated by the following Reference Examples, Comparative Examples and Examples. EXAMPLES

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

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

[0082] "Abeta1-42" represents human amyloid beta (1-42) protein fragment (CAS number 107761-42-2), 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. As soon as possible (within a maximum of 30 min), the sample was centrifuged at 1600 g for 10 min at room temperature. Plasma was aliquoted into six aliquots of 0.5 ml. All aliquots were frozen in a deep freezer (-80°C) within 10 min after centrifugation and stored until use.

[0084] I.2 Determination of Abeta in plasma Abeta measurements were performed using a bead-based INNO-BIA plasma Abeta format immunoassay (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 min to remove any possible debris, vortexed, and then diluted 3-fold using plasma diluent. After transfer to a filter plate, the diluted samples, controls, and standards were washed and incubated overnight with shaking at 4°C after the addition of the first conjugate. The next day, all wells were washed three times and incubated with the detection conjugate for 1 h at room temperature. After three further washes, reading solution was added to all wells and measurements were performed on a Luminex IS 100 (Luminex Corporation, Austin, TX, USA) platform after shaking for 2 min. The Luminex instrument settings used were gates 7500–15000, sample volume 50 μL, and counts of 100 beads per region. Standard curve calculations were performed using a four-parameter logistic fit (nl log4 command) using Stata 14.2 (StataCorp, College Station, TX, USA).

[0085] All standards, controls, and patient samples were analyzed in duplicate, and all samples from a given individual were assayed in one analytical unit. The averaged concentrations (pg / ml) of the duplicates of the two biomarkers (Abeta1-40 and Abeta1-42) were calculated. For all eight standard curve fitting models (4 units x 2 biomarkers), the adjusted R-squared statistic was higher than 0.995, demonstrating excellent quality of the curve fitting.

[0086] II Experiments and Results Hereinafter, thiethylperazine is used as thiethylperazine maleate, and the weight-based amount [mg] of thiethylperazine is 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. On day 1 (t=0 hours), blood samples were taken from all subjects. Immediately thereafter, on day 1, the subject received a first dose of 6.5 mg thiethylperazine (10.28 mg thiethylperazine maleate) and a blood sample was taken 4 hours after administration. Immediately after the blood sampling, a second dose of 6.5 mg thiethylperazine (10.28 mg 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 thiethylperazine (10.28 mg thiethylperazine maleate) were administered 4 hours later, with an overnight break between the fourth dose of the day and the first dose 12 hours later the following morning, so that overall, 26 mg thiethylperazine (41.12 mg thiethylperazine maleate) was administered per day for three consecutive days. Steady state was reached between the end of day 2 (48 hours, 4 half-lives of thiethylperazine) and the beginning of day 3 (52 hours, 5 half-lives of thiethylperazine). On the fourth day, when steady state was given, blood samples were taken 4 hours after administration of the second dose for analysis of steady state thiethylperazine concentrations etc. Thiethylperazine was always given orally in the form of a single tablet of 6.5 mg thiethylperazine (10.28 mg thiethylperazine maleate).

[0087] Plasma Abeta is considered an index of Abeta content and excretion in the brain, 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 treatment of subjects 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 3 days of 26 mg / day thiethylperazine (comparison) (41.12 mg thiethylperazine maleate).

[0088] Elevations in plasma Abeta 1-40 were found in 53% (8 of 15) of subjects after taking an initial dose of 6.5 mg thiethylperazine (10.28 mg thiethylperazine maleate) on day 1. After the second dose on day 1, i.e., a dose of 13 mg thiethylperazine (20.56 mg thiethylperazine maleate), 87% (13 of 15) of subjects had elevated plasma Abeta 1-40. Both doses produced a similar mean increase of 7.8% in plasma Abeta 1-40.

[0089] At a dose of 26 mg thiethylperazine per day (41.12 mg thiethylperazine maleate) for 3 consecutive days, plasma Abeta1-40 was elevated in only 40% (6 of 15) of study subjects at steady state, with a mean change of 6.5%.

[0090] That is, compared to only 40% (6 of 15) of study subjects showing elevations in plasma Abeta1-40, 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 thiethylperazine maleate) and 13 mg thiethylperazine (20.56 mg thiethylperazine maleate), respectively.

[0091] Furthermore, the mean elevation of plasma Abeta 1-40 was also significantly higher, specifically ≧20% higher, compared to subjects treated with the higher dose of 26 mg thiethylperazine (41.12 mg thiethylperazine maleate).

[0092] The mean differences in plasma Abeta 1-40 concentrations between responders and non-responders were 33.04 pg / ml, 28.07 pg / ml, and 16.53 pg / ml for 6.5 mg, 13 mg, and 26 mg thiethylperazine (10.28 mg, 20.56 mg, 41.12 mg thiethylperazine maleate), respectively. That is, the mean plasma Abeta1-40 concentration difference between responders and non-responders was also substantially increased by ≧10 pg / ml (or ≧60%) in the steady-state mode in subjects treated with lower doses of thiethylperazine in the range of 2-20 mg, specifically 6.5 mg (10.28 mg thiethylperazine maleate) and 13 mg thiethylperazine (20.56 mg thiethylperazine maleate), respectively, compared to subjects treated with the higher dose of 26 mg thiethylperazine (41.12 mg thiethylperazine maleate). Both Abeta1-40 difference and thiethylperazine dose were highly correlated with thiethylperazine plasma levels (R 2 =-0.999, R of dose 2 =0.998).

[0093] Thus, it has been surprisingly shown that the efficacy of and response to thiethylperazine treatment in humans is improved with lower doses of thiethylperazine, but not with higher doses of thiethylperazine.

[0094] The results of the determination of Abeta plasma concentrations after treatment are shown in FIG.

[0095] Inter-assay precision was estimated based on four replicates of two quality control (QC) samples (A+B), yielding the coefficients of variation (CV) presented in Table 1 below.

[0096] [Table 1]

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

[0098] [Table 2]

[0099] [Table 3]

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

[0101] [Table 4] [Brief description of the drawings]

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

[0103] [Non-Patent Document 1] Bateman, R. J. (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.

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Claims

1. A compound of formula (I) for use in the treatment and / or prevention of Alzheimer's dementia in humans. 【Chemistry 1】 [In the formula, R 1 is selected from the group consisting of a hydrogen atom, a halogen atom, a methoxy group, a perhalogenated alkyl group, and an -X-C1 to C2 alkyl group, 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 are each independently either a hydrogen atom or a C1-C4 alkyl group, or taken together form a 6-membered alkyl ring containing at least one additional nitrogen atom, where the at least one additional nitrogen is a C1-C3 alkyl-R 5 is substituted with an R 5 is a hydrogen atom or a hydroxyl group, n is 0 or 1, m is 0 or an integer selected from the range of 1 to 4; p is 0 or an integer selected from the range of 1 to 3; A compound of formula (I) administered at a dosage of ≦20 mg per day on each day of administration.

2. The compound of formula (I) for use according to claim 1, administered in a dosage ranging from 2 to 20 mg per day of administration.

3. A compound of formula (I) for use according to claim 1 or 2, having the formula (Ia) 【Chemistry 2】 [In the formula, R 1 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 are both methyl groups or taken together to form a six-membered alkyl ring containing one additional nitrogen atom, where the one additional nitrogen is replaced with a methyl group; n is 0 or 1.

4. It is administered at a dose ranging from 5 to 15 mg, preferably from 6 to 13.5 mg, per day on the administration day; More preferably, it is administered at 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 according to any one of claims 1 to 3.

5. 5. The compound of formula (I) or formula (Ia) for use according to any one of claims 1 to 4, wherein the compound of formula (I) or formula (Ia) is used as a pharma- ceutically acceptable salt of formula (I) or formula (Ia), the pharma- ceutically acceptable salt comprising one or more anions selected from the group consisting of chloride, sulfate, mesylate, besylate, tosylate, fumarate, malonate, malate, maleate, succinate, lactate, glycolate, citrate, aspartate and mandelate, preferably malate and / or maleate, more preferably maleate.

6. The compound of formula (I) or formula (Ia) for use according to any one of claims 1 to 5, wherein the compound of formula (I) or formula (Ia) or the pharma- ceutically acceptable salt of formula (I) or formula (Ia) is selected from the group consisting of levomepromazine, trifluoperazine and thiethylperazine and the pharma- ceutically acceptable salts of these compounds, preferably levomepromazine or thiethylperazine or a pharma- ceutically acceptable salt of levomepromazine or a pharma- ceutically acceptable salt of thiethylperazine, more preferably thiethylperazine or a pharma- ceutically acceptable salt of thiethylperazine.

7. The compound of formula (I) or formula (Ia) for use according to any one of claims 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 dosage of ≦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, more preferably in the range of 9.48 to 21.34 mg, per day of administration.

8. 8. The compound of formula (I) or formula (Ia) for use according to any one of claims 1 to 7, wherein the compound of formula (I) or formula (Ia) or a pharma- ceutically 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) or a pharma- ceutically acceptable salt of formula (I) or formula (Ia) as defined in any one of claims 1 to 8 and a pharma- ceutically acceptable excipient, wherein the preparation, in the form of a solution, contains in the range of 2 to 20 mg of a compound of formula (I) or formula (Ia), preferably in the range of 5 to 15 mg of a compound of formula (I) or formula (Ia), more preferably in the range of 6 to 13.5 mg of a compound of formula (I) or formula (Ia).

10. 10. The pharmaceutical composition according to claim 9, in the form of a solution suitable for injection, comprising a compound of formula (I) or formula (Ia) or a pharma- ceutically acceptable salt of formula (I) or formula (Ia).

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