WO2004062652A1

WO2004062652A1 - Prevention and treatment of alzheimer's disease

Info

Publication number: WO2004062652A1
Application number: PCT/FR2003/003654
Authority: WO
Inventors: Thierry Canton; Laurent Pradier; Jesus Benavides; Hubert Heuer; Hans-Ludwig Schaefer
Original assignee: Aventis Pharma S.A.
Priority date: 2002-12-12
Filing date: 2003-12-10
Publication date: 2004-07-29
Also published as: CN1726016A; NO20053341D0; RS20050420A; PE20040770A1; NZ540496A; CO5700712A2; ZA200504656B; JP2006514063A; BR0317280A; AU2003296802A1; MXPA05005556A; FR2848452A1; MA27500A1; FR2848452B1; EP1572174A1; KR20050084250A; RU2005121909A; HRP20050534A2; CA2507945A1; TW200503707A

Abstract

The invention concerns the use of biliary acid intestinal recapture inhibitors for preventing and treating Alzheimer's disease, optionally combined with a HMG-CoA reductase inhibitor, a cholesterol capture inhibitor, a cholesterol synthesis capture inhibitor or an APP secretase inhibitor.

Description

PREVENTION AND TREATMENT OF ALZHEIMER'S DISEASE

The present invention relates to the application of inhibitors of intestinal recapture of bile acids for the prevention and treatment of Alzheimer 's disease.

Alzheimer's disease ¹ (AD) is a progressive degenerative disease neuro- which affects a large proportion of the elderly population. This disease is clinically characterized by loss of memory and neuropathological decline in cognitive function by intracellular neurofibrillary deposits and extracellular deposits of β-amyloid peptide (A-β) forming in the brain. amyloid plaques (Yankner BA (1996) Neuron 16: 921-932). In addition to these signs, there are a number of other abnormal changes including altered immune and inflammatory systems and impaired mitochondrial function that can lead to increased oxidative stress, activation of the mechanisms of apoptosis and ultimate way to cell death.

The amyloid plaques are mainly composed of 40- or 42-residue A-β peptides that are generated during the proteolytic process of the β-amyloid precursor protein (APP). Extracellular deposits of A-β are very specific for AD and associated disorders. They represent the invariable characteristic of all forms of AD, including family forms (FAD). The early familial forms of the disease (onset between 40 and 60 years of age) are due to mutations in the APP gene and in the presenilin-1 (PSI) and presenilin-2 (PS2) genes. Mutations in these three genes induce changes in APP proteolysis, leading to overproduction of Aβ and early onset of pathology and symptoms that are similar to sporadic forms of AD. (Czech C, et al (2000) Progress in Neurobiology 60: 361-382). A link between cholesterol and Alzheimer's disease has also been established from epidemiological studies and recent biochemical and cell biology findings (see review Hartmann, T. (2001) TINS 24: S45-48 ). High cholesterol levels in adulthood and high blood pressure significantly increase the risk of Alzheimer's disease (Kivipelto et al., 2001 Br Med J. 322: 1447).

In contrast, a very low risk is recorded in populations treated with statin-like hypocholesterolemic agents (Wolozin et al., (2000) Arch Neurol 57: 1439, Jick et al (2000) Lancet 356: 1627 ).

The molecular link seems to have been recently established. In vitro and in vivo, a high cholesterol level increases the production of A-β peptide and accelerates the appearance of amyloid plaques (Sparks et al (1994) Exp Neurol 126: 88-94, Refolo et al. 2000) Neurobiol Dis., 7: 321-331, Puglielli et al (2001) NaT Cell Biol 3: 905, Shie et al (2002), Neuroreport 13: 455), and inhibitors of the cholesterol synthesis decreases them (Simons et al.

(1998) PNΑS USA 95: 6460-6464; Faβbender et al. (2001) PNAS USA 98: 5856, Refolo et al., (2001) Neurobiol. Say. 8: 890-899)

In order to reduce the level of β-amyloid peptide in vivo, and treat, prevent or reduce the progression of Alzheimer's disease, it has therefore been suggested to use inhibitors of cholesterol synthesis such as those of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase), an enzyme involved in the biosynthesis of cholesterol, as described in WO 00/28981 and in particular statins such as simvastatin (Hartman, 2001 TINS 24: S45- 48).

So far, it has not been determined whether the therapeutic effect of statins is due to direct action in the central nervous system or whether they act by decreasing plasma cholesterol. Indeed, a limited effect on plasma cholesterol levels seemed unlikely since it was generally accepted that the Cerebral cholesterol was independent of plasma cholesterol (Dietschy and Turley (2001) Curr Opin Lipidol 12: 105-112).

The applicant has demonstrated that a specific pharmacological class, the bile acid reuptake inhibitors (Biliary Acid Reuptake Inhibitor or BARI), which can reduce plasma cholesterol by blocking the reuptake of bile acids in the body. intestine, could also decrease levels of β-amyloid peptide in the brain.

Bile acid reuptake inhibitors are not absorbed, and their site of action is in the intestine where they block the reuptake of excreted bile acids, which are a large source of cholesterol precursors. The results obtained and described below in the experimental part make it possible to demonstrate that it is sufficient to reduce the levels of plasma cholesterol to reduce levels of β-amyloid peptide in the brain. Surprisingly, it has been shown that bile acid recapture inhibitors (BARI) are effective in an animal model of Alzheimer's disease by acting only through the regulation of plasma cholesterol levels. and in particular by not penetrating into the brain because they are not absorbed into the body.

Prevention or treatment of Alzheimer's disease means the possibility of preventing or delaying the onset and / or progression of Alzheimer's disease. The invention therefore relates to the application of bile acid recapture inhibitor compounds for the preparation of a medicament for preventing or treating Alzheimer's disease.

More generally, the subject of the invention is the application of compounds or mixtures of compounds which reduce plasma cholesterol levels without the need to be absorbed into the body after oral administration, to prevent or treat the disease. Alzheimer.

The molecules having a bile acid reuptake inhibitory activity (BARI) are described in US Pat. Nos. 6,221,897 and 6,245,744. The invention therefore more particularly relates to the application of bile acid recapture inhibitor compounds for the preparation of a medicament for preventing or treating Alzheimer's disease characterized in that the bile acid recapture inhibitors are compounds of formula (IA)

In which :

R ¹ represents methyl, ethyl, propyl or butyl

R ² represents H, OH, NH ₂ , or NH- (d-Cg) alkyl

R ³ is a monosaccharide, bi-saccharide, tri-saccharide or quadrisaccharide, said radical being unsubstituted or mono or polysubstituted by a protecting group of sugars;

R ⁴ is methyl, ethyl, propyl or butyl

R ⁵ is methyl, ethyl, propyl or butyl

Z is (C = O) _n - (Co-Cι ₆ ) -alkyl; (C = O) _n - (C ₀ -C ₆ ) -alkyl-NH; (C = O) _n - (C ₀ -C ₁₆ ) -alkyl-O; (C = O) _n - (C ₀ -C ₆ ) -alkyl- (C = O) -; or a covalent bond; n is 0 or 1 m is 0 or 1 and their pharmaceutically acceptable addition salts.

By monosaccharide radical is meant polyalcohols with

5, 6, 7 or 8 carbon atoms, also containing carbonyl groups (ketonic or aldehyde), which most often do not exist in the free state but are combined with one or more hydroxyl groups of the same molecule, in the form of hemiketal or cyclic hemiketal. It can be sugars with 5 carbon atoms such as L-arabinose, D-ribose, deoxy-2-D-ribose and D-xylose. These sugars are part of the series of pentoses (or aldopentoses).

It may also be 6-carbon sugars such as D-glucose, D-fructose, D-galactose and D-mannose. It may also be erythrose, glyceraldehyde, sedoheptulose, glocosa ine, galactosamine, glucoronic acid, galacturonic acid, gluconic acid, galactonic acid, mannonic acid, glucamine, 3-amino-1,2-propanediol, glucaric acid and galactaric acid. Among the preferred carbohydrates, mention may be made of the following radicals:

The subject of the invention is particularly the application of a bile acid recapture inhibitor compound for the preparation of a medicament for preventing or treating Alzheimer's disease characterized in that the recapture inhibitor of bile acids is the compound of formula (IA) (product A) below:

The invention also more particularly relates to the application of bile acid recapture inhibitor compounds for the preparation of a medicament for preventing or treating Alzheimer's disease characterized in that the bile acid recapture inhibitors are compounds of formula (IB):

wherein R ¹ is a phenyl radical or a heteroaryl group unsubstituted or substituted with one to three independent radicals selected from F, Cl, Br, I, -OH, -CF ₃ , -NO ₂ , -NHR ⁹ , -NR ⁹ R ¹⁰ , -CHO, -COR ₂ H, -COR ₂ R ⁿ , -COR ¹² , - (C ₁ -C ₆ ) -alkyl-OH, - (C ₁ -C ₆ ) -alkyl-OH-phenyl, - (C 1 -C ₆ ) -alkyl-CF ₃ , - (Cι-C ₆ ) -alkyl-N0 ₂ , - (Cι-C ₆ ) -alkyl-CN, - (Cι-C ₆ ) -alkyl-NH ₂ , - ( Cι-C ₆ ) - alkyl-NHR ⁹ , - (Cι-C ₆ ) -alkyl-NR ⁹ R ¹⁰ , - (Cι-C ₆ ) -alkyl-CHO, - (Cι-C ₆ ) -alkyl-C0 ₂ H, - (Cι-C ₆ ) -alkyl-C0 ₂ R, - (C ₁ -C ₆ ) -alkyl-COR- ^{1 1} 2 ^, -O- (C _r C ₆ ) -alkyl-OH, -0 - (dC ₆ ) -alkyl (-OH) -phenyl, -O- (C ₁ -C ₆ ) -alkyl-CF ₃ , -O- (C ₁ -C ₆ ) -alkyl-NO ₂ , -O- (C ₁ -C ₆ ) C ₆ ) -alkyl-CN, -O- (C ₁ -C ₆ ) -alkyl-NH ₂ , -O- (C ₁ -C ₆ ) -alkyl-NHR ⁹ , -O- (C ₁ -C ₆ ) -alkyl-NR ⁹ R ^10, -0- (Ci-Cg) alkyl-CHO, -0- (Ci-Ce) -NS ₃ H, -S ₂ -CH _3, -0- (Cι-C ₆₎ -alkyl- 0- (Cι-C ₆ ) -alkyl-phenyl, - (Cι-C ₆ ) -alkylthio or pyridyl, said alkyl derivatives may be substituted with one or more fluorine atoms and the phenyl or pyridyl groups may be monosubstituted by methyl, methoxy or halogen;

R ² represents H, OH, -CH ₂ OH, -OMe, -CHO or -NH ₂ R ³ is a monosaccharide, di-saccharide, tri saccharide or quadrisaccharide residue, said radical being unsubstituted or mono or polysubstituted by a protecting group of sugars, H0-S0 ₂ - or (HO) ₂ -PO-; R ⁴ is H, methyl, F or -OMe,

R ⁹ to R ¹² independently of one another H or - (C 1 -C ₈ ) -alkyl Z represents a covalent bond, a group -NH- (C ₀ -C ₃₆ ) -alkyl-CO-, - 0- (C ₀ -C ₃₆ ) -alkyl-CO-, - (CO) _m - (C ₀ -C ₃₆ ) -alkyl- (CO) _n -, an amino acid residue, a diamino acid residue, being understood that said amino acid residue or diamino acid residue may be mono or polysubstituted by an amino acid protecting group, as well as their pharmaceutically acceptable addition salts.

The invention more particularly relates to the application of a bile acid recapture inhibitor compound for the preparation of a medicament for preventing or treating Alzheimer's disease characterized in that the recapture inhibitor of bile acids is the compound of formula (IB) (product B) according to:

The preparations of these compounds are described in the patents cited above.

The bile acid recapture inhibitors in their application according to the invention can be administered such or in combination with one or more other compounds selected from:

inhibitors of HMG-CoA reductase such as statins, cholesterol-uptake inhibitors,

inhibitors of cholesterol synthesis and any other agent that reduces plasma and / or brain cholesterol levels,

the inhibitors of APP γ and β secretases. Among the inhibitors of cholesterol uptake, mention may be made of Ezetimibe. Among the inhibitors of γ and β secretase APAPs, mention may be made of the compounds as described by H. Josien (2002, Current Opinion in Drug Disc. & Dev. 5: 513-525) or in the MS Wolfe review (2002, Nat Rev. Drug Disc .: 1: 859-866).

The invention therefore also relates to the application of bile acid recapture inhibitor compounds for the preparation of a medicament for preventing or treating Alzheimer's disease characterized in that the bile acid recapture inhibitors are associated with one or more other compounds selected from a) HMG-CoA reductase inhibitors, or b) cholesterol uptake inhibitors, or c) cholesterol synthesis inhibitors, or d) APP secretase inhibitors.

The invention therefore also relates to the application of bile acid recapture inhibitor compounds for the preparation of a medicament for preventing or treating Alzheimer's disease characterized in that the bile acid recapture inhibitors are associated with an HMG-CoA reductase inhibitor, a cholesterol uptake inhibitor, a cholesterol synthesis inhibitor or an APP γ and β secretase inhibitor for simultaneous, separate or spread administration.

The invention also relates to a method for preventing or treating Alzheimer's disease for a patient at risk of developing this disease or being during development of the disease comprising administering to this patient a therapeutically effective amount of a compound having hypocholesterolemic activity and not entering the body after oral administration.

More specifically, the subject of the invention is a method for the prevention or treatment of Alzheimer's disease as defined above, characterized in that the compound having a hypocholesterolemic activity and not penetrating into the body is a reuptake inhibitor. bile acids

In particular, the subject of the invention is a method for preventing or treating Alzheimer's disease for a patient at risk of developing this disease or being in the process of developing this disease, comprising administering to this patient a therapeutically therapeutic amount. effective of a bile acid recapture inhibitor as defined by formulas (IA) and (IB) and in particular compound A or compound B. Moreover, the subject of the invention is a method of prevention or treatment of Alzheimer's disease as defined above characterized in that the bile acid reuptake inhibitors are administered in combination with one or more compounds selected from an inhibitor of HMG-CoA reductase, a cholesterol uptake inhibitor , an inhibitor of cholesterol synthesis or an inhibitor of APP γ and β secretases

The bile acid reuptake inhibitors can be administered in the form of a pharmaceutical preparation (pharmaceutical composition) which allows oral or peroral (eg sublingual) administration.

The invention therefore relates to the application of bile acid recapture inhibitors for the preparation of a medicament for preventing or treating Alzheimer's disease characterized in that the bile acid recapture inhibitors are in the in the form of orally administrable pharmaceutical compositions. More specifically, the subject of the invention is the application as defined above, characterized in that the pharmaceutical compositions contain an effective dose of at least one bile acid recapture inhibitor compound and one or more pharmaceutically inert carriers. and / or one or more customary additives for oral or oral administration.

The pharmaceutical compositions according to the invention normally contain from 0.01 to 100 mg, and preferably from 0.02 to 50 mg of bile acid recapture inhibitor.

The invention therefore more particularly relates to the application of bile acid recapture inhibitors for the preparation of a medicament for preventing or treating Alzheimer's disease characterized in that the pharmaceutical composition which can be administered orally contains 0.02 to 50 mg of bile acid recapture inhibitors.

The pharmaceutical compositions can be administered orally, for example in the form of pills, tablets, coated tablets, films, granules, soft capsules and capsules, solutions, syrups, emulsions, suspensions or blends. 'aerosol.

The pharmaceutical compositions are prepared according to methods known per se, organic or inorganic, pharmaceutically inert carriers being added to the bile acid recapture inhibitors.

For the production of pills, tablets, coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, cornstarch or its derivatives, talc, stearic acid or its salts, etc.

Suitable vehicles for the preparation of solutions, for example emulsions or syrups are for example water, alcohols, glycerol, polyols, sucrose, invert sugars, glucose, vegetable oils, etc. The pharmaceutical preparations normally contain from 0.05% to 90% by weight of recapture of bile acids.

In addition to the active ingredients and carriers, the pharmaceutical preparations may contain additives such as, for example, diluents, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweetening agents, dyes of flavoring agents or flavoring agents, thickeners, buffering agents, and also solvents or solubilizers or agents for obtaining a retarding effect and also salts for modifying osmotic pressure, coating agents or antioxidants.

The pharmaceutical preparations may also contain two or more bile acid reuptake inhibitors. Furthermore, in addition to at least one or more bile acid recapture inhibitors, they may contain at least one or more other active ingredients that can be used therapeutically or prophylactically, such as an inhibitor of HMG-CoA reductase, an inhibitor of cholesterol uptake, a cholesterol synthesis inhibitor or an inhibitor of APP γ and β secretases.

When bile acid reuptake inhibitors are used, doses may vary within wide limits and should be based on the individual to be treated. This depends, for example, on the compound used or the nature and severity of the disease to be treated and whether in severe or chronic conditions or if prophylactic treatment is used.

In the case of oral administration, the daily dose generally varies from 0.1 to 100 mg / kg and preferably from 0.1 to 50 mg / kg, in particular from 0.1 to 5 mg / kg. . For example, for a 75 kg adult, a daily dose ranging from 0.3 to 0.5 mg / kg can be considered.

The daily dose can be divided, especially in the case of administration of a large amount of active ingredient, in several, for example 2, 3 or 4 parts. If appropriate, depending on individual behavior, it may be necessary to administer the different doses of increasing or decreasing way.

The in vivo tests of the product A on the production of the amyloid peptide in a transgenic mouse model were carried out as follows: a) Experimental test 1 (FIG. 1)

- Animal treatment

Product A in powder form was mixed at a dosage of 0.01% (w / w) with the standard food in powder form. Tg53 transgenic mice (overexpressing the APP human transgene carrying the "Swedish" and "London" mutations, (2002 Wirths, et al., 2002) Brain Pa thol 12, 275-286), females 8-10 weeks old The mice were housed in individual cages with unlimited drink, and each day 6 grams of powdered food (supplemented or not with product A) were distributed in each cage. 12 animals (controlled diet or supplemented with product A) were used After the treatment, a blood sample was taken and the plasma cholesterol level determined using a biological analysis machine.

- Preparation of brain extracts

After euthanasia, the brain of the mice was removed and weighed. The tissue was homogenized individually on ice using a Potter in 10 volumes (w / v) of a buffer solution: 0.32 M sucrose, Tris 4 mM HCl, pH 7.4 containing a cocktail of protease inhibitors (Complete ™, Roche Diagnostics). The homogenate was then centrifuged at 50,000 x g, 2 h at 4 ° C and the supernatant removed to form the soluble fraction (soluble Aβ) of brain and stored at -80 ° C.

For total Aβ measurement, a homogenate aliquot was denatured by Guadinine Hydrochloride 6M (final concentration), followed by 3 cycles of 15 minutes at 4 ° C ultrasound (Bandelin Electronic Sonorex Super RK 102K - Germany) to solubilize all forms of Aβ peptide (total fraction). - Determination of the amyloid peptide by the immunoelectrochemiluminescence method.

The concentration of the Aβ peptide in the soluble or soluble and insoluble brain fractions of the transgenic mice was determined by immunoelectrochemiluminescence (Yang et al., 1994) Biotechnology (NY) 12 (2), 193-194). 2 mouse monoclonal antibodies against Aβ peptide (4G8 and 6E10) and the Origen M8 Analyzer reader (IGEN Europe Inc. Oxford) according to a modified protocol according to Khorkova et al. (J. Neurosci, Methods 82, 159-166 (1998)).

The monoclonal antibody 4G8 (Senetek PLC), recognizing the epitope residues 17-24 of the Aβ peptide, is ruthenylated using the TAG-NHS ester according to the supplier's protocol (IGEN Europe Inc., Oxford). Ru-4G8 and the biotinylated antibody 6E10, epitope 1-10 of the Aβ peptide (Senetek PLC) are placed in the presence of the soluble fraction or the total brain fraction and the quantified Ru-4G8 / Aβ / 6E10-biot tripartite complexes by the reader Origen. For the total fraction, the concentration of guanidine Hydrochloride is previously reduced to 0.3M by dilution for the Aβ peptide assay. A range of Aβ synthetic peptide (Bachem) is used to calibrate each experiment. The level of Aβ peptide is calculated in nanograms per g of initial weight of brain tissue. - Result:

Compared with the diet control group, the diet group supplemented with product A (0.01% of product A called BARI in FIG. 1) showed a decrease in the soluble brain Aβ peptide level of 18% [15.45 ± 0.71 ng / g tissue (n = 11) compared to 18.85 ± 0.96 ng / g tissue (n = 12), t unpaired test, p = 0.0103].

Plasma cholesterol level was also decreased by 14% [diet group supplemented with product A: 0.62 ± 0.030 g / l (n = 11) compared to control diet: 0.72 ± 0.023 g / l (n = 12); t unpaired test p = 0.0154] (See Figure 1)

b) Experimental Test No. 2 (Figures 2 and 3) In an experiment using female transgenic mice at 15.5 weeks of age at the end of treatment and therefore with higher levels of Aβ due to age, compared to the diet control group, the diet group supplemented with product A (0, 01%, named BARI in FIGS. 2 to 4) showed a decrease of the soluble brain Aβ peptide rate even more pronounced, by 40% [24.5 ± 1.2 ng / g of tissue (n = 8) compared to 40.8 ± 2.5 ng / g tissue (n = 7), t unpaired test, p = 0.0001] (Fig2). Brain levels of total Aβ peptide (including soluble forms and membrane or aggregated forms of Aβ peptide) were also significantly decreased by 46% [196.3 ± 17.8 ng / g tissue (n = 8) compared to 364.2 ± 40.9 ng / g of tissue (n = 7), t unpaired test, p = 0.0017] (Fig3). This effect on the pool of total forms of Aβ is of importance for the treatment of patients with Alzheimer 's disease and who have very high levels of aggregated Aβ peptide within the senile plaques. As before, the plasma cholesterol level was also decreased by 18% [diet group supplemented with product A: 0.70 ± 0.03 g / l (n = 8) compared to the control diet group: 0.85 ± 0, 03 g / 1 (n = 7); t unpaired test p = 0.0037] c) Exeprimental test No. 3 (FIG. 4) Under the same experimental conditions, the treatment with different doses of product A revealed that it could be reduced to at least a factor 100 the dose of product A (that is a supplement of the diet with 0.0001%) while keeping the effect of reduction on the cerebral levels of total Aβ peptide. In fact the total Aβ levels were reduced by 21% for 0.0001% of product A [85.4 ± 4.1 ng / g of tissue (n = 8) compared to the control group at 108.1 ± 8.5 ng / g of tissue (n = 10), t unpaired test, p = 0.04], of 20% for 0.001% of product A [86.5 ± 5.9 ng / g tissue (n = 10), p = 0.050] and

16% for 0.01% product A [90.5 ± 6.9 ng / g tissue (n = 10), p = 0.123, ns] (Fig4).

Claims

1) Application of bile acid recapture inhibitor compounds for the preparation of a medicament for preventing or treating Alzheimer 's disease.

2) Application according to claim 1 characterized in that the bile acid recapture inhibitors are compounds of formula (IA):

in which R ¹ represents methyl, ethyl, propyl or butyl

R ² represents H, OH, NH ₂ , or NH- (Cι-C ₆ ) alkyl

R ³ is a saccharide, bi-saccharide, tri-saccharide or quadrisaccharide radical, said radical being unsubstituted or mono or polysubstituted by a group protecting the sugars; R ⁴ is methyl, ethyl, propyl or butyl

R ⁵ is methyl, ethyl, propyl or butyl

Z is (C = O) _n - (Co-Cι ₆ ) -alkyl; (C = O) _n - (C ₀ -C ₆ ) -alkyl-NH;

(C = O) _n - (C ₀ -Cι) -alkyl-O; (C = O) _n - (C ₀ -C ₁₆ ) -alkyl- (C = O) -; or a covalent bond; n is 0 or 1 m is 0 or 1 and their pharmaceutically acceptable addition salts.

3) Application according to claim 1 or 2 characterized in that the bile acid recapture inhibitor is the compound of formula (IA) below:

4) Application according to claim 1 characterized in that the bile acid recapture inhibitors are compounds of formula (IB):

wherein R ¹ is a phenyl radical or a heteroaryl group unsubstituted or substituted with one to three independent radicals selected from F, Cl, Br, I, -OH, -CF ₃ , -NO ₂ , -NHR ⁹ , -NRR ¹⁰ , -CHO, -C0 ₂ H, -COR ₂ R ^u , -COR ¹² , - (C ₁ -C ₆ ) -alkyl-OH, - (C ₁ -C ₆ ) -alkyl-OH-phenyl, - (Cι-C) ₆ ) -alkyl-CF ₃ , - (C ₁ -C ₆ ) -alkyl-N0 ₂ , - (C ₁ -C ₆ ) -alkyl-CN, - (C ₁ -C ₆ ) -alkyl-NH ₂ , - (Cι-C) ₆ ) - alkyl-NHR ⁹ , - (Cι-C ₆ ) -alkyl-NR ⁹ R ¹⁰ , (Cι-C ₆ ) -alkyl-CHO, - (Cι-C ₆ ) -alkyl-C0 ₂ H, - ( C 1 -C ₆ ) -alkyl-CO ₂ R ^u - (C 1 -C ₆ ) alkyl-COR ¹ , -O- (C 1 -C ₆ ) -alkyl-OH, -O- (C ₁ -C ₆ ) -alkyl ( -OH) -phenyl, -O- (Cι-C ₆ ) -alkyl-CF ₃ , -O- (d-C ₈ ) -alkyl-NO ₂ , -O- (C ₁ -C ₆ ) -alkyl-CN, - O- (C ₁ -C ₆ ) -alkyl-NH ₂ , -O- (C ₁ -C ₆ ) -alkyl-NHR ⁹ , -O- (C ₁ -C ₆ ) -alkyl-NR ⁹ R ¹⁰ , -O- (C _1-6 ) Ce) -alkyl-CHO, -O- (Cι-C ₆ ) -NS ₃ H, -S ₂ -CH ₃ , -O- (Cι-C ₆ ) -alkyl-O- (Cι-C ₆ ) -alkyl -phenyl, - (Cι-C ₆ ) -alkylthio or pyridyl, said alkyl derivatives being substitutable by one or more fluorine atoms and phenyl or pyridyl groups which may be monosubstituted by methyl, methoxy or halogen;

R ² represents H, OH, -CH ₂ OH, -OMe, -CHO or -NH ₂ R ³ is a saccharide, di-saccharide, tri-saccharide or quadrisaccharide residue, said radical being unsubstituted or mono or polysubstituted by a protecting group of sugars, H0-S0 ₂ - or (H0) ₂ -PO-; R ⁴ is H, methyl, F or -OMe, R ⁹ to R ¹² independently of one another H or - (d-C ₈ ) -alkyl

Z represents a covalent bond, a group -NH- (Code) -alkyl-CO-, -O- (Co-C ₃₆ ) -alkyl-CO-, - (CO) _m - (C ₀ -C ₃₆ ) -alkyl - (C0) _n -, an amino acid residue, a diamino acid residue, it being understood that said amino acid residue or diamino acid residue may be mono or polysubstituted by an amino acid protecting group, as well as their pharmaceutically acceptable additions.

5) Application according to claim 1 or 4, characterized in that the bile acid recapture inhibitor is the compound of formula (IB) below:

6) Application according to any one of claims 1 to 5 characterized in that the bile acid recapture inhibitors are in the form of pharmaceutical compositions administrable orally.

7) Application according to claim 6 characterized in that the pharmaceutical composition administrable orally contains from 0.02 to 50 mg of bile acid recapture inhibitors. 8) Application as defined in any one of Claims 1 to 7, characterized in that one or more bile acid recapture inhibitors are combined with one or more compounds chosen from HMG-CoA reductase inhibitors, the inhibitors of cholesterol uptake, inhibitors of cholesterol synthesis or inhibitors of APP γ and β secretases.

9) Application according to claim 8, in a simultaneous administration, separate or spread over time of the different active ingredients.

10) Application of compounds which decrease plasma cholesterol levels without need to be absorbed into the body after oral administration for the preparation of a medicament for preventing or treating Alzheimer's disease.

11) A method for the prevention or treatment of Alzheimer's disease for a patient at risk of developing this disease or being in the course of developing the disease comprising administering to this patient a therapeutically effective amount of a compound have hypocholesterolemic activity and do not enter the body after oral administration.

12) A method of preventing or treating Alzheimer's disease as defined in claim 11 characterized in that the compound having a hypocholesterolemic activity and not entering the body is a bile acid recapture inhibitor.

13) A method of preventing or treating Alzheimer's disease as defined in claim 12 characterized in that the bile acid recapture inhibitors as defined in any one of claims 2 to 5.

14) A method of preventing or treating Alzheimer's disease as defined in claim 12 or 13 characterized in that the bile acid recapture inhibitors are administered in combination with one or several compounds selected from an inhibitor of HMG-CoA reductase, a cholesterol uptake inhibitor, a cholesterol synthesis inhibitor or an inhibitor of APP γ and β secretases.