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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to the application of inhibitors of intestinal recapture of bile acids for the prevention and treatment of Alzheimer 's disease.
• AD Alzheimer's disease 1
• A- ⁇ ⁇ -amyloid peptide
• amyloid plaques are mainly composed of 40- or 42-residue A- ⁇ peptides that are generated during the proteolytic process of the ⁇ -amyloid precursor protein (APP).
• Extracellular deposits of A- ⁇ 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 A ⁇ and early onset of pathology and symptoms that are similar to sporadic forms of AD.
• 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).
• HMG CoA reductase 3-hydroxy-3-methylglutaryl coenzyme A reductase
• statins such as simvastatin (Hartman, 2001 TINS 24: S45- 48).
• statins 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).
• bile acid reuptake inhibitors Biliary Acid Reuptake Inhibitor or BARI
• BARI Bile Acid Reuptake Inhibitor
• 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 ⁇ -amyloid peptide in the brain.
• BARI bile acid recapture inhibitors
• 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.
• 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 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)
• 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
• monosaccharide radical is meant polyalcohols with
• 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.
• 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-propan
• 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):
• 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 , - (C ⁇ -C 6 ) -alkyl-N0 2 , - (C ⁇ -C 6 ) -alkyl-CN, - (C ⁇ -C 6 ) -alkyl-NH 2 , - ( C ⁇ -C 6 ) - alkyl-NHR 9 , - (C ⁇ -C 6
• 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:
• 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:
• HMG-CoA reductase inhibitors of HMG-CoA reductase such as statins, cholesterol-uptake 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 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 ⁇ and ⁇ 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.
• 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 having a hypocholesterolemic activity and not penetrating into the body is a reuptake inhibitor.
• 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.
• 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 ⁇ and ⁇ 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.
• 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.
• 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.
• compositions are prepared according to methods known per se, organic or inorganic, pharmaceutically inert carriers being added to the bile acid recapture inhibitors.
• Suitable vehicles for the preparation of solutions 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.
• 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.
• 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 ⁇ and ⁇ secretases.
• active ingredients such as an inhibitor of HMG-CoA reductase, an inhibitor of cholesterol uptake, a cholesterol synthesis inhibitor or an inhibitor of APP ⁇ and ⁇ secretases.
• 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.
• 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. .
• 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.
• 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.
• 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 TM, 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 A ⁇ ) of brain and stored at -80 ° C.
• the concentration of the A ⁇ 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 A ⁇ 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 A ⁇ 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 A ⁇ peptide (Senetek PLC) are placed in the presence of the soluble fraction or the total brain fraction and the quantified Ru-4G8 / A ⁇ / 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 A ⁇ peptide assay. A range of A ⁇ synthetic peptide (Bachem) is used to calibrate each experiment. The level of A ⁇ peptide is calculated in nanograms per g of initial weight of brain tissue. - Result:
• This effect on the pool of total forms of A ⁇ is of importance for the treatment of patients with Alzheimer 's disease and who have very high levels of aggregated A ⁇ peptide within the senile plaques.

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