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WO2012093227A1 - Prodrugs for dispensing a statin to the liver - Google Patents

Prodrugs for dispensing a statin to the liver Download PDF

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Publication number
WO2012093227A1
WO2012093227A1 PCT/FR2012/000008 FR2012000008W WO2012093227A1 WO 2012093227 A1 WO2012093227 A1 WO 2012093227A1 FR 2012000008 W FR2012000008 W FR 2012000008W WO 2012093227 A1 WO2012093227 A1 WO 2012093227A1
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Prior art keywords
prodrug
statin
pharmaceutical composition
liver
carbon atoms
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PCT/FR2012/000008
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French (fr)
Inventor
Liliane JACQUOT épouse GUILMIN
Jacques DJIAN
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to novel prodrugs, their preparation and their use.
  • the prodrugs of the invention can be used to deliver therapeutic agents to the liver with high tissue specificity, including statins.
  • a prodrug or prodrug is a pharmacological substance, or drug, that is administered in an inactive form. Once administered, the prodrug is metabolized in vivo to an active metabolite.
  • a prodrug is generally used to optimize absorption, distribution, metabolism and excretion. It is generally designed to improve the oral bioavailability, or even to increase the selectivity of the product for the intended target.
  • the therapeutic agents of interest in the context of this invention may be any agent whose site of action is the liver, for example anti-cancer, antiparasitic, lipid-lowering or anti-diabetic drugs, or else therapeutic agents used in the metabolic diseases.
  • action site at the level of the liver is meant that the therapeutic molecule has its activity in the liver.
  • Anti-cancer agents used to treat liver cancer include, for example, 5-fluorouracil derivatives (5-FU), Mitomycins, Sorafenib.
  • oral hypoglycemic agents acting on the liver include biguanide derivatives (metformin, Glucophage®) or alpha-glucosidase inhibiting agents.
  • Lipid-lowering agents acting in the liver include, for example, fibrates or statins.
  • statins are more particularly described as a therapeutic agent. This should not, however, reduce the scope of the prodrugs described in the present invention.
  • Statins are a class of lipid-lowering drugs used to lower cholesterol levels in people with cardiovascular risk. Statins exert their lipid-lowering effects through the inhibition of the key cholesterol-synthesizing enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA reductase) in the liver. This effect is dose-dependent.
  • the known statins are in particular fluvastatin (6E) -7- [3- (4-fluorophenyl) -1- (propan-2-yl) -1H-indol-2-yl] -3,5-dihydroxyhept-6 acid.
  • Statins are rapidly absorbed intestinal tract, then enter the liver by passive diffusion or through liver transporters. They exert their hypolipidemic effect and are then rapidly metabolized and excreted via the bile. For this reason, the bioavailability of statins is reduced, it is dose dependent up to a certain level and at high doses, when there is saturation of hepatic metabolism, circulating levels of statins can increase considerably with many adverse effects.
  • statins Although the benefit / risk of statins is very favorable especially at low and intermediate doses, more and more cases of intolerance are reported in clinical practice in patients treated at higher doses. These side effects include muscle and liver effects.
  • statins eg fibrates, Verapamil®
  • pharmacovigilance studies of statins showed significant elevations (3 x ULN) of liver transaminases reported with an incidence of 1% at low doses and 2-3% at high doses (American Journal Cardiol. 2006 Apr 17; 97 (8A): 77C-81C, David E. Cohen et al. These elevations are dose dependent and common to all statins. The majority of increases occur in the first 3 months of treatment and require monitoring.
  • statins capable of eliminating or at least reducing the side effects observed during treatments, while preserving a specific activity related to the therapeutic agent, an effective or even improved activity.
  • WO 2009/054682 discloses prodrugs of atorvastatin to overcome certain problems related to the administration of atorvastatin. It describes the carboxymethyl ester of the atovar statin as a prodrug.
  • WO 2009/009152 mainly describes intermediate compounds used in processes for the preparation of rosuvastatin. Only synthetic intermediates are described to ultimately lead to the therapeutically effective compound, rosuvastatin.
  • WO 2006/136408 discloses intermediates used in processes for the preparation of rosuvastatin.
  • the n-butyl ester of rosuvastatin is described as intermediates in the synthesis of rosuvastatin.
  • WO 2003/070717 discloses a process for producing HMG-CoA inhibiting mevalonic acid derivatives in which certain intermediate derivatives of the process are C1-C7 alkyl esters, which derivatives are hydrolyzed to give the final compound therapeutically effective.
  • the examples describe the process for preparing pitivastatin and fluvastatin.
  • WO 2008/075165 discloses a novel method for synthesizing atorvastatin and its pharmaceutically acceptable salts, said method for reducing the number of steps necessary to convert a compound of formula (I) into the desired end product.
  • the only intermediate compounds claimed are the compounds of formula II in which R 1 and R 2 together with the oxygen atoms form a cyclopentylidene or cyclohexylidene group.
  • the inventors have discovered novel prodrugs of therapeutic agents which surprisingly allow to have a good therapeutic activity in the liver while decreasing the side effects.
  • they have discovered novel statin prodrugs that surprisingly effectively inhibit cholesterol synthesis in the liver while decreasing muscle and liver toxicity.
  • the subject of the invention is a prodrug according to the general formula (I)
  • X represents a therapeutic agent whose site of action is the liver
  • R represents a saturated or unsaturated fatty acid, linear or branched, comprising from 3 to 12 carbon atoms, optionally substituted by one or more hydroxyl group, halogen atom, and cyclic hydrocarbon comprising from 3 to 6 carbon atoms,
  • therapeutic agent whose site of action is the liver is meant for example anti-cancer drugs, anti-parasitic, lipid-lowering, anti-diabetic, or therapeutic agents used in metabolic diseases.
  • statin is meant any statin known or newly developed later, which can react with a fatty acid as defined below, to form a prodrug according to the invention.
  • the chemical reaction between the therapeutic agent whose site of action is the liver and the radical R is carried out so that once hydrolysed in the liver, the pro-drug releases an active therapeutic agent.
  • the chemical reaction is carried out between a statin and an R radical, it is carried out by esterification on the acid function common to all statins.
  • the statins are in particular those mentioned above and they specifically inhibit HMG-CoA reductase.
  • fatty acid means any carboxylic acid with a non-cyclic aliphatic chain. They comprise from 3 to 12 carbon atoms and are either saturated, that is to say that all the carbon atoms are saturated with hydrogen (without double bond), or unsaturated, ie they contain one or more carbon-carbon double bonds, they can be conjugated (double bond separated by a single bond) or non-conjugated (double bond separated by 2 single bonds).
  • the fatty acids can be linear, ie straight chain, or branched, that is to say comprising one or more short carbon radicals, especially methyl and ethyl radicals.
  • Cyclic hydrocarbon means hydrocarbons whose carbon chain is cyclic. They include cycloalkanes, cycloalkenes and cycloalkynes. There may be mentioned in particular cyclopropane, cyclobutene and cyclohexane.
  • the prodrugs according to the invention make it possible to obtain a better pharmaceutical efficacy of the hydrolysed therapeutic agents and / or a better tolerance of the latter.
  • the therapeutic agent X is chosen from anti-cancer, anti-parasitic, hypolipidemic, anti-diabetic, or therapeutic agents used in metabolic diseases.
  • the invention relates to a prodrug of a statin according to the general formula (I)
  • X represents a statin chosen from fluvastatin, pravastatin, atorvastatin, rosuvastatin, cerivastatin and pitivastatin,
  • R represents a saturated or unsaturated fatty acid, linear or branched, comprising from 3 to 12 carbon atoms, optionally substituted with one or more hydroxyl groups, halogen atom, and cyclic hydrocarbon comprising from 3 to 6 carbon atoms, or salt or stereoisomer thereof pharmaceutically acceptable.
  • Statin prodrugs preferentially inhibit hepatic cholesterol synthesis (better efficacy) while eliminating or at least reducing adverse effects (better tolerance). They also make it possible to reduce or even eliminate liver toxicity. These prodrugs thus provide a considerable advantage in terms of public health, especially for vulnerable patients treated with high doses of statins.
  • the prodrugs of statin according to the invention make it possible to increase the dose to be administered up to double that dose compared to the high doses used at the present time.
  • rosuvastatin is known to be administered at a high dose of 40 mg.
  • the prodrugs of the invention can thus be administered at a high dose of up to about 80 mg equivalent of rosuvastatin and with a better tolerance for the subject being treated.
  • atorvastatin administered at 80 mg in high doses.
  • the prodrugs according to the invention can thus be administered at a high dose of up to about 160 mg equivalent of atorvastatin (ie for example 184 mg of ProATV as described in Example 4 below), and this with a better tolerance for the subject treated.
  • the prodrug of statin according to the invention has a radical R preferably representing a linear or branched, saturated or unsaturated fatty acid comprising from 3 to 10 carbon atoms, preferably a linear or branched saturated fatty acid comprising from 3 to 8 carbon atoms. carbon.
  • the statin prodrug is the propanoic, propaenoic, butanoic, butanenoic, pentanoic, pentaenoic, hexanoic, hexaenoic, heptanoic or heptaenoic ester of fluvastatin, pravastatin, atorvastatin, rosuvastatin, cerivastatin and pitivastatin, or its pharmaceutically acceptable salt or stereoisomer.
  • the statin prodrug is: - the butanoic, pentanoic, hexanoic or heptanoic ester of fluvastatin, pravastatin, atorvastatin, rosuvastatin, cerivastatin and pitivastatin, C 3 and C 4 pentaenoic ester of fluvastatin, pravastatin, atorvastatin, rosuvastatin, cerivastatin and pitivastatin.
  • statin prodrug is pentaenoic ester C 3 and C 4 of atorvastatin and the butanoic ester of atorvastatin.
  • Another object according to the invention is a pharmaceutical composition containing at least one prodrug according to the invention, associated with a suitable vehicle.
  • the pharmaceutical composition according to the invention is preferably suitable for oral administration.
  • the prodrug according to the invention may be in the form of a solid formulation, such as, powder, granules, tablets, or capsules, for example, or in the form of a liquid formulation preferentially contained in a capsule, or a syrup.
  • any suitable pharmaceutical vehicle can be used for the formulation of such solid compositions, for example microcrystalline cellulose, lactose monohydrate, crosscarmellose, polysorbate 80 , hydroxypropyl cellulose, magnesium stearate, starch, lactose, glucose, rice, flour and chalk, and film-coating agents.
  • the compound may also be in the form of a capsule to be ingested, consisting for example of gelatin, containing the compound in solution, suspension or emulsion, or in the form of a syrup, a solution, an emulsion or a suspension.
  • Suitable pharmaceutical vehicles are, for example, dispersing agents, disintegrants, stabilizers, anti-oxidants (among which omega-3 such as eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) or omega-6), adsorbents agents for improving intestinal absorption, solubilizing agents, SEDDS "self-emulsifying drug delivery system", which can be added, for syrups, flavoring or coloring agents.
  • Sustained release formulations for example tablets containing an enteric coating, are also contemplated. All the ingredients and oral forms used will aim to improve the bioeffectiveness of the prodrugs according to the invention.
  • Another object according to the invention is the use of a prodrug according to the invention, or a pharmaceutical composition according to the invention, in the preparation of a medicament for the treatment or prevention of various diseases for which the Action site of the drug is located at the level of the liver.
  • a preferred embodiment according to the invention is the use of a prodrug or a pharmaceutical composition according to the invention in the preparation of a medicament for the treatment or prevention of various diseases which are due to a Excessive blood cholesterol, including the risk of recurrence of myocardial infarction, angina pectoris, peripheral arterial occlusive disease and cerebrovascular accident.
  • This embodiment is more particularly applicable to prodrugs or pharmaceutical compositions of statins.
  • another preferred embodiment according to the invention is the use of a prodrug or a pharmaceutical composition in the preparation of a medicament for treating heart failure, chronic renal failure, colon cancer and lung, reduction of fracture frequencies during osteoporosis, reduction of diabetes progression, deep vein thromboses or phlebitis, dementia, Alhzeimer's disease, multiple sclerosis and infections.
  • the process for preparing the prodrug according to the invention is generally carried out in one step, by chemical reaction of a therapeutic agent X with an R radical. This chemical reaction makes it possible to block the linkage which will subsequently be hydrolysed in the liver. .
  • the process for preparing the statin prodrug according to the invention is carried out by esterification between a molecule of statin and a hydroxy acid derivative of fatty acid.
  • the prodrug obtained may be an amorphous form or a crystalline form with several polymorphs, and will preferably be the most stable crystalline form from a thermodynamic point of view. It can then be used in its acid or salt form.
  • the reaction is presented below:
  • Example 1 Preparation of an oral tablet containing 92 mg of Pro-ATV (equivalent to 80 mg of atorvastatin) comprising the butanoic ester of atorvastatin in its most stable crystalline form (hereinafter referred to as ProATVV)
  • 270 mg film-coated tablet (hypromellose, titanium dioxide, talc, macrogol 6000, isopropyl alcohol, and dichloromethane).
  • EXAMPLE 2 Preparation of an Oral Suspension Comprising Pentaenoic Ester of Atorvastatin with a C 1 -C 4 Double Bond
  • the formulation is prepared extemporaneously. This is a 5 mg / ml suspension of this compound in 0.5% methylcellulose.
  • Example 3 Comparative study of hepatic uptake of fluvastatin and atorvastatin versus their respective prodrugs. Study carried out on preparation of human hepatocytes and on HepG2 cells. The capture reaction was initiated by adding the radiolabeled products to the cell suspension. After 2 minutes of incubation, the reaction is stopped, and the samples prepared to determine the amount of products captured in the liver by liquid scintillation measurement. In both cases, radioactivity levels showed greater hepatic uptake with prodrugs compared to reference agents.
  • Example 4 Oral administration to man of the butanoic ester prodrug of atorvastatin.
  • This single-center, randomized, open-label, 2-period, 2-sequence, crossover study assesses the safety, pharmacokinetic (PK) and pharmacodynamic (PD) profile of this ProATV entity at a dose of 92 mg compared to atorvastatin (ATV, Tahor®) at the 80 mg equimolar dose.
  • PK pharmacokinetic
  • PD pharmacodynamic
  • LDL-C LDL-Cholesterol
  • the selected male healthy volunteers and eligible subjects were randomized within 14 days of the selection visit.
  • Sequence 1 Period 1: ProATV (92 mg) - Period 2: ATV (80 mg)
  • Sequence 2 Period 1: ATV (80 mg) - Period 2: ProATV (92 mg)
  • ProATV and ATV were administered from J1 to J14 for period 1 and from J21 to J35 for period 2.
  • biomarkers such as: total cholesterol, LDL-C, Apo B.
  • ProATV 92 mg
  • the products administered are: ProATV (92 mg): in the form of a ProATV 92 mg tablet corresponding to that described in Example 1 above.
  • Placebo 1 oral tablet of identical appearance to the tested product.
  • the products are administered on an empty stomach with a glass of water (approximately 150 ml). Neither food nor water is administered for a period of at least 2 hours after administration of the products.
  • the evaluation criteria are:
  • AEs adverse reactions
  • SIAs serious adverse reactions
  • physical examination vital signs (blood pressure, heart rate), weight and body mass index, electrocardiogram (ECG), hematology (Hb, Ht, NFS, platelets), biochemistry (sodium, potassium, chloride, bicarbonate, calcium, albumin, AST, ALT, alkaline phosphatase, total bilirubin, CPK, creatinine, glucose, urea).
  • PD total cholesterol levels, LDL-C, Apo B, and HDL-C.
  • the number of subjects per sequence was evaluated to obtain first information on the tolerance, PK and PD of the proATV compared to the ATV.
  • the procedure :
  • Pre-dose at D14 and D35 and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 48 and 72 hours.
  • the samples (10 mL) are collected in chilled tubes and heparins with esterase inhibitors. Plasma is obtained by centrifugation (10 min at 1800 g and at 4 ° C) within 30 minutes after collection.
  • Plasma samples are divided into 2 aliquots of 1 mlL and 4 aliquots of 0.5 mL and immediately frozen at -80 ° C.
  • the relative bioavailability of ATV and its metabolites after repeated administration of ProATV 92 mg to healthy high cholesterol subjects is 50% compared to the reference product, ATV 80 mg (equimolar dose).
  • the half-life of the ATV is between 10 and 15 hours for the 2 products administered.
  • Pharmacodynamics The average decrease in LDL-C, total cholesterol and ⁇ after a 14-day repeated dose is similar for ProATV and the reference product, ATV: -60%, -50% and -50%, respectively.
  • the PK / PD data show that the effects of both products on LDL-C and total cholesterol levels are identical despite a 50% lower plasma exposure for ProATV (Atorvastatin Area under the curve). metabolites) compared with atorvastatin.
  • ProATV shows similar efficacy on lipid profile (LDL-C and total cholesterol) compared to atorvastatin, associated with a 50% decrease in systemic exposure. This decrease in exposure is commonly associated with a decrease in adverse effects such as: myalgia, CPK elevation, rhabdomyolysis.
  • ProATV is therefore of substantial interest for the 10% of patients treated at high doses of statins with muscle-related adverse effects as well as for at-risk populations such as the elderly, subjects on concomitant treatment interfering with the systemic exposure of the patients.
  • statins or for certain subjects with a phenotype associated with a reduction in hepatic transporter activity leading to an increase in plasma exposure to the product and its metabolites.
  • the effects observed on liver enzymes are less marked with proATV compared to equimolar dose ATV.
  • Hepatic deleterious effects are generally dose dependent and the best observed tolerance for proATV is a substantial benefit in patients requiring high dose therapy.

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Abstract

The invention relates to a prodrug intended to be specifically dispensed to the liver. The invention relates to a prodrug with the general formula (I) X—R, wherein X is a therapeutic agent, the site of action of which is the liver and R is a saturated or unsaturated, straight or branched fatty acid, including 3 to 12 carbon atoms, optionally substituted with one or more hydroxyl groupings, halogen atom and cyclic hydrocarbon including 3 to 6 carbon atoms, or a pharmaceutically acceptable salt or stereoisomer thereof. The invention also relates to a pharmaceutical composition containing at least one prodrug according to the invention associated with a suitable carrier, specifically for oral delivery. The invention further relates to the use of a prodrug according to the invention or of a pharmaceutical composition in the preparation of a drug for treating or preventing various diseases.

Description

PROMÉDICAMENTS POUR UNE DÉLIVRANCE AU NIVEAU DU FOIE D'UNE STATINE  PRODRUGS FOR LIVER-LEVEL DELIVERY OF STATIN

L'invention concerne de nouveaux promédicaments, leur préparation et leur utilisation.The invention relates to novel prodrugs, their preparation and their use.

Les promédicaments selon l'invention peuvent être utilisés pour délivrer des agents thérapeutiques au niveau du foie avec une spécificité tissulaire élevée, notamment des statines. The prodrugs of the invention can be used to deliver therapeutic agents to the liver with high tissue specificity, including statins.

Un promédicament ou prodrogue est une substance pharmacologique, ou médicament, qui est administré sous une forme inactive. Une fois administré, le promédicament est métabolisé in vivo en un métabolite actif. On utilise généralement un promédicament pour optimiser l'absorption, la distribution, le métabolisme et l'excrétion. Il est généralement conçu pour améliorer la biodisponibilité orale, voire pour augmenter la sélectivité du produit pour la cible visée. A prodrug or prodrug is a pharmacological substance, or drug, that is administered in an inactive form. Once administered, the prodrug is metabolized in vivo to an active metabolite. A prodrug is generally used to optimize absorption, distribution, metabolism and excretion. It is generally designed to improve the oral bioavailability, or even to increase the selectivity of the product for the intended target.

Les agents thérapeutiques d'intérêt dans le cadre de cette invention peuvent être tout agent dont le site d'action est le foie, par exemple les médicaments anti-cancéreux, antiparasitaires, hypolipémiants, anti-diabétiques, ou bien des agents thérapeutiques utilisés dans les maladies métaboliques.  The therapeutic agents of interest in the context of this invention may be any agent whose site of action is the liver, for example anti-cancer, antiparasitic, lipid-lowering or anti-diabetic drugs, or else therapeutic agents used in the metabolic diseases.

Par site d'action au niveau du foie selon l'invention, on entend que la molécule thérapeutique présente son activité au niveau du foie.  By action site at the level of the liver according to the invention is meant that the therapeutic molecule has its activity in the liver.

Parmi les agents anti-cancéreux utilisés pour traiter le cancer du foie, on peut citer par exemple les dérivés du 5-fluoro-uracil (5-FU), Mitomycins, Sorafenib.  Anti-cancer agents used to treat liver cancer include, for example, 5-fluorouracil derivatives (5-FU), Mitomycins, Sorafenib.

Parmi les agents hypoglycémiants oraux agissants au niveau du foie, on peut citer par exemple les dérivés biguanides (metformine, Glucophage ®) ou les agents inhibiteurs de l'alpha- glucosidase.  Examples of oral hypoglycemic agents acting on the liver include biguanide derivatives (metformin, Glucophage®) or alpha-glucosidase inhibiting agents.

Parmi les agents hypolipémiants agissant au niveau du foie, on peut citer par exemple les fibrates ou les statines.  Lipid-lowering agents acting in the liver include, for example, fibrates or statins.

Dans la présente invention, les statines sont plus particulièrement décrites en tant qu'agent thérapeutique. Ceci ne doit pas pour autant réduire l'étendue des promédicaments décrits dans la présente invention.  In the present invention, statins are more particularly described as a therapeutic agent. This should not, however, reduce the scope of the prodrugs described in the present invention.

Les statines forment une classe d'hypolipidémiants utilisés comme médicaments pour baisser la cholestérolémie des personnes à risque cardiovasculaire. Les statines exercent leurs effets hypolipémiants à travers l'inhibition, au niveau du foie, de l'enzyme clé de la synthèse du cholestérol, la 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA reductase). Cet effet est dose-dépendant. Les statines connues sont notamment la fluvastatine (acide (6E)-7-[3-(4-fluorophényl)-l- (propan-2-yl)-iH-indol-2-yl]-3,5-dihydroxyhept-6-énoïque), la pravastatine ou acide (3R,5R)- 3,5-dihydroxy-7-((lR,2S,6S,8R,8aR)-6-hydroxy-2-méthyl-8-{[(2S)-2-méthylbutanoyl] oxy}- l,2,6,7,8,8a-hexahydronaphthalén-l-yl) heptanoïque, l'ator-vastatine ou acide (3i?,5iî)-7-[2-(4- fluorophényl)-3-phényl-4-(phényl carbamoyl)-5-(propan-2-yl)- lH-pyrrol-l-yl]-3,5- dihydroxyheptanoïque, la rosuvastatine ou acide 7-{4-(4-Fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidin-5-yl}-3, 5-dihydroxyhept-6-enoïque, la cérivastatine ou acide 7-(4-(4-fluorophenyl)-5-(methoxymethyl)-2,6-bis(l-methylethyl)-3-pyridinyl)-3,5- dihydroxy-(S-(R*,S*-(E))) 6-heptanoïque, et la pitivastatine ou acide (3R,5S,6E)-7-[2- cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxyhept-6-enoïque. Il est reconnu que les statines sont efficaces sur la diminution du taux de cholestérol dans le sang et sur la diminution du risque de survenue ou de récidive de maladies résultants du rétrécissement ou de l'occlusion d'artères. Statins are a class of lipid-lowering drugs used to lower cholesterol levels in people with cardiovascular risk. Statins exert their lipid-lowering effects through the inhibition of the key cholesterol-synthesizing enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA reductase) in the liver. This effect is dose-dependent. The known statins are in particular fluvastatin (6E) -7- [3- (4-fluorophenyl) -1- (propan-2-yl) -1H-indol-2-yl] -3,5-dihydroxyhept-6 acid. -enoic), pravastatin or (3R, 5R) -3,5-dihydroxy-7 - ((1R, 2S, 6S, 8R, 8aR) -6-hydroxy-2-methyl-8 - {[2S] acid) 2-methylbutanoyloxy) -1,2,6,7,8,8a-hexahydronaphthalen-1-yl) heptanoic acid, ator-vastatin or acid (3i, 5i) -7- [2- (4- fluorophenyl) -3-phenyl-4- (phenylcarbamoyl) -5- (propan-2-yl) -1H-pyrrol-1-yl] -3,5-dihydroxyheptanoic acid, rosuvastatin or 7- {4- (4 -Fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl} -3,5-dihydroxyhept-6-enoic acid, cerivastatin or 7- (4- (4-fluorophenyl) -5 acid - (methoxymethyl) -2,6-bis (1-methylethyl) -3-pyridinyl) -3,5-dihydroxy- (S- (R *, S * - (E))) 6-heptanoic acid, and pitivastatin or (3R, 5S, 6E) -7- [2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxyhept-6-enoic acid. It is recognized that statins are effective in decreasing cholesterol levels in the blood and in reducing the risk of occurrence or recurrence of diseases resulting from narrowing or occlusion of arteries.

Les statines sont rapidement absorbées au niveau intestinal, puis pénètrent dans le foie par diffusion passive ou grâce à des transporteurs hépatiques. Elles y exercent leur effet hypolipidémiant puis sont ensuite rapidement métabolisées et excrétées via la bile. Pour cette raison, la biodisponibilité des statines est réduite, elle est dose dépendante jusqu'à un certain niveau et aux fortes doses, lorsqu'il y a saturation du métabolisme hépatique, les taux circulants de statines peuvent augmenter considérablement entraînant de nombreux effets indésirables.  Statins are rapidly absorbed intestinal tract, then enter the liver by passive diffusion or through liver transporters. They exert their hypolipidemic effect and are then rapidly metabolized and excreted via the bile. For this reason, the bioavailability of statins is reduced, it is dose dependent up to a certain level and at high doses, when there is saturation of hepatic metabolism, circulating levels of statins can increase considerably with many adverse effects.

Bien que le bénéfice / risque des statines soit très favorable notamment aux doses faibles et intermédiaires, de plus en plus de cas d'intolérance sont reportés en pratique clinique chez les patients traités aux plus fortes doses. Parmi ces effets indésirables, il existe notamment des effets musculaires et hépatiques. Les principaux effets indésirables observés affectent le système musculo-squelettique et sont la myalgie, les crampes, la réduction de la force musculaire ou fatigue, l'augmentation des créatines phospho kinases (CPK). Ces effets pouvant dans les cas les plus sévères entraîner des rhabdomyolyses. De récentes études estiment que le nombre de patients souffrants d'effets indésirables non sévères varie entre 5 et 10 % dans le cadre d'études cliniques randomisées et qu'il peut atteindre jusqu'à 20 % en pratique clinique (Fernandez G, Spatz ES, Jablecki C, Phillips PS. Statin myopathy: a coramon dilemma not reflected in clinical trials. Cleve Clin J Med 2011 ;78:393-403). Ces effets seraient d'ailleurs responsables de la faible observance après 2 ans de traitement qui est de 25 % chez les patients en prévention primaire et de 40 % chez les patients en prévention secondaire (Jackevicius CA, Mamdani M, Tu JV. Adhérence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 2002;288:462-7). Ces risques sont augmentés chez les patients vulnérables tels que les sujets âgés, les sujets insuffisants rénaux, les sujets présentant une modification génétique des transporteurs hépatiques ou les sujets avec traitements concomitants interférant avec le métabolisme hépatique des statines, par exemple les fibrates, le Verapamil®, et chez qui l'exposition systémique est augmentée. Pour ce qui concerne les effets hépatiques, les études de pharmacovigilances des statines ont montré des élévations significatives (3 x ULN) des transaminases hépatiques rapportées avec une incidence de 1% aux faibles doses et 2-3% aux fortes doses (American Journal Cardiol. 2006 Apr 17;97(8A):77C-81C. An assessment of statin safety by hepatologists. David E. Cohen et al.). Ces élévations sont dose dépendantes et communes à toutes les statines. La majorité des augmentations surviennent dans les 3 premiers mois de traitement et requièrent un monitoring. Although the benefit / risk of statins is very favorable especially at low and intermediate doses, more and more cases of intolerance are reported in clinical practice in patients treated at higher doses. These side effects include muscle and liver effects. The main undesirable effects observed affect the musculoskeletal system and are myalgia, cramps, reduction of muscle strength or fatigue, increase in creatine phosphokines (CPK). These effects may in the most severe cases lead to rhabdomyolysis. Recent studies estimate that the number of patients with non-severe adverse events varies between 5 and 10% in randomized clinical trials and up to 20% in clinical practice (Fernandez G, Spatz ES , Jablecki C., Phillips PS, Statin myopathy: a coronary dilemma not reflected in clinical trials, Cleve Clin J Med 2011; 78: 393-403). These effects would be responsible for poor compliance after 2 years of treatment, which is 25% in primary prevention patients and 40% in secondary prevention patients (Jackevicius CA, Mamdani M, Tu JV, Adherence with statin therapy in elderly patients with and without acute coronary syndromes, JAMA 2002; 288: 462-7). These risks are increased in vulnerable patients such as the elderly, patients with renal insufficiency, subjects with genetic modification of Hepatic transporters or subjects with concomitant treatments interfering with hepatic metabolism of statins, eg fibrates, Verapamil®, and in whom systemic exposure is increased. With respect to hepatic effects, pharmacovigilance studies of statins showed significant elevations (3 x ULN) of liver transaminases reported with an incidence of 1% at low doses and 2-3% at high doses (American Journal Cardiol. 2006 Apr 17; 97 (8A): 77C-81C, David E. Cohen et al. These elevations are dose dependent and common to all statins. The majority of increases occur in the first 3 months of treatment and require monitoring.

De ce fait, il existe un besoin de développer de nouveaux médicaments ou promédicaments, notamment de statine, capables d'éliminer ou au moins réduire les effets secondaires observés au cours des traitements, tout en préservant une activité spécifique liée à l'agent thérapeutique, une activité efficace voire améliorée.  As a result, there is a need to develop new drugs or prodrugs, in particular statins, capable of eliminating or at least reducing the side effects observed during treatments, while preserving a specific activity related to the therapeutic agent, an effective or even improved activity.

Le document WO 2009/054682 décrit des promédicaments de l'atorvastatine sensés résoudre certains problèmes liés à l'administration de l'atorvastatine. Il décrit l'ester carboxyméthylique de l'atovar statine en tant que promédicament.  WO 2009/054682 discloses prodrugs of atorvastatin to overcome certain problems related to the administration of atorvastatin. It describes the carboxymethyl ester of the atovar statin as a prodrug.

Le document WO 2009/009152 décrit principalement des composés intermédiaires utilisés dans des procédés de préparation de la rosuvastatine. Seuls des intermédiaires de synthèse sont décrits pour aboutir in fine au composé thérapeutiquement efficace, la rosuvastatine.  WO 2009/009152 mainly describes intermediate compounds used in processes for the preparation of rosuvastatin. Only synthetic intermediates are described to ultimately lead to the therapeutically effective compound, rosuvastatin.

Le document WO 2006/136408 décrit des composés intermédiaires utilisés dans des procédés de préparation de la rosuvastatine. L'ester n-butyl de la rosuvastatine est décrit en tant qu'intermédiaires de synthèse de la rosuvastatine.  WO 2006/136408 discloses intermediates used in processes for the preparation of rosuvastatin. The n-butyl ester of rosuvastatin is described as intermediates in the synthesis of rosuvastatin.

Le document WO 2003/070717 décrit un procédé pour fabriquer des dérivés d'acide mévalonique inhibiteur de la HMG-CoA dans lequel certains dérivés intermédiaires du procédé sont des esters d'alkyle en C1-C7, lesquels dérivés sont hydrolysés pour donner le composé final thérapeutiquement efficace. Les exemples décrivent le procédé de préparation de la pitivastatine et de la fluvastatine.  WO 2003/070717 discloses a process for producing HMG-CoA inhibiting mevalonic acid derivatives in which certain intermediate derivatives of the process are C1-C7 alkyl esters, which derivatives are hydrolyzed to give the final compound therapeutically effective. The examples describe the process for preparing pitivastatin and fluvastatin.

Le document WO 2008/075165 décrit un nouveau procédé pour synthétiser l'atorvastatine et ses sels pharmaceutiquement acceptables, ledit procédé permettant de réduire le nombre d'étapes nécessaire pour convertir un composé de formule (I) en produit final désiré. Les seuls composés intermédiaires revendiquées sont les composés de formule II dans lesquels RI et R2 forment ensemble avec les atomes d'oxygène un groupe cyclopentylidène ou cyclohexylidène. Les inventeurs ont découvert de nouveaux promédicaments d'agents thérapeutiques qui de manière surprenante permettent d'avoir une bonne activité thérapeutique au niveau du foie tout en diminuant les effets secondaires. Ils ont plus particulièrement découverts de nouveaux promédicaments de statine qui de manière surprenante inhibent efficacement la synthèse du cholestérol au niveau hépatique tout en diminuant la toxicité musculaire et hépatique. WO 2008/075165 discloses a novel method for synthesizing atorvastatin and its pharmaceutically acceptable salts, said method for reducing the number of steps necessary to convert a compound of formula (I) into the desired end product. The only intermediate compounds claimed are the compounds of formula II in which R 1 and R 2 together with the oxygen atoms form a cyclopentylidene or cyclohexylidene group. The inventors have discovered novel prodrugs of therapeutic agents which surprisingly allow to have a good therapeutic activity in the liver while decreasing the side effects. In particular, they have discovered novel statin prodrugs that surprisingly effectively inhibit cholesterol synthesis in the liver while decreasing muscle and liver toxicity.

Ainsi, l'objet de l'invention est un promédicament selon la formule générale (I)  Thus, the subject of the invention is a prodrug according to the general formula (I)

X— R (I) dans laquelle : X-R (I) in which:

X représente un agent thérapeutique dont le site d'action est le foie, X represents a therapeutic agent whose site of action is the liver,

R représente un acide gras saturé ou insaturé, linéaire ou ramifié, comprenant de 3 à 12 atomes de carbone, éventuellement substitué par un ou plusieurs groupe hydroxyle, atome d'halogène, et hydrocarbure cyclique comprenant de 3 à 6 atomes de carbone, R represents a saturated or unsaturated fatty acid, linear or branched, comprising from 3 to 12 carbon atoms, optionally substituted by one or more hydroxyl group, halogen atom, and cyclic hydrocarbon comprising from 3 to 6 carbon atoms,

ou un sel ou stéréoisomère de celui-ci pharmaceutiquement acceptable. or a pharmaceutically acceptable salt or stereoisomer thereof.

Par agent thérapeutique dont le site d'action est le foie on entend par exemple les médicaments anti-cancéreux, anti-parasitaires, hypolipémiants, anti-diabétiques, ou bien des agents thérapeutiques utilisés dans les maladies métaboliques. Par statine on entend toute statine connue ou nouvellement mise au point ultérieurement, qui peut réagir avec un acide gras tel que défini ci-après, pour former un promédicament selon l'invention. La réaction chimique entre l'agent thérapeutique dont le site d'action est le foie et le radical R s'effectue de manière à ce qu'une fois hydrolysé au niveau du foie, le pro-médicament libère un agent thérapeutique actif. Lorsque la réaction chimique est réalisée entre une statine et un radical R, elle s'effectue par estérification sur la fonction acide commune à toute les statines. Les statines sont notamment celles citées ci-dessus et elles inhibent de manière spécifique la HMG-CoA réductase. By therapeutic agent whose site of action is the liver is meant for example anti-cancer drugs, anti-parasitic, lipid-lowering, anti-diabetic, or therapeutic agents used in metabolic diseases. By statin is meant any statin known or newly developed later, which can react with a fatty acid as defined below, to form a prodrug according to the invention. The chemical reaction between the therapeutic agent whose site of action is the liver and the radical R is carried out so that once hydrolysed in the liver, the pro-drug releases an active therapeutic agent. When the chemical reaction is carried out between a statin and an R radical, it is carried out by esterification on the acid function common to all statins. The statins are in particular those mentioned above and they specifically inhibit HMG-CoA reductase.

Par acide gras, on entend tout acide carboxylique à chaîne aliphatique non cyclique. Ils comprennent de 3 à 12 atomes de carbones et sont soit saturés, c'est à dire que tous les atomes de carbone sont saturés en hydrogène (sans double liaison), soit insaturés, c'est à dire qu'ils comportent une ou plusieurs doubles liaisons carbone-carbone, ils peuvent être conjugués (double liaison séparée par une simple liaison) ou non conjugués (double liaison séparée par 2 simples liaisons). Les acides gras peuvent être linéaires, c'est à dire à chaîne droite, ou bien ramifiés, c'est à dire comprenant un ou plusieurs radicaux carbonés courts, notamment des radicaux méthyle et éthyle. The term "fatty acid" means any carboxylic acid with a non-cyclic aliphatic chain. They comprise from 3 to 12 carbon atoms and are either saturated, that is to say that all the carbon atoms are saturated with hydrogen (without double bond), or unsaturated, ie they contain one or more carbon-carbon double bonds, they can be conjugated (double bond separated by a single bond) or non-conjugated (double bond separated by 2 single bonds). The fatty acids can be linear, ie straight chain, or branched, that is to say comprising one or more short carbon radicals, especially methyl and ethyl radicals.

Par hydrocarbure cyclique, on entend les hydrocarbures dont la chaîne carbonée est cyclique. Ils comprennent les cycloalcanes, les cycloalcènes et les cycloalcynes. On peut citer notamment le cyclopropane, le cyclobutène et le cyclohexane.  Cyclic hydrocarbon means hydrocarbons whose carbon chain is cyclic. They include cycloalkanes, cycloalkenes and cycloalkynes. There may be mentioned in particular cyclopropane, cyclobutene and cyclohexane.

Les promédicaments selon l'invention permettent d'obtenir une meilleure efficacité pharmaceutique des agents thérapeutiques hydrolysés et/ou une meilleure tolérance de ces derniers. The prodrugs according to the invention make it possible to obtain a better pharmaceutical efficacy of the hydrolysed therapeutic agents and / or a better tolerance of the latter.

Dans un mode de réalisation préférentiel selon l'invention, l'agent thérapeutique X est choisi parmi les médicaments anti-cancéreux, anti-parasitaires, hypolipémiants, anti-diabétiques, ou bien des agents thérapeutiques utilisés dans les maladies métaboliques.  In a preferred embodiment of the invention, the therapeutic agent X is chosen from anti-cancer, anti-parasitic, hypolipidemic, anti-diabetic, or therapeutic agents used in metabolic diseases.

Dans un mode de réalisation plus préférentiel selon l'invention, l'invention concerne un promédicament de statine selon la formule générale (I)  In a more preferred embodiment of the invention, the invention relates to a prodrug of a statin according to the general formula (I)

X— R (I) dans laquelle : X représente une statine choisie parmi la fluvastatine, la pravastatine, l'atorvastatine, la rosuvastatine, la cérivastatine et la pitivastatine, X - R (I) in which: X represents a statin chosen from fluvastatin, pravastatin, atorvastatin, rosuvastatin, cerivastatin and pitivastatin,

R représente un acide gras saturé ou insaturé, linéaire ou ramifié, comprenant de 3 à 12 atomes de carbone, éventuellement substitué par un ou plusieurs groupement hydroxyle, atome d'halogène, et hydrocarbure cyclique comprenant de 3 à 6 atomes de carbone, ou un sel ou stéréoisomère de celui-ci pharmaceutiquement acceptable. R represents a saturated or unsaturated fatty acid, linear or branched, comprising from 3 to 12 carbon atoms, optionally substituted with one or more hydroxyl groups, halogen atom, and cyclic hydrocarbon comprising from 3 to 6 carbon atoms, or salt or stereoisomer thereof pharmaceutically acceptable.

Les promédicaments de statine inhibent de façon préférentielle la synthèse du cholestérol au niveau hépatique (meilleure efficacité) tout en éliminant ou du moins réduisant les effets indésirables (meilleure tolérance). Ils permettent également de diminuer voire d'éliminer la toxicité hépatique. Ces promédicaments permettent de ce fait d'apporter un avantage considérable en terme de santé publique notamment pour les patients vulnérables et traités à fortes doses de statines. Ainsi, les promédicaments de statine selon l'invention permettent d'augmenter la dose à administrer jusqu'à doubler celle-ci par rapport aux fortes doses utilisées à l'heure actuelle. Par exemple, on sait que la rosuvastatine est administrée à 40 mg à forte dose. Les promédicaments selon l'invention peuvent ainsi être administrés à une forte dose pouvant aller environ jusqu'à 80 mg équivalent de rosuvastatine et ce avec une meilleure tolérance pour le sujet traité. Un aure exemple est l'atorvastatine administrée à 80 mg à forte dose. Les promédicaments selon l'invention peuvent ainsi être administrés à une forte dose pouvant aller environ jusqu'à 160 mg équivalent d'atorvastatine (soit par exemple 184 mg de ProATV comme décrit dans F exemple 4 ci-après), et ce avec une meilleure tolérance pour le sujet traité. Statin prodrugs preferentially inhibit hepatic cholesterol synthesis (better efficacy) while eliminating or at least reducing adverse effects (better tolerance). They also make it possible to reduce or even eliminate liver toxicity. These prodrugs thus provide a considerable advantage in terms of public health, especially for vulnerable patients treated with high doses of statins. Thus, the prodrugs of statin according to the invention make it possible to increase the dose to be administered up to double that dose compared to the high doses used at the present time. For example, rosuvastatin is known to be administered at a high dose of 40 mg. The prodrugs of the invention can thus be administered at a high dose of up to about 80 mg equivalent of rosuvastatin and with a better tolerance for the subject being treated. An example is atorvastatin administered at 80 mg in high doses. The prodrugs according to the invention can thus be administered at a high dose of up to about 160 mg equivalent of atorvastatin (ie for example 184 mg of ProATV as described in Example 4 below), and this with a better tolerance for the subject treated.

Le promédicament de statine selon l'invention présente un radical R représentant de préférence un acide gras saturé ou insaturé, linéaire ou ramifié comprenant de 3 à 10 atomes de carbone, de préférence un acide gras saturé linéaire ou ramifié comprenant de 3 à 8 atomes de carbone.  The prodrug of statin according to the invention has a radical R preferably representing a linear or branched, saturated or unsaturated fatty acid comprising from 3 to 10 carbon atoms, preferably a linear or branched saturated fatty acid comprising from 3 to 8 carbon atoms. carbon.

Dans un mode préférentiel selon l'invention, le promédicament de statine est l'ester propanoïque, propaénoïque, butanoïque, butanénoïque, pentanoïque, pentaénoïque, hexanoïque, hexaénoïque, heptanoïque ou heptaénoïque de la fluvastatine, la pravastatine, l'atorvastatine, la rosuvastatine, la cérivastatine et la pitivastatine, ou son sel ou stéréoisomère pharmaceutiquement acceptable.  In a preferred embodiment according to the invention, the statin prodrug is the propanoic, propaenoic, butanoic, butanenoic, pentanoic, pentaenoic, hexanoic, hexaenoic, heptanoic or heptaenoic ester of fluvastatin, pravastatin, atorvastatin, rosuvastatin, cerivastatin and pitivastatin, or its pharmaceutically acceptable salt or stereoisomer.

Dans un mode encore plus préférentiel selon l'invention, le promédicament de statine est : - l'ester butanoïque, pentanoïque, hexanoïque ou heptanoïque de la fluvastatine, la pravastatine, l'atorvastatine, la rosuvastatine, la cérivastatine et la pitivastatine, l'ester pentaénoïque en C3 et C4 de la fluvastatine, la pravastatine, l'atorvastatine, la rosuvastatine, la cérivastatine et la pitivastatine. In an even more preferred embodiment according to the invention, the statin prodrug is: - the butanoic, pentanoic, hexanoic or heptanoic ester of fluvastatin, pravastatin, atorvastatin, rosuvastatin, cerivastatin and pitivastatin, C 3 and C 4 pentaenoic ester of fluvastatin, pravastatin, atorvastatin, rosuvastatin, cerivastatin and pitivastatin.

Dans un mode très préférentiel selon l'invention, le promédicament de statine est l'ester pentaénoïque en C3 et C4 de l'atorvastatine et l'ester butanoïque de l'atorvastatine. In a very preferred embodiment according to the invention, the statin prodrug is pentaenoic ester C 3 and C 4 of atorvastatin and the butanoic ester of atorvastatin.

Un autre objet selon l'invention est une composition pharmaceutique contenant au moins un promédicament selon l'invention, associé à un véhicule approprié. La composition pharmaceutique selon l'invention est préférentiellement appropriée pour être administrée par voie orale. Lorsqu'on administre le promédicament selon l'invention à l'homme par voie orale, il peut se présenter sous forme d'une formulation solide, telle que, poudre, granules, comprimés, ou capsules, par exemple, ou sous forme d'une formulation liquide préférentiellement contenue dans une capsule, ou d'un sirop. Lorsqu'il est sous forme d'un comprimé (pélliculé ou non), on peut utiliser n'importe quel véhicule pharmaceutique approprié à la formulation de telles compositions solides, par exemple la cellulose microcristalline, le lactose monohydrate, le crosscarmellose, le polysorbate 80, l'hydroxypropyl cellulose, le stéarate de magnésium, l'amidon, le lactose, le glucose, le riz, la farine et la craie, et des agents de pelliculage. Le composé peut également être sous forme d'une gélule à ingérer, constituée par exemple de gélatine, contenant le composé en solution, suspension ou émulsion, ou sous forme d'un sirop, d'une solution, d'une émulsion ou d'une suspension. Les véhicules pharmaceutiques appropriés sont par exemple les agents dispersants, désintégrants, stabilisants, anti-oxydants (parmi lesquels les oméga-3 tels que l'acide éicosapentaénoïque (EPA) ou l'acide docosahexaénoïque (DHA) ou les oméga-6), adsorbants, les agents visant à améliorer l'absorption intestinale, les agents solubilisants, les SEDDS « self Emulsifying Drug Delivery System », auxquels on peut ajouter, pour les sirops, des agents aromatisants ou colorants. On envisage également des formulations à libération prolongée, par exemple des comprimés contenant un enrobage entérosoluble. Tous les ingrédients et formes orales mises en œuvre auront pour but d'améliorer la bioeffïcacité des promédicaments selon l'invention. Another object according to the invention is a pharmaceutical composition containing at least one prodrug according to the invention, associated with a suitable vehicle. The pharmaceutical composition according to the invention is preferably suitable for oral administration. When the prodrug according to the invention is administered to man orally, it may be in the form of a solid formulation, such as, powder, granules, tablets, or capsules, for example, or in the form of a liquid formulation preferentially contained in a capsule, or a syrup. When it is in the form of a tablet (or not), any suitable pharmaceutical vehicle can be used for the formulation of such solid compositions, for example microcrystalline cellulose, lactose monohydrate, crosscarmellose, polysorbate 80 , hydroxypropyl cellulose, magnesium stearate, starch, lactose, glucose, rice, flour and chalk, and film-coating agents. The compound may also be in the form of a capsule to be ingested, consisting for example of gelatin, containing the compound in solution, suspension or emulsion, or in the form of a syrup, a solution, an emulsion or a suspension. Suitable pharmaceutical vehicles are, for example, dispersing agents, disintegrants, stabilizers, anti-oxidants (among which omega-3 such as eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) or omega-6), adsorbents agents for improving intestinal absorption, solubilizing agents, SEDDS "self-emulsifying drug delivery system", which can be added, for syrups, flavoring or coloring agents. Sustained release formulations, for example tablets containing an enteric coating, are also contemplated. All the ingredients and oral forms used will aim to improve the bioeffectiveness of the prodrugs according to the invention.

Un autre objet selon l'invention est l'utilisation d'un promédicament selon l'invention, ou d'une composition pharmaceutique selon l'invention, dans la préparation d'un médicament pour le traitement ou la prévention de diverses maladies pour lesquelles le site d'action du médicament est situé au niveau du foie. Another object according to the invention is the use of a prodrug according to the invention, or a pharmaceutical composition according to the invention, in the preparation of a medicament for the treatment or prevention of various diseases for which the Action site of the drug is located at the level of the liver.

Un mode de réalisation préférentiel selon l'invention est l'utilisation d'un promédicament ou d'une composition pharmaceutique selon l'invention dans la préparation d'un médicament pour le traitement ou la prévention de diverses maladies qui sont dues à un taux de cholestérol excessif dans le sang, notamment le risque de survenue ou de récidive de l'infarctus du myocarde, de l'angine de poitrine, de l'artériopathie oblitérante des membres inférieurs et de l'accident vasculaire cérébral. Ce mode de réalisation s'applique plus particulièrement aux promédicaments ou compositions pharmaceutiques de statines.  A preferred embodiment according to the invention is the use of a prodrug or a pharmaceutical composition according to the invention in the preparation of a medicament for the treatment or prevention of various diseases which are due to a Excessive blood cholesterol, including the risk of recurrence of myocardial infarction, angina pectoris, peripheral arterial occlusive disease and cerebrovascular accident. This embodiment is more particularly applicable to prodrugs or pharmaceutical compositions of statins.

Ainsi, un autre mode de réalisation préférentiel selon l'invention est l'utilisation d'un promédicament ou d'une composition pharmaceutique dans la préparation d'un médicament pour traiter l'insuffisance cardiaque, l'insuffisance rénale chronique , les cancers du côlon et du poumon, la réduction des fréquences des fractures lors de l'ostéoporose, la réduction de la progression du diabète, des thromboses veineuses profondes ou phlébites, la démence, la maladie d'Alhzeimer, la sclérose en plaque et les infections.  Thus, another preferred embodiment according to the invention is the use of a prodrug or a pharmaceutical composition in the preparation of a medicament for treating heart failure, chronic renal failure, colon cancer and lung, reduction of fracture frequencies during osteoporosis, reduction of diabetes progression, deep vein thromboses or phlebitis, dementia, Alhzeimer's disease, multiple sclerosis and infections.

Le procédé de préparation du promédicament selon l'invention s'effectue généralement en une étape, par réaction chimique d'un agent thérapeutique X avec un radical R. Cette réaction chimique permet de bloquer la liaison qui sera par la suite hydrolysée au niveau du foie. Par exemple, le procédé de préparation du promédicament de statine selon l'invention s'effectue par estérification entre une molécule de statine et un dérivé hydroxylé d'acide gras. Le promédicament obtenu pourra être une forme amorphe ou une forme cristalline avec plusieurs polymorphes, et sera préférentiellement la forme cristalline la plus stable d'un point de vue thermodynamique. Il pourra ensuite être utilisé sous sa forme acide ou de sel. La réaction est présentée ci-dessous : The process for preparing the prodrug according to the invention is generally carried out in one step, by chemical reaction of a therapeutic agent X with an R radical. This chemical reaction makes it possible to block the linkage which will subsequently be hydrolysed in the liver. . For example, the process for preparing the statin prodrug according to the invention is carried out by esterification between a molecule of statin and a hydroxy acid derivative of fatty acid. The prodrug obtained may be an amorphous form or a crystalline form with several polymorphs, and will preferably be the most stable crystalline form from a thermodynamic point of view. It can then be used in its acid or salt form. The reaction is presented below:

X-COOH + R-OH→ X-COOR. X-COOH + R-OH → X-COOR.

Les exemples qui suivent illustrent l'invention sans toutefois la limiter. The following examples illustrate the invention without limiting it.

Exemple 1 : Préparation d'un comprimé oral à 92 mg de Pro-ATV (équivalent à 80 mg d'atorvastatine) comprenant l'ester butanoïque de l'atorvastatine sous sa forme cristalline la plus stable (ci-après nommé ProATVV Example 1 Preparation of an oral tablet containing 92 mg of Pro-ATV (equivalent to 80 mg of atorvastatin) comprising the butanoic ester of atorvastatin in its most stable crystalline form (hereinafter referred to as ProATVV)

Pro-ATV 92 mg  Pro-ATV 92 mg

Cellulose microcristalline 126.5 mg.  Microcrystalline cellulose 126.5 mg.

Lactose monohydrate 35 mg  Lactose monohydrate 35 mg

Crosscarmellose 10 mg  Crosscarmellose 10 mg

Polysorbate 80 1.5 mg Polysorbate 80 1.5 mg

Hydroxypropyl Cellulose 2.0 mg  Hydroxypropyl Cellulose 2.0 mg

Stéarate de Magnésium 3.0 mg  Magnesium Stearate 3.0 mg

Comprimé de 270 mg pelliculé (hypromellose, dioxide de titane, talc, macrogol 6000, alcohool isopropyl, et dichloromethane).  270 mg film-coated tablet (hypromellose, titanium dioxide, talc, macrogol 6000, isopropyl alcohol, and dichloromethane).

Exemple 2 : Préparation d'une suspension orale comprenant l'ester pentaénoïque de l'atorvastatine avec une double liaison en C^et C4. La formulation est préparée extemporanément. Il s'agit d'une suspension à 5 mg/ml de ce composé dans du méthylcellulose à 0.5%. EXAMPLE 2 Preparation of an Oral Suspension Comprising Pentaenoic Ester of Atorvastatin with a C 1 -C 4 Double Bond The formulation is prepared extemporaneously. This is a 5 mg / ml suspension of this compound in 0.5% methylcellulose.

Exemple 3 : Etude comparative de la capture hépatique de la fluvastatine et de l'atorvastatine versus leurs pro-médicaments respectifs. Etude réalisée sur préparation d'hépatocytes humains et sur cellules HepG2. La réaction de capture a été initialisée par ajout des produits radiomarqués à la suspension de cellule. Après 2 minutes d'incubation, la réaction est arrêtée, et les échantillons préparés pour déterminer la quantité de produits capturé dans le foie par mesure de scintillation liquide. Dans les deux cas, les taux de radioactivité ont montré une plus grande capture hépatique avec les pro-médicaments comparés aux agents de référence. Example 3: Comparative study of hepatic uptake of fluvastatin and atorvastatin versus their respective prodrugs. Study carried out on preparation of human hepatocytes and on HepG2 cells. The capture reaction was initiated by adding the radiolabeled products to the cell suspension. After 2 minutes of incubation, the reaction is stopped, and the samples prepared to determine the amount of products captured in the liver by liquid scintillation measurement. In both cases, radioactivity levels showed greater hepatic uptake with prodrugs compared to reference agents.

Exemple 4 : Administration orale à l'homme du promédicament ester butanoïque de l'atorvastatine. Example 4: Oral administration to man of the butanoic ester prodrug of atorvastatin.

Cette étude mono-centrique, randomisée, ouverte, sur 2 périodes et 2 séquences, en cross-over, permet d'évaluer la tolérance, le profile pharmacocinétique (PK) et pharmacodynamique (PD) de cette entité ProATV à la dose de 92 mg comparée à l'atorvastatine (ATV, Tahor®) à la dose équimolaire de 80 mg. This single-center, randomized, open-label, 2-period, 2-sequence, crossover study assesses the safety, pharmacokinetic (PK) and pharmacodynamic (PD) profile of this ProATV entity at a dose of 92 mg compared to atorvastatin (ATV, Tahor®) at the 80 mg equimolar dose.

12 volontaires sains mâles, avec un taux de LDL-Cholestérol (LDL-C) compris entre 130 et 180 mg/dL et âgés de 18 à 55 ans ont sélectionnés pour la présente étude selon les critères suivants :  12 healthy male volunteers with LDL-Cholesterol (LDL-C) values of between 130-180 mg / dL and 18-55 years of age were selected for this study according to the following criteria:

Les volontaires sains mâles sélectionnés et les sujets éligibles ont été randomisés dans les 14 jours suivant la visite de sélection. The selected male healthy volunteers and eligible subjects were randomized within 14 days of the selection visit.

Les sujets ont été randomisés dans :  The subjects were randomized in:

Séquence 1 : période 1 : ProATV (92 mg) - période 2: ATV (80 mg) Séquence 2: période 1 : ATV (80 mg) - période 2: ProATV (92 mg) La ProATV et l'ATV ont été administrés de Jl à J14 pour la période 1 et de J21 à J35 pour la période 2.  Sequence 1: Period 1: ProATV (92 mg) - Period 2: ATV (80 mg) Sequence 2: Period 1: ATV (80 mg) - Period 2: ProATV (92 mg) ProATV and ATV were administered from J1 to J14 for period 1 and from J21 to J35 for period 2.

Les sujets ont été admis au centre clinique la veille de la première administration (J0 pour la période 1 et J20 pour la période 2). Ils y sont restés 48 h après la première administration de chaque période et ont quitté le site à J3 pour la période 1 et à J 23 pour la période 2.  Subjects were admitted to the clinic on the day before the first administration (D0 for period 1 and D20 for period 2). They remained there for 48 hours after the first administration of each period and left the site on D3 for period 1 and D 23 for period 2.

Une période de lavage de 7 jours sous placebo a été observée entre les 2 périodes.  A wash period of 7 days with placebo was observed between the 2 periods.

Les objectifs de l'étude sont : The objectives of the study are:

Primaires : Primary:

Evaluer la tolérance générale de ProATV administrée par voies orale pendant 14 jours à des sujets maies volontaires avec un LDL-C élevé.  To evaluate the general tolerability of oral ProATV for 14 days in volunteers with high LDL-C.

Secondaires : Evaluer le profile PK de l'atorvastatine et de ses principaux métabolites après 2 semaines de traitement de proATV ou d'atorvastatine. Secondary: To evaluate the PK profile of atorvastatin and its major metabolites after 2 weeks of treatment with proATV or atorvastatin.

Evaluer les effets PD de la proATV par la mesure de biomarqueurs tels que : cholestérol total, LDL-C, Apo B.  To evaluate the PD effects of proATV by measuring biomarkers such as: total cholesterol, LDL-C, Apo B.

Evaluer la biodisponibilité relative de l'atorvastatine après administration de ProATV ou de l'atorvastatine à doses équimolaires. To evaluate the relative bioavailability of atorvastatin after administration of ProATV or atorvastatin at equimolar doses.

Les produits administrés sont : La ProATV (92 mg): sous forme d'un comprimé de ProATV à 92 mg correspondant à celui décrit dans l'exemple 1 ci-dessus. The products administered are: ProATV (92 mg): in the form of a ProATV 92 mg tablet corresponding to that described in Example 1 above.

Placebo : 1 comprimé oral d'aspect identique au produit testé.  Placebo: 1 oral tablet of identical appearance to the tested product.

Les produits sont administrés à jeun avec un verre d'eau (environ 150 ml). Ni nourriture ni eau ne sont ensuite administrés pendant une période d'au moins 2 heures suivant l'administration des produits.  The products are administered on an empty stomach with a glass of water (approximately 150 ml). Neither food nor water is administered for a period of at least 2 hours after administration of the products.

Les critères d'évaluation sont : The evaluation criteria are:

Pour la tolérance: les effets indésirables (EIs)/Effets indésirables sérieux (EISs), l'examen physique, les signes vitaux (Pression artérielle, Fréquence cardiaque) , le poids et indice de masse corporelle, électrocardiogramme (ECG), l'hématologie (Hb, Ht, NFS, plaquettes), la biochimie (sodium, potassium, chlorure, bicarbonate, calcium, albumine, AST, ALT, phosphatase alkaline, bilirubine totale, CPK, creatinine, glucose, urée). For tolerance: adverse reactions (AEs) / serious adverse reactions (SIAs), physical examination, vital signs (blood pressure, heart rate), weight and body mass index, electrocardiogram (ECG), hematology (Hb, Ht, NFS, platelets), biochemistry (sodium, potassium, chloride, bicarbonate, calcium, albumin, AST, ALT, alkaline phosphatase, total bilirubin, CPK, creatinine, glucose, urea).

Pour la PK de P ATV et de ses métabolites (2-OH, 4-OH, et lactone) : la concentration (Cmax, Css,max, CSSjmin), le temps pour atteindre le pic (tmax) de concentration, l'aire sous la courbe (ASC) et la clairance totale (CL/F) et la demi-vie ÇTm)- Ces paramètres ont été évalués à J14 et J35. For the PK of P ATV and its metabolites (2-OH, 4-OH, and lactone): the concentration (C max , C ss , my x, C SSjm in), the time to reach the peak (t max ) concentration, area under the curve (AUC) and total clearance (LC / F) and half-life τTm) - These parameters were evaluated on D14 and D35.

Pour la PD : les taux de cholestérol total, LDL-C, Apo B, et HDL-C.  For PD: total cholesterol levels, LDL-C, Apo B, and HDL-C.

Ces paramètres ont été mesurés à Jl , J14, J21 et J35. These parameters were measured on D1, D14, D21 and D35.

Détermination du nombre de sujets : Determination of the number of subjects:

Le nombre de sujets de 6 par séquence a été évalué en vue d'obtenir une première information regardant la tolérance, la PK et la PD de la proATV comparée à l' ATV. La procédure : The number of subjects per sequence was evaluated to obtain first information on the tolerance, PK and PD of the proATV compared to the ATV. The procedure :

Les échantillons pour l'analyse de la PK:  Samples for PK analysis:

Pré-dose à J14 et J35 et à 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 48 et 72 heures. Pre-dose at D14 and D35 and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 48 and 72 hours.

Les échantillons (10 mL) sont prélevés dans des tubes réfrigérés et héparines avec inhibiteurs d'estérases. Le plasma est obtenu par centrifiigation (10 min à 1800 g et à 4°C) dans les 30 minutes après le prélèvement. The samples (10 mL) are collected in chilled tubes and heparins with esterase inhibitors. Plasma is obtained by centrifugation (10 min at 1800 g and at 4 ° C) within 30 minutes after collection.

Les échantillons plasmatiques sont divisés en 2 aliquots de 1 mlL et 4 aliquots de 0.5 mL et congelés immédiatement à -80°C.  Plasma samples are divided into 2 aliquots of 1 mlL and 4 aliquots of 0.5 mL and immediately frozen at -80 ° C.

Les échantillons pour l'analyse de la PD :  Samples for PD analysis:

A Jl et à J21 (avant la 1ère dose), J14 et à J35 à la fin de chaque période.  At D1 and D21 (before the first dose), D14 and D35 at the end of each period.

La procédure est représentée dans la figure 1.  The procedure is shown in Figure 1.

Les Résultats de l'étude sont les suivants: The results of the study are as follows:

Disposition, Démographie, Caractéristiques : Disposition, Demographics, Features:

Tous les sujets randomisés ont reçu et terminé leur traitement conformément au protocole.Tous ont un LDL-C élevé au départ.  All randomized subjects received and completed their treatment according to the protocol. All have high LDL-C initially.

Tolérance :  Tolerance:

Aucun sujet n'a interrompu l'étude.  No subject interrupted the study.

Aucun problème de tolérance n'est observé.  No problem of tolerance is observed.

Aucun paramètre biologique ou clinique n'est rapporté comme effet indésirable cliniquement significatif.  No biological or clinical parameters are reported as clinically significant adverse events.

Pharmacocinétique :  Pharmacokinetics:

Après l'administration des 2 produits, le taux d'absorption a été rapide (plus rapide pour la proATV comparé à F ATV).  After administration of the 2 products, the absorption rate was fast (faster for proATV compared to F ATV).

Le métabolite le plus important est, par ordre décroissant : 2-OH-ATV > ATV > 4-OH The most important metabolite is, in descending order: 2-OH-ATV> ATV> 4-OH

ATV. ATC.

La biodisponibilité relative de l'ATV et de ses métabolites après administration répétée de ProATV 92 mg, à des sujets sains hyper-cholesterolémiques, est de 50% comparée au produit de référence, ATV 80 mg (dose équimolaire).  The relative bioavailability of ATV and its metabolites after repeated administration of ProATV 92 mg to healthy high cholesterol subjects is 50% compared to the reference product, ATV 80 mg (equimolar dose).

La demi- vie de l'ATV est comprise entre 10 et 15 h pour les 2 produits administrés.  The half-life of the ATV is between 10 and 15 hours for the 2 products administered.

Pharmacodynamie : La baisse moyenne des taux de LDL-C, du cholestérol total et de ΓΑροΒ après une dose répétée de 14 jours est similaire pour la ProATV et le produit de référence, l'ATV : -60%, - 50% et -50%, respectivement. Pharmacodynamics: The average decrease in LDL-C, total cholesterol and ΓΑροΒ after a 14-day repeated dose is similar for ProATV and the reference product, ATV: -60%, -50% and -50%, respectively.

Une augmentation de 10% du taux de HDL-C est également observée avec les deux produits.  A 10% increase in HDL-C is also observed with both products.

PK/PD :  PK / PD:

Les données de PK/PD montrent que les effets des 2 produits sur les taux de LDL-C et de cholestérol total sont identiques en dépit d'une exposition plasmatique 50% plus basse pour la ProATV (Aire sous la courbe de l'atorvastatine et de ses métabolites) par comparaison à l' atorvastatine.  The PK / PD data show that the effects of both products on LDL-C and total cholesterol levels are identical despite a 50% lower plasma exposure for ProATV (Atorvastatin Area under the curve). metabolites) compared with atorvastatin.

Aucune corrélation entre les niveaux plasmatiques d' atorvastatine ou de ses hydroxy- métabolites et la baisse du cholestérol total ou du LDL-C n'est retrouvée.  There is no correlation between the plasma levels of atorvastatin or its hydroxy metabolites and the decrease in total cholesterol or LDL-C.

Conclusions: conclusions:

L'administration répétée pendant deux semaines de ProATV 92 mg à jeun, s'avère bien tolérée. Repeated administration for two weeks of ProATV 92 mg on an empty stomach is well tolerated.

La ProATV montre une efficacité similaire sur le profile lipidique (LDL-C et le Cholestérol total) comparé à l'atorvastatine, associé à une diminution de 50% de l'exposition systémique. Cette diminution de l'exposition est communément associée à une diminution des effets indésirables tels que : myalgies, élévation des CPK, rhabdomyolyses.  ProATV shows similar efficacy on lipid profile (LDL-C and total cholesterol) compared to atorvastatin, associated with a 50% decrease in systemic exposure. This decrease in exposure is commonly associated with a decrease in adverse effects such as: myalgia, CPK elevation, rhabdomyolysis.

La ProATV présente par conséquent un intérêt substantiel pour les 10% de patients qui traités à hautes doses de statines présentent des effets indésirables musculaires ainsi que pour des populations à risques telles que les sujets âgés, sujets sous traitement concomitants interférents avec l'exposition systémique des statines ou pour certains sujets présentant un phénotype associé à une réduction de l'activité des transporteurs hépatiques conduisant à une augmentation de l'exposition plasmatique au produit et à ses métabolites. De même les effets observés sur les enzymes hépatiques sont moins marqués avec la proATV comparés à l'ATV à dose équimolaire. Les effets délétères hépatiques sont en général dose dépendant et la meilleure tolérance observée pour la proATV constitue un avantage substantiel chez les patients nécessitant une thérapie à forte dose.  ProATV is therefore of substantial interest for the 10% of patients treated at high doses of statins with muscle-related adverse effects as well as for at-risk populations such as the elderly, subjects on concomitant treatment interfering with the systemic exposure of the patients. statins or for certain subjects with a phenotype associated with a reduction in hepatic transporter activity leading to an increase in plasma exposure to the product and its metabolites. Similarly, the effects observed on liver enzymes are less marked with proATV compared to equimolar dose ATV. Hepatic deleterious effects are generally dose dependent and the best observed tolerance for proATV is a substantial benefit in patients requiring high dose therapy.

Claims

REVENDICATIONS 1. Promédicament de statine selon la formule générale (I) 1. Statin prodrug according to general formula (I) X R (I) dans laquelle : X R (I) in which: X représente une statine choisie parmi la fluvastatine, la pravastatine, Patorvastatine, la rosuvastatine, la cérivastatine et la pitivastatine, X represents a statin chosen from fluvastatin, pravastatin, atatorvastatin, rosuvastatin, cerivastatin and pitivastatin, R représente un acide gras saturé ou insaturé, linéaire ou ramifié, comprenant de 3 à 12 atomes de carbone, éventuellement substitué par un ou plusieurs groupement hydroxyle, atome d'halogène, et hydrocarbure cyclique comprenant de 3 à 6 atomes de carbone, ou un sel ou stéréoisomère de celui-ci pharmaceutiquement acceptable. R represents a saturated or unsaturated fatty acid, linear or branched, comprising from 3 to 12 carbon atoms, optionally substituted with one or more hydroxyl groups, halogen atom, and cyclic hydrocarbon comprising from 3 to 6 carbon atoms, or salt or stereoisomer thereof pharmaceutically acceptable. 2. Promédicament de statine selon la revendication 3, caractérisé en ce que R représente un acide gras saturé ou insaturé, linéaire ou ramifié comprenant de 3 à 10 atomes de carbone. 2. Statin prodrug according to claim 3, characterized in that R represents a saturated or unsaturated fatty acid, linear or branched comprising from 3 to 10 carbon atoms. 3. Promédicament de statine selon la revendication 1 ou 2 caractérisé en ce que R représente un acide gras saturé ou insaturé, linéaire ou ramifié comprenant de 3 à 8 atomes de carbone. 3. A statin prodrug according to claim 1 or 2 characterized in that R represents a saturated or unsaturated fatty acid, linear or branched comprising from 3 to 8 carbon atoms. 4. Promédicament de statine caractérisé en ce qu'il est l'ester propanoïque, propaénoïque, butanoïque, butanénoïque, pentanoïque, pentaénoïque, hexanoïque, hexaénoïque, heptanoïque ou heptaénoïque de la fluvastatine, la pravastatine, Patorvastatine, la rosuvastatine, la cérivastatine et la pitivastatine, ou son sel ou stéréoisomère pharmaceutiquement acceptable. 4. A statin prodrug characterized in that it is the propanoic, propaenoic, butanoic, butanenoic, pentanoic, pentaenoic, hexanoic, hexaenoic, heptanoic or heptaenoic ester of fluvastatin, pravastatin, atatorvastatin, rosuvastatin, cerivastatin and pitivastatin, or its pharmaceutically acceptable salt or stereoisomer. 5. Promédicament de statine selon la revendication 4, caractérisé en ce qu'il est l'ester pentaénoïque en C3 et C4 de la fluvastatine, la pravastatine, Patorvastatine, la rosuvastatine, la cérivastatine et la pitivastatine. 5. A statin prodrug according to claim 4, characterized in that it is the C 3 and C 4 pentaenoic ester of fluvastatin, pravastatin, atatorvastatin, rosuvastatin, cerivastatin and pitivastatin. 6. Promédicament de statine selon la revendication 5, caractérisé en ce qu'il est l'ester pentaénoïque en C3 et C4 de l'atorvastatine. 6. A statin prodrug according to claim 5, characterized in that it is the pentaenoic ester C 3 and C 4 of atorvastatin. 7. Promédicament de statine selon la revendication 4, caractérisé en ce qu'il est l'ester butanoïque de l'atorvastatine. 7. A statin prodrug according to claim 4, characterized in that it is the butanoic ester of atorvastatin. 8. Composition pharmaceutique caractérisée en ce qu'elle contient au moins un promédicament selon l'une quelconque des revendications 1 à 7, associé à un véhicule approprié. 8. Pharmaceutical composition characterized in that it contains at least one prodrug according to any one of claims 1 to 7, associated with a suitable vehicle. 9. Composition pharmaceutique selon la revendication 8, caractérisée en ce qu'elle est appropriée pour l'administration orale. 9. Pharmaceutical composition according to claim 8, characterized in that it is suitable for oral administration. 10. Utilisation d'un promédicament selon les revendications 1 à 7 ou d'une composition pharmaceutique selon les revendications 8 et 9 dans la préparation d'un médicament pour le traitement ou la prévention de diverses maladies pour lesquelles le site d'action du médicament est situé au niveau du foie. Use of a prodrug according to claims 1 to 7 or a pharmaceutical composition according to claims 8 and 9 in the preparation of a medicament for the treatment or prevention of various diseases for which the site of action of the medicament is located at the level of the liver. 11. Utilisation d'un promédicament ou d'une composition pharmaceutique selon la revendication 10 dans la préparation d'un médicament pour le traitement ou la prévention de diverses maladies qui sont dues à un taux de cholestérol excessif dans le sang, notamment le risque de survenue ou de récidive de l'infarctus du myocarde, de l'angine de poitrine, de Partériopathie oblitérante des membres inférieurs et de l'accident vasculaire cérébral. Use of a prodrug or pharmaceutical composition according to claim 10 in the preparation of a medicament for the treatment or prevention of various diseases which are due to excessive blood cholesterol, including the risk of occurrence or recurrence of myocardial infarction, angina pectoris, peripheral obliterative artery disease and cerebrovascular accident. 12. Utilisation d'un promédicament ou d'une composition pharmaceutique selon la revendication 10 dans la préparation d'un médicament pour traiter l'insuffisance cardiaque l'insuffisance rénale chronique , les cancers du côlon et du poumon, la réduction des fréquences des fractures lors de l'ostéoporose, la réduction de la progression du diabète, des thromboses veineuses profondes ou phlébites, la démence, la maladie d'Alhzeimer, la sclérose en plaque et les infections. 12. Use of a prodrug or a pharmaceutical composition according to claim 10 in the preparation of a medicament for treating heart failure chronic renal failure, cancers of the colon and lung, reduction of fracture frequencies during osteoporosis, reducing the progression of diabetes, deep vein thromboses or phlebitis, dementia, Alhzeimer's disease, multiple sclerosis and infections.
PCT/FR2012/000008 2011-01-07 2012-01-06 Prodrugs for dispensing a statin to the liver Ceased WO2012093227A1 (en)

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FR1100060A FR2970178B1 (en) 2011-01-07 2011-01-07 PROMOTERS FOR SPECIFIC LIVER LEVEL DELIVERY AND BETTER TOLERANCE
FR11/00060 2011-01-07

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CN115025242B (en) * 2022-05-19 2023-10-20 南开大学 Statin prodrug and statin targeted delivery system as well as preparation methods and applications thereof

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FR2970178B1 (en) 2014-06-20

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