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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • 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
• • 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
• • 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
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to new compounds capable of modulating the activity of LXR nuclear receptors, their manufacturing process and pharmaceutical compositions containing them.
• the “liver X receptor” (LXR) receptors are transcription factors which belong to the super family of nuclear receptors which also include the “retinoic acid receptor” (RXR), “farnesoid X receptor” (FXR) and “peroxisome” receptors. proliferator-activated receptors ”(PPARs).
• the LXR receptors form, by binding to the RXR receptor, a heterodimer which specifically binds to the response elements of DNA (LXRE) to lead to the transactivation of target genes (Genes dev. 1995; 9: 1033-45).
• These receptors are involved in multiple metabolic pathways and participate in particular in the homeostasis of cholesterol, bile acids, triglycerides and glucose.
• the modulation of the activity of these nuclear receptors influences the progression of metabolic disorders such as type II diabetes, dyslipidemias and the development of atherosclerosis.
• LXR / RXR heterodimer can be activated by LXR and / or RXR ligands.
• the transactivation of target genes requires the recruitment of co-activators such as Grip-1. (Nature 1996; 383: 728-31).
• LXR and LXR ⁇ show a high degree of similarity in terms of their amino acid sequence but differ in their tissue distribution.
• LXR ⁇ is strongly expressed in the liver and to a lesser extent in the kidneys, intestine, adipose tissue and spleen.
• LXR ⁇ is distributed ubiquitously (Gene 2000; 243: 93-103, NY Acad. Sci. 1995; 761: 38-49).
• oxysterols mono-oxidized derivatives of cholesterol (oxysterols) do so and more particularly the 22 (R) -hydroxycholesterol, 24 (S) -hydroxycholesterol and 24 (S), 25-epoxycholesterol .
• These oxysterols are considered to be the physiological ligands of the LXR receptors (Nature 1996; 383: 728-31, J.Biol.chem 1997; 272: 3137-40).
• oxysterol 5,6,24 (S), 25-diepoxycholesterol has been shown to be a specific ligand for LXR ⁇ , suggesting that it is possible to develop specific ligands for LXR ⁇ and / or LXR ⁇ ( Proc. Natl.
• LXR ⁇ The high concentrations of LXR ⁇ in the liver and the identification of the endogenous ligands of LXR have suggested that these receptors play an essential role in the metabolism of cholesterol. Under physiological conditions, cholesterol homeostasis is maintained, via the regulation of the de novo synthesis and catabolism pathways. The accumulation of sterols in the liver leads to an inhibition of cholesterol biosynthesis by a feedback mechanism involving transcription factors such as SREBP-1 and SREBP-2. (Cell 1997; 89: 331-40). Excess cholesterol also activates another metabolic pathway that leads to the conversion of cholesterol to bile acids. The conversion of cholesterol to 7 ⁇ -hydroxy-cholesterol is carried out by an enzyme localized in the liver (CYP7A: 7 ⁇ -hydroxylase) (J. Biol. Chem.
• mice deficient in LXR ⁇ which, when subjected to a fatty diet, accumulate large amounts of cholesterol esters in the liver (Cell 1998; 93 693-704).
• Mice deficient in LXR ⁇ have the same physiological resistance as normal mice vis-à-vis a diet enriched in fats.
• the expression of unchanged LXR ⁇ in mice deficient in LXR tends to demonstrate that LXR ⁇ alone is unable to significantly increase the metabolism of cholesterol (J. Clin. Invest. 2001; 107: 565-573).
• the LXR receptors expressed at the macrophage level also play an important role in the regulation of certain functions thereof. They are more particularly involved in controlling the reverse transport of cholesterol which makes it possible to export excess cholesterol from peripheral tissues to the liver. Cholesterol is taken up by pre-bHDL via apoAl and ABCA1 to be transported to the liver where it is catabolized into bile acids and then eliminated. ABCAl is a member of the super family of transport proteins (ATP - binding cassette) whose importance is illustrated by the fact that a mutation in the ABCAl gene is responsible for Tangier disease (Nat Genet. 1999; 22: 336-45).
• LXR agonist ligands have also been shown to reduce atheromatous lesions in two different mouse models (ApoE - / - mice and LDLR - / - mice) (Proc. Natl. Acad. Sci. USA 2002; 99: 7604-7609, FEBS Letters 2003; 536: 6-11). These results suggest that LXR ligands may be therapeutic agents for treating atherosclerosis. Finally, we know that macrophages play an important role in inflammation, in particular in the pathogenesis of atherosclerosis. Activation of LXRs has been shown to inhibit the expression of genes involved in inflammation at the macrophage level.
• LXRs apolipoprotein E
• This protein is widely involved in the hepatic clearance of lipoproteins and promotes the efflux of cholesterol from macrophages rich in lipids.
• LXR receptors Activation of LXR receptors has been shown to lead to increased expression of ApoE via an LXR response element (LXRE) located in the ApoE promoter sequence (Proc. Natl. Acad. Sci. USA 2001; 98: 507-512). Activation of LXR receptors would also promote the reverse transport of cholesterol via the modulation of the expression of the CETP protein (cholesterol ester transfer protein) which is involved in the transfer of esterified cholesterol from HDL lipoproteins to lipoproteins rich in triglycerides eliminated by the liver (J. Clin. Invest. 2000; 105: 513-520). In summary, the activation of LXR receptors leads to an increase in the expression of many genes promoting the elimination of excess cholesterol from peripheral tissues.
• LXRE LXR response element
• LXRs receptors In the cholesterol-laden macrophage, activation of the LXRs receptors increases the expression of ABCAl, ABCGl, I ⁇ BCG5, I ⁇ BCG8 and ApoE leading to an increase in the efflux of cholesterol from macrophages to the liver where it is excreted. in the form of bile acids.
• the induction of the expression of CETP and CYP7A in the liver leads respectively to an increase in the hepatic clearance of the HDL lipoprotein cholesterol esters and to the catabolism of cholesterol.
• LXRs receptors play an important role in glucose metabolism. Treatment of diabetic rodents with an LXR agonist leads to a drastic decrease in plasma glucose levels.
• LXR phosphoenolpyruvate carboxykinase
• LXR receptors are involved in the processes of regulating inflammation (Nature Medicine 20039, 213-219).
• Compounds which modulate the activity of LXR receptors are known in the state of the art, in particular from documents WO 03/090869, WO 03/90746, WO 03/082192 or WO 03/082802; or documents WO 03/043985 and WO 04/005253 which describe compounds of the benzenesulfonamide type PPAR receptor agonists.
• the present invention aims to protect, as a new industrial product, a benzenesulfonamide compound, characterized in that it is chosen from: i) the compounds of formula:
• - (H) represents a saturated 5 or 6-membered nitrogen heterocycle condensed with a phenyl or cyclohexyl ring, optionally substituted by a halogen, an alkoxy group in - or an N (R) 2 group in which R represents the atom of hydrogen or a C ⁇ -C 4 alkyl group,
• - Ri represents: o a chlorine atom, o a C 3 -C 6 alkyl group, branched or cyclized, o a C 2 -C 6 linear, branched or C 3 -C 6 alkoxy group cyclized, o a group phenoxy optionally substituted by a halogen, o a phenyl group, or o an aminomethyl group optionally substituted by an acetyl or trifluoroacetyl group, - R 2 represents a hydrogen atom or a halogen, or,
• Ri and R 2 together form an oxygenated or nitrogen heterocycle, optionally substituted by one or more C ⁇ -C 3 alkyl groups, by an acyl group or by a C 2 -C 3 perfluoroacyl group,
• - Y represents: o a single bond, o an alkylene group C ⁇ -C 4 , linear or branched or C 3 -C 4 cyclized, optionally substituted by an alkoxy group - C 3 , a phenyl group, a group N ( R) 2 or a COOH group, o a group - (CH 2 ) n -O-, o a group - (CH 2 ) n -S-, or o a group - (CH 2 ) m -CO-, n est equal to 2 or 3, m is equal to 1, 2 or 3,
• R represents the hydrogen atom or a C ⁇ -C 4 alkyl group
• - Ar represents an aromatic or heteroaromatic ring chosen from phenyl, naphthalenyl, tetrahydronaphthalenyl, pyridinyl or indolyl groups, optionally substituted with one or two identical or different substituents R 3 , R 4 chosen from a halogen, a CC 4 alkyl group, C ⁇ -C 4 alkoxy, nitro, phenyl, phenoxy, trifluoromethyl, amino, hydroxy, or a group of formula -X- [C (R) 2 ] p -COR 5 in which: o X represents a single bond, an oxygen atom, a sulfur atom or an NH group, o R 5 represents OR or N (R) 2 , o R represents the hydrogen atom or a C ⁇ -C 4 alkyl group, op is equal to 0, 1 or 2; said substituents R 3 and R 4 possibly
• the invention relates to the abovementioned compounds for their use as a pharmacologically active substance.
• the invention relates to the use of at least one compound of formula (I) or one of its pharmaceutically acceptable salts as active principle for the preparation of a medicament intended for use in therapy, in particular to fight against hypercholesterolaemia, dyslipidemia, diabetes, obesity as well as cardiovascular diseases which are the consequence of an imbalance of serum lipoproteins.
• the compounds of formula I according to the invention find their utility for correcting the drift of the parameters which herald a metabolic syndrome.
• the compounds according to the invention are also useful as active principles of medicaments intended for preventing or treating atherosclerosis, myocardial infarction, certain inflammatory diseases such as for example dermatitis, and neurodegenerations such as for example Alzheimer's disease.
• Alkyl group means C 3 -C ⁇ branched or cyclized, a hydrocarbon chain having from 3 to 6 carbon atoms, branched or cyclic, for example and without limitation, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 1-methylbutyl, 1,1-dimethylpropyl, 1-methylpentyl, 1,1-dimethylbutyIe, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopentylmethyl.
• C ⁇ -C 4 alkyl group is understood to mean a hydrocarbon chain having from 1 to 4 carbon atoms, linear or branched, or alternatively cyclic having 3 or 4 carbon atoms.
• Examples of C ⁇ -C 4 alkyl groups include methyl, ethyl, propyl, butyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, cyclopropyl, methylcyclopropyl or cyclopropylmethyl groups.
• linear, branched or cyclic C 2 -C 6 alkoxy group is understood to mean in particular the ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, 1-methylethoxy, 1-ethylethoxy or cylohexyloxy groups.
• linear or branched CrC 4 alkoxy group is meant in particular the methoxy, ethoxy, propoxy, butoxy, 1- methylethoxy, 1-ethylethoxy, 1- or 2-methylpropoxy groups.
• linear or branched Qr alkylene group is understood to mean a disubstituted saturated chain comprising 1 to 4 carbon atoms, for example the groups -CH 2 -, - (CH 2 ) 2 -, - (CH 2 ) 3 -, - CH (CH 3 ) -CH 2 -, or -CH 2 -CH (CH 3 ) -CH 2 -.
• Halogen is understood to mean a fluorine, chlorine, bromine or iodine atom, fluorine and chlorine atoms being preferred.
• the compounds according to the invention comprise an asymmetric carbon (carrying the carboxamide function) which can be either racemic, or of R configuration or, preferably, of S configuration (FIG. 1a)
• the compounds according to the invention can be prepared according to a process using the steps consisting in: a) reacting an acid of formula
• (H) represents a 5 or 6-membered saturated nitrogen heterocycle condensed with a phenyl or cyclohexyl ring, optionally substituted by a halogen or an alkoxy group in -, or an N (R) 2 group in which R represents the atom of hydrogen or a CC 4 alkyl group, with an amine of formula
• Y represents: o a single bond, o a CC 4 alkylene group, linear or branched or C 3 -C 4 cyclized, optionally substituted by an alkoxy group C ⁇ -C 3 , a phenyl group, an amino group protected by a aminoprotective group (different from Boc) or a group N (R) 2 , in which R represents the hydrogen atom or a C ⁇ -C alkyl group, o a group - (CH 2 ) n -O-, o a group - (CH 2 ) n -S-, or o a group - (CH 2 ) m -CO-, n is equal to 2 or 3, m is equal to 1, 2 or 3, Ar represents an aromatic or heteroaromatic nucleus chosen from phenyl, naphthalenyl, tetrahydronaphthalenyl, pyridinyl or indolyl groups, optionally substituted with one or two substituents R 3 ,
• Ri represents a chlorine atom, a branched or cyclized C 3 -C 6 alkyl group, a linear, branched or cyclized C 2 -C 6 alkoxy group, a phenoxy group optionally substituted by a halogen, a phenyl group, an aminomethyl group optionally substituted by an acetyl or trifluoroacetyl group,
• R 2 represents a hydrogen atom or a halogen, or
• the compounds of formula I according to the invention can be obtained according to a process consisting in a) reacting a benzenesulfonyl chloride of formula VI
• - Ri represents a chlorine atom, a branched or cyclized C 3 -C 6 alkyl group, a branched or cyclized linear C 2 -C 6 alkoxy group, a phenoxy group optionally substituted by a halogen, a phenyl group , or an aminomethyl group substituted by an acetyl or trifluoroacetyl group
• - R 2 represents a hydrogen atom or a halogen
• - Ri and R 2 together form an oxygenated or nitrogenous heterocycle, optionally substituted by one or more C ⁇ alkyl groups -C 3 , by an acyl group or by a C 2 -C 3 perfluoroacyl group, with an ester of formula VII
• (H) represents a 5 or 6-membered saturated nitrogen heterocycle condensed with a phenyl or cyclohexyl ring, optionally substituted by a halogen or a C ⁇ -C 4 alkoxy group, in an anhydrous solvent such as, for example, dichloromethane, room temperature and for 2 to 10 hours to obtain the compound of formula VIII
• Y represents: o a single bond, o a linear, branched or branched C 3 -C 4 alkylene group, optionally substituted by a C 3 alkoxy group, a phenyl group , a group N (R) 2 or a group COOH, o a group - (CH 2 ) n -O-, o a group - (CH 2 ) n -S-, or o a group - (CH 2 ) m - CO-, n is 2 or 3; m is 1, 2 or 3; R represents the hydrogen atom or a C ⁇ -C 4 alkyl group,
• Ar represents an aromatic or heteroaromatic nucleus chosen from phenyl, naphthalenyl, tetrahydronaphthalenyl, pyridinyl or indolyl groups, optionally substituted by one or two identical or different substituents R 3 , R 4 chosen from a halogen, a C ⁇ -C 4 alkyl group, C 4 -C 4 alkoxy, nitro, phenyl, phenoxy, trifluoromethyl, hydroxy, N (R) 2 , an amino group protected by an aminoprotective group, or a group of formula -X- [C (R) 2 ] p -COR 5 in which: o X represents a single bond, an oxygen atom or a sulfur atom, o R 5 represents OH, OR or N (R) 2 , where R represents a CC 4 alkyl group, op is equal to 0, 1 or 2; said substituents R 3 and R 4 being able, moreover, to form together a
• Example 1 l - [[4- (1,1-dimethylethyl) phenyl] sulfonyl] -N- (2-phenylethyl) -l, 2,3,4-tetrahydro-2-quinolinylcarboxamide 150 mg (0.20 mmol) is conditioned ) of PS-carbodiimide resin (polystyrene resin functionalized with a carbodiimide group supplied by the company Argonaut Technologies) in 5 ml of dichloromethane for 30 min then the solvent is removed by filtration.
• PS-carbodiimide resin polystyrene resin functionalized with a carbodiimide group supplied by the company Argonaut Technologies
• the resin is rinsed with 4 ml of dichloromethane, then 50 mg (0.134 mmol) of the acid obtained according to preparation II is added in solution in 5 ml of dichloromethane, 25 ⁇ l (0.2 mmol) of 2-phenylethanamine and 5 mg of HOAT.
• This reaction mixture is stirred at room temperature for 18 hours, then 200 mg of IR120 resin is added and the reaction mixture is again stirred for 3 hours at room temperature.
• the liquid phase of the mixture is separated by filtration and concentrated under reduced pressure.
• the crude product is purified by chromatography on silica gel, eluting with the aid of a methylcyclohexane / ethyl acetate mixture (70/30; v / v).
• the resin is rinsed several times with 4 ml of dichloromethane, then a solution of 100 mg (0.278 mmol) of acid obtained according to preparation IV and 25.4 mg (0.185 mmol) of 2-phenoxyethanamine in solution in 6 ml of dichloromethane.
• the mixture is stirred for 20 hours at room temperature and 0.278 mmol of isocyanate resin is added.
• the mixture is stirred for 2 hours at room temperature and 0.278 mmol of Amberlite IRA 400 resin is added. mix again for 2 hours then remove the resins by filtration. The filtrate is then concentrated under reduced pressure.
• Example 3 1 - [[4- (1,1-dimethylethyl) phenyl] sulfonyl] -2,3-dihydro-N- [2- (4-nitro-phenyl) ethyl] - 2S-.
• Example 7 1 - [[4- (1,1-dimethylethyl) phenyl] sulfonyl] -2,3-dihydro-N- [2- (2-methylphenyl) ethyl] -2S- J ? / -Indole-2 carboxamide
• NC ⁇ CO 3.35 (m, 2H, CMNCO), 3.02 (dd, IH, CMCHCO), 2.81 (dd, IH,
• Example 41 1 - [[4- (1,1-dimethylethyl) phenyl] sulfonyl] -2,3-dihydro-N- [2- (4-aminophenyl) ethyl] -2S -.? Mindole-2-carboxamide
• a solution of 100 mg (0.278 mmol) of the acid obtained according to preparation IV is prepared in 4 ml of dichloromethane and 4 ml of THF and then 64 mg (0.334 mmol) of EDCI (1- (3-dimethylaminopropyl hydrochloride) is added.
• EDCI 1- (3-dimethylaminopropyl hydrochloride
• the crude product obtained is then purified by chromatography on silica gel, eluting with the aid of a dichloromethane / ethyl acetate mixture (95/5 then 90/10; v / v).
• Example 42 [[4- (1,1-dimethylethyl) phenyl] sulfonyl] -2,3-dihydro-N- [2- (4-hydroxyphenyl) ethyl] -2S- Mindole-2-carboxamide
• a solution is prepared 100 mg (0.278 mmol) of the acid obtained according to preparation IV in 4 ml of dichloromethane and 4 ml of THF and then 64 mg (0.334 mmol) of EDCI (1- (3-dimethylaminopropyl) hydrochloride) are added ethylcarbodiimide) and 7.8 mg (0.028 mmol) HOAT.
• EXAMPLE 43 1 - [[4- (1-methylethyl) phenyl] sulfonyl] -2,3-dihydro-N- (2-phenylethyl) -2S-iM indole-2-carboxamide 96 mg (0.38 mmol) is conditioned morpholine resin (Resin morpholinomethyl PS-HL 2% DVB Novabiochem) in 3 ml of dichloromethane.
• Example 50 l - [[4- (1,1-dimethyethyl) ⁇ henyl] sulfonyl] -2,3-dihydro-N- (2-phenyl-ethyl) - (2S) - _? Mindole-2-carboxamide
• a mixture of 144 mg (0.39 mmol) of the compound obtained according to preparation VIII and of 0.5 g of IRA400 resin in 2 ml of dichloromethane is prepared and this mixture is kept under stirring at room temperature for 3 hours. The resin is then removed by filtration and the filtrate is added to a suspension of 202 mg (0.787 mmol) of morpholine resin previously conditioned in 3 ml of dichloromethane.
• Example 54 Acid 4- [2 - [[[(2S) -1 - [[4- (1,1-dimethylethyl) phenyl] sulfonyl] -2,3-dihydro-1H- indol-2-yl] carbonyl] amino ] ethoxy] benzeneacetic, methyl ester
• a solution of 100 mg (0.278 mmol) of the acid obtained according to preparation IV in 4 ml of dichloromethane is prepared and 59 mg (0.306 mmol) of EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) are added. ) and 2.8 mg (0.028 mmol) of HOAT.
• the medium is then treated by adding 20 ml of water and then extracted 3 times with 50 ml of dichloromethane.
• the organic phases are then combined and washed 3 times with 50 ml of water, then dried over magnesium sulfate, and concentrated under reduced pressure.
• the crude product obtained is then purified by chromatography on silica gel, eluting with the aid of a dichloromethane / ethanol mixture (95/5; v / v).
• a solution of 132 mg (1.27 mmol) of / V, / V-dimethyl-4- (2-aminoethoxy) benzeneethanamine, bis trifluoroacetate in 10 ml of dichloromethane is prepared, 200 mg (0.529 mmol) of the product obtained according to preparation XIX and 402 mg (3.96 mmol) of triethylamine.
• the mixture is stirred for 16 hours at room temperature. Water is added to the reaction medium, then extraction is carried out with dichloromethane. The organic phase is dried over magnesium sulfate and the solvents are evaporated.
• the crude product is purified a first time by chromatography on silica gel, eluting with a toluene / ethanol / ammonia mixture (8/2 / 0.1; v / v / v), then a second time by reverse phase chromatography, eluting with an acetonitrile / water / trifluoroacetic acid mixture (volumetric gradient from 20/80/1 to 80/20/1).
• the expected product is obtained in the form of a colorless oil with a yield of 26%.
• reaction medium is washed with water, dried over magnesium sulfate, the solvents are evaporated and the evaporation residue is purified by chromatography on a silica column, eluting with the aid of a toluene / acetate mixture. ethyl (8/2; v / v).
• the expected product is obtained in the form of a white solid with a yield of 51%. Mp 94 ° C.
• Example 67 l - [[4- (1,1-dimethylethyl) phenyl] sulfonyl] - ⁇ t - [(4-chlorophenyl) methyl] -2,3- dihydro- (25) -lMindole-2-carboxamide
• Example 69
• Example 70 Acid 4 - [[[[(2S) -1 - [[4- (1,1-dimethylethyl) phenyl] sulfonyl] -2,3-dihydro-1Mindol-2-yl] carbonyl] amino] methyl] benzenepropanoic acid , methyl ester
• the reaction medium is taken up in 10 ml of dichloromethane, and washed with water.
• the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure.
• the evaporation residue is purified by chromatography on a silica column, eluting with the aid of a dichloromethane / methanol mixture (95/5; v / v).
• the expected product is obtained in the form of a white solid with a yield of 21%.
• Example 80 Acid 4- [2 - [[[(2S) -l - [(3,4-dihydro-2,2-dimethyl-2Ml-benzopyran-6-yl) sulfonyl] - 2,3-dihydro-1Mindol- 2-yl] carbonyl] amino] ethoxy] benzeneacetic
• Example 82 3-Chloro-4 acid - [[2 - [[[(2S) -1 - [[4- (1,1-dimethylethyl) phenyl) sulfonyl] -2,3-dihydro-1Mindol-2-yl] carbonyl] amino] ethyl] thio] benzeneacetic
• the oily residue is purified by chromatography on silica gel, eluting with the aid of a cyclohexane / ethyl acetate mixture (85/15; v / v).
• the expected product is thus obtained in the form of a gray powder with a yield of 38%.
• Example 93 Acid 4- [2 - [[[((25) -1 - [[4- (1,1-dimethylethoxy) phenyl] sulfonyl] -2,3-dihydro-1M indol-2-yl] carbonyl] amino] ethoxy] benzeneacetic, methyl ester
• the expected product is obtained under form of a light yellow solid with a yield of 50%.
• the COS7 cell transactivation test developed here aims to evaluate the effect of compounds on the activity of human LXRs: it makes it possible to validate the interaction of the compounds with the LXRs and to determine the interaction .C50. This test is based on the use of chimeric proteins “Gal4-LXR” containing the LBD of LXR (human LXR ⁇ or human LXR ⁇ ) fused with the DBD of Gal4.
• COS7 cells are thus trans-transfected with: - an expression vector coding for the chimeric protein “Gal4 (DBD) - LXR ⁇ (LBD)” or an expression vector coding for the chimera “Gal4 (DBD) - LXR ⁇ (LBD) " - A reporter vector comprising the Gal4-RE response element (Gal4-Response Element) recognizing the DB4 of Gal4, and located in front of the minimal promoter P T ⁇ which controls the luciferase gene.
• the luciferase activity thus produced generates luminescence in the presence of an excess of substrate, a quantifiable data which reflects the interaction of the compound with the LBD of the LXR.
• the compounds according to the invention are evaluated with respect to a reference compound (T-0901317, CAS RN: 293754-55-9). According to this test, the compounds according to the invention have an EC 50 of less than 1 ⁇ M.
• the biological properties of the compounds according to the invention demonstrate their potential interest and their usefulness for their application as active substances of medicaments intended for the treatment or the prevention of diseases dependent on a deregulation of the functions of the LXR ⁇ and LXR ⁇ receptors, including hypercholesterolemies, dyslipidemias, as well as obesity, diabetes, cardiovascular disease, certain neurodegenerations and inflammatory diseases.
• the compounds according to the invention are also of therapeutic interest when it is necessary to correct the drift of the parameters which herald a metabolic syndrome.
• the compounds according to the invention can be used alone or in combination with known treatments for diabetes such as, for example, metformin, sulfonylureas, acarbose, PPAR ⁇ activators, insulin or in combination with GLP-1 (Glucagon-like Peptide) analogues, DPP-IV inhibitors, PPARoc / ⁇ , PPAR ⁇ / ⁇ , PPAR ⁇ , panPPAR, ll ⁇ -HSDl (ll beta hydroxysteroid dehydrogenase) inhibitors, inhibitors of PTP-1B (Protein Tyrosin Phosphatase), CB1 (Cannabinoid) receptor antagonists, glucagon receptor antagonists, PDK (Pyruvate Dehydrogenase Kinase) inhibitors, Glucokinase Hepatic activators and GSK-3 (Glycogen Synthase inhibitors) kinase).
• GLP-1 Glucagon-like Peptide
• the invention also relates to pharmaceutical compositions intended for the prevention or treatment of the diseases mentioned above when they contain as active principle at least one of the compounds of formula I according to the invention.
• These pharmaceutical compositions use conventional formulations comprising pharmaceutically acceptable excipients in order to obtain forms which can be administered orally, for example tablets or capsules.
• the daily dosage in humans will preferably be between 5 and 500 mg.

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• 2004
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