WO2007081335A1 - Composes therapeutiques pour traiter des troubles dyslipidemiques - Google Patents

Composes therapeutiques pour traiter des troubles dyslipidemiques Download PDF

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Publication number
WO2007081335A1
WO2007081335A1 PCT/US2006/001071 US2006001071W WO2007081335A1 WO 2007081335 A1 WO2007081335 A1 WO 2007081335A1 US 2006001071 W US2006001071 W US 2006001071W WO 2007081335 A1 WO2007081335 A1 WO 2007081335A1
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Prior art keywords
propyl
benzisoxazol
trifluoromethyl
oxy
mmol
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PCT/US2006/001071
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English (en)
Inventor
Alan D. Adams
Shaei Y. Huang
Jason W. Szewczyk
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Merck & Co., Inc.
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Priority to PCT/US2006/001071 priority Critical patent/WO2007081335A1/fr
Publication of WO2007081335A1 publication Critical patent/WO2007081335A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • LXR ⁇ is a nuclear receptor that is required for the induction of cholesterol 7 ⁇ -hydroxylase in mouse liver following cholesterol feeding (Peet et al., Cell, 93, 693-704 (1998)).
  • LXR ⁇ (NR1H3) (for a unified system of nomenclature for the nuclear receptor superfamily see Cell 97, 161-163, 1999) and LXR ⁇ (NR1H2) are activated by 22-(R)-hydroxycholesterol and other oxysterols (Janowski et al. Proc. Natl. Acad.
  • LXR ⁇ and/or LXR ⁇ cause the induction or regulation of ABCAl expression
  • small molecule ligands of LXR are useful as drugs to increase the expression of ABCAl, increase levels of HDL and thereby decrease the risk of atherosclerosis, myocardial infarction and related conditions such as peripheral vascular disease and ischemic stroke.
  • statins which are HMG-CoA reductase inhibitors
  • bile acid sequestrants e.g., cholestyramine and colestipol
  • nicotinic acid niacin
  • statin class of drugs is used to modulate LDL and, to a lesser extent, HDL and triglycerides.
  • Conditions principally characterized by elevated plasma triglycerides and low HDL are frequently treated with drugs belonging to the f ⁇ brate class.
  • the fibrates are PPAR alpha agonists that lower triglycerides and raise HDL in many instances.
  • LXR ligands i.e., LXR ⁇ and/or LXR ⁇ ligands
  • LXR ⁇ and/or LXR ⁇ ligands LXR ligands
  • the instant compounds have been shown to raise plasma levels of HDL in animal models and to increase cholesterol efflux from cells in vitro. These biological activities are critical for reverse cholesterol transport.
  • novel compounds of this invention are intended as a treatment for dyslipidemias, especially low plasma HDL cholesterol levels, as well as for treatment and/or prevention of lipid accumulation in atherosclerotic plaques, which is an underlying cause or aggravating factor in atherosclerosis.
  • novel LXR ligands of the instant invention are compounds having Formula I
  • Y has one of the following structures:
  • R 1 is selected from -H, halogen, -C i -Cgalkyl and -OCi -Cgalkyl, wherein -C l -C6alkyl and -OCi-C ⁇ alkyl are each optionally substituted with 1-3 halogens;
  • R6 is Ci-C4alkyl; or alternatively Y and R ⁇ taken together form a bicyclic heterocyclic ring selected from the following group:
  • Z is a difunctional connecting moiety selected from the group consisting of Q-
  • R3 is -C1-C6 alkyl, which is optionally substituted with 1-3 halogens;
  • R2 is selected from the group consisting of H and Ci-C4alkyl
  • R5 is selected from the group consisting of H, halogen, Ci-Csalkyl, and -OCi-Csalkyl; and R7 is-Ci-Cg alkyl, which is optionally substituted with 1-3 halogens.
  • alkyl groups can be either linear or branched, unless otherwise stated.
  • Compounds of Formula I are novel LXR ligands and are useful in the treatment of dyslipidemic conditions such as low levels of HDL cholesterol.
  • One object of the instant invention is to provide a method for treating depressed plasma HDL cholesterol levels comprising administering a therapeutically effective amount of a compound of Formula I to a patient in need of such treatment.
  • Another object is to provide a method for preventing or treating dyslipidemic conditions comprising administering a prophylactically or therapeutically effective amount, as appropriate, of a compound of Formula I to a patient in need of such treatment.
  • methods for preventing or reducing the risk of developing atherosclerosis, as well as for halting or slowing the progression of atherosclerotic disease once it has become clinically evident, comprising the administration of a prophylactically or therapeutically effective amount, as appropriate, of a compound of Formula I to a patient who is at risk of developing atherosclerosis or who already has atherosclerotic disease.
  • the method of this invention also serves to remove cholesterol from tissue deposits such as xanthomas and atherosclerotic lesions by hastening the efflux of cholesterol from cells in those lesions.
  • Another object of the present invention is the use of the compounds of the present invention for the manufacture of a medicament useful in treating, preventing or reducing the risk of developing these conditions.
  • R 1 is selected from the group consisting of -H, halogen, -CH3, -CF3, -OCH3, and -OCF3;
  • R 6 is Ci-C4alkyl
  • Z is -Ci-CsalkyleneO- , wherein the O of -Ci-CsalkyleneO- is connected to the benzisoxazole ring in Formula I;
  • R 3 is -C1-C6 alkyl, which is optionally substituted with 1-3 halogens;
  • R5 is selected from the group consisting of H, halogen, -CH3, and -OCH3;
  • R? is -Ci-Cg alkyl, which is optionally substituted with 1-3 halogens.
  • R 1 is selected from the group consisting of -H, halogen, -CH3, -CF3, -OCH3, and -OCF3;
  • R 6 is CH3
  • Z is -CH2CH2CH2O- , wherein the -O- of -CH2CH2CH2O- is connected to the benzisoxazole ring in Formula I;
  • R3 is -CF3;
  • R5 is selected from the group consisting of H, halogen, -CH3, and -OCH3; and R7 is -CH2CH2CH3.
  • R 6 is Ci-C4alkyl
  • Z is -Ci-C3alkyleneO- , wherein the O of -C ⁇ -C3alkyleneO- is connected to the benzisoxazole ring in Formula I;
  • R3 is -C1-C6 alkyl, which is optionally substituted with 1-3 halogens
  • R4 is selected from the group consisting of-CO2R2 and -Ci_C4alkylCO2R2
  • R2 is selected from the group consisting of H and Ci-C4alkyl
  • R7 is -C1-C6 alkyl, which is optionally substituted with 1-3 halogens.
  • R 6 is CH3
  • Z is -CH2CH2CH2O- , wherein the -O- of -CH2CH2CH2O- is connected to the benzisoxazole ring in Formula I;
  • R3 is -CF3;
  • R4 is selected from the group consisting of-CO2H and -Ci_C4alkylCO2H; and R7 is -CH2CH2CH3.
  • inventions comprise compounds having Formula I, including pharmaceutically acceptable salts, esters and tautomers thereof, in which Y and R ⁇ taken together form a bicyclic heterocyclic ring which has one of the following structures:
  • Z is a difunctional connecting moiety selected from the group consisting of Ci- C4alkylene and -Ci-C ⁇ alkyleneO- , wherein the O of -Ci-CsalkyleneO- is connected to the benzisoxazole ring in Formula I;
  • IIS is -Ci-Cg alkyl, which is optionally substituted with 1-3 halogens;
  • R.4 is selected from the group consisting of -CO2R.2 and -CiX ⁇ alkylCC ⁇ R ⁇ ;
  • R2 is selected from the group consisting of H and Ci-C4alkyl
  • R5 is selected from the group consisting of H, halogen, -CH3, and -OCH3;
  • R7 is-Ci-C6 alkyl, which is optionally substituted with 1-3 halogens.
  • Z is -CH2CH2CH2O- , wherein the -O- of -CH2CH2CH2O- is connected to the benzisoxazole ring in Formula I;
  • R3 is -CF3;
  • R4 is selected from the group consisting of-CO2H and -Ci_C4alkylCO2H;
  • R5 is selected from the group consisting of H, halogen, -CH3, and -OCH3; and
  • R7 is -CH2CH2CH3.
  • R4 is -CO2H or-CH2CO2H.
  • R3 is CF3 or -CH2C(CH3)3.
  • R3 is CF3.
  • R2 is H.
  • R? is n-C3H7.
  • alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), n-propyl (Pr), n-butyl (Bu), n-pentyl, n-hexyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), secbutyl (s-Bu), tertbutyl (t-Bu), isopentyl, isohexyl and the like.
  • C h alky refers to branched- and straight-chain saturated aliphatic hydrocarbon groups having 1-6 carbon atoms.
  • alkylene means that an alkyl moiety is a difunctional alkyl moiety.
  • alkylene means that an alkyl moiety is a difunctional alkyl moiety.
  • C3alkyleneO- means a difunctional moiety, where one point of attachment is a carbon of the alkylene and the other point of attachment is the oxygen.
  • Alkylene groups can be linear or branched, unless otherwise specified.
  • C2-6alkenyl refers to a straight or branched 2-6 carbon chain with at least one carbon-carbon double bond.
  • alkenyl include, but are not limited to, vinyl, allyl, isopropenyl, pentenyl, hexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
  • C3-6cycloalkyl means a monocyclic saturated carbocyclic ring, having from 3 to 6 carbon atoms, wherein one carbocyclic ring carbon is the point of attachment.
  • Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • halo and “halogen” are meant to include fluoro, chloro, bromo and iodo, unless otherwise noted. Fluoro and chloro are preferred.
  • pharmaceutically acceptable salts shall mean non-toxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base, particularly those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well as those salts formed from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, 1-p- chlorobenzyl-2-pyrrolidine-r-yl-methylbenzimidazole, diethylamine, piperazine,
  • esters examples include, but are not limited to, -Ci_4 alkyl and -C 1-4 alkyl substituted with phenyl-, dimethylamino-, and acetylamino.
  • “Ci .4 alkyl” herein includes straight or branched aliphatic chains containing from 1 to 4 carbon atoms, for example methyl, ethyl, n- propyl, n-butyl, ⁇ -propyl, sec-butyl and tert-butyl.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids are particularly preferred.
  • unsubstituted, mono- or disubstituted with a substituent independently selected at each occurrence from the group consisting of and "unsubstituted, mono- or polysubstituted with a substituent independently selected at each occurrence from the group consisting of are intended to mean that the total number of substituents on the moiety overall may be zero, one or more than one, and that each carbon and nitrogen atom available for substitution in the given moiety may independently be unsubstituted or mono- or poly- substituted, with one or more substituents that are the same or different at each occurrence and which result in the creation of a stable structure.
  • poly-substituted is intended to mean two or more substituents, e.g. di-, tri-, terra-, penta- substitution and higher as appropriate, valence and stability permitting.
  • tautomers embraces the standard meaning of the term, i.e. a type of isomerism in which two or more isomers are rapidly interconverted so that they ordinarily exist together in equilibrium. Tautomers include, e.g., compounds that undergo facile proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers of the compounds of Formula I, as well as mixtures thereof, are included in the scope of this invention. By way of illustration, tautomers included in this definition include, but are not limited to:
  • racemic mixture means racemic mixture, which is defined as a mixture comprised of equal amounts of enantiomers.
  • racemic mixtures of compounds of Formula I may be separated by the coupling of a racemic mixture of the compounds of Formula I to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage and removal of the added chiral residue.
  • racemic mixture of the compounds of Formula I can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • any enantiomer of a compound of the general Formula I may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration. Such methods are well known in the art.
  • crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
  • Benzisoxazole intermediates may be prepared from commercially available or readily accessible resorcinols as shown in Scheme 1 or alternate synthetic pathways as reported in the literature. See for example: Shutske, G. M. et al. J. Med. Chem., 25 (1), 36, (1982); Poissonnet, G. Synth. Commun., 27 (22), 3839-3846, (1997); Crabbe, P. Villarino, A. Muchowski, J. M. J. Chem. Soc, Perkin Trans 1, 1973, 2220. SCHEME 1
  • these phenolic benzisoxazoles (3) may be converted to intermediate halo-alkyl or amino-alkyl reagents for condensation with a variety of nucleophiles or electrophiles as shown in SCHEME 2 below. Formation of the secondary amine 7 typically occurs in the presence of a large excess of the amine partner. Coupling with a completely elaborated nucleophilic amine reagent with the desired R residues can lead directly to the desired compounds such as compound 6. Some nucleophilic partners may contain other protected functionality which will need to be elaborated, or some, such as an ester, will be de-protected in a final step.
  • amino-aryl reagent for cases where the amino-aryl reagent is not readily available, many classes of amino-aryl can be prepared by displacement of a halogen catalyzed by base or transition metal catalyst as for compound 9. The most favorable cases for this route are typified by the ortho-haloazaheterocycles as shown for compound 8 in SCHEME 2.
  • a coupling partner may be used which carries a substituent which is used to construct the appended ring after coupling the partners, as in compound 12.
  • R 1 - R 6 are as desired for the analog of interest
  • X, Y and Z may be carbon or nitrogen atoms. Carbon atoms may be substituted as described in the examples.
  • T is a tether consisting of 2 or more carbon atoms.
  • the instant invention provides methods for treating lipid disorders, particularly for treating below-desired plasma HDL cholesterol levels, as well as for treating and/or reducing the risk for diseases and conditions affected by LXR activity, comprising administering a therapeutically effective amount of a compound of Formula I to a person in need of such treatment.
  • Any patient having a depressed plasma HDL cholesterol level, or desiring to increase their HDL cholesterol level may use this treatment.
  • Particularly suitable patients in need of such treatment are those whose plasma HDL cholesterol level is depressed, i.e., below the clinically desirable level.
  • the clinically desirable HDL cholesterol level is considered to be a minimum of 40 mg/dl in men and about 50 mg/dl or higher in women. NCEP guidelines define 60 mg/dl as a desirable, cardioprotective, HDL level.
  • the method of this invention also serves to prevent lipid accumulation in, or remove lipids from, tissue deposits such as atherosclerotic plaques or xanthomas in a patient with atherosclerotic disease manifested by clinical signs such as angina, claudication, Sons, one that has suffered a myocardial infarction or transient ischemic attack, or one diagnosed by angiography, sonography or MRI.
  • tissue deposits such as atherosclerotic plaques or xanthomas in a patient with atherosclerotic disease manifested by clinical signs such as angina, claudication, Sons, one that has suffered a myocardial infarction or transient ischemic attack, or one diagnosed by angiography, sonography or MRI.
  • a prophylactically or therapeutically effective amount, as appropriate, of a compound of Formula I to a mammal, including a human, who is at risk of developing atherosclerosis or who already has atherosclerotic disease.
  • Atherosclerosis encompasses vascular diseases and conditions that are recognized and understood by physicians practicing in the relevant fields of medicine.
  • Atherosclerotic cardiovascular disease including restenosis following revascularization procedures, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease including multi-infarct dementia, and peripheral vessel disease including erectile dysfunction are all clinical manifestations of atherosclerosis and are therefore encompassed by the terms "atherosclerosis” and "atherosclerotic disease.”
  • a compound of Formula I may be administered to prevent or reduce the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease event, a cerebrovascular event, and/or intermittent claudication.
  • Coronary heart disease (CHD) events are intended to include CHD death, myocardial infarction (i.e., a heart attack), and coronary revascularization procedures.
  • Cerebrovascular events are intended to include ischemic or hemorrhagic stroke (also known as cerebrovascular accidents) and transient ischemic attacks. Intermittent claudication is a clinical manifestation of peripheral vessel disease.
  • the term "atherosclerotic disease event" as used herein is intended to encompass coronary heart disease events, cerebrovascular events, and intermittent claudication. It is intended that persons who have previously experienced one or more non-fatal atherosclerotic disease events are those for whom the potential for recurrence of such an event exists.
  • the instant invention also provides a method for preventing or reducing the risk of a first or subsequent occurrence of an atherosclerotic disease event comprising the administration of a prophylactically effective amount of a compound of Formula I to a patient at risk for such an event.
  • the patient may or may not have atherosclerotic disease at the time of administration, or may be at risk for developing it.
  • Persons to be treated with the instant therapy include those with dyslipidemic conditions including depressed or below-desirable plasma levels of HDL cholesterol, as well as those at risk of developing atherosclerotic disease and of having an atherosclerotic disease event.
  • Standard atherosclerotic disease risk factors are known to the average physician practicing in the relevant fields of medicine. Such known risk factors include but are not limited to hypertension, smoking, diabetes, low levels of high density lipoprotein cholesterol, and a family history of atherosclerotic cardiovascular disease.
  • patient includes mammals, especially humans, who use the instant active agents for the prevention or treatment of a medical condition.
  • Administering of the drug to the patient includes both self-administration and administration to the patient by another person.
  • the patient may be in need of treatment for an existing disease or medical condition, or may desire prophylactic treatment to prevent or reduce the risk for diseases and medical conditions affected by reverse cholesterol transport.
  • terapéuticaally effective amount is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • prophylactically effective amount is intended to mean that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.
  • the dosage amount of a compound of Formula I that a patient receives can be selected so as to achieve the amount of lipid level modification desired, particularly to achieve a desired level of HDL cholesterol.
  • the dosage a patient receives may also be titrated over time in order to reach a target lipid profile.
  • the dosage regimen utilizing a compound of Formula I is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the potency of the compound chosen to be administered; drug combinations; the route of administration; and the renal and hepatic function of the patient. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition.
  • An effective amount of compound for use in the method of this invention is about 0.01 mg/kg to about 30 mg/kg of body weight per day, or about 0.7 mg to about 2100 mg per day for a 70 kg adult patient in single or divided doses per day. More particularly, examples of daily doses of a compound of this invention are 1, 2, 5, 10, 20, 50, 100, 250, 500, and 1000 mg per day, administered as a single dose or in divided doses 2-6 times per day, or in controlled release form. Dosage amounts will vary depending on factors as noted above, including the potency of the particular compound. Although the active drug of the present invention may be administered in divided doses, for example from one to four times daily, a single daily dose of the active drug is preferred.
  • the active drug employed in the instant therapy can be administered in such oral forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Oral formulations are preferred. Administration of the active drug can be via any pharmaceutically acceptable route and in any pharmaceutically acceptable dosage form. This includes the use of oral conventional rapid-release, time controlled-release and delayed-release (such as enteric coated) pharmaceutical dosage forms. Additional suitable pharmaceutical compositions for use with the present invention are known to those of ordinary skill in the pharmaceutical arts; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.
  • the active drug is typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • the active drug component can be combined with a non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methyl cellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, microcrystalline cellulose, sorbitol and other reducing and non-reducing sugars, magnesium stearate, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like.
  • a non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methyl cellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, microcrystalline cellulose, sorbitol and other reducing and non-reducing sugars, magnesium stearate, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium ste
  • suitable binders, lubricants, disintegrating agents (e.g. croscarmellose sodium) and coloring and flavoring agents can also be incorporated into the mixture.
  • Stabilizing agents such as antioxidants, for example butylated hydroxyanisole (BHA), 2,6-di-tert-butyl-4- methylphenol (BHT), propyl gallate, sodium ascorbate, citric acid, calcium metabisulphite, hydroquinone, and 7-hydroxycoumarin, can also be added to stabilize the dosage forms.
  • suitable components include gelatin, sweeteners, natural and synthetic gums such as acacia, tragacanth or alginates, carboxymethylcellulose, polyethylene glycol, waxes and the like. Tablets may also be coated with a film.
  • An example of a tablet formulation comprising a lOOmg dose of a compound of Formula
  • the tablet is made by a direct compression process.
  • a 100 mg potency tablet comprises 100 mg of the the compound, 130 mg of microcrystalline cellulose, 130 mg of mannitol (or 130 mg of dicalcium phosphate), 8 mg of croscarmellose sodium, 8 mg of magnesium stearate and 16 mg of Opadry White (a proprietary coating material made by Colorcon, West Point, PA).
  • the API, microcrystalline cellulose, mannitol (or dicalcium phosphate), and croscarmellose sodium are first blended, and the mixture is then lubricated with magnesium stearate and pressed into tablets. The tablets are then film coated with Opadry White.
  • the active drug can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Active drug may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. Active drug may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • active drug may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • the instant invention also encompasses a process for preparing a pharmaceutical composition comprising combining a compound of Formula I with a pharmaceutically acceptable carrier. Also encompassed is the pharmaceutical composition which is made by combining a compound of Formula I with a pharmaceutically acceptable carrier.
  • any suitable additional active agent or agents may be used in combination with the compound of Formula I in a single dosage formulation, or may be administered to the patient in a separate dosage formulation, which allows for concurrent or sequential administration of the active agents.
  • One or more additional active agents may be administered with a compound of Formula I.
  • the additional active agent or agents can be lipid modifying compounds or agents having other pharmaceutical activities, or agents that have both lipid-modifying effects and other pharmaceutical activities.
  • additional active agents which may be employed include but are not limited to HMG-CoA reductase inhibitors, which include statins in their lactonized or dihydroxy open acid forms and pharmaceutically acceptable salts and esters thereof, including but not limited to lovastatin (see US Patent No.
  • simvastatin see US Patent No. 4,444,784
  • dihydroxy open-acid simvastatin particularly the ammonium or calcium salts thereof
  • pravastatin particularly the sodium salt thereof
  • fluvastatin particularly the sodium salt thereof
  • at ⁇ rvastatin particularly the calcium salt thereof
  • pitavastatin also referred to as NK-104
  • rosuvastatin also known as ZD-4522, (CRESTOR®; see US Patent No. 5,260,440, and Drugs of the Future, 1999, 24(5), pp.
  • HMG-CoA synthase inhibitors include squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors), acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors including selective inhibitors of ACAT-I or ACAT-2 as well as dual inhibitors of ACAT-I and -2; microsomal triglyceride transfer protein (MTP) inhibitors; cholesteryl ester transfer protein (CETP) inhibitors, such as Pfizer's torcetrapib, CP 529,414 (WO/0038722 and EP 818448) and Pharmacia's SC- 744 and SC-795; niacin; probucol; bile acid sequestrants; LDL (low density lipoprotein) receptor inducers; platelet aggregation inhibitors, for example glycoprotein Db/DIa fibrinogen receptor antagonists and
  • Still another type of agent that can be used in combination with the compounds of this invention are cholesterol absorption inhibitors.
  • Cholesterol absorption inhibitors block the movement of cholesterol from the intestinal lumen into enterocytes of the small intestinal wall. This blockade is their primary mode of action in reducing serum cholesterol levels.
  • These compounds are distinct from compounds which reduce serum cholesterol levels primarily by mechanisms of action such as acyl coenzyme A- cholesterol acyl transferase (ACAT) inhibition, inhibition of triglyceride synthesis, MTP inhibition, bile acid sequestration, and transcription modulation such as agonists or antagonists of nuclear hormones.
  • ACAT acyl coenzyme A- cholesterol acyl transferase
  • MTP inhibition inhibition of triglyceride synthesis
  • MTP inhibition inhibition
  • bile acid sequestration bile acid sequestration
  • transcription modulation such as agonists or antagonists of nuclear hormones.
  • Patent 5,767,115 U.S. Patent 6,133,001, U.S. Patent 5,886,171, U.S. Patent 5,856,473, U.S. Patent 5,756,470, U.S. Patent 5,739,321, U.S. Patent 5,919,672, WO 02/066464, WO 00/63703, WO /0060107, WO 00/38725, WO 00/34240, WO 00/20623, WO 97/45406, WO 97/16424, WO 97/16455, and WO 95/08532, the entire contents of all of which are hereby incorporated by reference.
  • An exemplary cholesterol absorption inhibitor is ezetimibe, also known as SCH-58235, which is l-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2- azetidinone, described in U.S. Patent No.'s 5,767,115 and 5,846,966 and shown below as
  • Therapeutically effective amounts of cholesterol absorption inhibitors include dosages of from about 0.01 mg/kg to about 30 mg/kg of body weight per day, preferably about 0.1 mg/kg to about 15 mg/kg.
  • the dosage level is therefore from about 0.7 mg to about 2100 mg of drug per day, e.g. 10, 20, 40, 100 or 200 mg per day, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • This dosage regimen may be adjusted to provide the optimal therapeutic response when the cholesterol absorption inhibitor is used in combination with a compound of the instant invention.
  • a compound of Formula I for the manufacture of a medicament for the treatment, prevention, or reduction in risk of developing a LXR receptor mediated disease.
  • a therapeutically or prophylactically effective amount, as appropriate, of a compound of Formula I can be used for the preparation of a medicament useful for treating lipid disorders, particularly for treating depressed HDL cholesterol levels as well as for treating and/or reducing the risk for diseases and conditions affected by agonism of LXR and affected by reverse cholesterol transport, preventing or reducing the risk of developing atherosclerotic disease, halting or slowing the progression of atherosclerotic disease once it has become clinically manifest, and preventing or reducing the risk of a first or subsequent occurrence of an atherosclerotic disease event.
  • the medicament may be comprised of about 0.7 mg to about 2100 mg of a compound of Formula I, or more particularly about 7 mg to about 1050 mg.
  • the medicament comprised of a compound of Formula I may also be prepared with one or more additional active agents, such as those described supra.
  • LXR includes all subtypes of this receptor, e.g., designated as LXR ⁇ (NR1H3) and LXR ⁇ (NR1H2, Cell 97, 161-163, 1999).
  • the compounds of Formula I are LXR ligands and individually may vary in their selectivity for one or the other of LXR ⁇ and LXR ⁇ , or they may have mixed binding affinity for both LXR ⁇ and LXR ⁇ . More particularly, the tested compounds included within the scope of this invention have an IC 50 less than or equal to 2 ⁇ M for at least one of either the LXR ⁇ or LXR ⁇ receptors employing the LXR radioligand competition scintillation proximity assays described below in the Example section. Preferred tested compounds of Formula I bind to the human LXR ⁇ receptor and have an IC 50 less than or equal to 300 nM for the LXR ⁇ receptor.
  • Compound A is used in the following assays and has the following structural formula:
  • Recombinant human LXR receptors were purified by affinity chromatography on glutathione sepharose and receptor was eluted with glutathione. Glycerol was added to a final concentration of 50% to stabilize the receptor and aliquots were stored at - 80°C.
  • Binding to LXR ⁇ For each assay, an aliquot of human GST-LXR ⁇ receptor was incubated in a final volume of 100 ⁇ l SPA buffer (10 mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 10 mM Na molybdate, 1 mM dithiothreitol, and 2 ⁇ g/ml benzamidine) containing 1.25 mg/ml yttrium silicate protein A coated SPA beads (Amersham Pharmacia Biotech, Inc.), 8.3 ⁇ g/ml anti-GST antibody (Amersham Pharmacia Biotech, Inc.), 0.1% non-fat dry milk and 25 nM [3H2]Compound A (13.4 Ci/mmole), ⁇ test compound. After incubation for ⁇ 16 h at 15 °C with shaking, the assay plates were counted in a Packard Topcount. In this assay the Kd for Compound A for LXR ⁇ is ⁇ 15 nM.
  • Representative tested compounds of Formula I are ligands for human LXR ⁇ and/or human LXR ⁇ , each having an IC50 ⁇ 1,800 nM for at least one of the LXR ⁇ receptor or the LXR ⁇ receptor, and preferred tested compounds having an IC 50 of 300 nM or less for at least one of the LXR ⁇ receptor or the LXR ⁇ receptor.
  • Expression constructs were prepared by inserting the ligand binding domain (LBD) of human LXR ⁇ and LXR ⁇ cDNAs adjacent to the yeast GAL4 transcription factor DNA binding domain (DBD) in the mammalian expression vector pcDNA3 to create pcDNA3-LXR ⁇ /GAL4 and pcDNA3- LXR ⁇ /GAL4, respectively.
  • the GAL4-res ⁇ onsive reporter construct, ⁇ UAS(5X)-tk-luc contained 5 copies of the GAL4 response element placed adjacent to the thymidine kinase minimal promoter and the luciferase reporter gene.
  • the transfection control vector, pEGFP-Nl contained the Green Fluorescence Protein (GFP) gene under the regulation of the cytomegalovirus promoter.
  • GFP Green Fluorescence Protein
  • HEK-293 cells were seeded at 40,000 cells/well in 96 well plates in Dulbecco's modified Eagle medium (high glucose) containing 10% charcoal stripped fetal calf serum, 100 units/ml Penicillin G and 100 ⁇ g/ml Streptomycin sulfate at 37°C in a humidified atmosphere of 5% CO2- After 24 h, transfections were performed with Lipofectamine (Gibco-BRL, Gaithersburg, MD) according to the instructions of the manufacturer.
  • transfection mixes contained 0.002 ⁇ g of LXR ⁇ /GAL4 or LXR ⁇ /GAL4 chimeric expression vectors, 0.02 ⁇ g of reporter vector pUAS(5X)-tk-luc and 0.034 ⁇ g of pEGFP-Nl vector as an internal control of transfection efficiency.
  • Compounds were characterized by incubation with transfected cells for 48 h across a range of concentrations.
  • Cell lysates were prepared from washed cells using Cell Lysis Buffer (Promega) according to the manufacturer's directions.
  • Luciferase activity in cell extracts was determined using Luciferase Assay Buffer (Promega) in a ML3000 luminometer (Dynatech Laboratories).
  • GFP expression was determined using the Tecan Spectrofluor Plus at excitation wavelength of 485 nm and emission at 535 nm. Luciferase activity was normalized to GFP expression to account for any variation in efficiency of transfection
  • Caco-2 cells which are of human origin, were obtained from ATCC and grown in Opti-MEM (Gibco #51985-034) containing 10% FCS, non-essential amino acids (Gibco #11140-050), and vitamins (Gibco # 11120-052). Caco-2 cells were plated at 100,000 cells/well in 48-well plates.
  • Table 2 shows cholesterol efflux results for the cmpound made in Example 40. Results are given as mean of quadruplicate incubations.
  • Methyl acrylate (0.186 mL, 0.214 mmol) was added to a solution of the indicated iodide (0.3 g, 1.03 mmol), Pd(OAc) 2 (24 mg, 0.107 mmol) and Bu 3 N (0.246 mL, 0.107 mmol) in l-methyl-2-pyrrolidine ( 5 mL). The mixture was heated to 8O 0 C for 2 hours. The reaction mixture was cooled to room temperature and quenched with water, followed by extraction with ethyl acetate. The combined ethyl acetate extracts were washed with brine and dried over Na 2 SO 4 . Na 2 SO 4 was then filtered off and solvent was evaporated in vac. The residue was chromatographed on silica gel using ethyl acetate : hexanes (30 : 70) to give the titled compound.
  • the indicated aniline (0.225g, 1.46 mmol) was added to a solution of the bromide (prepared according to the procedure of Example 5, 0.178 g, 0.49 mmol) in DMF (5 mL) followed by Cs 2 CO 3 (0.18 g, 0.53 mmol).
  • the reaction mixture was heated to 80 0 C overnight.
  • the reaction mixture was partitioned between ethyl acetate and water.
  • the combined ethyl acetate extracts were dried over sodium sulfate and filtered.
  • the solvent was evaporated and the resulting solid was chromatographed on silica gel using ethyl acetate and hexanes (20:80) 1% Et 3 N to give the titled compound.
  • Aqueous NaOH 50 %, 2.0 mL was added to the nitrile (prepared according to the procedure of Example 14 Step 2,0.21 g, 0.46 mmol) in MeOH (5 mL) and THF (1.5 mL). The reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and neutralized with acetic acid, then extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine and dried over Na 2 SO 4 .
  • the indicated aniline (O.lg, 1.46 mmol) was added to a solution of the bromide (prepared according to the procedure of Example 5, 0.178 g, 0.49 mmol) and Cs 2 CO 3 (0.18 g, 0.54 mmol) in DMF (5 mL). The resulting mixture was heated at 80 0 C overnight. The reaction mixture was partitioned between ethyl acetate and water. The combined ethyl acetate extracts were dried over sodium sulfate and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel using ethyl acetate and hexanes (20:80) 1% Et 3 N to give the compound pictured above.
  • Aqueous NaOH 50 %, 1.0 mL was added to the nitrile (prepared according to the procedure of Example 15 Step 2, 60.0 mg, 0.12 mmol) in MeOH (5 mL) and THF (1.0 mL). The reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and neutralized with acetic acid, then extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine and dried over Na 2 SO 4 .
  • Aqueous NaOH (IN, 0.5 mL) was added to the aniline (prepared according to the procedure of Example 18 Step 2, 50.0 mg, 0.10 mmol) in MeOH (1 mL) and THF (1 mL). The resulting mixture was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and neutralized with acetic acid. The solvent was evaporated in vac and the residue was chromatographed on silica gel using, ethyl acetate : hexanes (30 : 70) 2.5% acetic acid to give the titled compound.
  • the 2-fluoro-4-nitrobenzoic acid (2.0 g, 10.8 mmol) was dissolved in C 2 H 5 OH (30 mL) with H 2 SO 4 (cone. 3.5 mL) and heated at reflux overnight.
  • the reaction mixture was poured into ice / H 2 O (200 mL) and neutralized with NaHCO 3 (solid).
  • the residue was extracted with ethyl acetate.
  • the combined ethyl acetate extracts were washed with brine and dried over Na 2 SO 4 .
  • Na 2 SO 4 was then filtered off and solvent was evaporated in vac.
  • the crude residue was dissolved in MeOH (30 mL) and reduced with Pd/C (10 %, 0.2 g) under 1 atmosphere of H 2 .
  • the mixture was filtered and solvent was evaporated in vac to give the titled compound.
  • Aqueous NaOH (IN, 0.5 mL) was added to the aniline (prepared according to the procedure of Example 20 Step 3, 50.0 mg, 0.10 mmol) in MeOH (1 mL) and THF (1 mL). The mixture was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and neutralized with acetic acid. The solvent was evaporated in vac and the residue chromatographed on silica gel using ethyl acetate : hexanes (20 : 80) 2.5% acetic acid to give the titled compound.
  • the 2-bromo-4-ammobenzoic acid (2.5 g, 11.5 mmol) was dissolved in C 2 H 5 OH (35 mL) with H 2 SO 4 (cone, 3.5 mL). The mixture was heated at reflux overnight. The reaction mixture was poured into ice / H 2 O (200 mL) and neutralized with NaHCO 3 (solid). The residue was extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine and dried over Na 2 SO 4 . Na 2 SO 4 was then filtered off and solvent was evaporated in vac to give the titled compound.
  • Aqueous NaOH (IN, 0.5 mL) was added to the aniline (prepared according to the procedure of Example 21 Step 2, 50.0 mg, 0.10 mmol) in MeOH (1 mL) and THF (1 mL) and stirred at RT overnight.
  • the reaction mixture was diluted with ethyl acetate and neutralized with acetic acid. Then the solvent was evaporated in vac and the residue chromatographed on silica gel using ethyl acetate : hexanes (20 : 80) 2.5% acetic acid to give the titled compound.
  • Aqueous NaOH (IN, 1.6 mL) was added to the aniline (prepared according to the procedure of Example 22 Step 1, 179.5 mg, 0.40 mmol) in MeOH (6.4 mL) and THF (1.1 mL). The mixture was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and neutralized with acetic acid. The solvent was evaporated in vac and the residue was chromatographed on silica gel using ethyl acetate : hexanes (30 : 70) 2.5% acetic acid to give the titled compound.
  • Aqueous NaOH (IN, 1.0 mL) was added to the aminopyrazine (prepared according to the procedure of Example 24 Step 1, 110.03 mg, 0.24 mmol) in MeOH (1.5 mL) and THF (1.OmL). The mixture was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and neutralized with acetic acid. The solvent was evaporated in vac and the residue was chromatographed on silica gel using ethyl acetate : hexanes (70 : 30) 2.5% acetic acid to give the titled compound.
  • Aqueous NaOH (IN, 90.0 ⁇ L) was added to the aminopyrimidine (prepared according to the procedure of Example 26 Step 2, 20.0 mg, 0.24 mmol) in MeOH (1.0 mL) and THF (0.5 mL). The mixture was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and neutralized with acetic acid. The solvent was evaporated in vac and the residue chromatographed on silica gel using ethyl acetate : hexanes (40 : 60) 2.5% acetic acid to give the titled compound.
  • the thiourea (prepared according to the procedure of Example 28 Step 2, 0.5 g, 0.266 mmol) was dissolved in absolute ethanol (1.5 ml) and bromomalonaldehyde was added (0.042 g, 0.28 mmol). The mixture was heated to reflux for 1 hour. The solution was poured into saturated sodium bicarbonate followed by aqueous/ethyl acetate work-up and silica gel chromatography ( acetone : dichloromethane (5:95:0.5% trjethylamine)) to give the titled compound.
  • the aldehyde (prepared according to the procedure of Example 29 Step 1, 0.070 g, 0.164 mmol) was dissolved in methanol (2.0 ml), sodium borohydride was added (0.010 g, 0.164 mmol) and the mixture stirred for 1 hour. The reaction mixture was poured into brine followed by aqueous/ethyl acetate work-up to give the titled compound.
  • the alcohol (prepared according to the procedure of Example 30 Step 1, 0.37 g, 0.85 mmol) was dissolved in dichloromethane (4.3 mL) and the solution cooled to -4O 0 C. Triethylamine (0.259 g, 2.56 mmol) and methanesulfonyl chloride (0.12 g, 1.109 mmol) were added and the solution stirred for 10 minutes. Tetrabutylammonium cyanide (0.72 g, 3.29 mmol) was added and the cooling bath removed.
  • the reaction mixture was cooled to room temperature poured into water, acidified with acetic acid, followed by aqueous/dichlormethane work-up and two silica gel chromatographies ( acetone : hexanes (3 :7:1% acetic acid) and (ethyl acetate : hexanes (90:10:1% acetic acid) to give the titled compound.
  • the bromide was prepared according to the procedure of Example 5. To a solution of this bromide (0.1 g, 0.273 mmol) in DMF (1.1 mL) was added methyl indole-5-carboxyaldehyde (0.079g, 0.546 mmol) and cesium carbonate (0.177g, 0.546 mmol). The reaction mixture stirred at room temperature for 2 hours. Water was added followed by aqueous/ethyl acetate work-up and silica gel chromatography (acetone : hexanes (3:7)) to give the titled compound.
  • the aldehyde (prepared according to the procedure of Example 31 Step 1, 0.041 g, 0.095 mmol) was dissolved in methanol (1 ml), and sodium borohydride was added (0.004 g, 0.095 mmol). The reaction mixture was stirred for 1 hour, poured into 1 N sodium hydroxide (20ml) followed by aqueous/ethyl acetate work-up to give the titled compound.
  • the ester (prepared according to the procedure of Step 1, 0.133 g, 0.28 mmol) was dissolved in THF (6 ml) and cooled to -20 0 C.
  • Diisobutyl aluminum hydride (1.0 M in hexanes) was added (1.4 ml, 1.4 mmol) and the reaction mixture stirred for 1 hour -20 0 C , after which the mixture was allowed to warm to 0 0 C.
  • the reaction mixture was poured into 1 N NaOH (20ml) followed by aqueous / dichloromethane work-up to give the titled compound.
  • the benzimidazole alcohol (prepared according to the procedure of Step 2, 0.05 g, 0.12 mmol) was dissolved in 6:4 tetrahydrofuran : benzene (1 mL). Acetone cyanohydrin (10 mg, 0.115 mmol), triphenyl phosphine (0.039g, 0.15 mmol), and diisopropyl azodicarboxylate (30 mg, 0.150 mmol) were added and the solution stirred overnight. The solvent was removed in vac.
  • Methyl iodide (19 mg, 0.136) was added and the solution then allowed to warm to RT. The mixture was poured into saturated sodium bicarbonate followed by aqueous/ethyl acetate work-up and silica gel chromatography (ethyl acetate : hexanes (1:4)) to give the titled compound.
  • the aldehyde (prepared according to the procedure of Example 31 Step 1, 0.19O g, 0.442 mmol) was dissolved in tetrahydrofuran (2.25 ml) and cooled to -20 0 C. Methyl magnesium bromide (in THF) was added (3.0 M, 0.162 ml, 0.486 mmol) and the mixture stirred for 1 hour. The solution was poured into water followed by aqueous/ethyl acetate work-up and silica gel chromatography ( ethyl acetate : hexanes (3:7)) to give the titled compound.
  • the ester (prepared according to the procedure of Step 1, 0.60 g, 0.13 mmol) was dissolved in THF (1.25 ml) and cooled to -2O 0 C.
  • Diisobutylaluminum hydride (1.0 M in hexanes, 0.288 ml, 0.288 mmol) was added dropwise and the mixture stirred for 1 hour being allowed to warm to room temperature.
  • the reaction mixture was poured into 1 N sodium hydroxide followed by aqueous/ethyl acetate work-up to give the titled compound.
  • the bromide starting material was prepared according to the procedure of Example 5.
  • the nitrile prepared according to the procedure of Step 1, 0.022 g, 0.143 mmol
  • DMF 0.7 mL
  • the nitrile prepared according to the procedure of Step 1, 0.022 g, 0.143 mmol
  • cesium carbonate (0.136 g, 0.42 mmol)
  • the resulting slurry was stirred for 1 hour.
  • the reaction mixture was poured into water, followed by aqueous / ethyl acetate work-up and silica gel chromatography ( ethyl acetate : hexanes (3:7) 4.0% acetic acid) to give the titled compound.
  • the iodide (prepared according to the procedure of Step 1, 125 mg, 0.384 mmol) was placed in an oven dried flask with copper iodide (7.0 mg, 0.038 mmol), dichloro bis(triphenylphosphine)palladiurn(II) (27.0 mg, 0.038 mmol) and the solids slurried in triethylamine (2.0 mL). Trimethylsilylacetylene was added dropwise (41 mg, 0.422 mmol) and the slurry stirred at room temperature for 3 hours. Ethyl acetate (100 ml) was then added and the resulting solution washed with brine and dried over MgSO 4 . The volatiles were removed in vacuo, and the residue was purified by silica gel chromatography ( ethyl acetate : hexanes (2:8) 1.0 % TEA) to give the titled compound.
  • the bromide was prepared according to the procedure of Example 5.
  • the indole prepared according to the procedure of Step 3, 0.02 g, 0.094 mmol
  • DMF 0.6 mL
  • the bromide 0.0.38 g, 0.103 mmol
  • cesium carbonate 0.092 g, 0.282 mmol
  • the resulting slurry was stirred for 3 hours.
  • the mixture was poured into water, followed by aqueous / ethyl acetate work-up and silica gel chromatography (ethyl acetate : hexanes (2:8)) to give the titled compound.
  • the ester (prepared according to the procedure of Step 4, 0.030 g, 0.59 mmol) in ethanol (1.0 mL) and THF (1.0 ml) was treated withl N sodium hydroxide (aq) (1.0 ml). The solution was heated at reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, poured into water, acidified with acetic acid, followed by aqueous / ethyl acetate work-up, and silica gel chromatography (ethyl acetate : hexanes (2:8) 2.0% acetic acid) to give the titled compound.
  • the iodide (prepared according to the procedure of Step 1, 636 mg, 1.95 mmol) was placed in an oven dried flask with copper iodide (37.0 mg, 0.195 mmol) and dichloro bis(triphenylphosphine)palladiurn(II) (137 mg, 0.195 mmol) and the solids slurried in triethylamine (10.2 mL). Trimethylsilylacetylene was added dropwise at 0 0 C (211 mg, 2.419 mmol) and the slurry stirred at room temperature overnight. Then ethyl acetate (100 ml) was added and the resulting solution washed with brine and dried over MgSO 4 . The volatiles were removed in vacuo followed by purification of the residue by silica gel chromatography ( ethyl acetate : hexanes (3:7) 1.0 % TEA) to give the titled compound.
  • the bromide was prepared according to the procedure of Example 5.
  • the indole (prepared according to the procedure of Step 3, 0.078 g, 0.35 mmol) in DMF (1.75 mL) was treated with the bromide (0.141 g, 0.385 mmol) and cesium carbonate (0.341 g, 1.049 mmol).
  • the resulting slurry was stirred overnight, then poured into water, followed by aqueous / ethyl acetate work-up and silica gel chromatography (acetone : hexanes (2:8)) to give the titled compound.
  • the ester (prepared according to the procedure of Example 38 Step 4, 0.363 g, 0.713 mmol) was dissolved in THF (7.1 ml) and cooled to -20 0 C.
  • Diisobutylaluminum hydride (1.0 M in hexanes, 1.5 ml, 1.5 mmol) was added and the reaction mixture stirred for 1 hour.
  • the reaction was allowed to warm to room temperature, ethyl acetate was added (12 ml) followed by addition of 0.54 g celite and saturated aqueous ammonium chloride (0.64 ml). The slurry was filtered and the resulting solids washed with ethyl acetate.
  • the alcohol (prepared according to the procedure of Step 1, 0.23 g, 0.49 mmol) was dissolved in THF (2.5 mL). Triethylamine was added (0.149 g, 1.5 mmol) and the solution was cooled to -2O 0 C. Methanesulfonyl chloride (.016 g, 0.14 mmol) was added and the solution stirred for 10 minutes. Tetrabutylammonium cyanide (0.19 g, 0.70 mmol) was added, the cooling bath was removed, and the reaction was stirred for 1 hour.
  • nitrile prepared according to the procedure of Step 2, 210.0 mg, 0.441 mmol
  • methanol 9.0 mL
  • THF 4.0 ml
  • Sodium hydroxide 50% wt. aq 2.5 ml
  • the reaction mixture was allowed to cool to room temperature, poured into water, acidified with acetic acid, followed by aqueous/ethyl acetate work-up and silica gel chromatography ( ethyl acetate : hexanes (4:6) 3.0% acetic acid) to give the titled compound.
  • the ester (prepared according to the procedure of Example 39 Step 4, 0.062 g, 0.12 mmol) was dissolved in THF (1.2 ml) and cooled to -20 0 C.
  • Diisobutylaluminum hydride (1.0 M in hexanes, 0.29 ml, 0.27 mmol) was added and the solution stirred for 1 hour.
  • the reaction was allowed to warm to room temperature, poured into water, acidified with acetic acid, followed by aqueous/ethyl acetate work-up and silica gel chromatography ( ethyl acetate : hexanes (3:7) 2.0% acetic acid) to give the titled compound.
  • nitrile prepared according to the procedure of Step 2, 37.0 mg, 0.441 mmol
  • methanol 1.8 mL
  • THF 0.8 ml
  • Sodium hydroxide 50% wt, aq 0.5 ml
  • the reaction mixture was allowed to cool to room temperature, poured into water, acidified with acetic acid, followed by aqueous / ethyl acetate work-up and silica gel chromatography ( ethyl acetate : hexanes (3:7) 3.0% acetic acid) to give the titled compound.
  • the indicated iodide (prepared according to the procedure of Step 1, 368 mg, 1.2 mmol) was placed in an oven dried flask with copper iodide (46.0 mg, 0.24 mmol) and dichloro bis(triphenylphosphme)palladium( ⁇ ) (168.0 mg, 0.24 mmol) and the solids slurried in triethylamine (6.0 mL). Trimethylsilylacetylene was added dropwise (130 mg, 1.32 mmol) and the slurry stirred at room temperature for 3.5 hours. Then ethyl acetate (400 ml) was added and the resulting solution washed with brine and dried over MgSO 4 . The volatiles were removed in vacuo, followed by purification of the residue by silica gel chromatography ( ethyl acetate : hexanes (4:6) 2.0 % TEA) to give the titled compound.
  • the bromide starting material was prepared according to the procedure of Example 5.
  • the indole (prepared according to the procedure of Step 3, 0.060 g, 0.292 mmol) in DMF (2.0 mL) was treated with the bromide (0.118 g, 0.321 mmol) and cesium carbonate (0.285 g, 0.877 mmol) and the resulting slurry stirred for 3 hours.
  • the reaction mixture was poured into water, followed by aqueous / ethyl acetate work-up and silica gel chromatography (ethyl acetate : hexanes (4:6)) to give the titled compound.
  • the ester (prepared according to the procedure of Step 4, 0.030 g, 0.061 mmol) in methanol (2.0 mL) was treated with 1 N sodium hydroxide (aq, 0.25 ml). The resulting solution was heated at reflux for 2 hours, allowed to cool to room temperature and stirred overnight. The reaction mixture was poured into water, acidified with acetic acid, followed by aqueous / ethyl acetate work-up, and silica gel chromatography (ethyl acetate : hexanes (4:6) 3.0% acetic acid) to give the titled compound.
  • the ester (prepared according to the procedure of Step 1, 0.150 g, 0.316 mmol) was dissolved in THF (3.0 ml) and cooled to -20 0 C.
  • Diisobutylaluminum hydride (1.0 M in hexanes, 0.695 ml, 695 mmol) was added, and the mixture stirred for 1 hour.
  • the solution was allowed to warm to room temperature, ethyl acetate was added (6.0 ml) followed by addition of 0.54 g celite and saturated aqueous ammonium chloride (0.35 ml).
  • the slurry was stirred 10 minutes, filtered, and the resulting solids washed with ethyl acetate.
  • the organics were combined, washed with water, brine, and dried over 19

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Abstract

La présente invention concerne des ligands du LXR innovants de formule (I) et leurs sels, esters et tautomères pharmaceutiquement acceptable, utilisables dans le traitement des troubles dyslipidémiques, en particulier des taux insuffisants de cholestérol HDL.
PCT/US2006/001071 2006-01-12 2006-01-12 Composes therapeutiques pour traiter des troubles dyslipidemiques WO2007081335A1 (fr)

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WO2009080555A2 (fr) * 2007-12-21 2009-07-02 F. Hoffmann-La Roche Ag Dérivés de benzimidazole substitués par carboxyle ou hydroxyle
WO2012033353A2 (fr) 2010-09-07 2012-03-15 서울대학교 산학협력단 Composés de sesterterpène et leur utilisation
WO2014028461A2 (fr) 2012-08-13 2014-02-20 The Rockefeller University Traitement et diagnostic du mélanome
US9428753B2 (en) 2013-03-15 2016-08-30 The Governing Council Of The University Of Toronto Use of LXR antagonists for treatment of side effects of elevated glucocorticoid levels
WO2017123568A2 (fr) 2016-01-11 2017-07-20 The Rockefeller University Méthodes pour le traitement de troubles associés à des cellules suppressives dérivées de cellules myéloïdes
US11174220B2 (en) 2019-12-13 2021-11-16 Inspirna, Inc. Metal salts and uses thereof
US11214536B2 (en) 2017-11-21 2022-01-04 Inspirna, Inc. Polymorphs and uses thereof

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009080555A2 (fr) * 2007-12-21 2009-07-02 F. Hoffmann-La Roche Ag Dérivés de benzimidazole substitués par carboxyle ou hydroxyle
WO2009080555A3 (fr) * 2007-12-21 2009-10-01 F. Hoffmann-La Roche Ag Dérivés de benzimidazole substitués par carboxyle ou hydroxyle
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