WO2004026243A2 - Utilisations therapeutiques de cetophosphonates lineaires - Google Patents

Utilisations therapeutiques de cetophosphonates lineaires Download PDF

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Publication number
WO2004026243A2
WO2004026243A2 PCT/US2003/029387 US0329387W WO2004026243A2 WO 2004026243 A2 WO2004026243 A2 WO 2004026243A2 US 0329387 W US0329387 W US 0329387W WO 2004026243 A2 WO2004026243 A2 WO 2004026243A2
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Prior art keywords
dimethyl
tert
oxo
butyl
phosphonate
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PCT/US2003/029387
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English (en)
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WO2004026243A3 (fr
Inventor
Lân Mong Nguyen
Vinh Van Diep
Hieu Trung Phan
Eric Joseph Niesor
Daniele Masson
Yves Guyon-Gellin
Emanuele Buattini
Carlo Severi
Raymond Azoulay
Craig Leigh Bentzen
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Ilex Oncology Research, Sarl
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Priority to AU2003272534A priority Critical patent/AU2003272534A1/en
Publication of WO2004026243A2 publication Critical patent/WO2004026243A2/fr
Publication of WO2004026243A3 publication Critical patent/WO2004026243A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to the use of linear ketophosphonate compounds that are potently inhibit the Mevalonate-Isoprenoid-Cholesterol pathway by enhancing the degradation of
  • HMG-CoA reductase and thus are useful in the treatment and/or prevention of diseases and conditions such as hypercholesterolemia, hyperhpidemia, and elevated production of ⁇ -amyloid protein.
  • cholesterol homeostasis is maintained by balancing cholesterol uptake and production.
  • Cholesterol uptake is regulated by modulating the levels of the cell surface LDL receptors that mediate internalisation of the cholesterol-rich low density lipoprotein (LDL) particles.
  • Cholesterol synthesis is mainly controlled by adapting the levels and the activity of the endoplasmic reticulum enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG- Co A) reductase that catalyzes the conversion of HMG-CoA into mevalonate.
  • HMG- Co A 3-hydroxy-3-methylglutaryl-coenzyme A
  • This process is the first committed step of the Mevalonate-Isoprenoid-Cholesterol pathway that leads to the synthesis of cholesterol as well as of essential nonsterol isoprenoid compounds.
  • levels of HMGR and LDL receptors are elevated, thus increasing the rate of endogenous sterol synthesis and of LDL uptake.
  • HMG-CoA reductase and LDL receptors decline, thereby lowering sterol production and LDL internalization.
  • the enzymatic biosynthesis of cholesterol is a complex process involving over 25 steps, and the first committed step thereof is the synthesis of mevalonate from 3-hydroxy-3-methylglutaryl Co A (HMG-CoA). This rate-limiting step is catalyzed by the microsomal enzyme HMG-CoA reductase.
  • statins a class of drugs that are competitive inhibitors of HMG-CoA reductase, have been shown to be quite effective for lowering total cholesterol and LDL cholesterol in humans.
  • WO002981 discloses the following in vitro data: human cortical cell cultures exposed to cholesterol carrying lipoproteins (VLDL and LDL) increased the production of ⁇ -amyloid protein; ⁇ -amyloid levels in the cerebral cortex of rats fed a high cholesterol diet are elevated by about 50% compared to ⁇ -amyloid levels of rats fed a low cholesterol diet; and human neuronal cultures treated with HMG-CoA reductase inhibitors have significantly decreased levels of ⁇ - amyloid production relative to controls.
  • VLDL and LDL cholesterol carrying lipoproteins
  • ⁇ -amyloid levels in the cerebral cortex of rats fed a high cholesterol diet are elevated by about 50% compared to ⁇ -amyloid levels of rats fed a low cholesterol diet
  • human neuronal cultures treated with HMG-CoA reductase inhibitors have significantly decreased levels of ⁇ - amyloid production relative to controls.
  • Statins are not preferred compounds for the systemic inhibition of cholesterol synthesis.
  • This class of compounds are designed to inhibit hepatic as opposed to brain HMG- CoA reductase and have low systemic availability.
  • the AUC 0-24 for lovastatin and pravastatin are, respectively, 0.285 ⁇ 0.025 and 0.189 ⁇ 0.013 ⁇ g /ml for patients receiving a 40 mg dose of each compound daily (Pan, 1990). Attempts to simply increase the amount of statin administered will be curtailed by side effects associated with such high doses of the statins.
  • statins exhibit musculoskeletal, hepatic, brain, ocular and gastric toxicity (Hrab et al, 1994; Smith, 1991; Smith et al, 1991(a); Kombrust et al, 1989; Berry etal, 1989; Kloss, 1991).
  • Compounds of Formula (I) decrease the amounts of the HMG-CoA reductase, not through direct inhibition of the enzyme, but by inducing its degradation.
  • HMGR is the rate limiting enzyme in the endogenous cholesterol synthesis, reduction of its levels leads to the inhibition of cholesterol.
  • Compounds of formula (I) are potentially useful as plasma cholesterol lowering agents.
  • Compounds of Formula (I) reduce the levels of this enzyme by accelerating its degradation.
  • a direct consequence of this difference in mechanisms is the use of Compounds of formula (I) to reduce plasma cholesterol in patients that are refractory to the statins, a figure estimated to be as high as 20 % of the hyperlipidemic population.
  • Another application is the use of Compounds (I) in combination with a statin in order to markedly reduce plasma cholesterol. Indeed it is to be expected that using a compound of Formula (I) and a low dose of a statin will be a safer way to reach the desired cholesterol level than raising the statin dose, in regard to safety concerns about side effects caused by high doses of statins.
  • a first aspect of the invention is a method for lowering cholesterol in a patient in need thereof by using an effective amount of a compound of the formula (I).
  • Another aspect of the invention is a method of lowering plasma cholesterol in a patient that has been shown not to respond to HMG-Co A reductase inhibitors, comprising administering to the patient an effective amount of a substituted phosphonate compound of the formula (I).
  • Another aspect of the invention is a method of lowering plasma cholesterol in a patient that has been shown not to respond to HMG-Co A reductase inhibitors, comprising administering to the patient a combination of an effective amount of a substituted phosphonate compound of the formula (I) and a HMG-CoA reductase inhibitor, which may be a statin, including compactin, lovastatin, simvastatin, pravastatin, fiuvastatin, atorvastatin, rosuvastatin and pivastatin.
  • a statin including compactin, lovastatin, simvastatin, pravastatin, fiuvastatin, atorvastatin, rosuvastatin and pivastatin.
  • Another aspect is a method for for treating and/or preventing a disease state associated with an elevated production of ⁇ -amyloid protein.
  • the disease state associated with an elevated production and/or deposition of ⁇ -amyloid protein is selected from the group consisting of Alzheimer's disease, head trauma or stroke.
  • the method further comprises administration to the subject an effective amount of a competitive inhibitor of HMG-CoA reductase inhibitor, which may be compactin, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and pivastatin.
  • the method further comprises administration of an effective amount of a therapeutic agent for the treatment of Alzheimer's disease, which may be Aricept, Exelon, Cognex, Reminyl, ALCAR, AN- 1792, Cerebrolysin, Ampalex, Avlosulfon and Memantine.
  • a therapeutic agent for the treatment of Alzheimer's disease which may be Aricept, Exelon, Cognex, Reminyl, ALCAR, AN- 1792, Cerebrolysin, Ampalex, Avlosulfon and Memantine.
  • linear ketophosphonate compounds of the present invention have the following Formula (I):
  • X° is H, OH or a straight or branched C ⁇ to C 6 alkoxy group
  • X 1 , X 2 and X 3 are independently H, OH, a straight, branched or cyclic C C 6 alkyl or alkoxy group;
  • X , X or X , X together may form a C j -C. optionally substituted alkylidenoxy or alkylidenedioxy group; with the proviso that X° is H when X 3 is H and X 1 and X 2 are independently straight or branched
  • X 4 , X 5 , X 6 are independently H, a straight or branched -C ⁇ alkyl group; q is zero or 1;
  • X 7 is H, a straight or branched -C 8 alkyl or alkoxy group, or an optionally substituted benzyl group;
  • Y is O or S; 7) and Z 2 are independently OR 1 or NR R , where R 1 , R , and R are independently H or a
  • L is a saturated or unsaturated -C ⁇ alkylene chain in which one or more of the methylene groups can be replaced by a sulfur atom, an oxygen atom, a carbonyl group wherein optionally one or more methylene groups can be substituted by one or more halogen atoms (F, Cl or Br), -C 6 alkyl, an optionally substituted aryl or heteroaryl group.
  • the present invention also encompasses pharmaceutically acceptable salts, solvates and hydrates of compounds of formula
  • R 4 ,R 5 are independently or different are, H, halogen (F, Cl, Br), C ! -C 6 straight or branched alkyl, an optionally substituted aryl or heteroaryl,
  • “-B-” is -C(R 6 )(R 7 )- where R 6 and R 7 are independently H, Halogen (F, Cl, Br), d-C 6 straight or branched alkyl, an optionally substituted aryl or heteroaryl, or R 6 and R 7 can form a ring of C 3 -C 7 carbon atoms.
  • X 1 , X 2 , X 3 , X 6 , X 7 , R 1 , R 2 , R 3 , R 4 and R 5 means as indicated saturated straight, branched or cyclic substitutents, i.e., straight or branched -(C n H 2n+1 ) or -O(C n H 2n + 1 ) or cyclic -(C n H 2n-1 )- or -O-(C n H 2n-1 )-, and also includes halogenated alkyl and alkoxy groups and derivatives thereof, such as fluoro-substituted groups, fluorohydroxy substituted groups wherein the degree of halogenation ranges from a single halo substituent, e.g., -CH 2 F and -OCH 2 F, to perhalo-substituted alkyl and alkoxy groups,
  • X° is H, OH, OMe
  • X 4 is H, a straight, branched or cyclic d-Cs alkyl or alkoxy group, more preferably X 4 is a tert- butyl group;
  • X 5 and X 6 are independently H, a d-C 4 alkyl group, more preferably X 5 and X 6 are H;
  • q is zero or 1, more preferably q is 1;
  • Y is O; Z and Z are the same and are OR wherein R is methyl, ethyl or isopropyl;
  • Ar is:
  • X° is H, OH, SH, OMe, SMe group
  • X 7 is H, a straight or branched d-C 8 alkyl or alkoxy group, preferably a t-butyl group or an optionally substituted benzyl group;
  • Y is O
  • Z 1 and Z 2 are the same and are OR 1 wherein R 1 is methyl, ethyl or isopropyl;
  • novel substituted phosphonate compound of formula 1 is novel substituted phosphonate compound of formula 1.
  • (I) is selected from the group consisting of: dimethyl 4-(3-methoxy-5-methyl-4-hydroxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l-yl- phosphonate; dimethyl 4-(3 ,5 -dimethoxy-4-hydroxyphenyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -yl-pho sphonate; dimethyl 4-(3,4,5-trimethoxyphenyl)-l , l-dimethyl-2-oxo-3 -buten- 1 -yl-phosphonate; dimethyl 4-(4,5-dimethoxy-3-hydroxyphenyl)-l , 1 -dimethyl-2-oxo-3-buten- 1 -yl-phosphonate; dimethyl 4-(3,5-diethoxy-4-hydroxyphenyl)- 1 , 1 -dimethyl-2-oxo-3-buten- 1 -yl-phosphonate; di
  • the compounds of formula (I) may at least in part have hypocholesterolemic activity by affecting the MIC pathway.
  • compounds of Formula (I) decrease the amount of the HMG-CoA reductase in the MIC pathway, not by direct inhibition of HMG-CoA reductase, but by inducing the degradation of this enzyme.
  • HMGR is the rate limiting enzyme in endogenous cholesterol synthesis, reduction of its levels leads to the inhibition of cholesterol.
  • compounds of formula (I) are potentially useful as plasma cholesterol lowering agents.
  • HMGal represents a convenient system to study the degradation of HMG-CoA reductase.
  • HMGal is a chimeric protein that results from the fusion protein between the membrane domain of HMG-CoA reductase and the bacterial ⁇ -galactosidase. When transfected into a variety of mammalian cells and expressed from a sterol-insensitive viral promoter, this fusion protein is constitutively made as an active enzyme.
  • any changes in HMGal' s enzymatic activity are solely due to changes in the rate of degradation of the HMGal protein, which in turn parallels the degradation of the endogenous HMG-CoA reductase.
  • the effect on HMG-CoA reductase degradation of compounds of Formula (I) can be studied in this system.
  • compounds of Formula (I) reduce the levels of this enzyme by accelerating its degradation.
  • a direct consequence of this difference in mechanisms is the use of compounds of Formula (I) to reduce plasma cholesterol in patients that are refractory to the statins, a figure estimated to be as high as 20% of the hyperlipidemic population.
  • Another application is the use of compounds (I) in combination with a statin in order to markedly reduce plasma cholesterol. Indeed, it is to be expected that using a compound of Formula (I) and a low dose of a statin will be a safer way to reach the desired cholesterol level than raising the statin dose, due to safety concerns about side effects caused by high doses of statins .
  • compositions for use in the present invention include those described by Berge et al. (1977). Such salts may be formed from inorganic and organic acids. Representative examples thereof include salts formed from alkali metals such as potassium and sodium. Since the compounds of the present invention are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds of Formula (I) may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of Formula (I). Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.
  • solvent of crystallization may be present in the crystalline product.
  • This invention includes within its scope such solvates.
  • some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases, water of hydration may be formed.
  • This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilization.
  • different crystallisation conditions may lead to the formation of different polymorphic forms of crystalline products.
  • This invention includes within its scope all polymorphic forms of the compounds of Formula (I).
  • the compounds of formula (I) can be administered by any of a variety of routes. Thus, for example, they can be administered orally, or by delivery across another mucosal surface (for example across the nasal, buccal, bronchial or rectal mucosa), transdermally, or by injection (for example intradermal, intraperitoneal, intravenous or intramuscular injection).
  • routes for example, they can be administered orally, or by delivery across another mucosal surface (for example across the nasal, buccal, bronchial or rectal mucosa), transdermally, or by injection (for example intradermal, intraperitoneal, intravenous or intramuscular injection).
  • the compounds When the compounds are intended for oral administration, they can be formulated, for example, as tablets, capsules, ovules, granules, pills, lozenges, powders, solutions, emulsions, syrups, elixirs, suspensions, or any other pharmaceutical form suitable for oral administration.
  • Oral dosage forms can, if desired, be coated with one or more release delaying coatings to allow the release of the active compound to be controlled or targeted at a particular part of the enteric tract. Tablets and other solid or liquid oral dosage forms can be prepared (e.g., in standard fashion) from the compounds of formula (I) and a pharmaceutically acceptable solubilizer, diluent or carrier.
  • solubilizers, diluents or carriers include sugars such as lactose, starches, cellulose and its derivatives, powdered tracaganth, malt, gelatin, talc, stearic acid, magnesium stearate, calcium sulfate, vegetable oils, polyols such as glycerol, propyleneglycol and polyethyleneglycols, alginic acids and alginates, agar, pyrogen free water, isotonic saline, phosphate buffered solutions, and optionally other pharmaceutical excipients such as disintegrants, lubricants, wetting agents such as sodium lauryl sulfate, coloring agents, flavoring agents and preservatives, etc.
  • sugars such as lactose, starches, cellulose and its derivatives, powdered tracaganth, malt, gelatin, talc, stearic acid, magnesium stearate, calcium sulfate, vegetable oils, polyols such
  • Capsules can be of the hard or soft variety and can contain the active compound in solid, liquid or semisolid form. Typically such capsules are formed from gelatine or an equivalent substance and can be coated or uncoated. If it is desired to delay the release of the active compound until the capsule has passed through the stomach and into the intestine, the capsule can be provided with a pH-sensitive coating adapted to dissolve at the pH found in the duodenum or ileum. Examples of such coatings include the Eudragits, the uses of which are well known.
  • Formulations for injection will usually be made up of the appropriate solubilizers such as detergents which may also include compounds and excipients such as buffering agents to provide an isotonic solution having the correct physiological pH.
  • the injectable solutions are typically pyrogen-free and can be provided in sealed vials or ampoules containing a unit dose of compound.
  • parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or coloring agents.
  • suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or coloring agents.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatine capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatine capsule.
  • Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • a typical suppository formulation comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
  • a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
  • composition is in unit dose form such as a tablet or capsule.
  • a unit dosage form of the compounds of the invention typically will contain from 0.1% to 99% by weight of the active substance, more usually from 5% to 75% of the active substance.
  • a unit dosage form can contain from lmg to lg of the compound, more usually from 10 mg to 500 mg, for example between 50 mg and 400 mg, and typically in doses of l00 mg to 200 mg.
  • Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the structure (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the compounds of the invention will be administered in amounts that are effective to provide the desired therapeutic effect.
  • concentrations necessary to provide the desired therapeutic effect will vary according to among other things the precise nature of the disease, the size, weight and age of the patient and the severity of the disease.
  • the doses administered will preferably be non-toxic to the patient, although in certain circumstances the severity of the disease under treatment may necessitate administering an amount of compound that causes some signs of toxicity.
  • the compounds of the invention will be administered in amounts in the range 0.01 mg/kg to 100 mg/kg body weight, more preferably 0.1 mg/kg to 10 mg/kg body weight and particularly 1 mg/kg to 5 mg/kg body weight.
  • the pharmaceutically acceptable compounds of the invention will normally be administered to a subject in a daily dosage regimen.
  • a daily dosage regimen for an adult patient this may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the structure (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
  • a typical daily dosage of the compounds of the invention would be in the range of 70 mg to 700 mg.
  • Such a dosage can be administered, for example, from two to four times daily.
  • Disease states which could benefit from the HMG-CoA reductase enhancing activity of compounds of formula (I) include, but are not limited to, diseases caused by elevated levels of plasma cholesterol, namely atheroaclerosis, cardiovascular diseases, diabetis and disease states asscoaited with an increased production of ⁇ -amyloid protein.
  • the compounds of this invention display HMG-CoA redutcase reducing activity and are therefore of value in the treatment of any of these conditions.
  • the compounds of the present invention can also be used in combination with an effective amount of a HMG-CoA reducatse inhibitor such as a statin, e.g., compactin, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and pivastatin.
  • a statin e.g., compactin, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and pivastatin.
  • a therapeutic agent for the treatment of Alzheimer's diseas including Aricept, Exelon, Cognex, Reminyl, ALCAR, AN- 1792, Cerebrolysin, Ampalex, Avlosulfon and Memantine.
  • Example 22 The procedure described in the Example 22 was followed, using 4-hydroxy-3-methoxy-5- methylbenzaldehyde (1.16 g, 6.6 mmol).
  • the crude compound obtained was purified by flash column chromatography (Si ⁇ 2, 98/2 AcOEt/MeOH). An amount of 0.93 g (2.7 mmol, 41 % yield) of the title compound was obtained.
  • n-Butyllithium (9.6 ml of a 1.6 M solution in hexane, 15.31 mmol) was added to 80 ml of THF cooled to -78°C, followed by diethyl ethylphosphonate (2.54 g, 15.31 mmol). The resulting solution was stirred for 15 min at -78°C, then a solution of ethyl 3,5-di-tert-butyl-2-(2- methoxyethoxymethoxy) cinnamate (2 g, 5.10 mmol) in 10 ml THF was added and the resulting reaction was left to stir at -78°C for 1 h.
  • the chloroform phase was separated, the aqueous phase further extracted with fresh chloroform, the combined chloroform phases were dried, evaporated to dryness.
  • the residue was purified by column chromatography (SiO2, dichloromethane (DCM)) to give 4.0 g (12.5 mmol, 62%) of ethyl 3,5-di-tert-butyl-2-methoxycinnamate.
  • diethyl methylphosphonate (3.04 g, 19.97 mmol) was added at -78° to a solution of n-butyllithium (12.5 ml of a 1.6 M solution in hexane, 19.97 mmol) in 70 ml anhydrous THF.
  • the reaction mixture was stirred at -78° for 30 min to allow for complete formation of the lithium anion.
  • the mixture was again cooled to -78° and a solution of ethyl 3,5-di-tert-butyl-2-methoxycinnamate (2.54 g, 7.99 mmol) in 20 ml dry THF was added.
  • Methyl iodide (2.7 ml, 6.1 g, 43 mmol) was added dropwise to a mixture of 3,5-di-tert- butyl-2-hydroxybenzaldehyde (5.0 g, 21.3 mol), potassium carbonate (4.4 g, 32 mmol), tetra-n- butylammonium bromide (0.69 g, 2.1 mmol) dissolved in 100 ml of 2-butanone and the resulting mixture was refluxed for 3 h. Further portions of methyl iodide were added (4 X 3 ml) at regular intervals and refluxing was resumed to complete the conversion.
  • n-Butyllithium (9.3 ml of a 1.6 M solution in hexane, 14.9 mmol) was added to 20 ml of THF cooled to -78°C, followed by diethyl ethylphosphonate (2.15 g, 12.9 mmol). The resulting solution was stirred for 15 min at -78°C, then a solution of methyl 3,5-di-tert-butyl-2- methoxybenzoate (1.8 g, 6.47 mmol) in 5 ml THF was added and the resulting reaction was left to reach room temperature over 2 h.
  • the chloroform phase was separated, the aqueous phase further extracted with fresh chloroform, the combined chloroform phases were dried, evaporated to dryness.
  • the residue was purified by column chromatography (SiO2, AcOEt/MeOH 9/1) to give 4.7 g (16.3 mmol, 71%) of ethyl 3,5- di-tert-butylcinnamate.
  • dimethyl methylphosphonate (2.37 g, 19 mmol) was added at -78°C to a solution of n-butyllithium (12 ml of a 1.6 M solution in hexane, 19.2 mmol) in 50 ml anhydrous THF.
  • the reaction mixture was stirred at -70°C for 30 min to allow for complete formation of the lithium anion (slight turbidity).
  • a solution of ethyl 3,5-di-tert-butylcinnamate (2.2 g, 7.64 mmol) in 5 ml dry THF was added. The resulting mixture was left to stir at room temperature (25°C) for 4 h.
  • diethyl methylphosphonate (3.3 g, 21.7 mmol) was added at - 78°C to a solution of n-butyllithium (13.6 ml of a 1.6 M solution in hexane, 21.7 mmol) in 75 ml anhydrous THF.
  • the reaction mixture was stirred at -78°C for 30 min to allow for complete formation of the lithium anion.
  • the mixture was again cooled to -60°C and a solution of ethyl 3,5-di-tert-butylcinnamate (2.5 g, 8.68 mmol) in 20 ml dry THF was added. The resulting orange-colored mixture was left to stir at room temperature (25 °C) for 2 h.
  • Example 25 Dimethyl 4-(3,5-di-tert-butylphenyl)-l,l-cyclopentyliden-2-oxo-3-buten-l-yl- phosphonate
  • n-Butyllithium (11.5 ml of a 1.6 M solution in hexane, 18.4 mmol) was added to 40 ml of THF cooled to -78°C, followed by dimethyl ethylphosphonate (3.94 g, 28.5 mmol). The resulting solution was stirred for 15 min at -78°C, then a solution of ethyl 3,5-di-tert- butylbenzoate (2.5 g, 9.6 mmol) in 10 ml THF was added and the resulting reaction was left to gradually reach room temperature overnight. A saturated ammonium chloride solution was added, the separated THF phase was collected and the aqueous phase was extracted with 3 portions of ethyl ether.
  • Example 28 Dimethyl 2 ⁇ (3,5 ⁇ di-tert-butylphenyl)-l,l-dimethyl-2-oxo-ethylphosphonate t -Bu
  • dimethyl methylphosphonate (1.8 ml, 16.6 mmol) was added at-78°C to a solution of n-butyllithium (16 ml of a 1.6 M solution in hexane, 40 mmol) in 25 ml anhydrous THF.
  • the reaction mixture was stirred at -70°C for 30 min to allow for complete formation of the lithium anion (slight turbidity).
  • a solution of ethyl 3-[3-tert-butyl-4-hydroxy- 5,6,7,8-tetrahydronaphthyl]-acrylate (2.5 g, 8.3 mmol) in 10 ml dry THF was added.
  • diethyl methylphosphonate (3.8 g, 25 mmol) was added at - 78°C to a solution of n-butyllithium (25 ml of a 1.6 M solution in hexane, 40 mmol) in 25 ml anhydrous THF.
  • the reaction mixture was stirred at -70°C for 30 min to allow for complete formation of the lithium anion (slight turbidity).
  • a solution of ethyl 3-[3-tert-butyl-4-hydroxy- 5,6,7,8-tetrahydronaphthylj-acrylate (2.0 g, 8.0 mmol) in 10 ml dry THF was added.
  • Example 37 Dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l-methyl-2- oxo-3-buten-l-yl-phosphonate
  • diethyl ethylphosphonate (2.89 g, 17.38 mmol) was added at -78°C to a solution of n-butyllithium (10.9 ml of a 1.6 M solution in hexane, 17.38 mmol) in 75 ml anhydrous THF.
  • the reaction mixture was sti ⁇ ed at -78°C for 30 min to allow for complete formation of the lithium anion.
  • a solution of ethyl 3-[3-tert-butyl-4-hydroxy-5,6,7,8- tetrahydronaphthyl] -acrylate (2.1 g, 6.95 mmol) in 10 ml dry THF was added.
  • the chloroform phase was separated, the aqueous phase further extracted with fresh chloroform, the combined chloroform phases were dried, evaoparted to dryness.
  • the resisue was purified by column chromatography (SiO2, AcOEt/hexane 5/95) to give 4 g (12.6 mmol, 70%) of ethyl 3-[3-tert-butyl-4-methoxy- 5,6,7,8-tetrahydronaphthyl]-acrylate. Under nitrogen atmosphere dimethyl methylphosphonate (2.5 g, 20 mmol) was added at
  • diethyl methylphosphonate (2.8 g, 18 mmol) was added at - 78°C to a solution of n-butyllithium (19 ml of a 1.6 M solution in hexane, 30 mmol) in 25 ml anhydrous THF.
  • the reaction mixture was sti ⁇ ed at -70°C for 30 min to allow for complete formation of the lithium anion.
  • a solution of ethyl 3-[3-tert-butyl-4-methoxy-5,6,7,8- tetrahydronaphthyl] -acrylate (1.9 g, 6.0 mmol) in 10 ml dry THF was added.
  • Methyl iodide (5.6 ml, 0.09 mol) was added dropwise to a mixture of 3-tert-butyl-4- hydroxy-5,6,7,8-tetrahydronaphthaldehyde (7.0 g, 0.031 mol), potassium carbonate (8 g, 0.06 mol), tetra-n-butylammonium bromide (0.8 g, 0.002 mol) dissolved in 10 ml of 2-butanone and the resulting mixture was refluxed for 3 h. The cooled mixture was filtered, the filtrate was concentrated under vacuum and partitioned between dichloromethane and water. Evaporation of the dried organic phase gave 7.3 g (0.030 mmol, 95% crude) of 3-tert-butyl-4-methoxy-5,6,7,8- tetrahydronaphthaldehyde.
  • Example 45 Dimethyl 4-(3-tert-butyl-4-methoxy ⁇ 5,6,7,8-tetrahydronaphthyl)-l,l- cyclopentyliden-2-oxo-3-buten-l-yl-phosphonate t-Bu
  • Example 46 Dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l-methyl-2- oxo-3-buten-l-yl-phosphonate
  • dimethyl ethylphosphonate (4.6 g, 29 mmol) was added at - 78°C to a solution of n-butyllithium (30 ml of a 1.6 M solution in hexane, 48 mmol) in 25 ml anhydrous THF.
  • the reaction mixture was sti ⁇ ed at -70° for 30 min to allow for complete formation of the lithium anion.
  • Example 48 Dimethyl 4-(3-tert-butyl-5,5-dimethyl-4-hydroxy-5,6,7,8-tetrahydro-l- naphthyl)-l,l-
  • Example 50 Dimethyl 4-(3-benzyl-4-hydroxy-l-naphthyl)-l,l-dimethyl-2-oxo-3-buten-l- yl-phosphonate
  • Example 51 Dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-2-oxo-l- butyl-phosphonate
  • the title compound was obtained in 40% yield by reducing a solution of dimethyl 4-(3- tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-2-oxo-3-buten-l-yl-phosphonate (0.20 g) over a suspension of Pd/C (0.15 g) in ethyl acetate.
  • Example 52 Dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8- tetrahydronaphthyl)-l,l-dimethyl-2-oxo-l -butyl-phosphonate t-Bu
  • Example 54 Dimethyl 4-(3,5-di-tert-butyl-2-hydroxyphenyl)-l,l-dimethyl-2-oxo-l-butyl- phosphonate
  • the title compound was obtained in 40% yield by reducing a solution of dimethyl 4-(3,5- di-tert-butyl-2-hydroxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l-yl-phosphonate (0.20 g) over a suspension of Pd/C (0.15 g) in ethyl acetate.
  • HMGR levels Quantification of HMGR levels by immunoblotting.
  • HeLa cells ATCC were seeded in 6 wells plates (8.10 5 cells per well) in DMEM containing 10% fetal calf serum (FCS) and grown for 1 day. Then, the medium was replaced by DMEM without FCS and the cells were further grown for 16 h. Products were tested at 1 and 10 ⁇ M final concentrations; they were added as 1000-fold concentrated stock solutions in 50% EtOH and 50% DMSO.
  • Compounds (I) were tested at two different concentrations: 1 and 10 ⁇ M.
  • the relative potencies of Compounds (I) for decreasing HMG-CoA reductase were expressed as approximative % change of samples treated with 10 ⁇ M test compounds of Formula (I) over control samples.
  • HMG-CoA reductase levels were estimated by comparing samples from treated cells with samples from non-treated cells. Estimation of the effect of the compounds was established as follows:
  • +++ is 100% decrease in HMGR levels at 10 ⁇ M /50-99% at 1 ⁇ M ++ is 50-99% decrease in HMGR levels at 10 ⁇ M / 0-50% at 1 ⁇ M + is 10-49% decrease in HMGR levels at 10 ⁇ M / 0% at 1 ⁇ M (+) is 1-10% decrease in HMGR levels at 10 ⁇ M / 0% at 1 ⁇ M.
  • ⁇ -Amyloid Protein determination by ELISA _Ninety-six well-microtiter plates are coated by incubating with a 1 ⁇ g/ml ⁇ -amyloid protein solution in 0.01 M phosphate buffer (pH 7.4) at the volume of 150 ⁇ l/well for 2 h at 37°C. The coating solution is removed and the wells are washed 3 times with 300 ⁇ l of bxrffer solution. Then 250 ⁇ l/well of the following blocking buffer:
  • PBS, 1% BSA is incubated for 1 hour at 37°C and the wells are washed 3 times.
  • Standards, samples and antibodies are diluted in the following buffer solution: PBS, 1% BSA, 0.1% Tween 20, pH 7.4.
  • Standards and samples (100 ⁇ l/well) and the primary antibody (mouse anti-human ⁇ -amyloid protein IgG) diluted 20000 fold are incubated for 2 h at 37°C. After the third wash,
  • 150 ⁇ l of the secondary antibody (anti-mouse IgG peroxidase conjugate) diluted 2000 fold is incubated for 1 h at 37°C.
  • Wells are washed 5 times and 150 ⁇ l/well of substrate (ortho- phenylenediamine dihydrochloride) is incubated for the appropriate time at room temperature in the dark.
  • the reaction is stopped by the addition of 50 ⁇ l/well of 3M sulfuric acid and incubation for 1 min at room temperature.
  • the absorbance at 492 nm versus 620 nm is read on a microplate photometer.
  • Example 57 Tablet Formation A tablet composition containing a compound of formula (I) is prepared by mixing and compressing in a tablet making machine the flowing ingredients: 200 mg. compound of formula (I); 200 mg lactose; and 20 mg magnesium stearate.

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Abstract

L'invention concerne l'utilisation de composés cétophosphonates linéaires pour réduire le cholestérol et les lipides chez des patients, notamment chez des patients n'ayant pas réagi à des statines, en utilisant les cétophosphonates linéaires seuls ou en combinaison avec une statine. L'invention concerne également l'utilisation de cétophosphonates linéaires pour réduire la production de la protéine β-amyloïde.
PCT/US2003/029387 2002-09-19 2003-09-18 Utilisations therapeutiques de cetophosphonates lineaires WO2004026243A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003272534A AU2003272534A1 (en) 2002-09-19 2003-09-18 Therapeutic uses of linear ketophosphonates

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US41209002P 2002-09-19 2002-09-19
US60/412,090 2002-09-19

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PCT/US2003/029322 WO2004026242A2 (fr) 2002-09-19 2003-09-18 Inhibiteurs de ketophosphonate substitue contre la proliferation d'une cellule tumorale
PCT/US2003/029387 WO2004026243A2 (fr) 2002-09-19 2003-09-18 Utilisations therapeutiques de cetophosphonates lineaires

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994019358A1 (fr) * 1993-02-19 1994-09-01 Symphar S.A. Phosphonates substitues, procedes de preparation et compositions pharmaceutiques les contenant

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5116954A (en) * 1988-04-06 1992-05-26 Lipha, Lyonnaise Industrielle Pharmaceutique Pharmaceutically useful flavonoic compounds containing at least one substituent on the benzopyranone ring moiety
CH690163A5 (fr) * 1995-07-28 2000-05-31 Symphar Sa Dérivés gem-diphosphonates substitués utiles en tant qu'agents anti-cancers.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994019358A1 (fr) * 1993-02-19 1994-09-01 Symphar S.A. Phosphonates substitues, procedes de preparation et compositions pharmaceutiques les contenant

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AU2003272534A8 (en) 2004-04-08
WO2004026243A3 (fr) 2004-06-03
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AU2003272534A1 (en) 2004-04-08
AU2003272513A1 (en) 2004-04-08
WO2004026242A2 (fr) 2004-04-01

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