WO2004026243A2 - Therapeutic uses of linear ketophosphonates - Google Patents

Therapeutic uses of linear ketophosphonates 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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French (fr)
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WO2004026243A3 (en
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/en
Publication of WO2004026243A3 publication Critical patent/WO2004026243A3/en

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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

The present invention relates to the use of linear ketophosphonate compounds to decrease cholesterol and lipids in patients, including those that have been shown not to respond to statins, using the linear ketophosphonates alone or in combination with a statin and also use of linear ketophosphonates to decrease the production of β-amyloid protein.

Description

DESCRIPTION
THERAPEUTIC USES OF LINEAR KETOPHOSPHONATES
FIELD OF INVENTION
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 β-amyloid protein.
BACKGROUND OF THE INVENTION
In mammalian cells, 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. 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. When cells are starved for cholesterol and/or Mevalonate, levels of HMGR and LDL receptors are elevated, thus increasing the rate of endogenous sterol synthesis and of LDL uptake. Conversely, in cholesterol-replete cells, the levels of HMG-CoA reductase and LDL receptors decline, thereby lowering sterol production and LDL internalization.
Elevated levels of plasma cholesterol, in particular cholesterol transported by LDL, is a key factor in the pathology of cardiovascular diseases. Inhibition of the biosynthesis of cholesterol has been established as one of the most effective approach to reduce plasma cholesterol, and several enzymes have been selected as target for hypolipidemic drug design. 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. The importance of HMG-CoA reductase is borne out by the fact that 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.
In addition to treatment of cardiovascular disease, there are currently attempts to treat Alzheimer's disease ("AD") through the administration of competitive inhibitors of HMG-CoA reductase inhibitors (the "statins"), a class of drugs used to inhibit cholesterol synthesis. WO002981 discloses the following in vitro data: human cortical cell cultures exposed to cholesterol carrying lipoproteins (VLDL and LDL) increased the production of β-amyloid protein; β-amyloid levels in the cerebral cortex of rats fed a high cholesterol diet are elevated by about 50% compared to β-amyloid levels of rats fed a low cholesterol diet; and human neuronal cultures treated with HMG-CoA reductase inhibitors have significantly decreased levels of β- amyloid production relative to controls. These in vitro results are confirmed by in vivo animal data showing that guinea pigs treated with high doses of simvastatin displayed a potent reduction of β-amyloid levels in cerebrospinal fluid and brain homogenates (Fassbender et al, 2001). Most recent clinical data also indicate that patients treated with lovastatin, an HMG-CoA reductase inhibitor, have blood levels of β-amyloid reduced by up to 40% (Wolozin, 2002). Thus, current evidence indicates that a decrease in cholesterol synthesis results in a reduction of β-amyloid secretion.
Statins, however, 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. For instance, the AUC0-24 for lovastatin and pravastatin are, respectively, 0.285 ± 0.025 and 0.189 ± 0.013 μg /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. Toxicity studies have revealed that 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).
It has now been discovered that Compounds of Formula (I) decrease the amounts of the HMG-CoA reductase, not through direct inhibition of the enzyme, but by inducing its degradation. As HMGR is the rate limiting enzyme in the endogenous cholesterol synthesis, reduction of its levels leads to the inhibition of cholesterol. Thus Compounds of formula (I) are potentially useful as plasma cholesterol lowering agents.
In contrast to the statins that are competitive inhibitors of HMG-CoA reductase, 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.
International Patent application WO9419358 discloses substituted monophosphonate compounds having a phenyl group linked through a short carbon or thio-carbon chain to a phosphonate group. The compounds are disclosed as being potential anti-atherosclerotic agents as a result of their activity in blocking the synthesis of cholesterol and their antioxidant activity.
SUMMARY OF THE INVENTION
The Applicants have now found that substituted phosphonates of formula (I), as set out below, reduce the levels of HMG-Co A reductase by accelerating its rate of degradation and therefore are useful for lowering cholesterol in hyperlipidemic patients and for decreasing β- amyloid protein in a patient subject to or at risk of a disease state associated with elevated production of β-amyloid protein. 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.
Another aspect is a method for for treating and/or preventing a disease state associated with an elevated production of β-amyloid protein. In some embodiments, the disease state associated with an elevated production and/or deposition of β-amyloid protein is selected from the group consisting of Alzheimer's disease, head trauma or stroke. In some embodiments, 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. In some embodiments, 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.
The linear ketophosphonate compounds of the present invention have the following Formula (I):
Ar- ( I )
wherein Ar is:
Figure imgf000005_0001
and X° is H, OH or a straight or branched C\ to C6 alkoxy group,
X1, X2 and X3 are independently H, OH, a straight, branched or cyclic C C6 alkyl or alkoxy group;
0 1 2 3 or X , X or X , X together may form a Cj-C. optionally substituted alkylidenoxy or alkylidenedioxy group; with the proviso that X° is H when X3 is H and X1 and X2 are independently straight or branched
CrC6 alkyl groups;
X4, X5, X6 are independently H, a straight or branched -Cδ alkyl group; q is zero or 1;
X7 is H, a straight or branched -C8 alkyl or alkoxy group, or an optionally substituted benzyl group;
Y is O or S; 7) and Z2 are independently OR1 or NR R , where R1, R , and R are independently H or a
1 2 straight or branched C.-C alkyl group, or Z , Z together may form a C2-C- alkylidenedioxy group; and
L is a saturated or unsaturated -Cπ 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), -C6 alkyl, an optionally substituted aryl or heteroaryl group. The present invention also encompasses pharmaceutically acceptable salts, solvates and hydrates of compounds of formula
(I)- In various embodiments of the present invention, L is -A-C(O)-B-, wherein "-A-" is a direct bond, -CH=C(R4)-,-CH2-C(R4)(R5)-, -C(R4)(R5)-, -O-C(R4)(R5)-, -S-C(R4)(R5)-, where
R4,R5 are independently or different are, H, halogen (F, Cl, Br), C!-C6 straight or branched alkyl, an optionally substituted aryl or heteroaryl,
"-B-" is -C(R6)(R7)- where R6 and R7 are independently H, Halogen (F, Cl, Br), d-C6 straight or branched alkyl, an optionally substituted aryl or heteroaryl, or R6 and R7 can form a ring of C3-C7 carbon atoms.
The term "alkyl" and "alkoxy" as used herein in relation to X°. X1, X2, X3, X6, X7, R1, R2, R3, R4 and R5 means as indicated saturated straight, branched or cyclic substitutents, i.e., straight or branched -(CnH2n+1) or -O(CnH2n+1) or cyclic -(CnH2n-1)- or -O-(CnH2n-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., -CH2F and -OCH2F, to perhalo-substituted alkyl and alkoxy groups, e.g., -CF3 and -OCF3. hi some embodiments, Ar is:
Figure imgf000006_0001
wherein X° is H, OH, OMe, X3 is H, OH, Me, OMe, X1 and X2 are independently a straight or branched -Cό alkyl, a straight or branched Ci to C6 alkoxy group; with the proviso that X° is H when X3 is H, and X1 and X2 are independently a straight or branched d-C6 alkyl groups; Y is O; } and Z2 are the same and are OR1 wherein R1 is methyl, ethyl or isopropyl; L is CH=C(R4)-CO-C(R6R7), or -COC(R6)(R7)-wherein R4, R6 and R7 are as previously defined, and in some embodiments L is CH=CH-CO-C(CH3)2, CH=CH-CO-CH2, CH=CH-CO-CF(CH3), CH=CH-CO-CF2, or CO-CH2, CO-C(CH3)2, CO-CF(CH3), CO-CF2. hi another embodiment, Ar is:
Figure imgf000007_0001
wherein X° is H, OH, OMe;
X4 is H, a straight, branched or cyclic d-Cs alkyl or alkoxy group, more preferably X4 is a tert- butyl group; X5 and X6 are independently H, a d-C4 alkyl group, more preferably X5 and X6 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;
L is CH=C(R4)-CO-C(R6R7), or -COC(R6)(R7)-wherein R4, R6 and R7 are as previously defined, and in some embodiments L is CH=CH-CO-C(CH3)2, CH=CH-CO-CH2, CH=CH-CO-CF(CH3), CH=CH-CO-CF2, or CO-CH2, CO-C(CH3)2, CO-CF(CH3), CO-CF2. In a further embodiments Ar is:
Figure imgf000007_0002
wherein X° is H, OH, SH, OMe, SMe group;
X7 is H, a straight or branched d-C8 alkyl or alkoxy group, preferably a t-butyl group or an optionally substituted benzyl group;
Y is O;
Z1 and Z2 are the same and are OR1 wherein R1 is methyl, ethyl or isopropyl;
L is CH=C(R4)-CO-C(R6R7), or -COC(R6)(R7)-wherein R4, R6 and R7 are as previously defined, and in some embodiments L is CH=CH-CO-C(CH3)2,CH=CH-CO-CH2, CH=CH-CO-CF(CH3), CH=CH-CO-CF2, or CO-CH2, CO-C(CH3)2, CO-CF(CH3), CO-CF2.
In various further embodiments, the novel substituted phosphonate compound of formula
(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; dimethyl 4-(4-hydroxy-3 -methoxy-5 -n-propylphenyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -ylphosphonate; dimethyl 4-(5-tert-butyl-2-hydroxy-3 -methoxyphenyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -ylphosphonate; dimethyl 4-(3 -cyclopentyloxy-4-methoxyphenyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -yl-pho sphonate; dimethyl 4-(3 ,5-di-cyclopentyl-4-hydroxyphenyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -ylphosphonate; diethyl 2-(3,4,5-trimethoxyphenyl)-l,l-dimethyl-2-oxo-ethylphosphonate; dimethyl 4-(3,5-di-tert-butyl-2-hydroxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3,5-di-tert-butyl-2-hydroxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l-yl phosphonate; dimethyl 4-(3 , 5-di-tert-butyl-2-hydroxyphenyl)- 1 , 1 -diethyl-2-oxo-3 -buten- 1 -yl phosphonate; diethyl 4-(3 ,5 -di-tert-butyl-2-hydroxyphenyl)- 1 , 1 -diethyl-2-oxo-3 -buten- 1 -yl phosphonate; dimethyl 4-(3 ,5 -di-tert-butyl-2-hydroxyphenyl)- 1 , 1 -cyclopentyliden-2-oxo-3 -buten- 1 -yl phosphonate; diethyl 4-(3,5-di-tert-butyl-2-hydroxyphenyl)-l,l-cyclopentyliden-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3 ,5 -di-tert-butyl-2-hydroxyphenyl)- 1 -fluoro- 1 -methyl-2-oxo-3 -buten- 1 -yl phosphonate; dimethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3 ,5 -di-tert-butyl-2-methoxyphenyl)-2-oxo-3 -buten- 1 -yl phosphonate; dimethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3 ,5 -di-tert-butyl-2-methoxyphenyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -yl phosphonate; diisopropyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l-yl phosphonate; dimethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-l-methyl-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-l-methyl-2-oxo-3-buten-l-yl phosphonate; dimethyl 4-(3 ,5 -di-tert-butyl-2-methoxyphenyl)- 1 -fluoro- 1 -methyl-2-oxo-3 -buten- 1 -yl phosphonate; diethyl 4-(3 ,5 -di-tert-butyl-2-methoxyphenyl)- 1 -fluoro- 1 -methyl-2-oxo-3 -buten- 1 -yl phosphonate; dimethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-l,l-difluoro-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-l,l-difluoro-2-oxo-3-buten-l-yl phosphonate; dimethyl 4-(3 , 5 -di-tert-butyl-2-methoxyphenyl)- 1 , 1 -diethyl-2-oxo-3 -buten- 1 -yl phosphonate; dimethyl 4-(3 , 5 -di-tert-butyl-2-methoxyphenyl)- 1 , 1 -cyclopentyliden-2-oxo-3 -buten- 1 -yl phosphonate; diethyl 2-(3,5-di-tert-butyl-2-methoxyphenyl)-l-methyl-2-oxoethylphosphonate; diethyl 2-(3,5-di-tert-butyl-2-methoxyphenyl)-l,l-dimethyl-2-oxoethylphosphonate; dimethyl 2-(3 ,5 -di-tert-butyl-2-methox yphenyl)- 1 -fluoro- 1 -methyl-2-oxoethylphosphonate; diethyl 2-(3 ,5-di-tert-butyl-2 -methoxyphenyl)- 1 -fluoro- 1 -methyl-2-oxoethylphosphonate; dimethyl 4-(3,5-di-tert-butylphenyl)-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3,5-di-tert-butylphenyl)-2-oxo-3-buten-l-yl phosphonate; dimethyl 4-(3,5-di-tert-butylphenyl)-l , 1 -dimethyl-2-oxo-3-buten-l -yl phosphonate; diethyl 4-(3 ,5 -di- cert-butyl-phenyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -yl phosphonate; dimethyl 4-(3 ,5 -di-tert-butylphenyl)- 1 -ethyl- 1 -methyl-2-oxo-3-buten- 1 -yl phosphonate; dimethyl 4-(3,5-di-tert-butylphenyl)-l,l-diethyl-2-oxo-3-buten-l-yl phosphonate; dimethyl 4-(3,5-di-tert-butylphenyl)-l,l-cyclopentyliden-2-oxo-3-buten-l-yl phosphonate; dimethyl 4-(3,5-di-tert-butylphenyl)-l,l-fluoro-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3 ,5 -di-tert-butyl-phenyl)- 1 , 1 -fluoro-2-oxo-3 -buten- 1 -yl phosphonate; dimethyl 2-(3,5-di-tert-butylphenyl)-l-methyl-2-oxoethylphosphonate; diethyl 2-(3,5-di-tert-butyl-phenyl)-l-methyl-2-oxoethylphosphonate; dimethyl 2-(3,5-di-tert-butylphenyl)-l,l-dimethyl-2-oxoethylphosphonate; diethyl 2-(3,5-di-tert-butyl-phenyl)-l,l-dimethyl-2-oxoethylphosphonate; dimethyl 2-(3,5-di-tert-butylphenyl)-l-fluoro-l-methyl-2-oxoethylphosphonate; diethyl 2-(3 ,5 -di-tert-butylphenyl)- 1 -fluoro- 1 -methyl-2-oxethylphosphonate; dimethyl 2-(3 ,5 -di-tert-butylphenyl)- 1 , 1 -difluoro-2-oxoethylphosphonate; dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-2-oxo-3-buten-l-yl- phosphonate; diethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-2-oxo-3-buten-l-yl-phosphonate; dimethyl 4-(3 -tert-butyl-4-hydroxy-5 ,6,7, 8-tetrahydronaphthyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 - yl-phosphonate; diethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l,l-din ethyl-2-oxo-3-buten-l-yl- phosphonate; dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l-methyl-2-oxo-3-buten-l-yl- phosphonate; diethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l-methyl-2-oxo-3-buten-l-yl- phosphonate; dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l-fluoro-l-methyl-2-oxo-3- buten- 1 -yl-phosphonate; diethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l-fluoro-l-methyl-2-oxo-3-buten- 1 -yl-phosphonate; dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l-ethyl-l-methyl-2-oxo-3-buten-
1 -yl-phosphonate; dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l , 1 -diethyl-2-oxo-3 -buten- 1 -ylphosphonate; dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l,l-cyclopentylidene-2-oxo-3- buten- 1 -yl-phosphonate; dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-2-oxo-3-buten-l-yl- phosphonate; diethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl-2-oxo-3-buten-l-yl-phosphonate; dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l,l-dimethyl-2-oxo-3-buten-l- yl-phosphonate; diethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l,l-dimethyl-2-oxo-3-buten-l-yl- phosphonate; diisopropyl 4-(3 -tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl-l , 1 -dimethyl-2-oxo-3-buten- 1 - yl-phosphonate; dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l-methyl-2-oxo-3-buten-l-yl- phosphonate; diethyl 4-(3 -tert-butyl-4-methoxy-5 ,6,7, 8-tetrahydronaphthyl)- 1 -methyl-2-oxo-3 -buten- 1 -ylphosphonate; dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l-fluoro-l-methyl-2-oxo-3- buten- 1 -yl-phosphonate; diethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l-fluoro-l-methyl-2-oxo-3-buten-
1 -yl-phosphonate; dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l-ethyl-l-methyl-2-oxo-3- buten-1 -yl-phosphonate; dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l,l-diethyl-2-oxo-3-buten-l-yl- phosphonate; dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l,l-cyclopentylidene-2-oxo-3- buten- 1 -yl-phosphonate; diethyl 2-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l-methyl-2-oxoethyl phosphonate; diethyl 2-(3 -tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)- 1 -fluoro- 1 -methyl-2-oxo- ethylphosphonate; dimethyl 4-(3-tert-butyl-5,5-dimethyl-4-hydroxy-5,6,7,8-tetrahydro-l-naphthyl)-l,l-dimethyl-2- oxo-3-buten- 1 -yl-phosphonate; dimethyl 4-(3 -tert-butyl-4-hydroxy- 1 -naphthyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -yl-pho sphonate; dimethyl 4-(3 -benzyl-4-hydroxy- 1 -naphthyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -yl-pho sphonate; dimethyl 4-(3 ,5 -di-tert-butyl-2-hydroxyphenyl)- 1 , 1 -dimethyl-2-oxo- 1 -butyl-phosphonate; dimethyl 4-(5 -tert-butyl-2-hydroxy-3 -methoxyphenyl)- 1 , 1 -dimethyl-2-oxo- 1 -butyl-phosphonate; and dimethyl 4-(3 -tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)- 1 , 1 -dimethyl-2-oxo- 1 -butyl- phosphonate.
DETAILED DESCRIPTION OF THE INVENTION
I. Substituted Phosphonate Inducers of HMG-CoA reductase degradation
While the present invention is not bound by any particular theory, it is believed that the compounds of formula (I) may at least in part have hypocholesterolemic activity by affecting the MIC pathway. In contrast to the statins that are direct inhibitors of HMG-CoA, 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. As HMGR is the rate limiting enzyme in endogenous cholesterol synthesis, reduction of its levels leads to the inhibition of cholesterol. Thus, compounds of formula (I) are potentially useful as plasma cholesterol lowering agents.
The effect of compounds of Formula (I) on HMG-CoA reductase was studied on the activity of HMGal expressed in Chinese Hamster Ovary (CHO) cells. 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 β-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. Thus, 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. Thus, the effect on HMG-CoA reductase degradation of compounds of Formula (I) can be studied in this system.
In contrast to the statins that are competitive inhibitors of HMG-CoA reductase, 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 .
Pharmaceutically acceptable salts 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.
When some of the compounds of this invention are allowed to crystallise or are recrystallised from organic solvents, solvent of crystallization may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, 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. In addition, 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).
II. Formulations and Administration 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).
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. Examples of 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.
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. For 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.
A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, 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.
Alternatively, 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.
Preferably the composition is in unit dose form such as a tablet or capsule.
The choice of form for administration as well as effective dosages will vary depending, inter alia, on the condition being treated. The choice of mode of administration and dosage is within the ability of the person skilled in the art.
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.
By way of example, 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. The 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.
Typically, 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. 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. Thus, for an average human of 70 kg weight, 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. Ultimately however, the size of the doses administered and the frequency of administration will be at the discretion and judgement of the physician treating the patient. 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 β-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. The compounds of the present invention can also be used in combination with an effective amount of a therapeutic agent for the treatment of Alzheimer's diseas, including Aricept, Exelon, Cognex, Reminyl, ALCAR, AN- 1792, Cerebrolysin, Ampalex, Avlosulfon and Memantine. EXAMPLES OF THE INVENTION
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following specific examples are intended merely to illustrate the invention and not to limit the scope of the disclosure or the scope of the claims in any way whatsoever.
Example 1: Dimethyl 4-(3-methoxy-5-methyl-4-hydroxyphenyl)-l,l-dimethyl-2-oxo-3- buten-1 -yl-p
Figure imgf000016_0001
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 (Siθ2, 98/2 AcOEt/MeOH). An amount of 0.93 g (2.7 mmol, 41 % yield) of the title compound was obtained. MS: m/e = 342: M+, 232: M1" - HPO3Me2, 191 (100%): M+- CMe2(PO3Me2) NMR: (CDC13) δ = 7.62 (d, J = 16Hz, 1H): Ph-CH=CH 7.27 (d, J = 16Hz, 1H): Ph-CH=CH 7.06 and 6.95 (two m, total 2H): arom. H 6.0 (s, 1H): OH
3.93 (s, 3H): arom. O-CH3
3.79 (d, J = 11 Hz, 6H): P-O-CH3
2.27 (s, 3H): arom. CH3
1.51 (d, J = 16.5Hz, 6H): -C(CH )2-P
Example 2: Dimethyl 4-(3,5-dimethoxy-4-hydroxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l- yl-phosphonate
Figure imgf000016_0002
The procedure described in the preceding example was followed, using 3,5-di-methoxy- 4-hydroxybenzaldehyde (1.2 g, 6.6 mmol). The crude compound obtained was purified by flash column chromatography (Siθ2, 98/2 AcOEt/MeOH). An amount of 0.56 g (1.6 mmol, 26 % yield) of the title compound was obtained. MS: m/e = 358: M+ 248: M+ - HPO3Me2, 207 (100%): M+- CMe2(PO3Me2) NMR: (CDC13) δ = 7.62 (d, J = 15.5Hz, 1H): Ph-CH=CH 7.28 (d, J = 16Hz, 1H): Ph-CH=CH 6.85 (s, 2H): arom. H 5.9 (s, 1H): OH
3.94 (s, 6H): arom. O-CH3
3.79 (d, J = 11 Hz, 6H): P-O-CH3
1.52 (d, J = 16.5Hz, 6H): -C(CH3)2-P
Example 3: Dimethyl 4-(3,4,5-trimethoxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l-yl- phosphonate
Figure imgf000017_0001
The procedure described in the preceding example was followed, using 3,4,5-tri- methoxybenzaldehyde (1.3 g, 6.6 mmol). The crude compound obtained was purified by flash column chromatography (Siθ2, 98/2 AcOEt/MeOH). An amount of 1.12 g (3.1 mmol, 45 % yield) of the title compound was obtained.
MS: m/e = 372: M+, 262: M+ - HPO3Me2, 221 (100%): M+- CMe2(PO3Me2) NMR: (CDCI3) δ = 7.61 (d, J = 15.5Hz, 1H): Ph-CH=CH 7.32 (d, J = 15.5Hz, 1H): Ph-CH=CH
6.83 (s, 2H): arom. H 3.91 and 3.89 (two s, total 9H): arom. O-CH3
3.79 (d, J = 11 Hz, 6H): P-O-CH3
1.52 (d, J = 16.5Hz, 6H): -C(CH3)2-P Example 4: Dimethyl 4-(3,5-diethoxy-4-hydroxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l-yl- phosphonate
Figure imgf000018_0001
The procedure described in the preceding example was followed, using 3,5-di-ethoxy-4- hydroxybenzaldehyde (1.4 g, 6.6 mmol). The crude compound obtained was purified by flash column chromatography (Siθ2, 98/2 AcOEt/MeOH). An amount of 1.6 g (4.1 mmol, 62 % yield) of the title compound was obtained.
MS: m/e = 386: M+, 276: M+ - HPO3Me2, 235 (100%): M+- CMe2(PO3Me2) NMR: (CDCI3) δ = 7.59 (d, J = 16Hz, 1H): Ph-CH=CH 7.26 (d, J = 16Hz, 1H): Ph-CH=CH 6.84 (s, 2H): arom. H 5.84 (s, 1H): OH 4.17 (q, J = 7Hz, 4H): arom. O-CH2-CH3
3.78 (d, J - 11 Hz, 6H): P-O-CH3
1.51 (d, J = 16.5Hz, 6H): -C(CH3)2-P
1.47 (t, J = 7Hz, 6H): arom. O-CH2-CH3
Example 5: Dimethyl 4-(4,5-dimethoxy-3-hydroxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l- yl-phosphonate
Figure imgf000018_0002
The procedure described in the preceding example was followed, using 4,5-di-methoxy-3- hydroxybenzaldehyde (1.2 g, 6.6 mmol). The crude compound obtained was purified by flash column chromatography (Siθ2, 98/2 AcOEt/MeOH). An amount of 0.72 g (2.0 mmol, 30 % yield) of the title compound was obtained.
MS: m e = 358: M+, 248: M+ - HPO3Me2, 207 (100%): M+- CMe2(PO3Me2) NMR: (CDCI3) δ = 7.57 (d, J = 15.5Hz, 1H): Ph-CH=CH 7.28 (d, J = 15.5Hz, 1H): Ph-CH=CH 6.95 and 6.69 (two d, J = 2Hz, 2H): arom. H 6.15 (s, 1H): OH 3.92 (d, J = 11 Hz, 6H): P-O-CH3
3.81 and 3.79 (two s, 6H): arom. O-CH3
1.51 (d, J = 16.5Hz, 6H): -C(CH3)2-P
Example 6: Dimethyl 4-(4-hydroxy-3-methoxy-5-n-propylphenyl)-l,l-dimethyl-2-oxo-3-
Figure imgf000019_0001
The procedure described in the preceding example was followed, using 4-hydroxy-3- methoxy-5-n-propylbenzaldehyde (1.28 g, 6.6 mmol). The crude compound obtained was purified by flash column chromatography (SiO2, 98/2 AcOEt/MeOH). An amount of 1.58 g
(4.27 mmol, 65 % yield) of the title compound was obtained.
MS: m/e = 370: M+, 260: M+ - HPO3Me2, 219 (100%): M+- CMe2(PO3Me2) NMR: (CDCI3) δ = 7.63 (d, J = 15.5Hz, 1H): Ph-CH=CH 7.27 (d, J = 15.5Hz, 1H): Ph-CH=CH
7.05 and 6.97 (two d, J = 2H, 2H): arom. H
5.98 (s, 1H): OH
3.93 (s, 3H): arom. O-CH3
3.79 (d, J = 11 Hz, 6H): P-O-CH3 2.62 (q, J = 7 Hz, 2H): arom. CH2-CH2-CH3
1.65 (sextet, J = 7 Hz, 2H): arom. CH2-CH2-CH3
1.51 (d, J = 16.5Hz, 6H): -C(CH3)2-P
0.97 (t, J = 7 Hz, 3H): arom. CH2-CH2-CH3 Example 7: Dimethyl 4-(5-tert-butyl-2-hydroxy-3-methoxyphenyl)-l,l-diniethyl-2-oxo-3- buten-1-yl-phosphonate
Figure imgf000020_0001
To 25 ml dry THF kept at 0°C were added sequentially ΗCI4 (2 ml, 18 mmol), 5-tert- butyl-2-hydroxy-3-methoxybenzaldehyde (1.4 g, 6.7 mmol), dimethyl l,l-dimethyl-2- oxopropylphosphonate (1.6 g, 7.92 mmol), N-methyl morpholine (2.5 ml, 26.4 mmol) then the reaction mixture was stirred for 1 h at room temperature. Work up was carried out by adding 100 ml of iced-water, extracting the resulting mixture with three portions of 100 ml chloroform, washing the chloroform phase with brine and drying over magnesium sulfate. Evaporation of the solvent gave an oil that was purified by flash column chromatography (SiO2, 7/3
AcOEt/hexane). An amount of 1.79 g (4.7 mmol, 70 % yield) of the title compound was obtained.
MS: m/e = 384: M+ 233: M+- CMe2(PO3Me2), 57: tBu+ NMR: (CDCI3) δ = 7.87 (d, J = 15.5Hz, 1H): Ph-CH=CH
7.61 (d, J = 15.5Hz, 1H): Ph-CH=CH
7.10 and 6.92 (2d, 2H): arom. H
6.20 (s, 1H): OH
3.93 (s, 1H): arom. O-CH3 3.80 (d, J = 11 Hz, 6H): P-O-CH3
1.52 (d, J = 16.5Hz, 6H): -C(CH3)2-P
1.32 (s, 9H): t-C_}H.9
Example 8: Dimethyl 4-(3-cyclopentyloxy-4-methoxyphenyl)~l,l-dimethyl-2-oxo-3- buten-1-yl-phosphonate
Figure imgf000020_0002
To 50 ml dry THF kept at 0°C were added sequentially TiC-4 (3.0 ml, 27.3 mmol), 3- cyclopentyloxy-4-methoxybenzaldehyde (2 g, 9.1 mmol), dimethyl l,l-dimethyl-2- oxopropylphosphonate (2.1 g, 10.9 mmol), N-methyl morpholine (3.0 ml, 52.4 mmol) then the reaction mixture was stirred for 1 h at room temperature. Work up was carried out by adding 100 ml of iced-water, extracting the resulting mixture with three portions of 100 ml diethyl ether, washing the ether phase with brine and drying over magnesium sulfate. Evaporation of the solvent gave an oil that was purified by flash column chromatography (Siθ2, pure AcOEt). An amount of 0.92 g (0.25 mmol, 26 % yield) of the title compound was obtained.
MS: m/e = 396: M+, 177 (100%): M+- CMe2(PO3Me2) - cC5H9 NMR: (CDC13) δ = 7.64 (d, J = 15.5Hz, 1H): Ph-CH=CH 7.2 (dd, 1H), 7.10 (d, 1H) and 6.86 (s, 1H): arom. H
7.24 (d, J = 15.5Hz, 1H): Ph-CH=CH 3.88 (s, 3H): OCH3 3.79 and 3.78 (2d, J = 11 Hz, 6H): P-O-CH3
4.82 (septuple., 2H), 2.0-1.8 (m, 4H), 1.88-1.80 (m, 4H) and 1.65-1.61 (m, 8H): cyclo C5H9
1.52 (d, J = 16.7Hz, 6H): -C(CH3)2-P
Example 9: Dimethyl 4-(3,5-dicyclopentyI-4-hydroxyphenyl)-l,l-dimethyl-2-oxo-3-buten- 1-yl-phosphonate
Figure imgf000021_0001
To 20 ml dry THF kept at 0°C were added sequentially ΗCI4 (0.4 ml, 3.72 mmol), 3,5- di-cyclopentyl-4-hydroxybenzaldehyde (0.4 g, 1.55 mmol), dimethyl l,l-dimethyl-2- oxopropylphosphonate (0.4 g, 1.86 mmol), N-methyl morpholine (0.9 ml, 7.44 mmol) then the reaction mixture was strrred for 1 h at room temperature. Work up was carried out by adding 100 ml of iced-water, extracting the resulting mixture with three portions of 100 ml diethyl ether, washing the ether phase with brine and drying over magnesium sulfate. Evaporation of the solvent gave an oil that was purified by flash column chromatography (Siθ2, 7/3
AcOEt/hexane). An amount of 0.14 g (0.32 mmol, 21 % yield) of the title compound was obtained. MS : m/e = 434: M+, 283 (100%): M+- CMe2(PO3Me2) NMR: (CDCI3) δ = 7.66 (d, J = 15.5Hz, 1H): Ph-CH=CH 7.31 (s, 2H): arom. H 7.42 (d, J = 15.5Hz, 1H): Ph-CH=CH ca 5.3: OH 3.84 and 3.78 (2d, J = 11 Hz, 6H): P-O-CH3
3.17 (quintet, 2H), 2.1-2.03 (m, 4H), 1.88-1.80 (m, 4H) and 1.75-1.61 (m, 8H): cyclo
C5H
1.52 (d, J = 16.7Hz, 6H): -C(CH3)2-P
Example 10: Dimethyl 4-(3,5-di-tert-butyl-2-hydroxyphenyl)-l,l-dimethyl-2-oxo-3-buten- 1-yl-phosphonate
Figure imgf000022_0001
To 30 ml dry THF kept at 0°C were added sequentially TiCl4 (2.9 g, 15.5 mmol), 3,5-di- tert-butyl-2-hydroxybenzaldehyde (1.55 g, 6.54 mmol), dimethyl l,l-dimethyl-2- oxopropylphosphonate (1.6 g, 7.83 mmol), N-methyl morpholine (2.5 ml, 3.12 g, 30.9 mmol) then the reaction mixture was stirred for 2 h at 0°C. Work up as previously described and purification by flash column chromatography (Siθ2, 98/2 CH2C12/MeOH) gave 0.87 g (2.2 mmol, 32% yield) of the title compound. Recrystalhzation from a mixture of petroleum ether and dichloromethane gave a white solid, mp= 142-144°C.
MS: m/e= 410: M+, 259 (27%): M+- CMe2(PO3Me2), 57 : tBu+, 152 (100%): CHMe2(PO3Me2)+ NMR: (CDCI3) δ = 7.92 (d, J = 15.5Hz, 1H): Ph-CH=CH
7.35 (d, J = 15.5Hz, 1H): Ph-CH=CH 7.37 and 7.30 (two d, J = 2Hz, 2H): arom. H
5.98 (broad s, 1H): phenol OH
3.80 (d, J = 11Hz, 6H): P-O-CH3
1.52 (d, 16.5Hz, 6H): -C(CH3)2-P
1.45 and 1.31 (two s, 9H each): t-C4H9 Example 11: Diethyl 4-(3,5-di-tert-butyl-2-hydroxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l- yl-phosphonate
Figure imgf000023_0001
To 30 ml dry THF kept at 0°C were added sequentially T1CI4 (7.79 g, 41.03 mmol), 3,5- di-tert-butyl-2-hydroxybenzaldehyde (4.0 g, 17.09 mmol), diethyl l,l-dimethyl-2- oxopropylphosphonate 4.55 g, 20.51 mmol), N-methyl morpholine (8.29 g, 82.05 mmol) then the reaction mixture was stirred for 2 h at 0°C. Work up as previously described and purification by flash column chromatography (SiO2, 98/2 CH2C12/MeOH) gave 0.87 g (1.96 mmol, 13 % yield) of the title compound. Recrystalhzation from a mixture of petroleum ether and dichloromethane gave a white solid, mp= 94-95°C.
MS: m/e = 438: M+, 259 (32%): M+- CMe2(PO3Et2), 180 (100%): CMe2(PO3Et2)+, 57: tBu+ NMR: (CDCI3) δ = 7.89 (d, J = 15.5Hz, 1H): Ph-CH=CH
7.37 (d, J = 15.5Hz, 1H): Ph-CH=CH 7.36 and 7.29 (two d, J = 2Hz, 2H): arom. H
5.98 (broad s, 1H): phenol OH
4.19-4.12 (m, 4H): P-O- CH2-CH3
1.52 (d, 16.5Hz, 6H): -C(CH3)2-P
1.44 and 1.31 (two s, 9H each): t-G|B_9 1.33 (t, J = 7Hz, 6H): P-O- CH2-CH3
Example 12: Diethyl 4-(3,5-di-tert-butyl-2-hydroxyphenyl)-l-fluoro-l-methyl-2-oxo-3- buten-1 -yl-phosphonate
Figure imgf000023_0002
To a suspension of sodium hydride (0.77g of a 60% suspension in mineral oil, 32.05 mmol) in 60 ml THF was added a solution of 3,5-di-tert-butyl-2-hydroxybenzaldehyde (3.0 g, 12.82 mmol) in 10 ml THF and the resulting mixture was stirred for 30 min at 0°C. 2- Methoxyethoxymethyl chloride (3.19 g, 25.64 mmol) was added dropwise and the resuting mixture was stirred for 4 h at room temperature. After hydrolysis by a saturated NH4C1 solution, the reaction mixture was partitioned between water and DCM. The dried organic phase was evaporated and the residue was purified by column chromatography (SiO2, DCM) to give 2.5 g of 3,5-di-tert-butyl-2-(2-methoxyethoxymethoxy) benzaldehyde (7.8 mmol, 61%). To a suspension of sodium hydride (0.93g of a 60% suspension in mineral oil, 38.82 mmol) in 60 ml THF was added a solution of triethyl phosphonoacetate (3.48 g, 15.53 mmol) in 10 ml THF and the resulting mixture was stirred for 30 min at 0°C. 3,5-di-tert-butyl-2-(2- methoxyethoxymethoxy)benzaldehyde (2.5 g, 7.8 mmol) was added dropwise and the resuting mixture was stirred for 2 h at room temperature. After hydrolysis by a saturated NH4C1 solution, the reaction mixture was partitioned between water and DCM. The dried organic phase was evaporated and the residue was purified by column chromatography (SiO2, 98/2 DCM/MeOH) to give 2.1 g of ethyl 3,5-di-tert-butyl-2-(2-methoxyethoxymethoxy)cinnamate (5.4 mmol, 68%). 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. A saturated NH4C1 solution was added, the separated THF phase was collected and the aqueous phase was extracted with DCM. The THF and DCM portions were pooled, reextracted with brine, dried over MgSO4 and evaporated. The residue was purified by column chromatography (SiO2, 98/2 DCM/MeOH) to give 2.2 g (4.3 mmol, 82 %) of diethyl 4-[3,5-di-tert-butyl-2-(2-methoxyethoxymethoxy)phenyl]-l-methyl-2-oxo-3-buten- 1 -ylphosphonate.
A solution of diethyl 4-[3,5-di-tert-butyl-2-(2-methoxyethoxymethoxy)phenyl]-l-methyl- 2-oxo-3 -buten- 1 -ylphosphonate (1.1 g, 2.15 mmol) dissolved in 10 ml MeCN was added to a suspension of sodium ethoxide (0.31 g, 4.51 mmol) in 50 ml MeCN kept at 0°C, the reaction was left to stir for 15 min then l-(chloromethyl)-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.6 g, 4.51 mmol) was added portion-wise and the reaction mixture was left to stir at room temperature for 15 min. Water was added, the mixture was extracted into DCM. The organic solution was extracted with brine, dried over MgSO4 and evaporated. The residue containing 1.1 g (2.07 mmol, 96% crude) of diethyl 2-[3,5-di-tert-butyl-4-(2- methoxyethoxymethoxy) phenyl]-l-fluoro-l-methyl-2-oxo-3-buten-l-ylphosphonate.
A mixture containing the latter compound (0.45 g, 0.89 mmol) was dissolved in a mixture of TFA (1.19 g, 10.4 mmol) in 15 ml dichloromethane was stirred at room temperature for lh. A 10% sodium hydroxide solution was added until pH 6, the aqueous solution extracted with dichloromethane, dried and evaporated to dryness. Purification by column chromatography (SiO2, 8/2 Hexane/AcOEt) gave 0.28 g (0.63 mmol, 30 %) of diethyl 4-(3,5-di-tert-butyl-2- hydroxyphenyl)- 1 -fluoro- 1 -methyl-2-oxo-3 -buten- 1 -ylphosphonate.
MS:m/e= 442: M+, 259 (56%): M+- CMeF-(PO3Et2), 184 (100%): HCMeF-(PO3Et2)+, 57: tBu + NMR: (CDC13) δ = 7.31 and 7.03 (two d, J = 2.4Hz, 2H): arom. H 6.79 (two d, J = 9.7Hz, 1H): Ph-CH=CH 6.00 (d, J = 9.7Hz, 1H): Ph-CH=CH 6.50 (broad s, 1H): phenol OH 4.42-4.25 (m, 4H): P-O- CH2-CH3
1.63(dd, J= 24.6Hz and 13.8 Hz, 3H): -CF(CH3) -P
1.46 and 1.30(two s, 9H each): t-C4H9
1.33 ( two overlapped t, J = 7Hz, 6H) : P-O- CH2-CH3
Example 13: Diethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-2-oxo-3-buten-l-yl phosphonate
Figure imgf000025_0001
A mixture of 3,5-di-tert-butyl-2-methoxybenzaldehyde (5g, 20.16 mmol), ethyl hydrogen malonate (7.45 g, 56.45 mmol), pyridine (7.52 ml, 93 mmol) and piperidine (0.39 ml, 4.03 mmol) was heated at 110°C for 12 h. Pyridine was removed by vacuum distillation then to the residue were added a few drops of 10% HCl to bring the pH to ca 5. The neutralised mixture was extracted with chloroform (three 50 ml portions), the separated organic phase was added to 100 ml of a sodium hydroxide solution (pH = 10) and the resulting mixture was heated for 15 min. 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.
Under nitrogen atmosphere 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. The resulting orange-colored mixture was left to stir at room temperature (25°C) for 2 h. Hydrolysis was carried out by adding 10 ml of a 10%ι HCl solution and the product was extracted into ether, dried over MgSO4 and evaporated. The residue was purified by column choromatography (SiO2, 98/2 DCM/MeOH) to yield a yellow viscous oil (1.2 g, 2.83 mmol, 59% yield) of diethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-2-oxo-3-buten-l-yl phosphonate. MS (m/e): 424: M+, 393 (100%): M+ -OMe, 367: M+ -tBu, 57 (100%): tBu NMR (CDCI3) δ = 7.94 (d, J = 16 Hz, 1H): Ph-CH=CH 7.43 (s, 1H): arom. H
6.87 (d, J - 16Hz, 1H): Ph-CH=CH 4.23-4.13 (m, 4H): P-O-CH2-CH3
3.80: OCH3
3.37 (d, J = 23 Hz, 2H): CH2-P 1.41 and 1.32 (2s, 9H each): t-C4H9
1.34 (t, J = 7Hz, 6H): P-O-CH2-CH3
Example 14: Dimethyl 4-(3,5-di-tert-butyl-2-methoxyphenyI)-l,l-dimethyl-2-oxo-3-buten- 1-yl-phosphonate
Figure imgf000026_0001
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. The cooled mixture was filtered, the filtrate was concentrated under vacuum and partitioned between dichloromethane and water. Evaporation of the dried organic phase gave 5.3 g (22.4 mmol, 101% crude) of 3,5-di-tert-butyl-2- methoxybenzaldehyde. To 30 ml dry THF kept at 0°C were added sequentially ΗCI4 (1.1 ml, 9.78 mmol), 3,5- di-tert-butyl-2-methoxybenzaldehyde (1.0 g, 4.03 mmol), dimethyl l,l-dimethyl-2- oxopropylphosphonate (0.94 g, 4.84 mmol), N-methyl morpholine (1.96 g, 19.4 mmol) then the reaction mixture was stirred for 4h at room temperature. Work up as previously described and purification by flash column chromatography (SiO , 95/5 AcOEt/hexane) gave 0.3 g (0.71 mmol, 18 % yield) of the title compound.
MS: m/e = 424: M+, 393 (100%): M+ - OMe, 273: M+- CMe2(PO3Me2), 57: tBu+ NMR: (CDCI3) δ = 7.97 (d, J = 15.7Hz, 1H): Ph-CH=CH 7.45 and 7.41 (2d, 2H): arom. H
7.38 (d, J = 15.5Hz, 1H): Ph-CH=CH 3.80 (d, J = 11 Hz, 6H): P-O-CH3
3.77 (s, 3H): O-Me
1.53 (d, J = 16.5Hz, 6H): -C(CH3)2-P 1.41 and 1.33 (2s, 9H each): .-C4H9
Example 15: Diethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l- yl-phosphonate
Figure imgf000027_0001
The method described for the preceding example SR- 163106 was followed, using the reactants in the following amounts: THF (15 ml), TiC_4 (0.8 ml, 7.26 mmol), 3,5-di-tert-butyl-2- methoxybenzaldehyde (0.75 g, 3.03 mmol), diethyl l,l-dimethyl-2-oxopropyl phosphonate (0.8 g, 3.63 mmol), N-methyl morpholine (1.6 ml, 14.5 mmol). An amount of 0.8 g (1.77 mmol, 58 % yield) of the title compound was obtained. MS: m/e = 452: M+, 451 (100%): M+ - OMe, 273: M+- CMe2(PO3Et2), 57: tBu+ NMR: (CDCI3) δ = 7.97 (d, J = 15.7Hz, 1H): Ph-CH=CH 7.45 and 7.40 (2d, 2H): arom. H 7.44 (d, J = 15.7 Hz, 1H): Ph-CH=CH 4.19-4.11 (m, 4H): P-O-CH2-CH3 3.76 (s, 3H): O-Me 1.52 (d, J = 16.5Hz, 6H): -C(CH3)2-P 1.40 and 1.33 (2s, 9H each): t-C4H9 1.33 (t, 7Hz, 6H): P-O-CH2-CH3
Example 16: Diisopropyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-l,l~dimethyl-2-oxo-3- buten-1-yl-phosphonate
Figure imgf000028_0001
The method described for the preceding example SR-163106 was followed, using the reactants in the following amounts: THF (15 ml), TiCLj (0.8 ml, 7.26 mmol), 3,5-di-tert-butyl-2- methoxybenzaldehyde (0.75 g, 3.03 mmol), diisopropyl l,l-dimethyl-2-oxopropyl phosphonate (0.9 g, 3.63 mmol), N-methyl mo holine (1.6 ml, 14.5 mmol). An amount of 1.08 g (2.08 mmol, 68%) yield) of the title compound was obtained.
MS: m/e = 480: M+, 449 (86%): M+ - OMe, 273: M+- CMe2(PO3iPr2), 57: tBu+ NMR: (CDC13) δ = 7.95 (d, J = 15.7Hz, 1H): Ph-CH=CH
7.45 and 7.40 (2d, J= 2.4Hz, 2H): arom. H 7.44 (d, J = 15.7Hz, 1H): Ph-CH-CH 4.74 (m, 2H): P-O-CH-(CH3)2 3.76 (s, 3H): O-Me
1.49 (d, J = 16.5Hz, 6H): -C(CH3)2-P
1.40 and 1.33 (2s, 9H each): .-C4H9
1.33 and 1.32 (2d, 6Hz, 6H each): P-O-CH-(CH3)2
1.33 and 1.32 (2d, 7Hz, 6H each): P-O-CH-(CH3)2 Example 17: Diethyl 2-(3,5-di-tert-butyl-2-methoxyphenyl)-l-methyl-2-oxo- ethylphosphonate
Figure imgf000029_0001
A solution of 5.74 g (36.3 mmol) potassium permanganate in 115 ml water was added to a mixture of 6.44 g (25.9 mmol) in 160 ml water heated to 75°C. Heating was continued for a further hour then the reaction mixture was basified with 10% sodium hydroxide, filtered hot over a Buchner funnel and rinsed with hot water. The combined filtrates were cooled and acidified with 10% HCl. A fine precipitate was formed which was extracted into chloroform. The dried organic phase was evaporated to give 3.8 g (55%) of a colorless solid. A 80 ml methanol solution containing 4.0 g (15.1 mmol) of the 3,5-di-tert-butyl-2- methoxybenzoic acid thus formed and 8 ml concentrated sulfuric acid was heated to reflux for 5h. The cooled solution was neutralized with a saturated sodium bicarbonate solution, methanol was evaporated then the residue was basified to pH 10 with 10% sodium hydroxide. The aqueous emulsion was extracted with chloroform, the organic phase was washed with sodium bicarbonate, dried and evaporated to yield 3.89 g (14.0 mmol, 93%) of methyl 3,5 di-tert-butyl- 2-methoxybenzoate as a light brown oil. 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. A saturated NH4C1 solution was added, the separated THF phase was collected and the aqueous phase was extracted with 3 portions of diethyl ether. The THF and ether portions were pooled, extracted with brine, dried over MgSO4 and evaporated. The residue was purified by column chromatography (SiO , 2/8 AcOEt/hexane) to give 2.36 g (5.72 mmol, 88 %) of the title compound as a yellow oil.
Example 18: Diethyl 2-(3,5-di-tert-butyl-2-methoxyphenyl)-l,l-dimethyl-2-oxo- ethylphosphonate
Figure imgf000029_0002
A solution of diethyl 2-(3,5-di-tert-butyl-2-methoxyphenyl)-l-methyl-2-oxo- ethylphosphonate (2.36 g, 5.92 mmol) dissolved in 7 ml THF was added to a suspension of sodium hydride (0.47 g of a 60% dispersion in mineral oil, 11.8 mmol) in 20 ml THF kept at 0°C, the reaction was left to stir for 15 min then methyl iodide (0.74 ml, 11.9 mmol) was added and the reaction mixture was left to stir at room temperature for 2h. Water was added, the separated THF phase was collected and the aqueous phase was extracted with 3 portions of dichloromethane. The THF and DCM portions were pooled, extracted with brine, dried over MgSO4 and evaporated. The residue was purified by column chromatography (SiO2, 95/5 DCM/MeOH) to give 1.03 g (2.41 mmol, 41 %) of the title compound. MS: m/&= 426: M+ , 247 (62%): M+-C(CH3)2-PO3Et2, 57 (100%): tBu+
NMR: (CDC13) δ = 7.34 and 7.13 (2d, 1H each): arom. H 4.21-4.15 (m, 4H): P-O-CH -CH3
3.66 (Is, 3H): arom. O-CH3 1.49 (d, J = 16.5 Hz, 6H): -C(CH.3)2-P
1.38 and 1.30 (2s, 9H each): .-C4H9
1.34 (t, J = 7Hz, 6H): P-O-CH2-CH3
Example 19: Dimethyl 2-(3,5-di-tert-butyl-2-methoxyphenyI)-l-fluoro-l-methyI-2-oxo- ethylphosphonate
Figure imgf000030_0001
A solution of dimethyl 2-(3,5-di-tert-buty-2-methoxylphenyl)-l-methyl-2-oxo- ethylphosphonate (0.5 g, 1.3 mmol) dissolved in 5 ml THF was added to a suspension of sodium hydride (0.06 g of a 60% dispersion in mineral oil, 1.56 mmol) in 10 ml THF kept at 0°C, the reaction was left to stir for 15 min then l-(chloromethyl)-4-fluoro-l,4-diazoniabicyclo [2.2.2] octane bis(tetrafluoroborate) (0.5 g, 1.5 mmol) was added and the reaction mixture was left to stir at room temperature for 2 h. Water was added, the separated THF phase was collected and the aqueous phase was extracted with 3 portions of DCM. The THF and DCM portions were pooled, extracted with brine, dried over MgSO4 and evaporated. The residue was purified by column chromatography (SiO2, 98/2 CHCl3/MeOH) to give 0.12 g (0.3 mmol, 22%) of the title compound. MS: 402: M÷, 247 (100%): M+ - C(F)(Me)PO3Me2 NMR: (CDC13) δ = 7.47 (d, 1H) and 7.45 (t, 1H): arom. H
3.90 and 3.83 (2 d,J = 10.7 Hz, 6H): P-O-CH3
3.72 (s, 3H): arom. O-CH3
1.98 (dd, J = 24.1 and 15.3 Hz, 3H): -CF(CH3)-P
1.41 and 1.32 2(s, 9H each): t-C4H9
Example 20: Dimethyl 4-(3,5-di-tert-butylphenyl)-2-oxo-3-buten-l-yl phosphonate t-Bu
Figure imgf000031_0001
A mixture of 3,5-di-tert-butylbenzaldehyde (5g, 22.94 mmol), ethyl hydrogen malonate (8.48 g, 64.22 mmol), pyridine (8.64 ml, 105 mmol) and piperidine (0.45 ml, 4.59 mmol) was heated at 110°C for 12 h. Pyridine was removed by vacuum distillation then to the residue were added a few drops of 10% HCl to bring the pH to ca 5. The neutralized mixture was extracted with chloroform (three 50 ml portions), the separated organic phase was added to 100 ml of a sodium hydroxide solution (pH = 9) and the resulting mixture was heated for 15 min. 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.
Under nitrogen atmosphere 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. Hydrolysis was carried out by adding 10 ml of a 10% HCl solution and the product was extracted into chloroform. After drying over MgSO4, chloroform was evaporated and the residue was purified by column chromatography (SiO2, AcOEt/hexane 8/2) to give 2 g (5.45 mmol, 72%) of the title compound. MS (m/e): 366 M+, 351 : M+-Me, 309: M+ - tBu, 256: M+-HPO3Me2, 57: fβu+ NMR (CDCI3) δ = 7.67 (d, J = 16Hz, 1H): Ph-CH=CH
7.51 (t, 1H) and 7.42 (d, 2H): arom. H 6.86 (d, J = 16 Hz, 1H): Ph-CH=CH 3.82 (d, J = 11Hz, 6H): P-O-CH3
3.37 (d, J = 22Hz, 2H: CH2-P
1.35 (s, 18H): 1-C4H9
Example 21: Diethyl 4-(3,5-di-tert-butylphenyl)-2-oxo-3-buten-l-yl phosphonate
Figure imgf000032_0001
Under nitrogen atmosphere 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. Hydrolysis was carried out by adding 10 ml of a 10% HCl solution and the product was extracted into ether. After drying over MgSO4, ether was evaporated to yield a yellow solid (2.8 g, 7.1 mmol, 81 % yield) of diethyl 4-(3,5-di-tert-butylphenyl)-2-oxo-3-buten-l-yl phosphonate. Mp=90-91°C MS (m/e): 394: M+, 379: M+ -Me, 337: M+ -tBu, 256: M+-HPO3Et2, 57 (100%): tBu
NMR (CDCI3) δ = 7.67 (d, J = 16 Hz, 1H): Ph-CH=CH 7.50 (t, 1H) and 7.42 (d, 2H): arom. H 6.88 (d, J = 16Hz, 1H): Ph-CH=CH 4.22-4.11 (m, 4H): P-O-CH2-CH3
3.36 (d, J = 23 Hz, 2H): CH2-P
Figure imgf000032_0002
1.35 (t, J = 7Hz, 6H): P-O-CH2-CH3 Example 22: Dimethyl 4-(3,5-di-tert-butylphenyl)-l,l-dimethyl-2-oxo-3-buten-l -ylphosphonate t-Bu
O t-Bu
P03Me2
Me Me
To 50 ml dry THF kept at 0°C were added sequentially TiCl4 (3.6 ml, 32.5 mmol), 3,5- di-tert-butylbenzaldehyde (1.0 g, 4.6 mmol), dimethyl l,l-dimethyl-2-oxopropylphosphonate (1.2 g, 5.95 mmol), N-methyl moφholine (1.85 g, 18.5 mmol) then the reaction mixture was stirred for 1 h at room temperature. Work up was carried out by adding 100 ml of iced-water, extracting the resulting mixture with three portions of 100 ml diethyl ether, washing the ether phase with brine and drying over magnesium sulfate. Evaporation of the solvent gave an oil that was purified by flash column chromatography (SiO2, 1/1 AcOEt/hexane). An amount of 1.0 g
(2.53 mmol, 56 % yield) of the title compound was obtained, mp = 50-52°C.
MS: m/e = 395: M+ + 1, 243 (100%): M+- CMe2(PO3Me2), 57: tBu+ NMR: (CDC13) δ = 7.77 (d, J = 15.6Hz, 1H): Ph-CH=CH 7.53 (t, 1H) and 7.48 (d, 2H): arom. H
7.42 (d, J = 15.6Hz, 1H): Ph-CH-CH 3.84 and 3.78 (2d, J = 11 Hz, 6H): P-O-CH3
1.57 (d, J = 16.7Hz, 6H): -C(CH3)2-P
1.39 (s, 18H): t-C4H9
Example 23: Diethyl 4-(3,5-di-tert-butylphenyl)-l,l-dimethyl-2-oxo-3-buten-l-yl- phosphonate t-Bu
Figure imgf000033_0001
The method described for the preceding example was followed, using the reactants in the following amounts: THF (10 ml), ΗCI4 (0.8 g, 4.14 mmol), 3,5-di-tert-butylbenzaldehyde (0.3 g, 1.38 mmol), diethyl l,l-dimethyl-2-oxopropyl phosphonate (0.4 g, 1.8 mmol), N-methyl morpholine (0.56 g, 5.52 mmol). An amount of 0.52 g (1.23 mmol, 89 % yield) of the title compound was obtained. MS: m/e = 423: M+ + 1, 243 (100%): M+- CMe2(PO3Et2), 57: tBu+ NMR: (CDCI3) δ = 7.75 (d, J = 16Hz, 1H): Ph-CH=CH 7.53 (t, 1H) and 7.48 (d, 2H): arom. H 7.45 (d, J = 16Hz, 1H): Ph-CH=CH 4.19 (m, 4H): P-O-CH2-CH
1.56 (d, J = 17Hz, 6H): -C(CH3)2-P
1.39 (s, 18H): t-C4H9
1.37 (t, J = 7Hz, 6H): P-O-CH2-CH3
Example 24: Dimethyl 4-(3,5-di-tert-butylphenyl)-l,l-diethyl-2-oxo-3-buten-l-yl- phosphonate t-Bu
Figure imgf000034_0001
MS: m e = 423: M++ 1, 243 (100%): M+- C(Et)2(PO3Me2), 57 : tBu+ NMR: (CDCI3) δ = 7.72 (d, J = 15.5Hz, 1H): Ph-CH=CH 7.49 (t, 1H) and 7.43 (d, 2H): arom. H 7.37 (d, J = 15.5Hz, 1H): Ph-CH=CH 3.79 (d, J = 11 Hz, 6H): P-O-CH3 2.08 (m, 4H): -C(CH2-CH3) -P
1.36 (s, 18H): t-C4H9
0.98 (t, J = 7 Hz, 6H): -C(CH2-CH3)2-P
Example 25: Dimethyl 4-(3,5-di-tert-butylphenyl)-l,l-cyclopentyliden-2-oxo-3-buten-l-yl- phosphonate
Figure imgf000034_0002
MS: m/e = 420: M+, 243 (100%): M+- (c-C5H8)(PO3Me2), 57: tBu+ NMR: (CDCI3) δ = 7.73 (d, J = 15.5Hz, 1H): Ph-CH=CH 7.49 (t, 1H) and 7.43 (d, 2H): arom. H 7.30 (d, J = 15.5Hz, 1H): Ph-CH=CH 3.79 (d, J = 11 Hz, 6H): P-O-CH3
2.47, 2.20, 1.74 and 1.55 (4m, 2H each): -(c-C5H8)-P 1.35 (s, 18H): t-C4H.9
Example 26: Dimethyl 2-(3,5-di-tert-butylphenyl)-l-methyI-2-oxo-ethylphosphonate
Figure imgf000035_0001
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. The THF and ether portions were pooled, extracted with brine, dried over MgSO4 and evaporated. The residue was purified by column chromatography (SiO2, 6/4 AcOEt/hexane) to give 2.36 g (6.67 mmol, 69 %) of the title compound. MS: m e= 354: M+, 217 (100%): M+- CH(CH3)-PO3Me2, 57: tBu
NMR: (CDCI3) δ = 7.86 (d, 2H) and 7.67 (t, 1H): arom. H
4.23 and 4.19 (2 quartets, J=22.3 Hz, 1H): -CH(CH3)-P 3.78 and 3.74 (2d, J = 11 Hz, 6H): P-O-CH3 1.56 (dd, J = 18.3 and 7 Hz, 3H): -CH(CH3)-P
1.37 (s, 18H): t-C4£E9 Example 27: Diethyl 2-(3,5-di-tert-butylphenyl)-l-methyl-2-oxo-ethylphosphonate
Figure imgf000036_0001
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 diethyl ethylphosphonate (4.75 g, 28.6 mmol). The resulting solution was stiπed 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 diethyl ether. The
THF and ether portions were pooled, extracted with brine, dried over MgSO4 and evaporated. The residue was purified by column chromatography (SiO2, 4/6 AcOEt/hexane) to give 2.32 g
(6.0 mmol, 63 %) of the title compound.
MS: m/e- 382: M+, 217 (100%): M+-CH(CH3)-PO3Et2, 57: tBu
NMR: (CDCI3) δ = 7.85 (d, 2H) and 7.65 (t, 1H): arom. H 4.20-4.05 (m, 4H): P-O-CH2-CH3
4.20 (overlapped m, 1H): -CH(CH3)-P 1.54 (dd, J = 18.1 and 7 Hz, 3H): -CH(CH3)-P 1.36 (s, 18H): t-C4H9
1.30 and 1.20 (2t, J = 7Hz, 6H): P-O-CH2-CH3
Example 28: Dimethyl 2~(3,5~di-tert-butylphenyl)-l,l-dimethyl-2-oxo-ethylphosphonate t -Bu
> Λ-PO Me,
A solution of dimethyl 2-(3,5-di-tert-butylphenyl)-l-methyl-2-oxo-ethylphosphonate (1.0 g, 2.82 mmol) dissolved in 10ml THF was added to a suspension of sodium hydride (0.23 g of a 60% dispersion in mineral oil, 5.6 mmol) in 20 ml THF kept at 0°C, the reaction was left to stir for 15 min then methyl iodide (1.2 g, 8.5 mmol) was added and the reaction mixture was left to stir at room temperature for 2h. Water was added, the separated THF phase was collected and the aqueous phase was extracted with 3 portions of dichloromethane. The THF and DCM portions were pooled, extracted with brine, dried over MgSO4 and evaporated. The residue was purified by column chromatography (SiO2, 4/6 AcOEt/hexane) to give 0.6 g (1.94 mmol, 68 %) of the title compound.
MS: m/e= 368: M+, 217 (100%): M+- CH(CH3)-PO3Me2, 57: tBu+
NMR: (CDC13) δ = . 7.86 (s, 2H) and 7.55 (t, 1H): arom. H 3.80 (d, J = 11 Hz, 6H): P-O-CH3
1.60 (d, J = 16.5 Hz, 6H): -C(CH3)2-P
1.36 (s, 18H): t-C4H9
Example 29: Diethyl 2-(3,5-di-tert-butylphenyl)-l,l-dimethyl-2-oxo-ethylphosphonate
Figure imgf000037_0001
A solution of diethyl 2-(3, 5 -di-tert-butylphenyl)- l-methyl-2-oxo-ethylphosphonate (1.0 g, 2.62 mmol) dissolved in 10ml THF was added to a suspension of sodium hydride (0.26 g of a 60% dispersion in mineral oil, 6.53 mmol) in 15 ml THF kept at 0°C, the reaction was left to stir for 15 min then methyl iodide (1.48 g, 10.5 mmol) was added and the reaction mixture was left to stir at room temperature for 2h. Water was added, the separated THF phase was collected and the aqueous phase was extracted with 3 portions of dichloromethane. The THF and DCM portions were pooled, extracted with brine, dried over MgSO4 and evaporated. The residue was purified by column chromatography (SiO2, 2/3 AcOEt/hexane) to give 0.65 g (1.7 mmol, 65 %) of the title compound.
MS: m/e= 396: M+, 217 (100%): M+- C (CH3) -PO3Et2, 57: tBu+
NMR: (CDCI3) δ = 7.85 (d, 2H) and 7.54 (t, 1H): arom. H 4.20-4.10 (m, 4H): P-O-CH2 -CH3
1.58 (d, J = 16.5 Hz, 6H): -C(CH3)2-P
1.35 (s, 18H): .-C4H9
1.30 (t, J=7 Hz, 6H): P-O-CH2 -CH3 Example 30: Diethyl 2-(3,4,5-trimethoxyphenyl)-l,l-dimethyl-2-oxo-ethylphosphonate
Figure imgf000038_0001
The procedure described in the preceding example was followed, using ethyl 3,4,5- trimethoxybenzoate as the starting compound. MS: m/e= 374: M+ , 195 (100%): M+-C(CH3)2-PO3Et2
NMR: (CDC13) δ = 7.54 (s, 2H): arom. H
4.15 (m, 4H): P-O-CH2-CH3
3.91(s, 9H): arom. O-CH3 1.58 (d, J - 16.5 Hz, 6H): -C(CH3)2-P
1.31 (t, J = 7Hz, 6H): P-O-CH2-CH3
Example 31: Dimethyl 2-(3,5-di-tert-butylphenyl)-l-fluoro-l~methyI-2-oxo- ethylphosphonate
Figure imgf000038_0002
A solution of dimethyl 2-(3,5-di-tert-butylphenyl)-l-methyl-2-oxo-ethylphosphonate (1.0 g, 2.82 mmol) dissolved in 10 ml THF was added to a suspension of sodium hydride (0.175 g of a 60%) dispersion in mineral oil, 4.35 mmol) in 20 ml THF kept at 0°C, the reaction was left to stir for 15 min then l-(chloromethyl)-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.3 g, 3.7 mmol) was added and the reaction mixture was left to stir at room temperature for 1 h. Water was added, the separated THF phase was collected and the aqueous phase was extracted with 3 portions of DCM. The THF and DCM portions were pooled, extracted with brine, dried over MgSO4 and evaporated. The residue was purified by column chromatography (SiO2, 2/3 AcOEt/hexane) to give 0.57 g (1.54 mmol, 59%) of the title compound.
MS: m/e= 372: M+, 217 (100%): M+- CF(CH3)-PO3Me2, 57: tBu NMR: (CDCI3) δ = 7.95 (d, J = 1.6 Hz, 2H) and 7.67 (t, 1H ): arom. H 3.92 and 3.90 (2 d,J = 10.7 Hz, 6H): P-O-CH3
1.95 (dd, J = 24.1 and 15.3 Hz, 3H): -CF(CH3)-P
1.46 (s, 18H): t-C4H9
Example 32: Diethyl 2-(3,5-di-tert-butylphenyl)-l-fluoro-l-methyl-2-oxo-ethylphosphonate
Figure imgf000039_0001
A solution of diethyl 2-(3,5-di-tert-butylphenyl)-l-methyl-2-oxo-ethylphosphonate (1.0 g, 2.61 mmol) dissolved in 5 ml THF was added to a suspension of sodium hydride (0.21 g of a 60% dispersion in mineral oil, 5.23 mmol) in 15 ml THF kept at 0°C, the reaction was left to stir for 15 min then l-(chloromethyl)-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.85 g, 5.23 mmol) was added and the reaction mixture was left to stir at room temperature for 2 h. Water was added, the separated THF phase was collected and the aqueous phase was extracted with 3 portions of DCM. The THF and DCM portions were pooled, extracted with brine, dried over MgSO4 and evaporated. The residue was purified by column chromatography (SiO2, 2/3 AcOEt/hexane) to give 0.50 g (1.25 mmol, 48%) of the title compound.
MS: m/e=400: M+, 217 (100%): M+- CF (CH3)-PO3Et2, 57: tBu+
NMR: (CDCI3) δ = 7.95 (t, J = 1.6 Hz, 2H) and 7.67 (t, 1H ): arom. H 4.32-4.20 (m, 4H): P-O-CH2-CH3 1.95 (dd, J = 24.1 and 15.3 Hz, 3H): -CF(CH3)-P
1.36 (s, 18H): t-C4H9
1.36 and 1.35 (two t, 6H): P-O-CH2-CH3 Example 33: Dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl )-2-oxo-3- buten-1-yl phosphonate t-Bu
Figure imgf000040_0001
A mixture of 3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaththaldehyde (5.09 g, 21.6 mmol), ethyl hydrogen malonate (8 g, 60.5 mmol), pyridine (8 ml, 99 mmol) and piperidine (0.43 ml, 4.3 mmol) was heated at 110°C for 7 h. To the cooled mixture were added water (50 ml) and a few drops of 10% HCl to bring the pH to about 5 then the mixture was extracted with chloroform (threee 150 ml portions). The separated organic phase was added to 100 ml of a sodium hydroxide solution (pH = 9) and the resulting mixture was heated for 30 min. 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 trituration in 40-60 petroleum ether to give 4 g (9.9 mmol, 46%) of ethyl 3-[3-tert-butyl-4- hydroxy-5 ,6,7, 8 -tetrahydronaphthyl] -acrylate.
Under nitrogen atmosphere 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. The resulting mixture was left to stir at room temperature (25°C) for 3 h. Hydrolysis was carried out by adding 10 ml of a saturated NH4C1 solution and the product was extracted into chloroform. After drying over MgSO4, chloroform was evaporated and the residue was purified by column chromatography (SiO2, AcOEt/hexane 7/3) to give 0.89 g (2.34 mmol, 23%) of the title compound.
MS: m e = 380: M+, 362: M+ - H2O, 252: M - H2O - HPO3Me2, 57 (100%): tBu+ NMR : (CDC13) δ = 7.98 (d, J = 16Hz, 1H): Ph-CH=CH 7.48 (s, 1H): arom. H 6.68 (d, J = 16Hz, 1H): Ph-CH=CH ca 5.3 (1H): OH " 3.82 (d, J = 11 Hz, 6H): P-O-CH3
3.35 (d, J = 22Hz, 2H): CH2-P 2.86 (t, 2H), 2.59 (t, 2H), 1.89-1.82 (m, 2H) and 1.83-1.77 (m, 2H): C4H8 1.44 (s, 9H): t-C H9
Example 34: Diethyl 4-(3-tert-butyI-4-hydroxy-5,6,7,8-tetrahydronaphthyl )-2-oxo-3- buten-1-yl phosphonate t-Bu
Figure imgf000041_0001
Under nitrogen atmosphere 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. The resulting mixture was left to stir at room temperature (25°C) for 3 h. Hydrolysis was carried out by adding 10 ml of a saturated NH4C1 solution and the product was extracted into chloroform. After drying over MgSO4, chlorofonn was evaporated and the residue was purified by column chromatography (SiO2, AcOEt/hexane 7/3) to give 0.77 g (2.34 mmol, 24%) of the title compound.
MS: m/e = 408: M+, 390: M+ - H20, 252: M+ - H2O - HPO3Et2, 57 (100%): tBu+ NMR: (CDC13) δ = 7.96 (d, J = 16Hz, 1H): Ph-CH=CH 7.46 (s, 1H): arom. H
6.70 (d, J = 16Hz, 1H): Ph-CH=CH ca 5.3 (1H): OH
4.22-4.12 (m, 4H): P-O-CH2-CH3
3.32 (d, J = 22Hz, 2H): CH2-P 2.86 (t, 2H), 2.57 (t, 2H), 1.89-1.82 (m, 2H) and 1.83-1.76 (m, 2H): C4H8-
1.41 (s, 9H): t-C4H9
1.34 (t, J = 7Hz, 6H): P-O-CH2-CH3 Example 35: Dimethyl 7,8-tetrahydronaphthyl)-l,l- dimethyl-2-
Figure imgf000042_0001
To 30 ml dry THF kept at 0°C were added sequentially ΗCI4 (3.5 g, 18.0 mmol), 3-tert- butyl-4-hydroxy-5,6,7,8-tetrahydronaphthaldehyde (1.5 g, 6.6 mmol), dimethyl l,l-dimethyl-2- oxopropylphosphonate (1.6 g, 8.6 mmol), N-methyl morpholine (2.6 g, 26.4 mmol) then the reaction mixture was stiπed for 45 min at room temperature. Work up was carried out by adding 50 ml of iced-water, extracting the resulting mixture with three portions of 100 ml dichloromethane, washing the organic phase with brine and drying over magnesium sulfate. Evaporation of the solvent gave a residue that was purified by trituration in petroleum ether. An amount of 1.7 g (4.16 mmol, 63 % yield) of the title compound was obtained.
MS: m/e = 408: M+, 298: M+ - HPO3Me2, 257: M+- CMe2(PO3Me2), 57 (100%): tBu+ NMR: (CDCI3) δ = 8.15 (d, J = 18Hz, 1H): Ph-CH=CH 7.50 (s, 1H): arom. H
7.18 (d, J = 18Hz, 1H): Ph-CH-CH ca 5.3 (1H): OH
3.81 (d, J = 11 Hz, 6H): P-O-CH3
2.86, 2.59, 1.89-1.82, 1.83-1.76 and 1.48-1.38 (total 8H): C4H8- 1.52 (d, J = 11 Hz, 6H): -C(CH3)2-P
1.44 (s, 9H): t-C H9
Example 36: Diethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l,l-dimethyl- 2-oxo-3-buten-l-yl-phosphonate
Figure imgf000042_0002
To 30 ml dry THF kept at 0°C were added sequentially ΗCI4 (2 ml, 18.0 mmol), 3-tert- butyl-4-hydroxy-5,6,7,8-tetrahydronaphthaldehyde (1.5 g, 6.5 mmol), diethyl l,l-dimethyl-2- oxopropylphosphonate (1.8 g, 8.0 mmol), N-methyl morpholine (2.5 ml, 26.4 mmol) then the reaction mixture was stiπed for 45 min at room temperature. Work up was carried out by adding 50 ml of iced-water, extracting the resulting mixture with three portions of 100 ml dichloromethane, washing the organic phase with brine and drying over magnesium sulfate. Evaporation of the solvent gave a residue that was purified by column chromatography (SiO2, AcOEt/hexane 7/3). An amount of 2.21 g (4.16 mmol, 78 % yield) of the title compound was obtained.
MS: m/e = 436: M+, 257: M+ - C(Me2)PO3Et2, 57 (100%): tBu+
Figure imgf000043_0001
δ = 7.99 (d, J = 16Hz, 1H): Ph-CH=CH 7.50 (s, 1H): arom. H
7.22 (d, J = 16Hz, 1H): Ph-CH=CH ca 5.3 (1H): OH
4.18-4.12 (m, 4H): P-O-CH2-CH3
2.86 (t, 2H), 2.57 (t, 2H), 1.88-1.82 (m, 2H) and 1.82-1.76 (m, 2H): C4H8- 1.51 (d, J = 16.7 Hz, 6H): -C(CH3)2-P
1.43 (s, 9H): t-C H9
1.33 (t, J = 7Hz, 6H): P-O-CH2-CH3
Example 37: Dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l-methyl-2- oxo-3-buten-l-yl-phosphonate
Figure imgf000043_0002
To a suspension of sodium hydride (1.55 g of a 60% suspension in mineral oil, 64.66 mmol) in 60 ml THF was added a solution of 3-tert-butyl-4-hydroxy-5,6,7,8- tetrahydronaphthaldehyde (6.0 g, 25.86 mmol) in 10 ml THF and the resulting mixture was stiπed for 30 min at 0°C. 2-Methoxyethoxymethyl chloride (6.44 g, 51.72 mmol) was added dropwise and the resuting mixture was stirred for 4 h at room temperature. After hydrolysis by a saturated NH4C1 solution, the reaction mixture was partitioned between water and DCM. The dried organic phase was evaporated and the residue was purified by column chromatography (SiO2, DCM) to give 4.8 g of 3-tert-butyl-4-(2-methoxyethoxymethoxy)-5,6,7,8- tetrahydronaphthaldehyde (58%). To a suspension of sodium hydride (0.90 g of a 60% suspension in mineral oil, 37.50 mmol) in 60 ml, THF was added a solution of triethyl phosphonoacetate (4.03 g, 18 mmol) in 10 ml THF and the resulting mixture was stiπed for 30 min at 0°C. 3-Tert-butyl-4-(2- methoxyethoxymethoxy)-5,6,7,8-tetrahydronaphthaldehyde (4.8 g, 15 mmol) was added dropwise and the resuting mixture was stiπed for 2 h at room temperature. After hydrolysis by a saturated NH4C1 solution, the reaction mixture was partitioned between water and DCM. The dried organic phase was evaporated and the residue was purified by column chromatography (SiO2, 98/2 DCM/MeOH) to give 2.71 g of ethyl 3-[3-tert-butyl-4-(2-methoxyethoxymethoxy)- 5,6,7,8-tetrahydronaphthyl] acrylate (46%). n-Butyllithium (10.86 ml of a 1.6 M solution in hexane, 17.37 mmol) was added to 80 ml of THF cooled to -78°C, followed by dimethyl ethylphosphonate (2.4 g, 17.37 mmol). The resulting solution was stiπed for 15 min at -78°C, then a solution of 2.71 g (6.95 mmol) of ethyl 3-[3-tert-butyl-4-(2-methoxyethoxymethoxy)-5,6,7,8-tetrahydronaphthyl] acrylate in 10 ml THF was added and the resulting reaction was left to stir at -78°C for 1 h. A saturated NH4C1 solution was added, the separated THF phase was collected and the aqueous phase was extracted with DCM. The THF and DCM portions were pooled, reextracted with brine, dried over MgSO4 and evaporated. The residue was purified by column chromatography (SiO2, 98/2 DCM/MeOH) to give 1.6 g (3.32 mmol, 47 %) of dimethyl 4-[3-tert-butyl-4-(2-methoxyethoxymethoxy)- 5,6,7,8-tetrahydronaphthyl]-l-methyl-2-oxo-3-buten-l-yl-phosphonate . A mixture containing the latter compound (1.6 g, 3.32 mmol) and TFA (1.89 g, 16.6 mmol) in 50 ml DCM was stirred at room temperature for 1 h. A 10%) sodium hydroxide solution was added until pH = 5-6, the aqueous solution extracted with DCM, dried and evaporated to dryness. Purification by column chromatography (SiO2, 98/2 DCM/MeOH gave 0.35 g (30%) of the title compound (mp=128-130°C after recrystallisation from DCM/Petroleum ether). MS: m/e = 394: M+, 376: M+ - H2O, 257: M+- CHMe (PO3Me2), 57 (79%): tBu+, 138 (100 %): HCHMe (PO3Me2) + NMR: (CDC13) δ = 7.98 (d, J = 15.6Hz, 1H): Ph-CH=CH 7.49 (s, 1H): arom. H 6.79 (d, J = 15.6Hz, 1H): Ph-CH=CH ca 5.3 (1H): OH 3.81 (2d, J = 11 Hz, 6H): P-O-CH3
3.58-3.48 (2 quartets, 1H): CH(CH3) -P 2.86, 2.59, 1.89-1.83 and 1.82-1.78 (total 8H): C4H8- 1.49 (2d, J = 7 Hz, 3H): -CH(CH3) -P
1.43 (s, 9H): t-C4H9
Example 38: Diethyl 4-(3-tert-butyI-4-hydroxy-5,6,7,8-tetrahydronaphthyI)-l-methyI-2- oxo-3-buten-l-yl-phosphonate
Figure imgf000045_0001
Under nitrogen atmosphere 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 stiπed 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 resulting mixture was left to stir at -78°C for 2 h, then at 25°C for lh. Hydrolysis was carried out by adding 10 ml of a saturated NH C1 solution and the product was extracted into DCM. After drying over MgSO4, DCM was evaporated and the residue was purified by column chromatography (SiO2, 98/2 DCM/MeOH) to give an oil that was further purified by recrystalhzation from petroleum ether/DCM. An amount of 1.3 g (3.08 mmol, 44 %) of the title compound was obtained; mp=l 10-111°C.
MS: m e = 422: M+, 257: M+ - CH(Me)PO3Et2, 57 (77%): tBu+ NMR: (CDC13) δ = 7.99 (d, J = 15.6Hz, 1H): Ph-CH=CH 7.49 (s, 1H): arom. H 6.82 (d, J = 15.6Hz, 1H): Ph-CH=CH ca 5.3 (1H): OH 4.18-4.12 (m, 4H): P-O-CH2-CH3
3.53-3.43 (2 quartets, J= 7Hz, 1H): CH(CH3) -P
2.86 (t, 2H), 2.57 (t, 2H), 1.88-1.82 (m, 2H) and 1.82-1.76 (m, 2H): C4H8- 1.49 and 1.45 (2d, J = 7 Hz, 3H): -CH(CH3) -P
1.43 (s, 9H): t-C4U9 1.33 (2t overlapped, J = 7Hz, 6H): P-O-CH2-CH Example 39: Dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl )-2-oxo-3- buten-1-yl phosphonate
Figure imgf000046_0001
A mixture of 3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthaldehyde (4.8 g, 18 mmol), ethyl hydrogen malonate (8 g, 61 mmol), pyridine (8 ml, 99 mmol) and piperidine (0.43 ml, 4.3 mmol) was heated at 110°C for 8 h. To the cooled mixture were added water (50 ml) and a few drops of 10% HCl to bring the pH to ca 5 then the mixture was extracted with chloroform (three 150 ml portions). The separated organic phase was added to 100 ml of a sodium hydroxide solution (pH = 9) and the resulting mixture was heated for 15 min. 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
-78°C to a solution of n-butyllithium (21 ml of a 1.6 M solution in hexane, 33 mmol) in 25 ml anhydrous THF. The reaction mixture was stiπed at -70° for 30 min to allow for complete formation of the lithium anion (slight turbidity). A solution of ethyl 3-[3-tert-butyl-4-methoxy- 5,6,7,8-tetrahydronaphthyl]-acrylate (2.0 g, 6.6 mmol) in 10 ml dry THF was added. The resulting mixture was left to stir at room temperature (25°C) for 18 h. Hydrolysis was caπied out by adding 10 ml of a 10% HCl solution and the product was extracted into chloroform. After drying over MgSO4, chloroform was evaporated and the residue was purified by column chromatography (SiO2, AcOEt/hexane 8/2) to give 0.51 g (1.29 mmol, 20%) of the title compound. MS: m/e = 394: M+, 376: M+ - H20, 266: M1" - H2O - HPO3Me2, 57 (100%): tBu+ NMR: (CDC13) δ = 8.01 (d, J = 16Hz, 1H): Ph-CH=CH 7.50 (s, 1H): arom. H 6.73 (d, J = 16Hz, 1H): Ph-CH=CH 3.86 (d, J = 11 Hz, 6H): P-O-CH3
3.84 (s, 3H): arom. O-CH3 3.39 (d, J = 22Hz, 2H): CH2-P
2.92 (t, 2H), 2.81 (t, 2H), 1.91-1.86 (m, 2H) and 1.80-1.76 (m, 2H): C4H8- 1.44 (s, 9H): t-C4H9
Example 40: Diethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl )-2-oxo-3- buten-1-yl phosphonate t-Bu
Figure imgf000047_0001
Under nitrogen atmosphere 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 stiπed 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. The resulting mixture was left to stir at room temperature (25°C) for 4 h. Hydrolysis was caπied out by adding 10 ml of a 10% HCl solution and the product was extracted into chloroform. After drying over MgSO4, chloroform was evaporated and the residue was purified by column chromatography
(SiO2, AcOEt/hexane 8/2) to give 0.79 g (1.87 mmol, 31%) of the title compound. MS: m e = 423: M1" + 1, 404: M1" - H20, 266: M+ - H2O - HPO3Et2, 57 (100%): tBu+ NMR: (CDC13) δ = 7.96 (d, J = 16Hz, 1H): Ph-CH=CH 7.45 (s, 1H): arom. H
6.71 (d, J = 16Hz, 1H): Ph-CH=CH
4.22-4.12 (m, 4H): P-O-CH2-CH3
3.79 (s, 3H): arom. O-CH3
3.33 (d, J = 22Hz, 2H): CH2-P 2.87 (t, 2H), 2.77 (t, 2H), 1.85-1.81 (m, 2H) and 1.74-1.71 (m, 2H): C4H8-
1.39 (s, 9H): t-C4H9
1.33 (t, J = 7Hz, 6H): P-O-CH2-CH.3 Example 41 : Dimethyl 4-(3-tert~butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l ,1- dimethyl-2-oxo-3-buten-l -yl-phosphonate t-Bu
Figure imgf000048_0001
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.
To 30 ml dry THF kept at 0°C were added sequentially ΗCI4 (1.2 ml, 10.5 mmol), 3-tert- butyl-4-methoxy-5,6,7,8-tetrahydronaphthaldehyde (1.0 g, 4.1 mmol), dimethyl l,l-dimethyl-2- oxopropylphosphonate (1.02 g, 5.3 mmol), N-methyl morpholine (2 ml, 16.4 mmol) then the reaction mixture was stirred for 2 h at room temperature. Work up was carried out by adding 50 ml of iced-water, extracting the resulting mixture with three portions of 100 ml dichloromethane, washing the organic phase with brine and drying over magnesium sulfate. Evaporation of the solvent gave a residue that was purified by trituration in petroleum ether. An amount of 0.52 g (1.23 mmol, 30 % yield) of the title compound was obtained.
MS: m/e =422: M+, 312 (100%): M+ -HPO3Me2, 271: M+-CMe2(PO3Me2), 57: tBu+ NMR: (CDCI3) δ = 8.04 (d, J = 15.4Hz, 1H): Ph-CH=CH 7.53 (s, 1H): arom. H 7.24 (d, J = 15.4Hz, 1H): Ph-CH=CH 3.84 (d, J = 11 Hz, 6H): P-O-CH3 3.83 (s, 3H): arom. O-CH3
2.90 (t, 2H), 2.80 (t, 2H), 1.90-1.83 (m, 2H) and 1.79-1.75 (m, 2H): Gβs-
1.56 (d, J = 16.7 Hz, 6H): -C(CH3)2-P
1.46 (s, 9H): t-C4H9 Example 42: Diethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l,l-dimethyl- 2-oxo-3-buten-l-yl-phosphonate
Figure imgf000049_0001
The method described for the preceding example was followed, using the reactants in the following amounts: THF (50 ml), ΗCI4 (1.2 ml, 10.5 mmol), 3-tert-butyl-4-methoxy-5,6,7,8- tetrahydronaphthaldehyde (1.0 g, 4.1 mmol), diethyl l,l-dimethyl-2-oxopropyl phosphonate (1.4 g, 5.3 mmol), N-methyl morpholine (2 ml, 16.4 mmol). An amount of 1.26 g (2.8 mmol, 68 % yield) of the title compound was obtained.
MS: m e =450: M+, 312 (100%): M+ -HPO3Et2, 271: M+-CMe2(PO3Et2), 57: tBu+ NMR: (CDC13) δ = 8.03 (d, J = 15.5Hz, lH): Ph-CH=CH 7.53 (s, 1H): arom. H 7.23 (d, J = 15.5Hz, 1H): Ph-CH=CH 4.22-4.16 (quintet, 4H): P-O-CH2-CH3 3.83 (s, 3H): arom. O-CH3
2.91 (t, 2H), 2.80 (t, 2H), 1.89-1.84 (m, 2H) and 1.79-1.75 (m, 2H): C4H8- 1.55 (d, J = 16.7 Hz, 6H): -C(CH3)2-P
1.45 (s, 9H): t-C4H9
1.37 (t, J = 7Hz, 6H): P-O-CH2-CH3
Example 43: Diisopropyl 4-(3-tert-butyI-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l,l- dimethyl-2-oxo-3-buten-l-yl-phosphonate
Figure imgf000049_0002
The method described for the preceding example was followed, using the reactants in the following amounts: THF (30 ml), TiC-4 (1.4 ml, 12.2 mmol), 3-tert-butyl-4-methoxy-5,6,7,8- tetrahydronaphthaldehyde (1.0 g, 4.1 mmol), diisopropyl l,l-dimethyl-2-oxopropyl phosphonate (1.3 g, 5.3 mmol), N-methyl morpholine (1.8 ml, 16.3 mmol). An amount of 0.93 g (1.95 mmol,
48 % yield) of the title compound was obtained. MS: m/e =478: _V_+, 312 (100%): M+ -HPO3iPr2, 271: M+-CMe2(PO3iPr2), 57: tBu+
NMR: (CDC13) δ = 7.96 (d, J = 15.5Hz, 1H): Ph-CH=CH 7.48 (s, 1H): arom. H 7.27 (d, J = 15.5Hz, 1H): Ph-CH=CH
4.74 (m, 4H): P-O-CH-(CH3)2
3.78 (s, 3H): arom. O-CH3
2.86 (t, 2H), 2.76 (t, 2H), 1.84-1.79 (m, 2H) and 1.75-1.70 (m, 2H): C4H8- 1.47 (d, J = 16.7 Hz, 6H): -C(CH3)2-P 1.41 (s, 9H): t-C4H9
1.32 and 1.31 (2 d, 7Hz, 6H each): P-O-CH-(CH3)2
1.47 (s, 18H): t-C4H9
1.37 and 1.36 (2t, J = 7Hz, 6H): P-O-CH2-CH3
Example 44: Dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l,l-diethyl- 2-oxo-3-buten-l-yl-phosphonate
Figure imgf000050_0001
The method described for the preceding example was followed, using the reactants in the following amounts: THF (20 ml), TiCLj. (1.45 ml, 13.2 mmol), 3-tert-butyl-4-methoxy-5,6,7,8- tetrahydronaphthaldehyde (0.47 mmol,1.83 mmol), dimethyl l,l-diethyl-2-oxopropyl phosphonate (0.59 g, 2.36 mmol), N-methyl morpholine (0.80 ml 7.26 mmol). An amount of 0.25 g (0.56 mmol, 30 % yield) of the title compound was obtained.
MS: m/e =450: M+, 271: M+-CEt2(PO3Me2), 57 (100%): tBu+ NMR: (CDCI3) δ = 7.98 (d, J = 15.4Hz, 1H): Ph-CH=CH 7.48 (s, 1H): arom. H 7.20 (d, J = 15.4Hz, 1H): Ph-CH=CH 3.80 (d, J= 11Hz, 6H): P-O-CH3
3.79 (s, 3H): arom. O-CH3 2.88 (t, 2H), 2.78 (t, 2H), 1.85-1.80 (m, 2H) and 1.75-1.70 (m, 2H): C4H8- 2.11-2.00 (m,4H): -C(CH2-CH3)2-P
1.42 (s, 9H): t-C4H9
0.98 (t, J = 7.5 Hz, 6H): -C(CH2-CH3)2-P
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
Figure imgf000051_0001
The method described for the preceding example SR-158806 was followed, using the reactants in the following amounts: THF (20 ml), ΗCI4 (1.45 ml, 13.2 mmol), 3-tert-butyl-4- methoxy-5,6,7,8-tetrahydronaphthaldehyde (0.47 g, 1.83 mmol), dimethyl 1,1-cyclopentyliden- 2-oxopropyl phosphonate (0.59 g 2.36 mmol), N-methyl moφholine 0.80 ml, 7.26 mmol). An amount of 0.31 g (0.69 mmmol, 38 % yield) of the title compound was obtained.
MS: m/e =448: M+, 271: M+-c-C5H8 (PO3Me2), 57 (100%): tBu+ NMR: (CDCI3) δ = 8.00 (d, J = 15.4Hz, 1H): Ph-CH=CH 7.48 (s, 1H): arom. H 7.12 (d, J = 15.4Hz, 1H): Ph-CH=CH 3.80 (d, J= 10.3Hz, 6H): P-O-CH3
3.79 (s, 3H): arom. O-CH3 2.88 (t, 2H), 2.78 (t, 2H), 1.85-1.78 (m, 2H) and 1.77-1.70 (m, 2H) (total 8H): C4H8-
2.50-2.44 (m,2H), 2.25-2.15 (m,2H), 1.77-1.70 (m,2H),1.60-1.55 (m,2H) ( total 8 H):-c- C5H8-P 1.41 (s, 9H): t-C4H9
Example 46: Dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l-methyl-2- oxo-3-buten-l-yl-phosphonate
Figure imgf000051_0002
Under nitrogen atmosphere 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 stiπed at -70° 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 (3.0 g, 9.5 mmol) in 10 ml dry THF was added. The resulting mixture was left to stir at room temperature (25°C) for 4 h. Hydrolysis was caπied out by adding 10 ml of a saturated NH4C1 solution and the product was extracted into chloroform. After drying over MgSO4, chloroform was evaporated and the residue was purified by column chromatography (SiO2, AcOEt/hexane 8/2) to give 0.98 g (2.4 mmol, 25%) of the title compound.
MS: m/e =408: M+, 271: M+-CHMe (PO3Me2), 138 (100%): HCHMe (PO3Me2), 57: tBu+ NMR: (CDCI3) δ = 7.98 (d, J = 15.6Hz, 1H): Ph-CH=CH 7.47(s, 1H): arom. H 6.81 (d, J = 15.6Hz, 1H): Ph-CH=CH
3.80 and 3.79 (2d, J= 11Hz, 6H): P-O-CH3
3.79 (s, 3H): arom. O-CH3
3.56 and 3.50 (2 quartets, J=7 Hz, 1H): CH(CH3)-P
2.87 (t, 2H), 2.76 (t, 2H), 1.85-1.80 (m, 2H) and 1.75-1.70 (m, 2H): C4H8- 1.49 (2d, J = 7 Hz, H): -CH(CH3) -P
1.40 (s, 9H): t-C4H9
Example 47: Diethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l-methyl-2- oxo-3-buten-l-yl-phosphonate
Figure imgf000052_0001
Under nitrogen atmosphere diethyl ethylphosphonate (2.63 g, 15.8 mmol) was added at -
78°C to a solution of n-butyllithium (9.9 ml of a 1.6 M solution in hexane, 15.8 mmol) in 25 ml anhydrous THF. The reaction mixture was stiπed at -78°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 (2.0 g, 6.3 mmol) in 10 ml dry THF was added. The resulting mixture was left to stir -78°C for 1 h. Hydrolysis was caπied out by adding 10 ml of a saturated ammonium chloride solution and the product was extracted into dichloromethane (DCM). After drying over MgSO4, DCM was evaporated and the residue was purified by column chromatography (SiO2, DCM/MeOH 98/2) to give 2.2 g (4.3 mmol, 82 %) of the title compound.
MS: m/e =436: M+, 271: M+-CHMe(PO3Et2), 57: tBu+ NMR: (CDC13) δ = 7.97 (d, J = 15.5Hz, 1H): Ph-CH=CH 7.48 (s, 1H): arom. H 6.84 (d, J = 15.5Hz, 1H): Ph-CH=CH
4.20-4.12 (m, 4H): P-O-CH2-CH3
3.79 (s, 3H): arom. O-CH3
3.51 and 3.46 (2 quartets, J= 7Hz, 1H): -CH(CH3)-P
2.98 (t, 2H), 2.78 (t, 2H), 1.86-1.82 (m, 2H) and 1.76-1.70 (m, 2H): C4H8- 1.49 and 1.46 (2d, J = 7 Hz, 3H): -CH(CH3)-P
1.40 (s, 9H): t-C4H9 ca 1.37 (2 overlapped t, J = 7Hz, 6H): P-O-CH2-CH3
Example 48: Dimethyl 4-(3-tert-butyl-5,5-dimethyl-4-hydroxy-5,6,7,8-tetrahydro-l- naphthyl)-l,l-
Figure imgf000053_0001
To 5 ml dry THF kept at 0°C were added sequentially ΗCI4 (87 mg, 0.46 mmol), 5,5- dimethyl-3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthaldehyde (50 mg, 0.192 mmol), dimethyl l,l-dimethyl-2-oxopropylphosphonate (45 mg, 0.23 mmol), N-methyl morpholine (93 mg, 0.92 mmol) then the reaction mixture was stiπed for 45 min at room temperature. Work up was carried out by adding iced-water, extracting the resulting mixture with dichloromethane, washing the organic phase with brine and drying over magnesium sulfate. Evaporation of the solvent gave a residue that was purified by column chromatography (SiO2, 8/2 AcOEt/Hexane). An amount of 15 mg (0.034 mmol, 18 % yield) of the title compound was obtained. Example 49: Dimethyl 4-(3-tert-butyl-4-hydroxy-l-naphthyl)-l,l-dimethyl-2-oxo-3-buten- 1-yl-phosphonate
Figure imgf000054_0001
To 30 ml dry THF kept at 0°C were added sequentially ΗCI4 (2 ml, 2.9 g, 15.5 mmol), 3-tert-butyl-4-hydroxynaphthaldehyde (1.5 g, 6.6 mmol), dimethyl l,l-dimethyl-2- oxopropylphosphonate (1.6 g, 7.83 mmol), N-methyl morpholine (2.5 ml, 3.12 g, 30.9 mmol) then the reaction mixture was stirred for 1 h at room temperature. Work up as previously described and purification by flash column chromatography (SiO2, 7/3 AcOEt/hexane) gave 2.21 g (5.5 mmol, 82 % yield) of the title compound. MS: m/e = 404: M+, 253 (100%): M+- CMe2(PO3Me2), 57 : tBu+ NMR: (CDCI3) δ = 8.48 (d, J = 15 Hz, 1H): Ph-CH=CH
8.20, 8.13, 7.91, 7.53 (4m, 5H total): naphthyl H 7.39 (d, J = 15 Hz, 1H): Ph-CH=CH 6.30 (broad s, 1H): OH
3.80 (d, J = 11Hz, 6H): P-O-CH3 1.55 (d, J = 16.5 Hz, 6H): -C(CH3)2-P 1.54 (s, 9H): t-C4H9
Example 50: Dimethyl 4-(3-benzyl-4-hydroxy-l-naphthyl)-l,l-dimethyl-2-oxo-3-buten-l- yl-phosphonate
Figure imgf000054_0002
To 20 ml dry THF kept at 0°C were added sequentially ΗCI4 (1.0 g, 5.3 mmol), 3- benzyl-4-hydroxynaphthaldehyde (0.6 g, 2.2 mmol), dimethyl l,l-dimethyl-2- oxopropylphosphonate (0.54 g, 2.78 mmol), N-methyl moφholine (0.95 g, 9.3 mmol) then the reaction mixture was stiπed for 1 h at room temperature. Work up as previously described and purification by flash column chromatography (SiO2, 7/3 AcOEt/hexane) gave 0.91 g (2.1 mmol,
85 % yield) of the title compound. MS: m/e = 438: M+, 287 (100%): M+- CMe2(PO3Me2), 91 (100%) : C7H7 + NMR: (CDC13) δ = 8.50 (d, J = 15.3 Hz, 1H) :Ph-CH=CH
8.20, 8.22, 7.70, 7.55, 7.50: (5m, 5H total): naphthyl H 7.25 (m, 5H total): benzyl H
6.15 (broad s, lH): OH 3.79 (d, J = 11Hz, 6H): P-O-CH3 1.55 (d, J = 16.5 Hz, 6H): -C(CH3)2-P
Example 51: Dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-2-oxo-l- butyl-phosphonate
Figure imgf000055_0001
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.
MS: m/e=382: M+, 325: M+-t-Bu, 57 (100%): tBu+ NMR (CDC13) δ = 6.93 (s, 2H): arom. H 4.77 (s, 1H): OH 3.79 (d, J = 11.3Hz, 6H): P-O-CH3
3.10 (d, J = 22.6Hz, 2H): CH2-P
2.88-2.79 (2m, 2H): Ph-CH2- CH2 and Ph-CH2-CH2
2.66 (t, 2H), 2.58 (t, 2H), 1.86-1.82 (m, 2H) and 1.81-1.76 (m, 2H): C4H8- 1.41 (s, 9H): t-C H9
Example 52: Dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8- tetrahydronaphthyl)-l,l-dimethyl-2-oxo-l -butyl-phosphonate t-Bu
Figure imgf000055_0002
A solution of dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l,l- dimethyl-2-oxo-3-buten-l -yl-phosphonate (0.50 g, 1.22 mmol) in 30 ml AcOEt was added to a suspension of Palladium over active charcoal (0.25 g) and the mixture was submitted to hydrogenation at room temperature in a Parr hydrogenation apparatus for 10 min. The reaction mixture was filtered over a pad of MgSO4, the filtrate was evaporated and the residue was purified by column chromatography (SiO2, 3/2 AcOEt/hexane). An amount of 0.4 g (1.07 mmol, 88%o) of the title compound was obtained.
MS: m/e = 410: M+, 353: M+ - t-Bu, 300: M+ - HPO3Me2, 57: tBu+
Figure imgf000056_0001
δ = 6.93 (s, 1H): arom. H
4.80 (s, 1H): OH
3.76 (d, J = 11Hz, 6H): P-O-CH3
2.91 (distorted t, J = 7 Hz, 2H): Ph-CH2-CH
2.80 (distorted t, J = 7 Hz, 2H): Ph-CH2-CH2 2.67 (t, 2H), 2.59 (t, 2H), 1.88-1.83 (m, 2H) and 1.80-1.75 (m, 2H): C4H8-
1.43 (d, J = 17Hz, 6H): -C(CH3)2-P
1.41 (s, 9H): t-C4H9
Example 53: Dimethyl 4-(5-tert-butyl-2-hydroxy-3-methoxyphenyl)-l,l-dimethyl-2-oxo-l- butyl-phosphonate
MeO OH
t-Bu
P03Me2
Me Me
The title compound was obtained in 80% yield by reducing a solution of dimethyl 4-(5- tert-butyl-2-hydroxy-3 -methoxyphenyl)- l,l-dimethyl-2-oxo-3 -buten- 1 -yl-phosphonate (0.20 g) over a suspension of Pd/C (0.15 g) in ethyl acetate. MS: m/e = 386: M+, 233: M+- 2H - CMe2(PO3Me2), 57 : tBu+ NMR: (CDCI3) δ = 6.77 and 6.75 (2d, 2H): arom. H 5.7 (s, 1H): OH 3.89 (s, 3H): arom. O-CH3 3.75 (d, J = 11 Hz, 6H): P-O-CH3 3.03 (t, J = 7 Hz, 2H): Ph-CH2-CH2 2.89 (t, J = 7 Hz, 2H): Ph-CH2-CH2 1.42 (d, J = 16.9Hz, 6H): -C(CH3)2-P 1.29 (s, 9H): t-C4H9
Example 54: Dimethyl 4-(3,5-di-tert-butyl-2-hydroxyphenyl)-l,l-dimethyl-2-oxo-l-butyl- phosphonate
Figure imgf000057_0001
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.
MS: m/e = 412: M+, 259: M+- 2H - CMe2(PO3Me2), 57: tBu+
BIOLOGICAL RESULTS
Example 55: HMG-CoA Reductase Assay
The ability of compounds of Formula (I) to affect HMG-CoA levels was investigated in the HeLa cell line obtained from the American Type Culture Collection organization (ATCC).
A. Experimental Protocol
Quantification of HMGR levels by immunoblotting. HeLa cells (ATCC) were seeded in 6 wells plates (8.105 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 μM final concentrations; they were added as 1000-fold concentrated stock solutions in 50% EtOH and 50% DMSO. After a 5 h incubation period, cells were washed in ice cold PBS and lysed in 200 μl/well of the following buffer: 20 mM Hepes pH 7.4, 50 mM NaCl, 10 mM EDTA, 10 mM EGTA, 2.2% DMSO, 1% Triton X-100 and the Complete Protease Inhibitor cocktail (Roche Diagnostics). Cells were kept for 15 min on ice; then, cell lysates were collected and spun at 14K φm for 20 min. The supernatants were kept and protein concentrations were determined using the BioRad DC protein assay (BioRad). Samples were diluted in sample buffer containing 5% β-mercaptoethanol and loaded on 7.5% SDS-PAGE without prior boiling. HMG-CoA reductase levels were analysed by subsequent immunoblotting using mouse A9 mAbs (hybridoma cells CRL-1811; ATCC). Bound A9 antibodies were revealed by goat anti-mouse IgG peroxidase-coupled antibodies (Sigma) and SuperSignal West Dura Extended Duration Substrate (Pierce) followed by autoradiography.
B. Results
Compounds (I) were tested at two different concentrations: 1 and 10 μM. The relative potencies of Compounds (I) for decreasing HMG-CoA reductase were expressed as approximative % change of samples treated with 10 μM 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 and at 1 μM
+++ is 100% decrease in HMGR levels at 10 μM /50-99% at 1 μM ++ is 50-99% decrease in HMGR levels at 10 μM / 0-50% at 1 μM + is 10-49% decrease in HMGR levels at 10 μM / 0% at 1 μM (+) is 1-10% decrease in HMGR levels at 10 μM / 0% at 1 μM.
The results are summarized in TABLE 1.
TABLE 1 - Reduction in the amount of HMG-CoA reductase by Compounds of Formula
(I) wherein Y is O
Ar- ■IT (I)
<
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Example 56: Effect of Linear Ketophosponate Compounds on β-Amyloid Protein
Groups of 34 week old female ovariectomized rats (n=8), five weeks after ovariectomy, are treated orally with linear ketophosphonate compounds, e.g., compounds 1 - 81, at a suitable dose, e.g., 50, 100 or 150 mg/kg/day administered as a suspension in 20% Tween 80 and 0.5%
Carboxymethyl cellulose) for 8 weeks. The decrease in β-amyloid protein in the cerebrospinal fluid of treated animals is compared to control animals. β-Amyloid Protein determination by ELISA:_Ninety-six well-microtiter plates are coated by incubating with a 1 μg/ml β-amyloid protein solution in 0.01 M phosphate buffer (pH 7.4) at the volume of 150 μl/well for 2 h at 37°C. The coating solution is removed and the wells are washed 3 times with 300 μl of bxrffer solution. Then 250μl/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 μl/well) and the primary antibody (mouse anti-human β-amyloid protein IgG) diluted 20000 fold are incubated for 2 h at 37°C. After the third wash,
150μl 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 μl/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 μl/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.
REFERENCES
The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.
Berge et al, J. Pharm. Sci., 66:1-19,1977.
Berry et al, Am.J. Pathology, 132:427-443, 1989
Fassbender et al, Proc. Nat. Acad. Sci. USA, 98:5856-5861, 2001.
Hrab et al, Teratology 50:19-26, 1994. Kloss, Fd. Chem. Toxic, 29:621-628, 1991.
Kombrust et al, J. Phaπnacol. Exp. Therapeutics, 248:498-505, 1989.
Mathey & Savignac, Tetrahedron 34:649-654, 1978.
Pan, J. Clin. Pharmacol., 30:1128-1135, 1990.
Roussis & Wiemer, J. Org. Chem., 54:627-631, 1989. Smith, Toxicology & Pathology 19:197-205, 1991.
Smith et al, J. Pharmacol. Exp. Therapeutics 257: 1225-1235, 1991(a).
Wolozin, Biochem. Soc. Trans. 30:525-529, 2002.

Claims

1. A method of treating or preventing hypercholesterolemia, comprising administering to a subject in need of such treatment an amount of a substituted phosphonate compound of the formula (I) effective to decrease cholesterol:
Y
Ar - ( i )
<
Z' wherein Ar is:
Figure imgf000069_0001
and X is H, OH or a straight or branched CrC6 alkoxy group,
X1, X2 and X3 are independently H, OH, a straight, branched, or cyclic C C6 alkyl or alkoxy group;
0 1 2 3 or X , X or X , X together may form a Cj-C- optionally substituted alkylidenoxy or alkylidenedioxy group; with the proviso that X° is H when X3 is H and X1 and X2 are independently straight or branched
C C6 alkyl groups;
X4, X5, X6 are independently H, a straight or branched -Cό alkyl group; q is zero or 1;
X7 is H, a straight or branched -C8 alkyl or alkoxy group, or an optionally substituted benzyl group;
Y is O or S;
Z and Z are independently OR or NR R , where R , R , and R are independently H or a
1 2 straight or branched Cχ-C6 alkyl group, or Z , Z together may form a C_-C8 alkylidenedioxy group; and L is a saturated or unsaturated -Cπ 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, C1-6 alkyl, an optionally substituted aryl or heteroaryl group; and pharmaceutically acceptable salts, solvates and hydrates thereof.
2. A method of treating or preventing hypercholesterolemia, comprising administering to a subject in need of such treatment and that has been shown to not to respond to HMG-CoA reductase inhibitors, an amount of a substituted phosphonate compound of the formula (I) effective to decrease cholesterol:
II z1
Ar L — Pχ ( I) z 2
wherein Ar is:
Figure imgf000070_0001
and X° is H, OH or a straight or branched C\ to C6 alkoxy group,
X1, X2 and X3 are independently H, OH, a straight, branched, or cyclic - alkyl or alkoxy group;
0 1 2 3 or X , X or X , X together may form a Cj-C- optionally substituted alkylidenoxy or alkylidenedioxy group; with the proviso that X° is H when X3 is H and X1 and X2 are independently straight or branched -C6 alkyl groups;
X4, X5, X6 are independently H, a straight or branched Ci-C6 alkyl group; q is zero or 1;
X7 is H, a straight or branched -Cs alkyl or alkoxy group, or an optionally substituted benzyl group;
Y is O or S;
Z1 and Z2 are independently OR1 or NR R , where R1, R , and R are independently H or a
1 2 straight or branched C.-C6 alkyl group, or Z , Z together may form a C2-C8 alkylidenedioxy group; and L is a saturated or unsaturated -Cπ 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, C1-6 alkyl, an optionally substituted aryl or heteroaryl group; and pharmaceutically acceptable salts, solvates and hydrates thereof.
3. A method of treating or preventing hypercholesterolemia, comprising administering to a subject in need of such treatment, a combination of a HMG-CoA reductase inhibitor and an amount of a substituted phosphonate compound of the formula (I) effective to decrease cholesterol:
Figure imgf000071_0001
wherein Ar is:
Figure imgf000071_0002
and X° is H, OH or a straight or branched C\ to C6 alkoxy group,
X1, X2 and X3 are independently H, OH, a straight, branched, or cyclic C Cό alkyl or alkoxy group;
0 1 2 3 or X , X or X , X together may form a Cj-C- optionally substituted alkylidenoxy or alkylidenedioxy group; with the proviso that X° is H when X3 is H and X1 and X2 are independently straight or branched
Ci- alkyl groups;
X4, X5, X6 are independently H, a straight or branched -Ce alkyl group; q is zero or 1;
X is H, a straight or branched -Cs alkyl or alkoxy group, or an optionally substituted benzyl group;
Y is O or S;
1 0 Λ 2, i 2- i
Z and Z are independently OR or NR R , where R , R , and R are independently H or a
1 2 straight or branched C.-C6 alkyl group, or Z , Z together may form a C.-C- alkylidenedioxy group; and L is a saturated or unsaturated Ci-Cπ 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, C1-6 alkyl, an optionally substituted aryl or heteroaryl group; and pharmaceutically acceptable salts, solvates and hydrates thereof.
4. The method of claim 3 wherein said HMG CoA reductase inhibitor is a statin.
5. The method of claim 4, wherein said statin is selected from the group consisting of compactin, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and pivastatin.
6. A method for decreasing the production of β-amyloid protein, comprising administering to a subject who is at risk or presents the symptoms of a disease state associated with an elevated production of β-amyloid protein, an amount of a substituted phosphonate compound of formula (I) effective to decrease β-amyloid production:
Figure imgf000072_0001
wherein Ar is:
Figure imgf000072_0002
and X° is H, OH or a straight or branched to C6 alkoxy group,
X , X and X are independently H, OH, a straight, branched, or cyclic CΪ-C6 alkyl or alkoxy group;
0 1 2 3 or X , X or X , X together may form a C--C-. optionally substituted alkylidenoxy or alkylidenedioxy group; with the proviso that X° is H when X3 is H and X1 and X2 are independently straight or branched
Ci-Cδ alkyl groups;
X4, X5, X6 are independently H, a straight or branched -Cό alkyl group; q is zero or 1;
X7 is H, a straight or branched -Cs alkyl or alkoxy group, or an optionally substituted benzyl group;
Y is O or S; Z1 and Z2 are independently OR1 or NR R , where R1, R , and R are independently H or a
1 2 straight or branched Cj-C8 alkyl group, or Z , Z together may form a C_-C8 alkylidenedioxy group; and
L is a saturated or unsaturated -Cπ 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, C1-6 alkyl, an optionally substituted aryl or heteroaryl group; and phaπnaceutically acceptable salts, solvates and hydrates thereof.
7. The method of claim 6, wherein said disease state associated with an elevated production and/or deposition of β-amyloid protein is selected from the group consisting of Alzheimer's disease, head trauma or stroke.
8. The method of claim 6, further comprising administration to said subject an effective amount of a competitive inhibitor of HMG-CoA reductase inhibitor.
9. The method of claim 8, wherein said competitive inhibitor of HMG-CoA reductase inhibitor is selected from the group consisting of compactin, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and pivastatin.
10. The method of claim 6, further comprising administration of an effective amount of a therapeutic agent for the treatment of Alzheimer's disease.
11. The method of claim 10, wherein said therapeutic agent for the treatment of Alzheimer's disease is selected from the group consisting of Aricept, Exelon, Cognex, Reminyl, ALCAR,
AN-1792, Cerebrolysin, Ampalex, Avlosulfon and Memantine.
12. The method of claims 1, 2, 3 and 6, wherein L is -A-C(O)-B- and A is a direct bond, - CH=C(R4)-, -CH2-C(R4)(R5)-, -C(R4)(R5)-, -O-C(R4)(R5)-, -S-C(R4)(R5)-, where R4,R5 are independently H, F, Cl, Br, -Cό straight or branched alkyl, or an optionally substituted aryl or heteroaryl, and B is -C(R6)(R7)- where R6 and R7 are independently H, F, Cl, Br, d-C6 straight or branched alkyl, or an optionally substituted aryl or heteroaryl, or R6 and R7 can form a saturated ring of C3-C carbon atoms.
13. The method of claim 12, wherein A is a direct bond, -CH=C(R4)-, -CH2-C(R4)(R5)- and R4 and R5 are H, and R6 and R7 are independently H, F, CH3, C2H5 or R6 and R7 together form cyclic C5H8.
14. The method of claim 12, wherein is A is a direct bond, -CH=CH-, or -CH2-CH2-.
15. The method of claim 14, wherein B is -CH2-, -CF2-, -CH(CH3)-, -CF(CH3)-, -C(CH3)2-, -C(CH3)(C2H5)-,-C(C2H5)2- or -CH(c C5H8)-.
16. The method of claim 12, wherein Y is O.
17. The method of claim 16, wherein X4 is butyl and X5 is H or methyl and q is 1.
18. The method of claim 17, wherein X4 is tert-butyl and X5 is H.
19. The method of claim 18, wherein Z1 and Z2 are the same and aie OR1.
20. The method of claim 19, wherein R1 is methyl, ethyl or isopropyl.
21. The method of claims 1, 2, 3 and 6, wherein said substituted phosphonate compound of the formula (I) is selected from the group consisting of:
dimethyl 4-(3 -methoxy-5-methyl-4-hydroxyphenyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -yl- phosphonate; dimethyl 4-(3,5-dimethoxy-4-hydroxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l-yl-phosphonate; dimethyl 4-(3 ,4,5-trimethoxyphenyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -yl-phosphonate; dimethyl 4-(4, 5-dimethoxy-3 -hydroxyphenyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -yl-pho sphonate; dimethyl 4-(3,5-diethoxy-4-hydroxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l-yl-phosphonate; dimethyl 4-(4-hydroxy-3 -methoxy-5 -n-propylphenyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -ylphosphonate; dimethyl 4-(5 -tert-butyl-2-hydroxy-3-methoxyphenyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -ylphosphonate; dimethyl 4-(3-cyclopentyloxy-4-methoxyphenyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -yl-phosphonate; dimethyl 4-(3 ,5 -di-cyclopentyl-4-hydroxyphenyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -ylphosphonate; diethyl 2-(3 ,4,5-trimethoxyphenyl)- 1 , 1 -dimethyl-2-oxo-ethylphosphonate; dimethyl 4-(3,5-di-tert-butyl-2-hydroxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3,5-di-tert-butyl-2-hydroxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l-yl phosphonate; dimethyl 4-(3,5-di-tert-butyl-2-hydroxyphenyl)-l,l-diethyl-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3,5-di-tert-butyl-2-hydroxyphenyl)-l,l-diethyl-2-oxo-3-buten-l-yl phosphonate; dimethyl 4-(3,5-di-tert-butyl-2-hydroxyphenyl)-l,l-cyclopentyliden-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3 , 5 -di-tert-butyl-2-hydroxyphenyl)- 1 , 1 -cyclopentyliden-2-oxo-3 -buten- 1 -yl phosphonate; diethyl 4-(3 ,5-di-tert-butyl-2 -hydroxyphenyl)- 1 -fluoro- 1 -methyl-2-oxo-3 -buten- 1 -yl phosphonate; dimethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-2-oxo-3-buten-l -yl phosphonate; diethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-2-oxo-3-buten-l-yl phosphonate; dimethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)- 1 , 1 -dimethyl-2-oxo-3-buten- 1 -yl phosphonate; diisopropyl 4-(3 , 5 -di-tert-butyl-2-methoxyphenyl)- 1 , 1 -dimethyl-2-oxo-3-buten- 1 -yl phosphonate; dimethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-l-methyl-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3 ,5 -di-tert-butyl-2-methoxyphenyl)- 1 -methyl-2-oxo-3-buten- 1 -yl phosphonate; dimethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-l-fluoro-l-methyl-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3 ,5 -di-tert-butyl-2-methoxyphenyl)- 1 -fluoro- 1 -methyl-2-oxo-3 -buten- 1 -yl phosphonate; dimethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-l,l-difluoro-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-l , 1 -difluoro-2-oxo-3-buten-l -yl phosphonate; dimethyl 4-(3 ,5-di-tert-butyl-2-methoxyphenyl)- 1 , 1 -diethyl-2-oxo-3 -buten- 1 -yl phosphonate; dimethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-l,l-cyclopentyliden-2-oxo-3-buten-l-yl phosphonate; diethyl 2-(3,5-di-tert-butyl-2-methoxyphenyl)-l-methyl-2-oxoethylphosphonate; diethyl 2-(3,5-di-tert-butyl-2-methoxyphenyl)-l,l-dimethyl-2-oxoethylphosphonate; dimethyl 2-(3,5-di-tert-butyl-2-methoxyphenyl)-l-fluoro-l-methyl-2-oxoethylphosphonate; diethyl 2-(3,5-di-tert-butyl-2-methoxyphenyl)-l-fluoro-l-methyl-2-oxoethylphosphonate; dimethyl 4-(3,5-di-tert-butylphenyl)-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3,5-di-tert-butylphenyl)-2-oxo-3-buten-l-yl phosphonate; dimethyl 4-(3 ,5-di-tert-butylphenyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -yl phosphonate; diethyl 4-(3 ,5 -di-tert-butyl-phenyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -yl phosphonate; dimethyl 4-(3,5-di-tert-butylphenyl)-l-ethyl-l-methyl-2-oxo-3-buten-l-yl phosphonate; dimethyl 4-(3 , 5 -di-tert-butylphenyl)- 1 , 1 -diethyl-2-oxo-3 -buten- 1 -yl phosphonate; dimethyl 4-(3 ,5-di-tert-butylphenyl)- 1 , 1 -cyclop entyliden-2-oxo-3 -buten- 1 -yl phosphonate; dimethyl 4-(3,5-di-tert-butylphenyl)-l,l-fluoro-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3 ,5 -di-tert-butyl-phenyl)- 1 , 1 -fluoro-2-oxo-3 -buten- 1 -yl phosphonate; dimethyl 2-(3,5-di-tert-butylphenyl)-l-methyl-2-oxoethylphosphonate; diethyl 2-(3,5-di-tert-butyl-phenyl)-l-methyl-2-oxoethylphosphonate; dimethyl 2-(3,5-di-tert-butylphenyl)-l,l-dimethyl-2-oxoethylphosphonate; diethyl 2-(3,5-di-tert-butyl-phenyl)-l , 1 -dimethyl-2-oxoethylphosphonate; dimethyl 2-(3 ,5-di-tert-butylphenyl)- 1 -fluoro- 1 -methyl-2-oxoethylphosphonate; diethyl 2-(3 ,5-di-tert-butylphenyl)- 1 -fluoro- 1 -methyl-2-oxethylphosphonate; dimethyl 2-(3 ,5-di-tert-butylphenyl)- 1 , 1 -difluoro-2-oxoethylphosphonate; dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-2-oxo-3-buten-l-yl- phosphonate; diethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-2-oxo-3-buten-l-yl-phosphonate; dimethyl 4-(3 -tert-butyl-4-hydroxy-5 ,6,7, 8-tetrahydronaphthyl)- 1 , 1 -dimethyl-2-oxo-3-buten- 1 - yl-phosphonate; diethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l,l-dimethyl-2-oxo-3-buten-l-yl- phosphonate; dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l-methyl-2-oxo-3-buten-l-yl- phosphonate; diethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l-methyl-2-oxo-3-buten-l-yl- phosphonate; dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l-fluoro-l-methyl-2-oxo-3- buten- 1 -yl-phosphonate; diethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l-fluoro-l-methyl-2-oxo-3-buten-
1 -yl-phosphonate; dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l -ethyl-1 -methyl-2-oxo-3-buten-
1 -yl-phosphonate; dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l,l-diethyl-2-oxo-3-buten-l-yl- phosphonate; dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l,l-cyclopentylidene-2-oxo-3- buten- 1 -yl-phosphonate; dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-2-oxo-3-buten-l-yl- phosphonate; diethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl-2-oxo-3-buten-l-yl-phosphonate; dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l,l-dimethyl-2-oxo-3-buten-l- yl-phosphonate; diethyl 4-(3 -tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -ylphosphonate; diisopropyl 4-(3 -tert-butyl-4-methoxy-5 ,6,7, 8-tetrahydronaphthyl- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 - yl-phosphonate; dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l-methyl-2-oxo-3-buten-l-yl- phosphonate; diethyl 4-(3 -tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)- 1 -methyl-2-oxo-3 -buten- 1 -ylphosphonate; dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l-fluoro-l-methyl-2-oxo-3- buten- 1 -yl-phosphonate; diethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l-fluoro-l-methyl-2-oxo-3-buten- 1 -yl-phosphonate; dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l-ethyl-l-methyl-2-oxo-3- buten- 1 -yl-phosphonate; dimethyl 4-(3 -tert-butyl-4-methoxy-5 ,6,7, 8-tetrahydronaphthyl)- 1 , 1 -diethyl-2-oxo-3 -buten- 1 -yl- phosphonate; dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l,l-cyclopentylidene-2-oxo-3- buten- 1 -yl-phosphonate; diethyl 2-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l-methyl-2-oxoethyl phosphonate; diethyl 2-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l-fluoro-l-methyl-2-oxo- ethylphosphonate; dimethyl 4-(3-tert-butyl-5,5-dimethyl-4-hydroxy-5,6,7,8-tetrahydro-l-naphthyl)-l,l-dimethyl-2- oxo-3-buten-l-yl-phosphonate; dimethyl 4-(3 -tert-butyl-4-hydroxy- 1 -naphthyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -yl-phosphonate; dimethyl 4-(3-benzyl-4-hydroxy- 1 -naphthyl)- 1 , 1 -dimethyl-2-oxo-3-buten- 1 -yl-phosphonate; dimethyl 4-(3,5-di-tert-butyl-2-hydroxyphenyl)-l,l-dimethyl-2-oxo-l-butyl-phosphonate; dimethyl 4-(5-tert-butyl-2-hydroxy-3 -methoxyphenyl)- 1 , 1 -dimethyl-2-oxo- 1 -butyl-phosphonate; and dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l,l-dimethyl-2-oxo-l-butyl- phosphonate.
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