WO2004026242A2 - Substituted ketophosphonate inhibitors of tumor cell proliferation - Google Patents

Substituted ketophosphonate inhibitors of tumor cell proliferation Download PDF

Info

Publication number
WO2004026242A2
WO2004026242A2 PCT/US2003/029322 US0329322W WO2004026242A2 WO 2004026242 A2 WO2004026242 A2 WO 2004026242A2 US 0329322 W US0329322 W US 0329322W WO 2004026242 A2 WO2004026242 A2 WO 2004026242A2
Authority
WO
WIPO (PCT)
Prior art keywords
dimethyl
tert
oxo
butyl
phosphonate
Prior art date
Application number
PCT/US2003/029322
Other languages
French (fr)
Other versions
WO2004026242A3 (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
Original Assignee
Ilex Oncology Research, Sarl
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ilex Oncology Research, Sarl filed Critical Ilex Oncology Research, Sarl
Priority to AU2003272513A priority Critical patent/AU2003272513A1/en
Publication of WO2004026242A2 publication Critical patent/WO2004026242A2/en
Publication of WO2004026242A3 publication Critical patent/WO2004026242A3/en

Links

Classifications

    • 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 substituted phosphonates compounds in the treatment and/or prevention of neoplastic diseases requiring antiproliferative activity.
  • Cancer is a leading cause of morbidity and mortality in the developed countries.
  • One of the major objectives of new anticancer drug research is to develop agents that suppress cancer cell growth without having deleterious effects on normal cells.
  • New agents that affect cell growth, cell differentiation, and apoptosis (programmed cell death) via certain signal transduction pathways may have increased specificity for neoplastic cells (see Hartwell et al, 1994).
  • substituted phosphonates of formula (I) inhibit the proliferation of tumor cells and are thereby useful in the treatment of neoplastic diseases.
  • One aspect of the invention is a method of inhibiting the proliferation of a tumor cell, comprising contacting the tumor cell with an effective amount of a substituted phosphonate compound of the formula (I).
  • the generic structure of the compounds of the present invention is represented by:
  • X° is H, OH or a straight or branched d-C ⁇ alkoxy group
  • X , X and X are independently H, OH, a straight, branched or cyclic Ci-C ⁇ alkyl or alkoxy group;
  • X , X or X , X together may form a C j -C 8 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 C ⁇ -C 6 alkyl groups; X 4 , X 5 , X 6 are independently H, a straight or branched Ci-C ⁇ alkyl group; q is zero or 1;
  • X is H, a straight or branched Ci-Cg alkyl or alkoxy group, or an optionally substituted benzyl group;
  • Y is O or S;
  • Z 1 and Z2 are independently OR 1 or NR 2 R 3 , where R 1 , R 2 , and R 3 are independently H or a
  • L is a saturated or unsaturated Ci-Cn 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, CI or Br), Ci-C ⁇ alkyl, an optionally substituted aryl or heteroaryl group.
  • the present invention also encompasses pharmaceutically acceptable salts, solvates and hydrates of compounds of formula
  • alkyl and "alkoxy" as used herein in relation to X°, X 1 , X 2 , X 3 , X 6 , 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 n+1 ) or -O(C n H 2 n+ ⁇ ) or cyclic -(C n H 2n-1 )- or -O-(CnH 2n - ⁇ )-, 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, e.g.
  • Ar is:
  • X° is H, OH, OMe, X 3 is H, OH, Me, OMe, X 1 and X 2 are independently a straight or branched C Ce alkyl, a straight or branched C C 6 alkoxy group; with the proviso that X° is H when X 3 is H, and X 1 and X 2 are independently a straight or branched -C 6 alkyl groups;
  • Y is O;
  • Z 1 and Z 2 are the same and are OR 1 wherein R 1 is methyl, ethyl or isopropyl;
  • Ar is:
  • X° is H, OH, OMe
  • X 4 is H, a straight, branched or cyclic Ci-Cg alkyl or alkoxy group, more preferably X 4 is a tert- butyl group;
  • X 5 and X 6 are indepdently H, a C C alkyl group, more preferably X 5 and X 6 are H; q is zero or 1, more preferably q is 1 ; 1 1 1
  • Ar is:
  • X° is H, OH, SH, OMe, SMe group
  • X is H, a straight or branched C ⁇ -C 8 alkyl or alkoxy group, preferably a t-butyl group or an optionally substituted benzyl group;
  • Y is O;
  • R is methyl, ethyl or isopropyl
  • the substituted phosphonate compound of formula (I) is selected from the group consisting of:
  • the tumor cells are non-small cell lung cancer tumor cells, colon cancer tumor cells, melanoma tumor cells, ovarian cancer tumor cells, renal cancer tumor cells, prostate cancer tumor cells, breast cancer tumor cells, pancreatic cancer tumor cells, thyroid cancer tumor cells, head and neck cancer tumor cells, lung cancer tumor cells, kidney cancer tumor cells, liquid tumor cells, or central nervous system cancer tumor cells.
  • Another aspect of the present invention is a method to treat cancer in a patient comprising administering an effective amount of a substituted phosphonate compound of formula (I).
  • the cancer may be non-small cell lung cancer, colon cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, pancreatic cancer, thyroid cancer, head and neck cancer, lung cancer, lymphoma, leukemia, or central nervous system cancer.
  • the compounds of formula (I) may at least in part inhibit the proliferation of tumor cells by inhibiting the synthesis of the precursors required for isoprenoid synthesis, i.e., mevalonate and isopentenylpyrophosphate.
  • the mevalonate/isoprenoid pathway of steroid synthesis is involved in cell proliferation wherein, in addition to being the precursor of cholesterol, mevalonate also provides downstream isoprenoids, i.e., farnesylpyrophosphate and geranylgeranylpyrophosphate.
  • isoprenoids i.e., farnesylpyrophosphate and geranylgeranylpyrophosphate.
  • compositions of formula (1) have previously been disclosed in WO9419358, herein incorporated by reference.
  • 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.
  • solvent of crystallisation 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.
  • 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 admimstered 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 1 mg to 1 g of the compound, more usually from 10 mg to 500 mg, for example between 50 mg and 400 mg, and typically in doses of 100 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 tolOO 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.
  • the size of the doses admimstered 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 antiproliferative activity of compounds of formula (I) include, but are not limited to, non-small cell lung cancer, colon cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, pancreatic cancer, thyroid cancer, head and neck cancer, lung cancer, kidney cancer, liquid tumors such as leukemias, and cancer of the central nervous system.
  • the compounds of this invention display antiproliferative activity and are therefore of value in the treatment of any of these conditions.
  • 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.
  • 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° 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° 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° for 30 min to allow for complete formation of the lithium anion.
  • the mixture was again cooled to -60° 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.
  • 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 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.
  • Example 28 Dimethyl 2-(3,5-di-tert-butylphenyl)-l,l-dimethyl-2-oxo-ethylphosphonate t -Bu
  • Example 33 Dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl )-2-oxo-3- buten-1-yl phosphonate 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° 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-tetrahydrona ⁇ hthyl]-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° 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 (2.0 g, 8.0 mmol) in 10 ml dry THF was added.
  • Example 35 Dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l,l- dimethyl-2 ⁇ oxo-3-buten-l-yl-phosphonate
  • 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 stirred at -78° 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.
  • Example 39 Dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl )-2-oxo-3- buten-1-yl phosphonate t-Bu
  • 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-tetrahydronaphthylj-acrylate.
  • 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 stirred 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-tetrahydrona ⁇ hthyl]-acrylate (2.0 g, 6.6 mmol) in 10 ml dry THF was added.
  • 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 stirred 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 (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.
  • Example 41 Dimethyl 4-(3-tert-butyI-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l,l- dimethyl-2-oxo-3-buten-l-yl-phosphonate t-Bu
  • 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 t-Bu
  • 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 stirred at -78° 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.
  • 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-butyI-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l,l- dimethyl-2-oxo-l-butyl-phosphonate t-Bu
  • 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-l-yl-phosphonate (0.20 g) over a suspension of Pd/C (0.15 g) in ethyl acetate.
  • Example 54 Dimethyl 4-(3,5-di-tert-butyl-2-hydroxyphenyl)-l,l-dimethyl-2-oxo-l-butyl- phosphonate
  • 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.
  • a compounds of Formula (I), e.g., compounds 1 through 81 above, are screened to determine their potential for inhibiting the proliferation of two human tumor cell lines, e.g., SW620 (colon cancer) and HL60 (leukemia) cells.
  • Cell types are commercially avaialbel, i.e., SW620 and HL60 are obtained from the American Type Culture Collection (ATCC).
  • SW60 cells are seeded at a density of 4 x 10 4 cells in 24-well plates and are allowed to attach for 48 hr.
  • HL60 cells are seeded at a density of 5 x 10 4 cells in 24-well plates with no plating time required.
  • Complete dose-response curves are obtained with test compounds that were added at 0, 2, 5, 10, 20 and 40 ⁇ M concentrations in 1 % ethanol solutions in triplicate directly to the medium along with fetal calf serum.
  • the cells were cultured for 48 hr in the presence of the test compounds, the SW60 cells are frypsinized, both cell types are resuspended in 7 ml total solution by dilution with an electrolyte based on 0.9 % saline solution and 500 ⁇ l of the final solution are counted twice using a Coulter ZI counter.
  • the size window is set at a range from 10 to 20 microns.
  • the anticancer drug Tamoxifen may be tested under the same conditions to validate the testing methodology.
  • the antiproliferative effects are Tamoxifen expressed as per cent inhibition relative to control at 10 and 20 ⁇ M were 30% and 50% inhibition respectively on SW620 cells and the antiproliferative effects of Tamoxifen at 10 and 20 ⁇ M were 24% and 62% inhibition respectively on HL60 cells.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides for methods of treatment of cancer and the inhibition of the proliferation of tumor cells by substituted phosphonate compounds.

Description

DESCRIPTION
SUBSTITUTED KETOPHOSPHONATE INHIBITORS OF TUMOR CELL
PROLIFERATION
FIELD OF INVENTION
The present invention relates to the use of substituted phosphonates compounds in the treatment and/or prevention of neoplastic diseases requiring antiproliferative activity.
BACKGROUND OF THE INVENTION
Cancer is a leading cause of morbidity and mortality in the developed countries. One of the major objectives of new anticancer drug research is to develop agents that suppress cancer cell growth without having deleterious effects on normal cells. New agents that affect cell growth, cell differentiation, and apoptosis (programmed cell death) via certain signal transduction pathways may have increased specificity for neoplastic cells (see Hartwell et al, 1994).
SUMMARY OF THE INVENTION
The Applicants have now found that substituted phosphonates of formula (I), as set out below, inhibit the proliferation of tumor cells and are thereby useful in the treatment of neoplastic diseases. One aspect of the invention is a method of inhibiting the proliferation of a tumor cell, comprising contacting the tumor cell with an effective amount of a substituted phosphonate compound of the formula (I). The generic structure of the compounds of the present invention is represented by:
Figure imgf000002_0001
wherein Ar is:
Figure imgf000003_0001
and X° is H, OH or a straight or branched d-Cό alkoxy group,
X , X and X are independently H, OH, a straight, branched or cyclic Ci-Cβ alkyl or alkoxy group;
0 1 2 3 or X , X or X , X together may form a Cj-C8 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 Cι-C6 alkyl groups; X4, X5, X6 are independently H, a straight or branched Ci-Cβ alkyl group; q is zero or 1;
X is H, a straight or branched Ci-Cg alkyl or alkoxy group, or an optionally substituted benzyl group; Y is O or S; Z 1 and Z2 are independently OR 1 or NR 2 R 3 , where R 1 , R 2 , and R 3 are independently H or a
1 2 straight or branched Cj-C6 alkyl group, or Z , Z together may form a C2-C8 alkylidenedioxy group; and
L is a saturated or unsaturated Ci-Cn 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, CI or Br), Ci-Cβ alkyl, an optionally substituted aryl or heteroaryl group. The present invention also encompasses pharmaceutically acceptable salts, solvates and hydrates of compounds of formula
CD-
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, CI, Br), Cι-C6 straight or branched alkyl, an optionally substituted aryl or heteroaryl, "-B-" is -C(R6)(R7)- where R6,R7 identical or different are H, Halogen (F, CI, Br), d-C6 straight or branched alkyl, an optionally substituted aryl or heteroaryl, or R and R can form a ring of C -C carbon atoms.
The term "alkyl" and "alkoxy" as used herein in relation to X°, X1, X2, X3, X6, R1, R2, R3, R4 and R5 means as indicated saturated straight, branched or cyclic substitutents, i.e., straight or branched -(CnH n+1) or -O(CnH2n+ι) or cyclic -(CnH2n-1)- or -O-(CnH2n-ι)-, 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., -CF and -OCF3.
In some embodiments, Ar is:
Figure imgf000004_0001
wherein X° is H, OH, OMe, X3 is H, OH, Me, OMe, X1 and X2 are independently a straight or branched C Ce alkyl, a straight or branched C C6 alkoxy group; with the proviso that X° is H when X3 is H, and X1 and X2 are independently a straight or branched -C6 alkyl groups;
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- C(CH3)(F), CH=CH-CO-C(F)2, or CO-CH2, CO-C(CH3)2, CO-C(CH3)(F), CO-C(F)2. In another embodiment, Ar is:
Figure imgf000004_0002
wherein X° is H, OH, OMe;
X4 is H, a straight, branched or cyclic Ci-Cg alkyl or alkoxy group, more preferably X4 is a tert- butyl group;
X5 and X6 are indepdently H, a C C alkyl group, more preferably X5 and X6 are H; q is zero or 1, more preferably q is 1 ; 1 1 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- C(CH3)(F), CH=CH-CO-C(F)2, or CO-CH2, CO-C(CH3)2, CO-C(CH3)(F), CO-C(F)2. In a further embodiments Ar is:
Figure imgf000005_0001
wherein X° is H, OH, SH, OMe, SMe group;
X is H, a straight or branched CΪ-C8 alkyl or alkoxy group, preferably a t-butyl group or an optionally substituted benzyl group; Y is O;
1 9 1 1
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- C(CH3)(F), CH=CH-CO-C(F)2, or CO-CH2, CO-C(CH3)2, CO-C(CH3)(F), CO-C(F). In various further embodiments, the substituted phosphonate compound of formula (I) is selected from the group consisting of:
dimethyl 4-(3 -methoxy-5-methyι-4-hydroxyphenyI)- 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-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 -yl- phosphonate; dimethyl 4-(5-tert-butyl-2-hydroxy-3-methoxyphenyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -yl- phosphonate; dimethyl 4-(3-cyclopentyloxy-4-methoxyphenyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -yl-phosphonate; dimethyl 4-(3,5-di-cyclopentyl-4-hydroxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l-yl- phosphonate; diethyl 2-(3,4,5-trimethoxyphenyl)-l , 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)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -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)- 1 , 1 -diethyl-2-oxo-3 -buten- 1 -yl phosphonate; dimethyl 4-(3 ,5-di-tert-butyl-2-hydroxyphenyl)- 1 , 1 -cyclop entyliden-2-oxo-3 -buten- 1 -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-hydrox yphenyl)- 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)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -yl phosphonate; diethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l-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-methox yphenyl)- 1 -methyl-2-oxo-3 -buten- 1 -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)- 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)-l,l-diethyl-2-oxo-3-buten-l-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-1 -methyl-2-oxoethylphosphonate; diethyl 2-(3,5-di-tert-butyl-2-methoxyρhenyl)-l-fluoro-l-methyl-2-oxoethylphosphonate; dimethyl 4-(3 ,5-di-tert-butylphenyl)-2-oxo-3-buten- 1 -yl phosphonate; diethyl 4-(3,5-di-tert-butylphenyl)-2-oxo-3-buten-l-yl phosphonate; dimethyl 4-(3,5-di-tert-butylphenyl)-l,l-dimethyl-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3,5-di-tert-butyl-phenyl)-l,l-dimethyl-2-oxo-3-buten-l-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)-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)-l,l-fluoro-2-oxo-3-buten-l-yl phosphonate; dimethyl 2-(3 ,5-di-tert-butylphenyl)- 1 -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)-l,l-dimethyl-2-oxo-3-buten-l- yl-phosphonate; diethyl 4-(3 -tert-butyl-4-hydroxy-5 ,6,7, 8-tetrahydronaphthyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -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,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 -yl- phosphonate; 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)-l-methyl-2-oxo-3-buten-l-yl- phosphonate; 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)- 1 -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-l-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-phosphonate; 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-l -butyl-phosphonate; and dimethyl 4-(3 -tert-butyl-4-hydroxy-5 ,6,7, 8-tetrahydronaphthyl)- 1 , 1 -dimethyl-2-oxo- 1 -butyl- phosphonate. In some embodiments the tumor cells are non-small cell lung cancer tumor cells, colon cancer tumor cells, melanoma tumor cells, ovarian cancer tumor cells, renal cancer tumor cells, prostate cancer tumor cells, breast cancer tumor cells, pancreatic cancer tumor cells, thyroid cancer tumor cells, head and neck cancer tumor cells, lung cancer tumor cells, kidney cancer tumor cells, liquid tumor cells, or central nervous system cancer tumor cells. Another aspect of the present invention is a method to treat cancer in a patient comprising administering an effective amount of a substituted phosphonate compound of formula (I). In various embodiments, the cancer may be non-small cell lung cancer, colon cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, pancreatic cancer, thyroid cancer, head and neck cancer, lung cancer, lymphoma, leukemia, or central nervous system cancer.
DETAILED DESCRIPTION OF THE INVENTION
I. Substituted Phosphonate Inhibitors of Tumor Proliferation
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 inhibit the proliferation of tumor cells by inhibiting the synthesis of the precursors required for isoprenoid synthesis, i.e., mevalonate and isopentenylpyrophosphate. The mevalonate/isoprenoid pathway of steroid synthesis is involved in cell proliferation wherein, in addition to being the precursor of cholesterol, mevalonate also provides downstream isoprenoids, i.e., farnesylpyrophosphate and geranylgeranylpyrophosphate. Several proteins have been identified that are post-translationally modified by the covalent attachment of these mevalonate-derived isoprenoid groups. These proteins must be prenylated as a prerequisite for membrane association, which is necessary for the function of a number of cellular processes including cell signalling, differentiation and proliferation. The discovery that the compounds of formula (I) decrease the level of HMG-CoA reductase, and thus the pool of isoprenoids, tends to indicate that these compounds may be useful for the inhibition of tumor cells, as verified by direct tumor cell proliferation assays.
Some of the compounds of formula (1) have previously been disclosed in WO9419358, herein incorporated by reference. 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 crystallisation 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 admimstered 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 1 mg to 1 g of the compound, more usually from 10 mg to 500 mg, for example between 50 mg and 400 mg, and typically in doses of 100 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 tolOO 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 admimstered 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 antiproliferative activity of compounds of formula (I) include, but are not limited to, non-small cell lung cancer, colon cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, pancreatic cancer, thyroid cancer, head and neck cancer, lung cancer, kidney cancer, liquid tumors such as leukemias, and cancer of the central nervous system. The compounds of this invention display antiproliferative activity and are therefore of value in the treatment of any of these conditions.
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-phosphonate
Figure imgf000013_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: M+ - HPO3Me2, 191 (100%): M+- CMe2(PO3Me2) NMR: (CDC13) δ = 7.62 (d, J = 16Hz, IH): Ph-CH=CH 7.27 (d, J = 16Hz, IH): Ph-CH=CH 7.06 and 6.95 (two m, total 2H): arom. H
6.0 (s, IH): 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(CH3)2-P
Example 2: Dimethyl 4-(3,5-dimethoxy-4-hydroxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l- yl-phosphonate
Figure imgf000014_0001
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: M1" - HPO3Me2, 207 (100%): M+- CMe2(PO3Me2) NMR: (CDCI3) δ = 7.62 (d, J = 15.5Hz, IH): Ph-CH=CH 7.28 (d, J = 16Hz, IH): Ph-CH=CH 6.85 (s, 2H): arom. H 5.9 (s, IH): 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 imgf000014_0002
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: (CDC13) δ = 7.61 (d, J = 15.5Hz, IH): Ph-CH=CH 7.32 (d, J = 15.5Hz, IH): 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 imgf000015_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 (SiO2, 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, IH): Ph-CH=CH 7.26 (d, J = 16Hz, IH): Ph-CH=CH 6.84 (s, 2H): arom. H 5.84 (s, IH): 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 imgf000016_0001
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 (SiO2, 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: (CDC13) δ = 7.57 (d, J = 15.5Hz, IH): Ph-CH=CH 7.28 (d, J = 15.5Hz, IH): Ph-CH=CH 6.95 and 6.69 (two d, J = 2Hz, 2H): arom. H 6.15 (s, IH): 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- buten-1-yl-phosphonate
Figure imgf000016_0002
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, IH): Ph-CH=CH 7.27 (d, J = 15.5Hz, IH): Ph-CH=CH 7.05 and 6.97 (two d, J = 2H, 2H): arom. H 5.98 (s, IH): 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-CH-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-dimethyl-2-oxo-3- buten-1-yl-phosphonate
Figure imgf000017_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 (SiO , 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, IH): Ph-CH=CH
7.61 (d, J = 15.5Hz, IH): Ph-CH=CH
7.10 and 6.92 (2d, 2H): arom. H
6.20 (s, IH): OH
3.93 (s, IH): 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-C4H9
Example 8: Dimethyl 4-(3-cyclopentyloxy-4-methoxyphenyl)-l,l-dimethyl-2-oxo-3- buten-1-yl-phosphonate
Figure imgf000018_0001
To 50 ml dry THF kept at 0°C were added sequentially TiCl (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 (SiO2, 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, IH): Ph-CH=CH
7.2 (dd, IH), 7.10 (d, IH) and 6.86 (s, IH): arom. H 7.24 (d, J = 15.5Hz, IH): Ph-CH=CH 3.88 (s, 3H): OCH3
3.79 and 3.78 (2d, J = 11 Hz, 6H): P-O-CH3
4.82 (septuplet, 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-dicyclopentyl-4-hydroxyphenyl)-l,l-dimethyl-2-oxo-3-buten- 1-yl-phosphonate
Figure imgf000019_0001
To 20 ml dry THF kept at 0°C were added sequentially TiCl4 (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 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, 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: (CDC13) δ = 7.66 (d, J = 15.5Hz, IH): Ph-CH=CH 7.31 (s, 2H): arom. H 7.42 (d, J = 15.5Hz, IH): 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) -P
Example 10: Dimethyl 4-(3,5-di-tert-butyI-2-hydroxyphenyl)-l,l-dimethyl-2-oxo-3-buten- 1 -yl-phosphonate
Figure imgf000019_0002
To 30 ml dry THF kept at 0°C were added sequentially ΗCI4 (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 2h at 0°C. Work up as previously described and purification by flash column chromatography (SiO2, 98/2 CH2C12/MeOH) gave 0.87 g (2.2 mmol, 32 % yield) of the title compound. Recrystallization 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, IH): Ph-CH=CH
7.35 (d, J - 15.5Hz, IH): Ph-CH=CH
7.37 and 7.30 (two d, J = 2Hz, 2H): arom. H
5.98 (broad s, IH): 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 imgf000020_0001
To 30 ml dry THF kept at 0°C were added sequentially ΗCI4 (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. Recrystallization 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, IH): Ph-CH=CH 7.37 (d, J = 15.5Hz, IH): Ph-CH=€H 7.36 and 7.29 (two d, J = 2Hz, 2H): arom. H 5.98 (broad s, IH): 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-C4H9 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 imgf000021_0001
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 portionwise 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] - 1 -fluoro- 1 -methyl-2-oxo-3 -buten- 1 -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)-l -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: (CDC1 ) δ = 7.31 and 7.03 (two d, J = 2.4Hz, 2H): arom. H
6.79 (two d, J = 9.7Hz, IH): Ph-CH=CH 6.00 (d, J = 9.7Hz, IH): Ph-CH=CH
6.50 (broad s, IH): 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 t-Bu O-Me
t-Bu _poβEt 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% HC1 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% HC1 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%o 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, IH): Ph-CH=CH 7.43 (s, IH): arom. H 6.87 (d, J = 16Hz, IH): 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-C^o, 1.34 (t, J = 7Hz, 6H): P-O-CH -CH3
Example 14: Dimethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-l,l-dimethyl-2-oxo-3-buten- 1-yl-phosphonate
Figure imgf000024_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, IH): Ph-CH=CH 7.45 and 7.41 (2d, 2H): arom. H 7.38 (d, J = 15.5Hz, IH): 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): t-C4H9
Example 15: Diethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-l,l-dimethyl-2-oxo-3-buten-l- yl-phosphonate
Figure imgf000025_0001
The method described for the preceding example SR- 163106 was followed, using the reactants in the following amounts: THF (15 ml), TiCl4 (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%): M1" - OMe, 273: M+- CMe2(PO3Et2), 57: tBu+ NMR: (CDC13) δ = 7.97 (d, J = 15.7Hz, IH): Ph-CH=CH 7.45 and 7.40 (2d, 2H): arom. H
7.44 (d, J = 15.7 Hz, IH): 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 imgf000025_0002
The method described for the preceding example SR- 163106 was followed, using the reactants in the following amounts: THF (15 ml), ΗC 4 (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 morpholine (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, IH): Ph-CH=CH
7.45 and 7.40 (2d, J= 2.4Hz, 2H): arom. H 7.44 (d, J = 15.7Hz, IH): 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): t-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 imgf000026_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% HC1. 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 imgf000027_0001
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 e= 426: M+ , 247 (62%): M+-C(CH3)2-PO3Et2, 57 (100%): tBu+
NMR: (CDC13) δ = 7.34 and 7.13 (2d, IH each): arom. H 4.21-4.15 (m, 4H): P-O-CH2-CH3
3.66 (Is, 3H): arom. O-CH3 1.49 (d, J = 16.5 Hz, 6H): -C(CH3)2-P 1.38 and 1.30 (2s, 9H each): t-C4H9 1.34 (t, J = 7Hz, 6H): P-O-CH2-CH3
Example 19: Dimethyl 2-(3,5-di-tert-butyl-2-methoxyphenyl)-l-fluoro-l-methyl-2-oxo- ethylphosphonate
Figure imgf000028_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 cliromatography (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: (CDCI3) δ = 7.47 (d, IH) and 7.45 (t, IH): 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 1.322(s, 9H each): t-C^g
Example 20: Dimethyl 4-(3,5-di-tert-butylphenyl)-2-oxo-3-buten-l-yl phosphonate
Figure imgf000028_0002
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% HC1 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 = 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° 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% HC1 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: tBu "
NMR (CDC13) δ = 7.67 (d, J = 16Hz, IH): Ph-CH=CH
7.51 (t, IH) and 7.42 (d, 2H): arom. H 6.86 (d, J = 16 Hz, IH): Ph-CH=CH 3.82 (d, J = 11Hz, 6H): P-O-CH3
3.37 (d, J = 22Hz, 2H: CH2-P 1.35 (s, 18H): t-C4H9
Example 21: Diethyl 4-(3,5-di-tert-butylphenyl)-2-oxo-3-buten-l-yI phosphonate
Figure imgf000029_0001
Under nitrogen atmosphere diethyl methylphosphonate (3.3 g, 21.7 mmol) was added at - 78° 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° for 30 min to allow for complete formation of the lithium anion. The mixture was again cooled to -60° 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+-HPO Et2, 57 (100%): tBu
NMR (CDC13) δ = 7.67 (d, J = 16 Hz, IH): Ph-CH=CH 7.50 (t, IH) and 7.42 (d, 2H): arom. H 6.88 (d, J = 16Hz, IH): Ph-CH=CH 4.22-4.11 (m, 4H): P-O-CH2-CH3
3.36 (d, J = 23 Hz, 2H): CH -P 1.35 (s, 18H): t-C4H9
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-yl- phosphonate t-Bu
Figure imgf000030_0001
To 50 ml dry THF kept at 0°C were added sequentially ΗCI4 (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 morpholine (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: (CDCI3) δ = 7.77 (d, J = 15.6Hz, IH): Ph-CH=CH 7.53 (t, IH) and 7.48 (d, 2H): arom. H 7.42 (d, J = 15.6Hz, IH): Ph-CH=CH 3.84 and 3.78 (2d, J = 11 Hz, 6H): P-O-CH3
1.57 (d, J = 16.7Hz, 6H): -C(CH.3)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 imgf000031_0001
The method described for the preceding example was followed, using the reactants in the following amounts: THF (10 ml), TiCl4 (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, IH): Ph-CH=CH 7.53 (t, IH) and 7.48 (d, 2H): arom. H 7.45 (d, J = 16Hz, IH): 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
Figure imgf000031_0002
MS: m e = 423: M++ 1, 243 (100%): M+- C(Et)2(PO3Me2), 57 : tBu+ NMR: (CDC13) δ = 7.72 (d, J = 15.5Hz, IH): Ph-CH=CH 7.49 (t, IH) and 7.43 (d, 2H): arom. H 7.37 (d, J = 15.5Hz, IH): Ph-CH=CH 3.79 (d, J = 11 Hz, 6H): P-O-CH3
2.08 (m, 4H): -C(CH2-CH3)2-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 imgf000032_0001
MS: m/e = 420: M+, 243 (100%): M+- (c-C5H8)(PO3Me2), 57: tBu+ NMR: (CDCI3) δ = 7.73 (d, J = 15.5Hz, IH): Ph-CH=CH 7.49 (t, IH) and 7.43 (d, 2H): arom. H 7.30 (d, J = 15.5Hz, IH): 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-C5Hs)-P 1.35 (s, 18H): t-C4H9
Example 26: Dimethyl 2-(3,5-di-tert-butylphenyl)-l-methyl-2-oxo-ethylphosphonate
Figure imgf000032_0002
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: (CDC13) δ = 7.86 (d, 2H) and 7.67 (t, IH): arom. H 4.23 and 4.19 (2 quartets, J=22.3 Hz, IH): -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-C4H9
Example 27: Diethyl 2-(3,5-di-tert-butylphenyl)-l-methyl-2-oxo-ethylphosphonate
Figure imgf000033_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 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 ammomum 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, IH): arom. H 4.20-4.05 (m, 4H): P-O-CH2-CH3 4.20 (overlapped m, IH): -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
O
P03Me2 t-Bu M Mee 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)-PO Me2, 57: tBu+
NMR: (CDC13) δ = 7.86 (s, 2H) and 7.55 (t, IH): 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 imgf000034_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) 2 -PO3Et2, 57: tBu+
NMR: (CDC13) δ = 7.85 (d, 2H) and 7.54 (t, IH): 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): t-C4H9
1.30 (t, J=7 Hz, 6H): P-O-CH2 -CHg
Example 30: Diethyl 2-(3,4,5-trimethoxyphenyl)-l,l-dimethyl-2-oxo-ethylphosphonate
Figure imgf000035_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: (CDCI3) 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~methyl~2-oxo- ethylphosphonate
POsMe2
Figure imgf000036_0001
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: (CDC13) δ = 7.95 (d, J = 1.6 Hz, 2H) and 7.67 (t, IH ): 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 imgf000036_0002
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: (CDC13) δ = 7.95 (t, J = 1.6 Hz, 2H) and 7.67 (t, IH ): 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 imgf000037_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 ca 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° 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-tetrahydronaρhthyl]-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+ - H20, 252: M+ - H2O - HPO3Me2, 57 (100%): tBu+ NMR : (CDC13) δ = 7.98 (d, J = 16Hz, IH): Ph-CH=CH 7.48 (s, IH): arom. H 6.68 (d, J = 16Hz, IH): Ph-CH=CH ca 5.3 (IH): 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-C4H9
Example 34: Diethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl )-2-oxo-3- buten-1-yl phosphonate t-Bu
Figure imgf000038_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° 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 (2.0 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, chloroform 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+
Figure imgf000038_0002
δ = 7.96 (d, J = 16Hz, IH): Ph-CH=CH 7.46 (s, IH): arom. H
6.70 (d, J = 16Hz, IH): Ph-CH=CH ca 5.3 (IH): 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-C H9
1.34 (t, J = 7Hz, 6H): P-O-CH2-CH3
Example 35: Dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l,l- dimethyl-2~oxo-3-buten-l-yl-phosphonate
Figure imgf000039_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 stirred 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, IH): Ph-CH=CH 7.50 (s, IH): arom. H 7.18 (d, J = 18Hz, IH): Ph-CH=CH ca 5.3 (IH): 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-C4H9 Example 36: Diethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l,l-dimethyl- 2-oxo-3-buten-l-yl-phosphonate t-Bu
Figure imgf000040_0001
To 30 ml dry THF kept at 0°C were added sequentially ΗC14 (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 stirred 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+ NMR: (CDC13) δ = 7.99 (d, J = 16Hz, IH): Ph-CH=CH
7.50 (s, IH): arom. H
7.22 (d, J = 16Hz, IH): Ph-CH=CH ca 5.3 (IH): 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 imgf000040_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 stirred 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 stirred 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 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 2.71 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 stirred 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, reexfracted 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-methoxyethoxvmethoxy)- 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). S: m/e = 394: M+, 376: M+ - H2O, 257: M+- CHMe (PO3Me2), 57 (79%): tBu+, 138 (100 %):
HCHMe (P03Me2) + NMR: (CDC13) δ = 7.98 (d, J = 15.6Hz, IH): Ph-CH=CH 7.49 (s, IH): arom. H
6.79 (d, J = 15.6Hz, IH): Ph-CH=CH ca 5.3 (IH): OH
3.81 (2d, J = 11 Hz, 6H): P-O-CH3
3.58-3.48 (2 quartets, IH): CH(CH3) -P 2.86, 2.59, 1.89-1.83 and 1.82-1.78 (total 8H): C4H
1.49 (2d, J = 7 Hz, 3H): -CH(CH3) -P
1.43 (s, 9H): t-C4H9
Example 38: Diethyl 4-(3~tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l-methyl-2- oxo-3-buten-l -yl-phosphonate t-Bu
Figure imgf000042_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 stirred at -78° 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 CI 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 recrystallization 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, IH): Ph-CH=CH 7.49 (s, IH): arom. H 6.82 (d, J = 15.6Hz, IH): Ph-CH=CH ca 5.3 (IH): OH
4.18-4.12 (m, 4H): P-O-CH2-CH3
3.53-3.43 (2 quartets, J= 7Hz, IH): 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-C4H9
1.33 (2t overlapped, J = 7Hz, 6H): P-O-CH2-CH3
Example 39: Dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl )-2-oxo-3- buten-1-yl phosphonate t-Bu
Figure imgf000043_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-tetrahydronaphthylj-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 stirred 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-tetrahydronaρhthyl]-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 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 0.51 g (1.29 mmol, 20%) of the title compound.
MS: m/e = 394: M+, 376: M+ - H2O, 266: M1" - H2O - HPO3Me2, 57 (100%): tBu+ NMR: (CDC13) δ = 8.01 (d, J = 16Hz, IH): Ph-CH=CH
7.50 (s, IH): arom. H
6.73 (d, J = 16Hz, IH): 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 imgf000044_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 stirred 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 (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 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 0.79 g (1.87 mmol, 31%) of the title compound.
MS: m/e = 423: M+ + 1, 404: M+ - H2O, 266: M+ - H2O - HPO3Et2, 57 (100%): tBu+
Figure imgf000044_0002
δ = 7.96 (d, J = 16Hz, IH): Ph-CH=CH 7.45 (s, IH): arom. H 6.71 (d, J = 16Hz, IH): 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-CH3
Example 41 : Dimethyl 4-(3-tert-butyI-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l,l- dimethyl-2-oxo-3-buten-l-yl-phosphonate t-Bu
Figure imgf000045_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, IH): Ph-CH=CH 7.53 (s, IH): arom. H 7.24 (d, J = 15.4Hz, IH): 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): C4H8-
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 t-Bu
Figure imgf000046_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- tetraliydronaphthaldehyde (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: (CDCI3) δ = 8.03 (d, J = 15.5Hz, lH): Ph-CH=CH 7.53 (s, IH): arom. H 7.23 (d, J = 15.5Hz, IH): Ph-CH=CH 4.22-4.16 (quintet, 4H): P-O-CH -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): 1-C4H9 1.37 (t, J = 7Hz, 6H): P-O-CH2-CH3 Example 43: Diisopropyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l,l- dimethyl-2-oxo-3-buten-l-yl-phosphonate t-Bu
Figure imgf000047_0001
The method described for the preceding example was followed, using the reactants in the following amounts: THF (30 ml), TiCLj (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: M+, 312 (100%): M+ -HPO3iPr2, 271: M+-CMe2(PO3iPr2), 57: tBu+ NMR: (CDC13) δ - 7.96 (d, J = 15.5Hz, IH): Ph-CH=CH 7.48 (s, IH): arom. H 7.27 (d, J = 15.5Hz, IH): 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 imgf000047_0002
The method described for the preceding example was followed, using the reactants in the following amounts: THF (20 ml), TΪCI4 (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, IH): Ph-CH=CH 7.48 (s, IH): arom. H 7.20 (d, J = 15.4Hz, IH): 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 imgf000048_0001
The method described for the preceding example SR-158806 was followed, using the reactants in the following amounts: THF (20 ml), TiCl4 (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 morpholine 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, IH): Ph-CH=CH 7.48 (s, IH): arom. H 7.12 (d, J = 15.4Hz, IH): 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 t-Bu
Figure imgf000049_0001
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 stirred 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 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 8/2) to give 0.98 g (2.4 mol, 25%) of the title compound. MS: m e =408: M+ 271 : M+-CHMe (PO3Me2), 138 (100%): HCHMe (PO3Me2), 57: tBu+ NMR: (CDC13) δ = 7.98 (d, J = 15.6Hz, IH): Ph-CH=CH 7.47(s, IH): arom. H 6.81 (d, J = 15.6Hz, IH): 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, IH): CH(CH3)-P
2.87 (t, 2H), 2.76 (t, 2H), 1.85-1.80 (m, 2H) and 1.75-1.70 (m, 2H): C^s- 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 t-Bu
Figure imgf000050_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 stirred at -78° 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 carried 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 cliromatography (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, IH): Ph-CH=CH
7.48 (s, IH): arom. H
6.84 (d, J = 15.5Hz, IH): 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, IH): -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-CH.3 Example 48: Dimethyl 4-(3-tert-butyl-5,5-dimethyl-4-hydroxy-5,6,7,8-tetrahydro-l- naphthyl)-l,l-
Figure imgf000051_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 stirred 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 imgf000051_0002
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, IH): Ph-CH=CH 8.20, 8.13, 7.91, 7.53 (4m, 5H total): naphthyl H
7.39 (d, J = 15 Hz, IH): Ph-CH=CH 6.30 (broad s, IH): 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 imgf000052_0001
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 morpholine (0.95 g, 9.3 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 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: (CDCI3) δ = 8.50 (d, J = 15.3 Hz, lH) :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, IH): OH
3.79 (d, J = 11Hz, 6H): P-O-CH, 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 imgf000052_0002
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 (CDCI3) δ = 6.93 (s, 2H): arom. H 4.77 (s, IH): 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-C4H9
Example 52: Dimethyl 4-(3-tert-butyI-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l,l- dimethyl-2-oxo-l-butyl-phosphonate t-Bu
Figure imgf000053_0001
A solution of dimethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l,l- dimethyl-2-oxo-3 -buten- 1 -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%) of the title compound was obtained.
MS: m/e = 410: M+, 353: M+ - t-Bu, 300: M+ - HPO3Me2, 57: tBu+ NMR (CDC13) δ = 6.93 (s, IH): arom. H
4.80 (s, IH): OH
3.76 (d, J = 11Hz, 6H): P-O-CH3
2.91 (distorted t, J = 7 Hz, 2H): Ph-CH2-CH2 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): QHs- 1.43 (d, J = 17Hz, 6H): -C(CH3)2-P
1.41 (s, 9H): t-C H9 Example 53: Dimethyl 4-(5-tert-butyl-2-hydroxy-3-methoxyphenyl)-l,l-dimethyl-2-oxo-l- butyl-phosphonate
Figure imgf000054_0001
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-l-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: (CDC13) δ = 6.77 and 6.75 (2d, 2H): arom. H 5.7 (s, IH): 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 imgf000054_0002
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 rpm 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
Y -,
Z
Ar- ■ L - ( I)
<
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Example 56: Antiproliferative Activity
A compounds of Formula (I), e.g., compounds 1 through 81 above, are screened to determine their potential for inhibiting the proliferation of two human tumor cell lines, e.g., SW620 (colon cancer) and HL60 (leukemia) cells. Cell types are commercially avaialbel, i.e., SW620 and HL60 are obtained from the American Type Culture Collection (ATCC).
SW60 cells are seeded at a density of 4 x 104 cells in 24-well plates and are allowed to attach for 48 hr. HL60 cells are seeded at a density of 5 x 104 cells in 24-well plates with no plating time required. Complete dose-response curves are obtained with test compounds that were added at 0, 2, 5, 10, 20 and 40 μM concentrations in 1 % ethanol solutions in triplicate directly to the medium along with fetal calf serum. The cells were cultured for 48 hr in the presence of the test compounds, the SW60 cells are frypsinized, both cell types are resuspended in 7 ml total solution by dilution with an electrolyte based on 0.9 % saline solution and 500 μl of the final solution are counted twice using a Coulter ZI counter. The size window is set at a range from 10 to 20 microns.
The anticancer drug Tamoxifen may be tested under the same conditions to validate the testing methodology. The antiproliferative effects are Tamoxifen expressed as per cent inhibition relative to control at 10 and 20 μM were 30% and 50% inhibition respectively on SW620 cells and the antiproliferative effects of Tamoxifen at 10 and 20 μM were 24% and 62% inhibition respectively on HL60 cells.
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.
Hartwell & Kasten, "Cell cycle control and cancer," Science, 226: 1821-1828 (1994) Berge et al, "Pharmaceutical salts," J. Pharm. Sci., 66:1-19,1977. Mathey & Savignac, Tetrahedron 34:649-654, 1978. Roussis & Wiemer, J. Org. Chem., 54:627-631, 1989.

Claims

1. A method of inhibiting the proliferation of tumor cells, comprising contacting said tumor cells with an effective amount of a substituted phosphonate compound of the formula (I):
,ι
/
Ar - ( i )
\
wherein Ar is:
Figure imgf000066_0001
and X° is H, OH or a straight or branched Ci to C6 alkoxy group, X , X and X are independently H, OH, a straight, branched, or cyclic Ci- alkyl or alkoxy group;
0 1 2 3 or X , X or X , X together may form a Ct - Cg 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 -Cό alkyl groups;
X4, X5, X6 are independently H, a straight or branched - C6 alkyl group; q is zero or 1;
X7 is H, a straight or branched d - C8 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-C6 alkyl group, or Z , Z together may form a C2 - C8 alkylidenedioxy group;
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, CI or Br, C1-6 alkyl, an optionally substituted aryl or heteroaryl group; and pharmaceutically acceptable salts, solvates and hydrates thereof.
2. The compound of claim 1, 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, CI, Br, Ci-C6 straight or branched alkyl, or an optionally substituted aryl or heteroaryl, and B is -C(R6)(R7)- where R6,R7 are independently H, F, CI, Br, Cι-C6 straight or branched alkyl, or an optionally substituted aryl or heteroaryl, or R6 and R7 can form a saturated ring of C3-C7 carbon atoms.
3. The compound of claim 2, 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, C H5 or R6 and R7 together form cyclic C5H8.
4. The compound of claim 2, wherein is A is a direct bond, -CH=CH-, or -CH2-CH2-.
5. The compound of claim 4, wherein B is -CH2,-, -CF2-, -CH(CH3)-, -CF(CH3)-, -C(CH3)2-, -C(CH3)(C2H5)-,-C(C2H5)2- or -CH(c C5H8)-.
6. The compound of claim 1, wherein Y is O.
7. The compound of claim 6, wherein X4 is butyl and X5 is H or methyl and q is 1.
8. The compound of claim 7, wherein X4 is tert-butyl and X5 is H.
1 7 1
9. The compound of claim 8, wherein Z and Z are the same and are OR .
10. The compound of claim 9, wherein R1 is methyl, ethyl or isopropyl.
11. The compound of claim 1 , wherein said substituted phosphonate compound of the 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)- 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-phosphonate; dimethyl 4-(3 , 5 -diethoxy-4-hydroxyphenyl)- 1 , 1 -dimethyl-2-oxo-3-buten- 1 -yl-pho sphonate; dimethyl 4-(4-hydroxy-3-methoxy-5-n-propylphenyl)-l,l-dimethyl-2-oxo-3-buten-l-yl- phosphonate; dimethyl 4-(5 -tert-butyl-2-hydroxy-3-methoxyphenyl)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -yl- phosphonate; 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)-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)- 1 , 1 -dimethyl-2-oxo-3 -buten- 1 -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)-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)-l-fluoro-l-methyl-2-oxo-3-buten-l-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)- 1 -methyl-2-oxo-3 -buten- 1 -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)-l-fluoro-l-methyl-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)-l-fluoro-l-methyl-2-oxo-3-buten-l-yl phosphonate; dimethyl 4-(3,5-di-tert-butyl-2-methoxyphenyl)- 1 , 1 -difluoro-2-oxo-3-buten- 1 -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)-l,l-diethyl-2-oxo-3-buten-l-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-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)-l,l-dimethyl-2-oxo-3-buten-l-yl phosphonate; diethyl 4-(3,5-di-tert-butyl-phenyl)-l,l-dimethyl-2-oxo-3-buten-l-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)- 1 , 1 -fluoro-2-oxo-3 -buten- 1 -yl phosphonate; diethyl 4-(3,5-di-tert-butyl-phenyl)-l,l-fluoro-2-oxo-3-buten-l-yl phosphonate; dimethyl 2-(3,5-di-tert-butylphenyl)- 1 -methyl-2-oxoethylphosphonate; diethyl 2-(3,5-di-tert-butyl-phenyl)- 1 -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)-l-fluoro-l-methyl-2-oxethylphosphonate; dimethyl 2-(3,5-di-tert-butylphenyl)-l,l-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-tetrahydronaρhthyl)-l,l-dimethyl-2-oxo-3-buten-l- yl-phosphonate; diethyl 4-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-l , 1 -dimethyl-2-oxo-3 -buten- 1 -ylphosphonate; 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)- 1 -fluoro- 1 -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,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)-l-methyl-2-oxo-3-buten-l-yl- phosphonate; 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-tefrahydronaphthyl)-l-fluoro-l-methyl-2-oxo-3-buten-
1 -yl-phosphonate; dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tefrahydronaphthyl)-l-ethyl-l-methyl-2-oxo-3- buten- 1 -yl-phosphonate; dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tefrahydronaphthyl)-l,l-diethyl-2-oxo-3-buten-l-yl- phosphonate; dimethyl 4-(3-tert-butyl-4-methoxy-5,6,7,8-tetrahydronaphthyl)-l , 1 -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-phosphonate; dimethyl 4-(3-benzyl-4-hydroxy-l -naphthyl)-l , 1 -dimethyl-2-oxo-3 -buten- 1 -yl-phosphonate; 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.
12. The method of claim 1, wherein said tumor cells are non-small cell lung cancer tumor cells, colon cancer tumor cells, melanoma tumor cells, ovarian cancer tumor cells, renal cancer tumor cells, prostate cancer tumor cells, breast cancer tumor cells, pancreatic cancer tumor cells, thyroid cancer tumor cells, head and neck cancer tumor cells, lung cancer tumor cells, kidney cancer tumor cells, liquid tumor cells, or central nervous system cancer tumor cells.
13. A method of treating cancer in a patient comprising administering to said patient an effective amount of a substituted phosphonate compound of claim 1.
14. The method of claim 13, wherein said cancer is selected from the group consisting of non-small cell lung cancer, colon cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, pancreatic cancer, thyroid cancer, head and neck cancer, lung cancer, lymphoma, leukemia, or central nervous system cancer.
PCT/US2003/029322 2002-09-19 2003-09-18 Substituted ketophosphonate inhibitors of tumor cell proliferation WO2004026242A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003272513A AU2003272513A1 (en) 2002-09-19 2003-09-18 Substituted ketophosphonate inhibitors of tumor cell proliferation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US41209002P 2002-09-19 2002-09-19
US60/412,090 2002-09-19

Publications (2)

Publication Number Publication Date
WO2004026242A2 true WO2004026242A2 (en) 2004-04-01
WO2004026242A3 WO2004026242A3 (en) 2004-07-15

Family

ID=32030801

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2003/029322 WO2004026242A2 (en) 2002-09-19 2003-09-18 Substituted ketophosphonate inhibitors of tumor cell proliferation
PCT/US2003/029387 WO2004026243A2 (en) 2002-09-19 2003-09-18 Therapeutic uses of linear ketophosphonates

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/US2003/029387 WO2004026243A2 (en) 2002-09-19 2003-09-18 Therapeutic uses of linear ketophosphonates

Country Status (2)

Country Link
AU (2) AU2003272534A1 (en)
WO (2) WO2004026242A2 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5116954A (en) * 1988-04-06 1992-05-26 Lipha, Lyonnaise Industrielle Pharmaceutique Pharmaceutically useful flavonoic compounds containing at least one substituent on the benzopyranone ring moiety
US6127350A (en) * 1995-07-28 2000-10-03 Symphar S.A. Use of phenol substituted diphosphonates as antineoplastic agents

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA941088B (en) * 1993-02-19 1995-09-27 Symphar Sa Substituted ketophosphonates the processes for their preparation and pharmaceutical compositions containing them

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5116954A (en) * 1988-04-06 1992-05-26 Lipha, Lyonnaise Industrielle Pharmaceutique Pharmaceutically useful flavonoic compounds containing at least one substituent on the benzopyranone ring moiety
US6127350A (en) * 1995-07-28 2000-10-03 Symphar S.A. Use of phenol substituted diphosphonates as antineoplastic agents

Also Published As

Publication number Publication date
AU2003272513A8 (en) 2004-04-08
WO2004026243A3 (en) 2004-06-03
AU2003272534A1 (en) 2004-04-08
AU2003272513A1 (en) 2004-04-08
WO2004026242A3 (en) 2004-07-15
AU2003272534A8 (en) 2004-04-08
WO2004026243A2 (en) 2004-04-01

Similar Documents

Publication Publication Date Title
AU679344B2 (en) Phosphonic diester derivative
JP3526575B2 (en) Phosphonic acid derivatives
JPH0822865B2 (en) Phenol-substituted gem-diphosphonate derivative, its preparation method and pharmaceutical composition containing the same
AU705206B2 (en) Compounds and pharmaceutical compositions containing them
EP0559079B1 (en) Substituted aminophosphonate derivatives, process for their preparation and pharmaceutical compositions containing them
CA2036407A1 (en) Phosphorus-containing hmg-coa reductase inhibitors, new intermediates and method
JPH07507046A (en) Novel phosphonosuccinic acid derivatives, their production methods and pharmaceuticals containing these compounds
US5635495A (en) Pyrimidine bisphosphonate esters and (alkoxymethylphosphinyl)alkyl phosphonic acids as anti-inflammatories
MXPA98000189A (en) Compounds and pharmaceutical compositions that contains them
EP0248854B1 (en) Novel bisphosphonic derivatives, a method for their production and a pharmaceutical composition
KR100233986B1 (en) Novel methylenebisphosphonic acid derivatives
BG103574A (en) Aminophosphonic acid derivatives having pharmaceutical activity
SK279601B6 (en) Methylenebisphosphonic acid derivatives, method of their preparation and pharmaceutical compounds them containing
IL102171A (en) Pyrimidinyl bisphosphonic esters as anti-inflammatories and pharmaceutical compositions containing them
IE62212B1 (en) N-heterocyclic propylidene-1, 1-bisphosphonic acids, their production and a pharmaceutical composition
JPS6140294A (en) 2_substituted_1,3_propylidenediphosphonate, manufacture and drug composition
US5278153A (en) Aryl and heteroaryl (phosphinylmethyl)phosphonate squalene synthetase inhibitors and method
AU657554B2 (en) Dialkyl (dialkoxyphosphinyl)methyl phosphates as anti-inflammatory agents
JPH05239075A (en) Phosphorus-containing isoprenoid derivative
JPH07506121A (en) Substituted phosphonates, their preparation and pharmaceutical compositions containing the compounds
WO2004026242A2 (en) Substituted ketophosphonate inhibitors of tumor cell proliferation
EP1551418A1 (en) Substituted ketophosphonate compounds having bone anabolic activity
AU730345B2 (en) Naphthyridine derivatives
AU756940B2 (en) Phosphonic acid diester derivatives
PT100991A (en) HETEROCYCLIC DERIVATIVES OF BIPHOSPHONIC ACIDS, AND PROCESS FOR THEIR PREPARATION

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP