EP0638084A1 - Substituted phosphonates, the processes for their preparation and pharmaceutical compositions containing them - Google Patents

Substituted phosphonates, the processes for their preparation and pharmaceutical compositions containing them

Info

Publication number
EP0638084A1
EP0638084A1 EP94909033A EP94909033A EP0638084A1 EP 0638084 A1 EP0638084 A1 EP 0638084A1 EP 94909033 A EP94909033 A EP 94909033A EP 94909033 A EP94909033 A EP 94909033A EP 0638084 A1 EP0638084 A1 EP 0638084A1
Authority
EP
European Patent Office
Prior art keywords
butyl
tert
phosphonate
hydroxyphenyl
dimethyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP94909033A
Other languages
German (de)
French (fr)
Inventor
Lân Nguyen
Vinh Van Diep
Hieu Phan
Simon Floret
Raymond Azoulay
Yves Guyon-Gellin
Pierre Maechler
Eric Niesor
Craig L. Bentzen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Symphar SA
Original Assignee
Symphar SA
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 Symphar SA filed Critical Symphar SA
Publication of EP0638084A1 publication Critical patent/EP0638084A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
    • C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4015—Esters of acyclic unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4056—Esters of arylalkanephosphonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4056—Esters of arylalkanephosphonic acids
    • C07F9/4059—Compounds containing the structure (RY)2P(=X)-(CH2)n-C(=O)-(CH2)m-Ar, (X, Y = O, S, Se; n>=1, m>=0)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/44—Amides thereof
    • C07F9/4403—Amides thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4411—Amides of acyclic unsaturated acids

Definitions

  • This invention relates to novel phosphonates substituted with a dialkyl phenol moiety and the processes for their preparation. It further relates to pharmaceutical compositions containing these compounds and their therapeutic use in diseases in which reactive oxygen radicals have been implicated and more specifically in the treatment of atherosclerosis.
  • antioxidant products would be useful as therapeutic agents.
  • the tests performed by the inventors show that the phosphonates of formula (I) through their dialkyl phenol and phosphonate moieties display potent antioxidant activities and therefore offer this therapeutic potential.
  • the phosphonate compounds (I) of this invention inhibit markedly the synthesis of cholesterol in human cell lines similarly to the HMGCoA reductase enzyme inhibitors (lovastatin, simvastatin) which are potent hypocholesterolemic drugs in man.
  • HMGCoA reductase enzyme inhibitors lovastatin, simvastatin
  • the combination of their antioxidant and hypocholesterolemic activities confer to the phosphonates of this invention the potential for treating diseases associated with elevated cholesterol levels and pathological lipid oxidation.
  • the lipophilicity of these compounds predicts that they will become incorporated in the LDL and protect these particles against the damages caused by oxidative species.
  • X 1 , X 2 identical or different are straight or branched C 1 to C 6 alkyl groups
  • - Y is O or S
  • - Z 1 , Z 2 identical or different, are:
  • R is H, a straight or branched C 1 -C 6 alkyl group
  • R 1 , R 2 identical or different are H or a straight or branched C 1 - C 6 alkyl group,
  • D is a saturated or unsaturated C 1 -C 11 alkylene chain in which one or more of the methylene groups can be replaced by a sulphur atom, an oxygen atom, a carbonyl group; optionally one or more methylene groups can be substituted by one or more halogen atoms (F, Cl or Br), C 1-6 alkyl, phenyl, hydroxy or
  • X 1 and X 2 are identical and are butyl groups, in particular t-butyl groups.
  • Y is oxygen
  • Z 1 and Z 2 are identical, in particular OR in which R is H, or a straight or branched C 1-6 alkyl group. More preferably, Z 1 and Z 2 are identical OR groups in which R is C 1-6 alkyl, in particular methyl, ethyl or i-propyl.
  • G is OH.
  • Suitable bioprecursors of the group OH as defined for G include, for example, OR 3 groups where R 3 is a straight or branched C 1 -C 6 alkyl group, a perfluorinated C 1 -C 6 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, suitable bioprecursors can also be a R 3 -C(O)O- group, a R 3 O-C(O)O- group, a R 3 NH-C(O)O- group, a R 3 C(O)OCH 2 O- group, a R 3 -SO 2 O- group where R 3 is defined as above.
  • - X 3 is H, a straight or branched alkyl C 1 -C 6 group, a substituted or unsubstituted phenyl group,
  • - X 4 , X 5 identical or different are H, a straight or branched C 1 -C 4 alkyl group,
  • B is CH 2 , CH-X 6 , X 6 -C-X 7 , where X 6 and X 7 identical or different are halogen atoms (F,Cl, Br), straight or branched C 1 -C 6 alkyl groups, a substituted or unsubstituted phenyl group;
  • D can also be A'-CH(O-CO-X 8 )-B' where A' is (CH 2 ) t ,
  • Suitable salts included within the scope of formula (I) include, for example, corresponding salts of the group OR (in Z 1 / Z 2 ), for example salts formed with alkali metal atoms such as sodium or potassium.
  • the present invention also relates to the processes used for preparing substituted phosphonates (I).
  • D is A-C(O)-B
  • Fig. 1 p. 10 consists in reacting the commercially available alkylphosphonate III with a suitable base such as n-butyllithium or lithium diisopropylamide.
  • a suitable base such as n-butyllithium or lithium diisopropylamide.
  • the lithium anion of compound HI thus formed is then reacted in situ with the appropriate ester II to give the substituted phosphonates (I).
  • the reaction is carried out in an ether solvent such as dimethoxyethane or tetrahydrofuran (THF), preferably in THF, at a temperature between -78°C and room temperature (25°C).
  • THF dimethoxyethane or tetrahydrofuran
  • a second procedure described in Fig 2 p. 11 consists in condensing the unsaturated aldehyde IV with the starting compound ketophosphonate V using titanium tetrachloride and N-methyl morpholine as condensation agents.
  • the reaction is carried out in an ether solvent such as tetrahydrofuran, dioxane or dimethoxyethane, preferably THF, at a temperature between -30°C and the boiling point of the solvent (66°C in the case of THF).
  • (CH 2 ) t -CHX 3 can be prepared by reacting the starting compound ketophosphonate V with an excess of a base or combination of bases.
  • the bases are sodium hydride, sodium alkoxides, n-butyl lithium or lithium diisopropylamide.
  • the reaction is carried out in tetrahydrofuran, dimethoxyethane, dioxane, benzene or toluene. The temperature of the reaction varies between 0°C and the boiling point of the solvent.
  • the process described in Fig. 3 p. 12 consists in condensing an ester of formula VII with the dianion of ketophosphonate V at the gamma position.
  • the dianion is generated by stepwise reaction of V with an equivalent of sodium hydride and an excess of a stronger base, e.g. n-butyl lithium or lithium diisopropylamide (LDA) in tetrahydrofuran at a temperature between -30° and 30°C.
  • LDA lithium diisopropylamide
  • the excess of dianion is then reacted with the ester VII at a temperature between -70° and 30°C to yield the ketophosphonate (I) according to Fig. 3.
  • reaction is carried out in an ether solvent, such as dimethoxyethane or tetrahydrofuran in presence of a base such as sodium hydride or lithium
  • ketophosphonates of formula (I) previously described can be reduced to the corresponding hydroxyphosphonate derivatives.
  • the reduction can be carried out with complex hydride reagents such as sodium borohydride, lithium borohydride, sodium bis (2-methoxyethoxy) aluminum hydride, sodium trimethoxyborohydride, sodium cyanoborohydride.
  • Suitable solvents include ether, tetrahydrofuran, toluene, methanol, ethanol, isopropanol.
  • Prefered reduction conditions are sodium borohydride in methanol at a temperature between -20°C and 65°C.
  • D is A'-CH(O-CO-X 8 )-B'
  • hydroxyphosphonates can be esterified to the corresponding acyloxy-phosphonate derivatives by employing known procedures. Suitable reaction conditions involve heating the hydroxyphosphonates with an appropriate acid anhydride (X 8 -CO) 2 O or an appropriate acid chloride X 8 -CO-Cl in presence of a tertiary amine, eg. triethyl amine or pyridine.
  • the reaction temperature can range between 0°C to the boiling point of the acylating agent.
  • ketophosphonates (I) can be reduced to the corresponding alkylphosphonates and alkenylphosphonates by reduction of the p-toluenesulfonylhydrazone derivatives with sodium borohydride, sodium cyanoborohydride or catechol borane.
  • the starting compounds alkylphosphonates III are commercially available.
  • the starting compounds ketophosphonates V are prepared according to known literature methods: E. J. Corey and G. T. Kwiatkowski, J. Am. Chem. Soc.90, p. 6816-6821 (1968) and F. Mathey and P. Savignac, Tetrahedron 34, P- 649-654 (1978).
  • n- is normal, i- is iso-, sec is secondary-, t is tertiary.
  • s is singlet, d is doublet, t is triplet, m is multiplet. The temperatures are measured in degree Celsius and the melting points are uncorrected.
  • FIG 1 SYNTHETIC FRQCESS
  • FIG 3 SYNTHETIC PROCESS
  • Titanium tetrachloride (114.5g, 0.6 mol) was added dropwise with stirring to 300 ml of dry tetrahydrofuran (THF) kept under nitrogen at -20°C.
  • THF dry tetrahydrofuran
  • Solid 3,5-di-tert-butyl-4- hydroxy benzaldehyde (58.7g, 0.25 mol) was added, followed by 200 ml THF then dimethyl 2-oxopropylphosphonate (50 g, 0.3 mol) was added.
  • N-methyl morpholine (121.7g, 1.2 mol) was introduced slowly and the reaction mixture was stirred at room temperature for 1 h.
  • Cold water 200 ml
  • the ether fraction was washed with water until neutral pH, dried over magnesium sulfate and evaporated in vacuo. Purification was carried out by chromatography on silica gel using a 98
  • the first compound (5.5 g, 4%) to elute from the column was identified as dimethyl 1,5-bis(3,5-di-tert-butyl-4-hydroxyphenyl)-3-oxo-1,4-pentadien-2-yl phosphonate.
  • Titanium tetrachloride 137.1 g, 0.72 mol was added dropwise to 300 ml dry THF at -15°C.
  • 3,5-Di-tert-butyl-4-hydroxybenzaldehyde 70.4 g, 0.30 mol was added followed by diethyl 2-oxopropylphosphonate (70 g, 0.36 mol).
  • N-methyl morpholine 145.8 g, 1.44 mol
  • Work up was carried out by addition of 200 ml water and 800 ml diethyl ether. The ether phase was washed with water to neutral pH, dried over MgSO 4 and evaporated. The residue was chromatographed on silicagel using 98/2 CHCl 3 /MeOH as eluent.
  • the first product (15 g, 8% yield) to elute was identified as diethyl 1,5-bis(3,5-di- tert-butyl-4-hydroxyphenyl)-3-oxo-1,4-pentadien-2-yl phosphonate.
  • the second product was identified as diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)- 2-oxo-3-buten-1-yl phosphonate (44 g, 36% yield)
  • the second compound was diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1- butyl phosphonate: 2.2 g (18% yield) of an oil was obtained which slowly solidified upon standing.
  • Diethyl 1-methyl-2-oxopropylphosphonate was prepared according to Mathey and Savignac as cited as example 5.
  • dimethyl methylphosphonate (3.17 g, 25.6 mmol) was added at -60° to a solution of n-butyllithium (16 ml of a 1.6 M solution in hexane, 25.6 mmol) in 15 ml anhydrous THF.
  • the reaction mixture was stirred at -50° for 30 min to allow for complete formation of the lithium anion (slight turbidity).
  • the mixture was again cooled to -60° and a solution of ethyl 3,5-di-tert-butyl-4-hydroxycinnamate (2.6 g, 8.5 mmol) in 20 ml dry THF was added.
  • the resulting orange-colored mixture was left to stir at room temperature (25°C) for 18 h.
  • the title compound can also be obtained by using as the bases a mixture of n-BuLi and LDA (lithium diisopropylamide).
  • n-BuLi and LDA lithium diisopropylamide.
  • n-butyllithium 16ml of a 1.6 M solution, 25.6 mmol
  • -60°C diisopropyl amine 0.86 g, 8.5 mmol
  • the resulting mixture was stirred at -40° for 15min, then dimethyl memylphosphonate (2.11 g, 17 mmol) was added.
  • a solution of dimethyl lithi omethylphosphonate was prepared under nitrogen by adding dimethyl memylphosphonate (3.2 g, 25.6 mmol) to a solution of n- butyllithium (16 ml of a 1.6 M solution in hexane, 25.6 mmol) in 15 ml dry THF at - 60°C. To this solution was added at -60° a solution of eth yl 3,5-di-tert-butyl-4- hydroxyhydrocinnamate (2.6 g, 8.5 mmol) in 20ml THF. The resulting solution was stirred at -60° for 30 min and then was allowed to reach room temperature (25°C) overnight. 25 ml 10% HCl was added and the mixture was extracted into ether. The residue of the ether phase was purified by column chromatography (SiO 2 , 8/2
  • Diethyl 2-oxopropylphosphonate (3.4 g, 17 mmol) was added at room temperature under nitrogen to a suspension of sodium hydride (0.82 g of a 60% dispension, 20 mmol) in 35 ml dry THF. The mixture was stirred at room temperature for 60 min, then diisopropylamine (1.71 g, 17 mmol) was added at 0°, followed by n- butyllithium (21 ml of a 1.6 M solution, 34 mmol).
  • Diethyl 2-oxopropylphosphonate (2.02 g, 10 mmol) was added at room temperature to sodium hydride (0.48 g of a 60% dispersion, 12 mmol) suspended in 30 ml THF. After 30 min the mixture was cooled to 0° and diisopropylamine (1.01 g, 10 mmol) and n-butyllithium (13 ml of a 1.6 M solution, 21 mmol) were added. After 30 min, the mixture was cooled to -60° and eth yl 3,5-di-tert-butyl-4-hydroxy hydrocinnamate (1.6 g, 5.2 mmol) dissolved in 15 ml THF was added.
  • dimethyl methylthionophosphonate (3.1 g, 25 mmol) was added at -60°C to a solution of n-butyllithium (16ml of a 1.6M solution, 25.6 mmol) in 50ml THF. The mixture was stirred at -60°C for 15 min then a solution of ethyl 3,5-di-tert-butyl-4-hydroxy cinnamate (2.5g, 8.2 mmol) in 20 ml THF was added. The resulting mixture was stirred at -60°C for 30 min and at room temperature (25°C) for 2 h.
  • Wistar rats were euth anasied by ether inhalation.
  • the livers were dissected out and homogenised with a potter homogeneiser in 4 volumes of phosphate buffer (4°C, pH 7.4). After centrifugation at 2000 rpm for 10 min the supernatant obtained was kept at 4°C.
  • the prolongation of the lag phase was used to quantify the antioxidant activity of the compounds tested, this prolongation was expressed in percent of the value measured in absence of exogen antioxidant (controls).
  • the phosphonates of Formula (I) as noted in Table 3 prolong the lag phase compared to control. An inhibitory activity on LDL oxidation is thus demonstrated which is clearly superior to that of Probucol and vitamin E. Since these two antioxidants have been shown to be anti-atherosclerotic in animal models, the therapeutic potential of phosphonates of Formula (I) is obvious.
  • the human intestinal cell line CaCo2 cells (ATCC HTB37) was used to study the effect of compounds of formula (I) on cholesterol synthesis.
  • the cells were grown in 6 wells dishes (Falcon) in 2 ml of Dulbecco's modified Eagle culture medium
  • DMEM fetal calf serum
  • Flow fetal calf serum
  • Lipids were extracted by the Folch method and separated on silica gel TLC plates developed in petroleum ether: diethyl ether: acetic acid (70:30: 0.5). After exposition to iodine vapors, the bands corresponding to cholesterol and cholesteryl esters were scrapped off and radioactivity was measured in a liquid scintillator counter.
  • the amount of radioactivity incorporated in cholesterol and cholesteryl esters in presence of compounds to be tested was compared to that of the control cells.
  • HMGCoA reductase inhibitors such as simvastatin (1 ⁇ M) served to validate the measurement of 14 C-acetate incorporation in cholesterol and cholesteryl esters.
  • Phosphonates of formula (I) display an inhibitory activity on cholesterol and cholesteryl esters and can be considered as therapeutic agents in the treatment of hyperlipidemia and ath erosclerosis.
  • Thoracic aortas were cleared of connective tissues and cut into rings of approximately 2mm in length. Each ring was mounted under a resting tension of 2g and was equilibrated for 1 hour at 37°C in a 10 ml organ bath containing a HEPES buffer Ringer solution (Buffer composition (mM): NaCl 139.0, KC15.0, MgCl 2 3.7, D-Glucose 11.0, HEPES 5.0, pH 7.4) aerated with 95% O 2 :5% CO 2 .
  • Buffer composition (mM): NaCl 139.0, KC15.0, MgCl 2 3.7, D-Glucose 11.0, HEPES 5.0, pH 7.4 aerated with 95% O 2 :5% CO 2 .
  • the compounds of formula (I) are thus potentially useful in the treatment of cardiovascular diseases via their calcium entry blocking activity.
  • the primary indications of these compounds would be the treatment of atherosclerosis, angina pectoris, congestive heart failure and hypertension.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Vascular Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to novel phosphonates substituted by dialkylphenol group of formula (I), in which G, X1, X2, D, Y, Z?1 and Z2¿ are defined in Claim 1, as well as their preparations and the pharmaceutical compositions comprising them.

Description

SUBSTITUTED PHOSPHONATES, THE PROCESSES FOR
THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS
CONTAINING THEM This invention relates to novel phosphonates substituted with a dialkyl phenol moiety and the processes for their preparation. It further relates to pharmaceutical compositions containing these compounds and their therapeutic use in diseases in which reactive oxygen radicals have been implicated and more specifically in the treatment of atherosclerosis.
Reactive oxygen species are involved in a number of pathologies, pharmacological and clinical evidence have been firmly established in the following cases (Halliwell, B. et al. "Role of Free Radicals and Catalytic Metal Ions in Human Disease: an Overview", Methods Enzymol.186, 1-85, 1990):
- inflammatory and immunologic injuries (autoimmune diseases, rheumatoid arthritis),
- ischemia/reperfusion injury,
- radiation injury,
- premature ageing,
- Parkinson's and Alzheimer's diseases,
- cancer and anti-cancer treatments,
- conditions associated with impaired blood circulation such as intermittent claudication, excessive platelet aggregation, myocardial infarction and
atherosclerosis.
In these pathological situations antioxidant products would be useful as therapeutic agents. The tests performed by the inventors show that the phosphonates of formula (I) through their dialkyl phenol and phosphonate moieties display potent antioxidant activities and therefore offer this therapeutic potential.
In the particular case of atherosclerosis, it is now clearly proven that cholesterol carried in LDL is the most atherogenic form of plasma cholesterol. On the other hand current research shows that the uptake of oxidized LDL by macrophages leads to the formation of lipid-laden foam cells, which is the first step in the development of atherosclerosis. Numerous epidemiological studies have now firmly established that high blood cholesterol is a major risk factor for coronary heart disease. Based on the above, it can be postulated that the combination of a cholesterol lowering regimen with an antioxidant treatment might be more effective than either one. A drug which possesses the dual hypocholesterolemic and antioxidant property could therefore be highly effective in the treatment of atherosclerosis. The phosphonate compounds (I) of this invention inhibit markedly the synthesis of cholesterol in human cell lines similarly to the HMGCoA reductase enzyme inhibitors (lovastatin, simvastatin) which are potent hypocholesterolemic drugs in man. The combination of their antioxidant and hypocholesterolemic activities confer to the phosphonates of this invention the potential for treating diseases associated with elevated cholesterol levels and pathological lipid oxidation. Furthermore, the lipophilicity of these compounds predicts that they will become incorporated in the LDL and protect these particles against the damages caused by oxidative species.
The generic structure of the compounds of the present invention is represented by formula (I)
where
- X1, X2 identical or different are straight or branched C1 to C6 alkyl groups,
- Y is O or S, - Z1, Z2, identical or different, are:
- OR where R is H, a straight or branched C1-C6 alkyl group,
- NR1R2 where R1, R2, identical or different are H or a straight or branched C1- C6 alkyl group,
- Z1, Z2 together may form a C2-C8 alkylidenedioxy group,
- G is OH or a bioprecursor thereof; D is a saturated or unsaturated C1-C11 alkylene chain in which one or more of the methylene groups can be replaced by a sulphur atom, an oxygen atom, a carbonyl group; optionally one or more methylene groups can be substituted by one or more halogen atoms (F, Cl or Br), C1-6 alkyl, phenyl, hydroxy or
acyl oxy groups, and salts, solvates and hydrates thereof.
Preferably, X1 and X2 are identical and are butyl groups, in particular t-butyl groups.
Preferably, Y is oxygen.
Preferably Z1 and Z2 are identical, in particular OR in which R is H, or a straight or branched C1-6alkyl group. More preferably, Z1 and Z2 are identical OR groups in which R is C1-6alkyl, in particular methyl, ethyl or i-propyl.
Preferably, G is OH. Suitable bioprecursors of the group OH as defined for G include, for example, OR3 groups where R3 is a straight or branched C1-C6 alkyl group, a perfluorinated C1-C6alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, suitable bioprecursors can also be a R3-C(O)O- group, a R3O-C(O)O- group, a R3NH-C(O)O- group, a R3C(O)OCH2O- group, a R3-SO2O- group where R3 is defined as above.
Preferably, D is A-C(O)-B, A-CH(OH)-B, A-CH2-B, (CH2)t-(CH=CH)n-(CH2)t or S-(CH2)t, where
- A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3, S-(CH2)t-(CH=CH)n,
S-CX4X5,
(CH=CH)n-CH=CH-C(O)-CHX3, (CH2)p-CH=CH-C(O)-CHX3,
(CH2)t-C(O)-CHX3, S-(CH2)r(CH=CH)n-C(O)-CHX3, S-CX4X5-C(O)-CHX3, (CH=CH)n-CH=CH-CH(OH)-CHX3, (CH2)p-CH=CH-CH(OH)-CHX3,
(CH2)t-CH(OH)-CHX3, S-(CH2)t-(CH=CH)n-CH(OH)-CHX3,
S-CX4X5-CH(OH)-CHX3, where n is zero, 1 or 2, t is a number from 0 to 4, p is a number from 1 to 3,
- X3 is H, a straight or branched alkyl C1-C6 group, a substituted or unsubstituted phenyl group,
- X4, X5 identical or different are H, a straight or branched C1-C4 alkyl group,
- B is CH2, CH-X6, X6-C-X7, where X6 and X7 identical or different are halogen atoms (F,Cl, Br), straight or branched C1-C6 alkyl groups, a substituted or unsubstituted phenyl group; when A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3, S-(CH2)t(CH=CH)n, S-CX4X5, then B is also CH=CH-(CH2)p, CH=CH-CHX6, CH=CH-CX6X7, where p and X6, X7 are defined as above.
Preferably, D can also be A'-CH(O-CO-X8)-B' where A' is (CH2)t,
(CH=CH)n-CH=CX3, (CH2)t-CHX3, S-(CH2)t-(CH=CH)n, S-CX4X5, B' is CH2, CH-X6, X6-C-X7, CH=CH-(CH2)p, CH=CH-CHX6, CH=CH-CX6X7 where t, n, p, X3, X4, X5, X6 and X7 are as described above, and X8 is a saturated or unsaturated C1-C6alkyl or alkenyl chain.
Suitable salts included within the scope of formula (I) include, for example, corresponding salts of the group OR (in Z1 / Z2), for example salts formed with alkali metal atoms such as sodium or potassium.
PROCESSES FOR PREPARING COMPOUNDS OF FORMULA (I)
The present invention also relates to the processes used for preparing substituted phosphonates (I).
D is A-C(O)-B
--------------------------- A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3, S(CH2)t-(CH=CH)n or
S-CX4X5
----------------------------------------------------------------------------------------------------- B is CH2, CH-X6 or C-X6X7
-------------------------------------------- The procedure described in Fig. 1 p. 10 consists in reacting the commercially available alkylphosphonate III with a suitable base such as n-butyllithium or lithium diisopropylamide. The lithium anion of compound HI thus formed is then reacted in situ with the appropriate ester II to give the substituted phosphonates (I). The reaction is carried out in an ether solvent such as dimethoxyethane or tetrahydrofuran (THF), preferably in THF, at a temperature between -78°C and room temperature (25°C).
A second procedure described in Fig 2 p. 11 consists in condensing the unsaturated aldehyde IV with the starting compound ketophosphonate V using titanium tetrachloride and N-methyl morpholine as condensation agents. The reaction is carried out in an ether solvent such as tetrahydrofuran, dioxane or dimethoxyethane, preferably THF, at a temperature between -30°C and the boiling point of the solvent (66°C in the case of THF). A compound of formula (I) where A is
(CH=CH)n-CH=CX3 is obtained. Compounds of formula (I) where A is
(CH2)t-CHX3 can be prepared by reacting the starting compound ketophosphonate V with an excess of a base or combination of bases. The bases are sodium hydride, sodium alkoxides, n-butyl lithium or lithium diisopropylamide. The anion of ketophosphonate V thus formed is then reacted with the halide VI, where Hal = Br or Cl. The reaction is carried out in tetrahydrofuran, dimethoxyethane, dioxane, benzene or toluene. The temperature of the reaction varies between 0°C and the boiling point of the solvent.
Examples 1, 2, 3 and 4 further illustrate the experimental aspects of the process described in Fig 2.
Concerning condensation reactions, in the case where B is a CH2 group, i.e. when the carbon alpha to the phosphonate functional group has two protons, in addition to the main reaction product formed by monocondensation at the gamma position, a side product is also formed by double condensation with the dialkyl phenol groups at the alpha and gamma positions (see ex 1 and 2). In the case where B = CHX6 or X6- C-X7, e.g. when two protons are not available at the alpha position, the compound formed by monocondensation at the gamma position is the sole reaction product (see ex 4 and 10). Likewise, when the alpha position is completely unsubstituted (B=CH2), in addition to the main reaction compound formed by monoaddition, these is also formed a side product occurring by double additions at the alpha and gamma positions (see ex 3). A is (CH=CH)n-CH=CH-C(O)-CHX3, (CH2)p-CH=CH-C(O)-CHX3,
(CH2)t-C(O)-CHX3, S(CH2)r(CH=CH)n-C(O)-CHX3 or
S-CX4X5-C(O)-CHX3 ----------------------------------------------------------------------------------------------- B is CH2, CH-X6 or C-X6X7
--------------------------------------------
The process described in Fig. 3 p. 12 consists in condensing an ester of formula VII with the dianion of ketophosphonate V at the gamma position. The dianion is generated by stepwise reaction of V with an equivalent of sodium hydride and an excess of a stronger base, e.g. n-butyl lithium or lithium diisopropylamide (LDA) in tetrahydrofuran at a temperature between -30° and 30°C. The excess of dianion is then reacted with the ester VII at a temperature between -70° and 30°C to yield the ketophosphonate (I) according to Fig. 3.
Compounds (I) which possess two ketone groups in their structures may in solution be in tautomeric equilibrium with enol forms. The diketone and enol forms of compounds (I) are integral part of this invention. A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3 or S(CH2)t-(CH=CH)n or S-CX4X5
--------------------------------------------------------------------------------------------------
B is CH=CH-CX6X7 or CH=CH-(CH2)p
--------------------------------------------
The procedure for preparing compounds of formula (I) where D is A-C(O)-B, where A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3,
S(CH2)t-(CH=CH)n or S-CX4X5, B is CH=CH-CX6X7 or CH=CH-(CH2)p consists in reacting an aldehyde of formula VIlla or VIIIb with a phosphorus reagent which may be a phosphonate compound of formula IX or a phosphonium salt of formula X:
CH2 - PO3 (Alkyl) 2
— CH2 -P (C6 H5 ) 3 Br The reaction is carried out in an ether solvent, such as dimethoxyethane or tetrahydrofuran in presence of a base such as sodium hydride or lithium
diisopropylamine.
D is A-CH(OH)-B
------------------------
The ketophosphonates of formula (I) previously described can be reduced to the corresponding hydroxyphosphonate derivatives. The reduction can be carried out with complex hydride reagents such as sodium borohydride, lithium borohydride, sodium bis (2-methoxyethoxy) aluminum hydride, sodium trimethoxyborohydride, sodium cyanoborohydride.
Suitable solvents include ether, tetrahydrofuran, toluene, methanol, ethanol, isopropanol. Prefered reduction conditions are sodium borohydride in methanol at a temperature between -20°C and 65°C. D is A'-CH(O-CO-X8)-B'
-------------------------------------
The above-mentioned hydroxyphosphonates can be esterified to the corresponding acyloxy-phosphonate derivatives by employing known procedures. Suitable reaction conditions involve heating the hydroxyphosphonates with an appropriate acid anhydride (X8-CO)2O or an appropriate acid chloride X8-CO-Cl in presence of a tertiary amine, eg. triethyl amine or pyridine. The reaction temperature can range between 0°C to the boiling point of the acylating agent.
D is A-CH2-B, (CH2)t-(CH=CH)n-(CH2)t, S-(CH2)t
-----------------------------------------------------------------------------------
The ketophosphonates (I) can be reduced to the corresponding alkylphosphonates and alkenylphosphonates by reduction of the p-toluenesulfonylhydrazone derivatives with sodium borohydride, sodium cyanoborohydride or catechol borane.
Phosphonic acids of structure (I) where Z1=Z2 =OH can be prepared from the corresponding phosphonate esters by reaction with bromotrimethyl silane to produce bis (trimethylsilyl) phosphonates which are reacted in situ with water or methanol.
The starting compounds alkylphosphonates III are commercially available. The starting compounds ketophosphonates V are prepared according to known literature methods: E. J. Corey and G. T. Kwiatkowski, J. Am. Chem. Soc.90, p. 6816-6821 (1968) and F. Mathey and P. Savignac, Tetrahedron 34, P- 649-654 (1978).
X3 - CH2 - C - L + M
L = Cl or OEt M = Li or Cu The structures of new compounds of formula (I) are determined by infrared (IR), mass (MS) and nuclear magnetic resonance (NMR) spectroscopies. The purity of the compounds is verified by elemental analysis and standard chromatographic methods: thin layer chromatography, gas liquid chromatography or high performance liquid chromatography. The abbreviations used in this patent application are as follows:
In the tables n- is normal, i- is iso-, sec is secondary-, t is tertiary. In the NMR spectra, s is singlet, d is doublet, t is triplet, m is multiplet. The temperatures are measured in degree Celsius and the melting points are uncorrected.
The present invention will be further described by the examples 1 to 22 which are typical of the synthetic procedures used.
FIG 1: SYNTHETIC FRQCESS
A = (CH2)t, (CH=CH)n-CH=C-X3,(CH2)t-CHX3, S-(CH2)t- (CH=CH) n or S-CX4X5
B = CH2, CH-X6 or C-X6X7
FIG 3: SYNTHETIC PROCESS
where E is (CH=CH) n-CH=CH , (CH2)p-CH=CH , (CH2)t , S (CH2) t- (CH=CH) n or S-CX4X5
Example 1
Dimethyl 1.5-bis(3,5-di-tert-butyl-4-hydroxyphenyl)3-oxo-1,4-pentadien-2-yl phosphonate
and
Dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate
Titanium tetrachloride (114.5g, 0.6 mol) was added dropwise with stirring to 300 ml of dry tetrahydrofuran (THF) kept under nitrogen at -20°C. Solid 3,5-di-tert-butyl-4- hydroxy benzaldehyde (58.7g, 0.25 mol) was added, followed by 200 ml THF then dimethyl 2-oxopropylphosphonate (50 g, 0.3 mol) was added. Finally N-methyl morpholine (121.7g, 1.2 mol) was introduced slowly and the reaction mixture was stirred at room temperature for 1 h. Cold water (200 ml) was introduced and the mixture was extracted with 1000 ml diethyl ether. The ether fraction was washed with water until neutral pH, dried over magnesium sulfate and evaporated in vacuo. Purification was carried out by chromatography on silica gel using a 98/2
chloroform/methanol mixture.
The first compound (5.5 g, 4%) to elute from the column was identified as dimethyl 1,5-bis(3,5-di-tert-butyl-4-hydroxyphenyl)-3-oxo-1,4-pentadien-2-yl phosphonate.
C35H51O6P Theor. %C 70.21 %H 8.59 %P 5.17
Found %C 69.96 %H 8.55 %P 5.31 mp = 190-191°C.
IR (KBr): 3620 cm-1: OH, 1610: C=O, 1580: C=C, 1430 and 1420: t-Bu, 1240:
P=O, 1020: P-O-C
MS: m/e = 599: M++1, 598: M+, 488: M+-H-PO3Me2, 367 (100%) NMR (CDCI3)
δ = 7.75 (d, J = 26 Hz, 1H): Ph-CH=C-P
7.57 (d, J = 16 Hz, 1H): Ph-CH=CH-
7.3 and 7.23 (2 s, 2H each): arom. H
6.60 (d, J= 16Hz, 1H): Ph-CH=CH
5.55 and 5.51 (2s, 1H each): OH
3.82 (d, J = 11Hz, 6H): P-O-CH3
1.40 and 1.34 (2 s, 18H each): t-C4H9 The second compound (36 g, 38 % yield) was identified by IR, MS and NMR as dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten- 1-yl phosphonate
CH=CH - CH2 -PO3Me2 mp = 107-109° (ligroin, 80-95 fraction)
IR (KBr): 3420 cm-1: OH, 1650: C=O, 1590: C=C, 1420: t-Bu, 1260: P=O and 1030: P-O-C MS (m/e): 382 M+, 367: M+-Me, 272: M+-HPO3Me2, 259:M+-CH2PO3Me2, 151: M+-CO-CH2-PO3Me2
NMR (CDCI3)
δ = 7.61 (d, J = 16Hz, 1H): Ph-CH=CH
7.42 (s, 2H): arom. H
6.73 (d, J = 16 Hz, 1H): Ph-CH=CH
5.62 (s, 1H): OH
3.81 (d, J = 11Hz, 6H): P-O-CH3
3.35 (d, J = 22Hz, 2H) CH2-P
1.40 (s, 18H): t-C4H9
C20H31O5P Theor. % C 62.81 % H 8.17 % P 8.10
Found. % C 62.63 % H 7.97 % P 8.24 Example 2
Diethyl 1 ,5-bis(3,5-di-tert-hutyl-4-hydroxyphenyl)-3-oxo-1,4-pentadien-2-yl phosphonate
and
Diethyl 4-( 3,5-di-tert-butyl-4-hydroxyphenyn-2-oxo-3-buten-1-yl phosphonate
Titanium tetrachloride (137.1 g, 0.72 mol) was added dropwise to 300 ml dry THF at -15°C. 3,5-Di-tert-butyl-4-hydroxybenzaldehyde (70.4 g, 0.30 mol) was added followed by diethyl 2-oxopropylphosphonate (70 g, 0.36 mol). N-methyl morpholine (145.8 g, 1.44 mol) was introduced and the reaction mixture was stirred at room temperature for 2 h. Work up was carried out by addition of 200 ml water and 800 ml diethyl ether. The ether phase was washed with water to neutral pH, dried over MgSO4 and evaporated. The residue was chromatographed on silicagel using 98/2 CHCl3/MeOH as eluent.
The first product (15 g, 8% yield) to elute was identified as diethyl 1,5-bis(3,5-di- tert-butyl-4-hydroxyphenyl)-3-oxo-1,4-pentadien-2-yl phosphonate.
C37H55O6P Theor. % C 70.90 % H 8.84 % P 4.94
Found % C 71.18 % H 8.67 % P 4.75 mp = 174-175°C
IR: (KBr): 3620 cm-1: OH, 1640: C=O, 1585: C=C, 1430 and 1415: t-Bu,
1230: P=O and 1030: P-O-C MS: m/e = 626: M+, 488: M+-HPO3Et2, 395 (100%) NMR (CDCI3)
δ = 7.7 (d, J = 26 Hz, 2H): Ph-CH=C-P
7.59 (d, J = 16Hz, 2H): Ph-CH=CH
7.30 and 7.25 (2s, 2H each): arom. H
6.63 (d, J = 16 Hz, 2H): Ph-CH=CH
5.54 and 5.48 (2s, 1H each): OH
4.18 (quint, J = 7Hz, 4H): P-O-CH2-CH3
1.40 and 1.34 (2s, 18H each): t-C4H9
1.34 (t, J= 7 Hz, 6H): P-O-CH2-CH3
The second product was identified as diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)- 2-oxo-3-buten-1-yl phosphonate (44 g, 36% yield)
mp = 110-111°C (recrystallized from ligroin 80-95 fraction).
IR (KBr): 3620 cm-1: OH, 1680:C=O, 1590: C=C, 1430 and 1415: tBu, 1240: P=O and 1230: P-O-C
MS (m/e): 411: M+1, 410: M+, 272: M+-H-PO3Et2, 259: M+-CH2PO3Et2, 57 (100%): tBu+
NMR (CDCI3)
δ = 7.61 (d, J = 16 Hz, 1H): Ph-CH=CH
7.40 (s, 2H): arom. H
6.74 (d, J = 16Hz, 1H): Ph-CH=CH
5.6 (s, 1H): OH
4.16 (m, 4H): P-O-CH2-CH3
3.33 (d, J = 23 Hz, 2H): CH2-P
1.45 (s, 18H): t-C4H9
1.34 (t, J = 7Hz, 6H): P-O-CH2-CH3 C22H35O5P Theor % C 64.37 % H 8.59 % P 7.55
Found % C 64.52 % H 8.65 % P 7.36 Example 3
Diethyl 1 ,5-bis(3,5-di-tert-butyl-4-hydroxyphenyl)-3-oxo-2-pentyl phosphonate
and
Diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-butyl phosphonate
Sodium hydride (1.45 g of a 60% dispersion in mineral oil, 36.25 mmol) was suspended under nitrogen in hexane, this latter was pipetted out and replaced by 60 ml dry THF. Diethyl 2-oxopropylphosphonate (7.0 g, 36 mmol) was introduced. The mixture was stirred at room temperature for 30 min then was cooled to 0° C then n- butyl lithium (37.5 ml of a 1.6 M solution, 60 mmol) was added. Finally a solution of 3,5-di-tert-butyl-4-hydroxybenzyl bromide (9.0 g, 30.1 mmol) in 40 ml THF was added and the reaction mixture was stiιτed at room temperature overnight. Work-up was carried out by partition between 150 ml 15% HCl and two fractions of 150 ml ether. The ether phase was washed with sodium bicarbonate and saturated sodium chloride to neutral pH. After drying and solvent evaporation, the crude mixture was purified by column chromatography (SiO2, 8/2 CHCl3/AcOEt).
The first compound (1.5 g, 8% yield) to elute was diethyl 1,5-bis(3,5-di-tert-butyl-4- hydroxy-phenyl)-3-oxo-2-pentyl phosphonate, mp = 60-61°C.
IR (KBr): 3620 cm-1: OH, 1710: C=O, 1430: t-Bu, 1230: P=O and 1010:
P-O-C
MS:m/e= 630: M+, 493: M+-HPO3Et2 NMR (CDCI3)
δ = 6.89 (2s, 2H each): arom. H
5.09 and 5.03 (2s): OH
4.1 (m, 4H): P-O-CH2-CH3
3.5 and 3.25 (2m, 2H): Ph-CH2-CH-P
3.04 (txd, 1H): Ph-CH2-CH(P)-CO
2.9 - 2.4 (2m, 4H): Ph-CH2-CH2-CO- 1.14 and 1.39 (2s, 18H each): t-C4H9
1.32 (2t, J=7Hz, 6H): P-O-CH2-CH3
The second compound was diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1- butyl phosphonate: 2.2 g (18% yield) of an oil was obtained which slowly solidified upon standing.
IR (film): 3620 cm-1: OH, 1710: C=O, 1430: t-Bu, 1250: P=O, 1010: P-O-C MS m/e= 412: M+, 274: M-HPO3Et2
NMR : (CDCI3)
δ = 6.98 (s, 2H): arom. H
5.1 (s, 1H): OH
4.14 (m, 4H): P-O-CH2CH3
3.05 (d, J=25Hz, 2H): CH2-P
2.94 (m, 2H): Ph-CH2-CH2
2.83 (m, 2H): Ph-CH2-CH2
1.42 (s, 18H): t-C4H9
1.32 (t, J=7Hz, 6H): P-O-CH2-CH3 Example 4
Diethyl 4-(3,5-di-tert-butyl-4-hydroxyρhenyl)-1,1-dimethyl-2-oxo-3-buten-1-yl- phosphonate
Diethyl 1,1-dimethyl-2-oxo-propylphosphonate (bp = 60º/0 .2 mbar) was synthesized according to V. Roussis and D.F. Wiemer, J. Org. Chem.54, p. 627-631 (1989). To 20 ml dry THF kept at 0°C were added sequentially ΗCI4 (1.72 g, 9 mmol), 3,5- di-tert-butyl-4-hydroxybenzaldehyde (0.9 g, 3.8 mmol), diethyl 1,1-dimethyl-2- oxopropylphosphonate (1.0 g, 4.5 mmol), N-methyl morpholine (1.82 g, 18 mmol) then the reaction mixture was stirred for 1 h at room temperature. Work up carried out in the usual manner gave an oil which was purified by column chromatography (SiO2, 8/2 CHCI3/ACOEt). An amount of 1.1 g (68% yield) of the title compound was obtained. Mp = 91-92°C (petroleum ether 40-60).
IR: (KBr): 3440 cm-1: OH, 1670: C=O, 1590: C=C, 1430 and 1410: t-Bu, 1210: P=O and 1030: P-O-C
MS: m/e= 439: M+ + 1, 259: M+-C(CH3)2-PO3Et2, 57 (100%): tBu
NMR: (CDCI3)
δ = 7.66 (d, J = 16Hz, 1H): Ph-CH=CH
7.43 (s, 2H): arom. H
7.26 (d, J = 16Hz, 1H): Ph-CH=CH
5.55 (s, 1H): OH
4.15 (m, 4H): P-O-CH2-CH3
1.50 (d, J = 17Hz, 6H): -C(CH3)2-P
1.46 (s, 18H): t-C4H9
1.32 (t, J = 7Hz, 6H): P-O-CH2-CH3
C24H39O5P Calc. % C 65.73 % H 8.96 % P 7.06
Found % C 66.00 % H 8.98 % P 6.82 Example 5 Diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methyl-2-oxo-3-buten-1-yl phosphonate
Diethyl 2-oxobutylphosphonate (bp = 90º/0.6 mbar) was prepared according to F. Mathey and P. Savignac, Tetrahedron 34, P- 649-654 (1978).
To 20 ml dry THF kept at 0°C were added successively TiCI4 (1.82 g, 9.6 mmol), 3,5-di-tert-butyl-4-hydroxybenzaldehyde (0.94 g, 4 mmol), diethyl 2- oxobutylphosphonate (1 g, 4.8 mmol) and N-methyl morpholine (1.86 g, 18.4 mmol). The reaction mixture was stirred at room temperature for 30 min then was heated to reflux for 1 h. After the usual work-up and extraction the crude reaction mixture was purified by column chromatography (SiO2, 8/2 CHCl3/AcOEt). A small amount of unreacted benzaldehyde was first collected then 0.35 g (21%) of the title compound was obtained. Mp = 97-101°C (petroleum ether 40-60).
IR (KBr): 3400 cm-1: OH, 1680: C=O, 1610 and 1590: C=C, 1440: t-Bu, 1250: P=O and 1020: PO-C
MS: m/e = 424: M+, 409: M+-CH3, 367: M+-tBu, 286: M+-HPO3Et2, 57 (100%): tBu+
NMR (CDCI3):
δ = 7.56 (s, 1H): Ph-CH=C
7.33 (s, 2H): arom. H
5.5 (s, 1H): OH
4.16 (m, 4H): P-O-CH2-CH3
3.51 (d, J=22Hz, 2H): CH2-P
2.1 (s, 3H): CH3
1.46 (s, 18H): t-C4H9
1.32 (t, J= 7Hz, 6H): P-O-CH2-CH3 C23H37O5P Calc. % C 65.07 % H 8.79 % P 7.30
Found % C 65.35 % H 8.58 % P 7.51
Example 6
Dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(n-butyl)-2-oxo-3-buten-1-yl phosphonate
A mixture of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (3.65 g, 15 mmol), dimethyl 2-oxoheptylphosphonate (4.0 g, 18 mmol), TiCI4 (6.84 g, 36 mmol) and N-methyl morpholine (7.27 g, 72 mmol) in 80 ml dry THF was refluxed as described in example 7. Purification by column chromatography (SiO2, 8/2 CHCl3/AcOEt) gave 1.2 g (20% yield) of the title compound. Mp = 82-85° (petroleum ether 40-60)
MS: m/e 439 M++ 1, 438 M+, 381 M+-C4H9, 57 (100%): tBu
NMR (CDCI3)
δ = 7.48 (s, 1H): Ph-CH=C(C4H9)
7.32 (s, 2H): arom. H
5.5 (s, 1H): OH
3.81 (d, J = 11Hz, 6H): P-O-CH3
3.52 (d, J = 22Hz, 2H): CH2-P
2.57 (m, 2H): CH2-C3H7
1.5-1.4 (m, 4H) CH2-(CH2)2-CH3
1.5 (s, 18H): t-C4H9
0.94 (t, J = 7Hz, 3H): (CH2)3-CH3 Example 7
Diethyl 4-(3,5-di-tert-hutyl-4-hydroxyphenyl)-2-oxo-3-phenyl-3-buten-1-yl phosphonate
The procedure described in example 5 was employed, using as the phosphonate reagent diethyl 2-oxo-3-phenylpropylphosphonate (bp= 15070.5 mbar). The title compound was isolated by column chromatography under the usual conditions (SiO2, 8/2 CHCl3/AcOEt) at ca 18% yield. mp=139-143°C IR (KBr): 3500: OH, 1640: C=O, 1610 and 1590: C=C, 1430: t-Bu, 1230: P=O, 1020: P-O-C.
MS: m/e=486 (100%) M+, 348: M+-HPO3Et2, 335: M+-CH2PO3Et2 NMR: (CDCI3)
δ = 7.70 (s, 1H): Ph-CH=C
7.45 - 7.25 (m, 5H): C6H5
6.97 (s, 2H): arom. H
5.46 (s, 1H): OH
4.15 (m, 4H): P-O-CH2-CH3
3.33 (d, J=22Hz, 2H): CH2-P
1.32 (t, J=7Hz, 6H): P-O-CH2-CH3
1.23 (s, 18H): C4H9 C28H39O5P Calc. % C 69.11 % H 8.08 % P 6.37
Found % C 69.37 % H 8.11 % P 6.61 Example 8 Diethyl 4-( 3,5-di-tert-butyl-4-hydroxyphenyl)-1-methyl-2-oxo-3-huten-1-yl phosphonate
Diethyl 1-methyl-2-oxopropylphosphonate was prepared according to Mathey and Savignac as cited as example 5.
A mixture of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (7J9 g, 29 mmol), diethyl 1- methyl-2-oxopropylphosphonate (8.20 g, 35 mmol), TiCI4 (13.47 g, 71 mmol), N- methyl morpholine (14.34 g, 140 mmol) in 150 ml dry THF was reacted at room temperature for 1 h, then at reflux temperature for 18 h. After work up, column chromatography (SiO2, 8/2 CHCl3/AcOEt) gave 4.7 g (38%) of the title compound. mp=92-94°C
NMR (CDCI3)
δ = 7.63 (d, J = 16Hz, 1H): Ph-CH=CH
7.42 (s, 2H): arom. H
6.87 (d, J = 16Hz, 1H): Ph-CH=CH
5.6 (s, 1H): OH
4J5 (m, 4H): P-O-CH2-CH3
3.53 and 3.46 (two q, J = 24Hz and 7Hz, 1H): CH-P
1.50-1.43 (two d, J = 7Hz): CH-(P)-CH3
1.46 (s, 18H): C4H9
1.32 (two t, J = 7Hz): P-O-CH2CH3 Example 9 Dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate
Under nitrogen atmosphere dimethyl methylphosphonate (3.17 g, 25.6 mmol) was added at -60° to a solution of n-butyllithium (16 ml of a 1.6 M solution in hexane, 25.6 mmol) in 15 ml anhydrous THF. The reaction mixture was stirred at -50° for 30 min to allow for complete formation of the lithium anion (slight turbidity). The mixture was again cooled to -60° and a solution of ethyl 3,5-di-tert-butyl-4-hydroxycinnamate (2.6 g, 8.5 mmol) in 20 ml dry THF was added. The resulting orange-colored 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 die product was extracted into ether. After drying over MgSO4, ether was evaporated to yield a yellow solid. Recrystallization in 40 - 60 petroleum ether gave 3.0 g (92% yield) of dimethyl 4-(3,5-di-tert-butyl-4- hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate. mp=107-109°C
The title compound can also be obtained by using as the bases a mixture of n-BuLi and LDA (lithium diisopropylamide). To a solution of n-butyllithium (16ml of a 1.6 M solution, 25.6 mmol) in 20 ml dry THF was added at -60°C diisopropyl amine (0.86 g, 8.5 mmol). The resulting mixture was stirred at -40° for 15min, then dimethyl memylphosphonate (2.11 g, 17 mmol) was added. After 15 min, ethyl 3,5-di-tert-butyl- 4-hydroxycinnamate (2.6 g, 8.5 mmol) was added and die reaction mixture was stirred at room temperature (25°C) for 15 h. Work up by addition of 10% HCl and extraction into ether gave 3J0 g (95%) of dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo- 3-buten-1-yl phosphonate.
mp=107-109°C The compound prepared by either of these two variant processes has spectroscopic data identical to those of the same product described in example 1. C20H31O5P Theor. %C 62.81 %H 8.17 %P 8.10
Found %C 62.56 %H 8.21 %P 8.24
Example 10
Diethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-3,5-hexadien-1-yl phosphonate
To 15 ml dry THF kept at 0° were added ΗCI4 (1.23 g, 6.47 mmol), 3,5-di-tert-butyl- 4-hydroxy cinnamaldehyde (0.7 g, 2.67 mmol), diethyl 1,1-dimethyl-2- oxopropylphosphonate (0.72 g, 3.24 mmol) and N-methylmorpholine (1.31 g, 12.97 mmol). The reaction mixture was stirred for 1 h at 20°C then 1 h at 30°C. Work-up gave a dark oil which was purified by column chromatography (SiO2, 8/2
CHCl3/AcOEt). 650 mg (52%) of yellow crystals were obtained, mp = 130-133°C.
NMR (CDCI3)
δ = 7.40 (d x d, J = 11 and 15Hz, 1H): Ph-CH=CH-CH=CH
7.2 (s, 2H): arom. H
6.87 and 6.85 (2 d, J = 15Hz, 2H): Ph-CH=CH-CH=CH
6.75 (d x d, J = 11.5 and 16Hz, 1H): Ph-CH=CH-CH=CH
5.4 (s, 1H): OH
4.1 (m, 4H): P-O-CH2-CH3
1.40 (d, J = 16Hz, 6 H): C(CH3)2
1.39 (s, 18H): t-C4H9
1.24 (t, J = 7Hz, 6 H): P-O-CH2-CH3 MS: m/e=464: M+, 326: M+- HPO3Et2, 285 (100%): M+- CMe2-PO3Et2
C26H41O5P Calc. % C 67.22 % H 8.90 % P 6.67
Found % C 66.68 % H 8.56 % P 6.21 Example 11
Dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-butyl phosphonate
A solution of dimethyl lithi omethylphosphonate was prepared under nitrogen by adding dimethyl memylphosphonate (3.2 g, 25.6 mmol) to a solution of n- butyllithium (16 ml of a 1.6 M solution in hexane, 25.6 mmol) in 15 ml dry THF at - 60°C. To this solution was added at -60° a solution of eth yl 3,5-di-tert-butyl-4- hydroxyhydrocinnamate (2.6 g, 8.5 mmol) in 20ml THF. The resulting solution was stirred at -60° for 30 min and then was allowed to reach room temperature (25°C) overnight. 25 ml 10% HCl was added and the mixture was extracted into ether. The residue of the ether phase was purified by column chromatography (SiO2, 8/2
CHCl3/AcOEt) to yield a white solid. Recrystallization in petroleum ether gave 2.1 g (64% yield) of the title compound. mp=78-79°C
MS: m/e=384: M+, 284: M+-HPO3Me2, 57 (100%): tBu+
NMR (CDCI3)
δ = 6.98 (s, 2H): arom. H
5.06 (s, 1H): OH
3.75 (d, J = 11.5Hz, 6H): P-O-CH3
3.08 (d, J = 22.5Hz, 2H): CH2-P
2.90 (m, 2H): Ph-CH2-CH2
2.81 (m, 2H): Ph-CH2-CH2
1.41 (s, 18H): t-C4H9 Example 12 Diethyl 6-( 3,5-di-tert-hutyl-4-hydroxyphenyl-2,4-dioxo-5-hexen-1-yl phosphonate
Diethyl 2-oxopropylphosphonate (3.4 g, 17 mmol) was added at room temperature under nitrogen to a suspension of sodium hydride (0.82 g of a 60% dispension, 20 mmol) in 35 ml dry THF. The mixture was stirred at room temperature for 60 min, then diisopropylamine (1.71 g, 17 mmol) was added at 0°, followed by n- butyllithium (21 ml of a 1.6 M solution, 34 mmol). After 30 min at 0°, the mixture was cooled to -60° and a solution of etiiyl 3,5-di-tert-butyl-4-hydroxycinnamate (2.6 g, 8.5 mmol) in 25 ml THF was induced dropwise. The resulting mixture was stirred at 0° for 2 h, at 25°C for 1 h, hydrolyzed with 60 ml H2O whereupon it separated into two phases. The aqueous phase was acidified with 10% HCl and was extracted with two 100 ml portions of ether. The ether extracts were pooled with the THF phase, dried and evaporated. The residue was purified by column chromatography (SiO2, 8/2 CHCl3/AcOEt) to yield a viscous orange oil. Recrystallization in ligroin gave 2.25 g (60% yield) of the title compound, mp=109- 110°C
NMR (CDCI3)
δ = 7.60 (d, J=16Hz, 1H): Ph-CH=CH
7.37 (s, 2H): arom. H
6.35 (d, J= 16Hz, 1H): Ph-CH=CH
5.83 (s, 1H): CO-CH=C-OH
5.54 (s, 1H): phenol OH
4.17 (m, 4H): P-O-CH2-CH3
3.02 (d, J = 22Hz, 2H): CH2-P
1.46 (s, 18H): t-C4H9
1.34 (t, J = 7Hz, 3H): P-O-CH2-CH3
MS: m/e 452 M+, 314 M+ - HPO3Et2, 57 (100%) tBu Example 13
Diethyl 6-(3,5-di-tert-butyI-4-hydroxyphenyl)-2,4-dioxo-1-hexyl phosphonate
Diethyl 2-oxopropylphosphonate (2.02 g, 10 mmol) was added at room temperature to sodium hydride (0.48 g of a 60% dispersion, 12 mmol) suspended in 30 ml THF. After 30 min the mixture was cooled to 0° and diisopropylamine (1.01 g, 10 mmol) and n-butyllithium (13 ml of a 1.6 M solution, 21 mmol) were added. After 30 min, the mixture was cooled to -60° and eth yl 3,5-di-tert-butyl-4-hydroxy hydrocinnamate (1.6 g, 5.2 mmol) dissolved in 15 ml THF was added. The mixture was left to react at -60° for 15 min then at 0° for 2 h and 25°C for 1 h and was hydrolyzed with 10% HCl and extracted widi ether. Column chromatography (SiO2, 8/2 CHCl3/AcOEt) gave 1.0 g (42%) of the title compound as a colorless oil.
NMR (CDCI3)
δ = 6.98 (m, 2H): arom. H
5.70 (s, 1H): CO-CH=C-OH
5.09 (s, 1H): phenol OH
4J5 (m, 4H): P-O-CH2-CH3
2.92 (d, J = 22.5Hz, 2H): CH2-P
2.85 (m, 2H): Ph-CH2-CH2
2.59 (m, 2H): Ph-CH2-CH2
1.43 (s, 18H): t-C4H9
1.33 (t, J = 7Hz, 6H): P-O-CH2-CH3
MS: 455 M+ +1, 454 M+, 436 M+ -H2O, 57 (100%) tBu Example 14
Dimethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-5-hexen-1-yl
phosphonate
The procedure described in example 12 was followed using dimethyl 2-oxo- propylphosphonate to give the tide compound at 79% yield, yellow solid with mp = 145-146°C.
Example 15
2-[4-(3,5-di-tert-hutyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl]
(2-oxo-1,3,2-dioxaphosphorinan)
Under nitrogen atmosphere, 2-methyl-2-oxo-1,3,2-dioxaphosphorinan (2.62g, 19.2 mmol) dissolved in THF/dioxane (30ml each) was added to an equimolar amount of n-butyllithium in 35ml THF at -60°C. The mixture was stirred at -60°C for 30 min then a solution of ethyl 3,5-di-tert-butyl-4-hydroxycinnamate (2g, 6.4 mmol) in 20ml THF was added. The resulting mixture was stirred at -60°C for 30 min and left to attain room temperature (25°C) over 16 h. After the usual work up, column chromatography (silicagel, 98/2 CΑCl3/M eOH) gave 0.76g of the title compound (30%).
mp = 158-161°C
MS: m/e = 394 M+, 57 (100%): tBu NMR (CDCI3):
δ = 7.65 (d, J= 16Hz, 1H): Ph-CH=CH
7.42 (s, 2H): arom. H
6.74 ( d, J = 16Hz, 1H): Ph-CH=CH
5.7 (s, 1H): OH
4.5-4.4 (large m, 2H): P-O-CH2
3.45 (d, J = 22Hz): CH2-P
2.1 and 2.0 (2m, 2H): P-O-CH2-CH2
1.45 (s, 18H): t-C4H9
Example 16
Diethy] 4-(3,5-di-tert-butyl-4-hydroxy)-4-oxo-2-buten-1-yl phosphonate
To a suspension of 730mg 60% sodium hydride (18 mmol) in 20ml THF was added 3.0g (8.4 mmol) of dimethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1 ethylphosphonate in 25ml THF. The mixture was stirred for 30 min then it was cooled to 0° and 3.1 g (18 mmol) dieth yl formylmethylphosphonate was added. The resulting mixture was stirred at 0°C for 1 h then at 25°C for 16h, partitioned into ether and water and the organic phase was evaporated. Purification by means of column chromatography (silicagel 98/2 dichloromethane/methyl t-butyl ether) gave 550mg (16%) of the title compound.
mp = 68-70°C
MS=m/e: 410 M+, 395: M+-CH3, 272: M+-HPO3Et2,
233 (100%) M+-CH=CH-CH2PO3Et2 NMR: CDCI3
δ = 7.83 (m, 2H): arom. H,
7.1 (dd, J=15 and 4.5Hz, 1H), Ph-CO-CH=CH
6.9 (m, 2H): Ph-CO-CH=CH
5.7 (s, 1H): OH
4.15 (m, 4H): P-O-CH2-CH3
2.86 (dd, J=23 and 7Hz): CH2-P
1.48 (s, 18H): t-C4H9
1.34 (t, 6H): P-O-CH2-CH3
Example 17
Dimethyl 4-(3,5-di-tert-butyl-4-hydroxy phenyl)-2-hydroxy-3-huten-1-yl
phosphonate
To 100 ml of a methanol solution of dimeth yl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)- 2-oxo-3-buten-1-yl phosphonate (1.9g, 5 mmol) cooled to -10°C were added 0.75g sodium borohydride. The reacting mixture was stirred at -10°C for 1 h then at room temperature (25°C) for 2 h. Work up was carried out by addition of 100ml ether and 60ml sodium bicarbonate solution. The ether phase was washed with brine, dried over MgSO4 and evaporated to yield 1.6g (85%) of the title compound. mp = 122-123°C
MS (m/e)= 384:M+, 366: M+-H2O, 256: M+-H2O-HPO3Me2 NMR (CDCI3):
δ= 7.21 (s, 2H): arom. H
6.59 (d, J = 16Hz, 1H): Ph-CH=CH,
6.08 (dd, J = 16 and 6Hz, 1H): Ph-CH=CH
5.26 (s, 1H): OH (phenol)
4.7 (m, 1H): CH-OH
3.78 (2xd, 6H): PO3Me2
3.4 (hump, 1H): CH-OH
2.15 (distorted dd, 2H): CH2-P
1.44 (t, 18H): t-C4H9
Example 18
Dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl
thionophosphonate
Under nitrogen atmosphere dimethyl methylthionophosphonate (3.1 g, 25 mmol) was added at -60°C to a solution of n-butyllithium (16ml of a 1.6M solution, 25.6 mmol) in 50ml THF. The mixture was stirred at -60°C for 15 min then a solution of ethyl 3,5-di-tert-butyl-4-hydroxy cinnamate (2.5g, 8.2 mmol) in 20 ml THF was added. The resulting mixture was stirred at -60°C for 30 min and at room temperature (25°C) for 2 h. After the usual hydrolysis and work up, the compound was purified by column chromatography (SiO2, 9/1 CHCl3/AcOEt) and recrystallization in CHCl3/petroleum ether to yield 1.7g (52%) of a yellow solid, mp = 88-90°C
MS: m/e = 398: M+, 259: M+-CH2P(S)(OMe)2, 125: P(S)(OMe)2,
57 (100%) NMR (CDCI3)
δ= 7.60 (d, J = 16Hz, 1H): Ph-CH=CH
7.42 (s, 2H): arom. H
6.75 (d, J = 16Hz, 1H): Ph-CH=CH
5.6 (s, 1H): OH
3.78 (d, J = 14Hz, 6H): P(S)-OCH3
3.56 (d, J = 20Hz, 2H): CH2-P
1.46 (s, 18H): t-C4H9 C20H31O4PS Theor. %C 60.28 %H 7.84 %P 7.77 %S 8.04
Found %C 60.58 %H 8.04 %P 8.05 %S 8.30
Example 19 Dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenylthio)-2-oxo-1-propyl phosphonate
To a THF solution of dimethyl lithiomethylphosphonate (24.6 mmol) kept at -60°C was added a solution of ethyl 3,5-di-tert-butyl-4-hydroxyphenyl thioacetate (2g, 6.2 mmol) in 15ml THF. The resulting mixture was stirred at -60°C for 30 min and was allowed to reach room temperature (25°C) over 4 h. After addition of 15ml 10% HCl, the reaction mixture was partitioned between ether and water. The residue after evaporation of the organic phase was purified by column chromatography (SiO2, 8/2 CHCl3/AcOEt) and recrystallization in petroleum ether to give 0.95g of the title compound (38%).
mp = 63-65°C
MS: m/e 402: M+, 251: M+-(CO-CH2-PO3Me2), 57 NMR (CDCI3)
δ = 7.21 (s, 2H): arom H
5.3 (s, 1H): OH
3.75 (d, J = 11Hz, 6H): P-O-CH3
3.72 (s, 2H): S-CH2-CO
3.33 (d, J = 22Hz, 2H): CH2-P
1.41 (s, 18H): t-C4H9
Example 20
Dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenylthio)-3,3-dimethyl-2-oxo-1-propyl phosphonate
To 10ml of a THF solution of dimethyl lithiomethylphosphonate (68.2 mmol) kept at -60°C was added a solution of eth yl 2-(3,5-di-tert-butyl-4-hydroxyphenyl-thio-2- methylpropionate (6g 17.1 mmol) in 15ml THF. The resulting mixture was stirred at -60°C for 30 min and was allowed to reach room temperature (25°C) over 4 h. After addition of 15ml 10% HCl, the reaction mixture was partitioned between ether and water. The residue after evaporation of the organic phase was purified by column chromatography (SiO2, 8/2 CHCl3AcOEt). Recrystallization in petroleum ether gave 4.16g of the title compound (57%).
mp = 105-106°C
MS: m/e 430: M+, 279: M+-(CO-CH2-PO3Me2), 194 (100%), 57
NMR (CDCI3)
δ = 7.15 (s, 2H): arom H
5.38 (s, 1H): OH
3.80 (d, J = 11Hz, 6H): P-O-CH3
3.46 (d, J = 22Hz, 2H): CH2-P
1.41 (m, 24H):t-C4H9 + C(CH3)2 Example 21 Dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-butadien-1-yl phosphonate
CH=CH-CH=CH - PO3Me2
A mixture of dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl) 2-hydroxy-3-buten-1- yl phosphonate (2.3g, 6 mmol) in 1.70ml acetic anhydride and 1.26ml triethylamine was stirred at 60°C for 3h. Following hydrolysis with 10ml H2O, the reaction mixture was extracted with 20ml diethyl ether. The ether phase was extracted with 10% HCl and dried over MgSO4. The residue after evaporation was purified by column chromatography to give 1.0g (46%) of the title compound.
mp = 113-115°C MS : m/e: 366 M+, 351 M+-Me, 57 (tBu)
NMR (CDCl3)
δ = 7.32-7.20 (m, 3H): arom H + CH=CH-CH=CH-P
6.82 (1H,d): -CH=CH-CH=CH-P
6.74-6.66 (1H, m) CH=CH-CH=CH-P
5.67 (1H, dd, J = 16.6 and 19.5Hz): CH=CH-CH=CH-P
3.75 (d, 6H): PO-CH3
1.46 (19H, s): t-C4H9
Example 22 Dimethyl 4-( 3,5-di-tert-buty l-4-hydroxyphenyn-2-(4-pentenoyloxy)-1-butyl phosphonate
To a mixture of acetyl-4-pentenoate (0.66g, 4.6 mmol) and triethylamine (0.24ml, 1.7 mmol) was added 0.50g (1.37 mmol) of dimethyl 4-(3,5-di-tert-butyl-4- hydroxyphenyl)-2-hydroxy-1-butyl phosphonate. The reaction mixture was kept at 60°C for 6 h, cooled and extracted into diediyl etiier and water. The residue of the dried organic phase was purified by column chromatography (SiO2, 7/3
CHCl3/Methyl-tert-butyl ether) to yield 0.4g of a colorless oil (62%). MS: m/e: 468: M+, 368: M+- CH2=CH-CH2-COOH, 258: 368 - HPO3Me2
NMR (CDCI3)
δ = 6.94 (s, 2H): arom H
5.85 (m, 1H): CH2=CH -CH2-CH2-COO
5.18 (m, 1H): Ph-CH2-CH2-CH-CH2-P
5.0 - 5.1 (m, 2H): CH2=CH-CH2-CH2-COO
5.15 (s, 1H): OH (phenol)
3.72 (2xd, 6H): PO3Me2
2.55 (m, 2H): Ph-CH2-CH2-CH-CH2-P
2.41 (m, 4H): CH2=CH-CH2-CH2-COO-
1.43 (s, 18H): t-C4H9 BIOLOGICAL ACTIVITIES
A. Antioxidant Activity
1) Iron induced peroxide formation in rat liver homogenate
Wistar rats were euth anasied by ether inhalation. The livers were dissected out and homogenised with a potter homogeneiser in 4 volumes of phosphate buffer (4°C, pH 7.4). After centrifugation at 2000 rpm for 10 min the supernatant obtained was kept at 4°C.
A mixture containing 0.2 ml of liver homogenate, 1.7 ml of phosphate buffer was incubated with 0.1 ml of a 2mM FeSO4 solution to induce peroxide formation according to the method described by A. T. Quintanilha et al., Ann. N. Y. Acad. Sci., 393, 32-47, 1982.
Compounds to be tested for antioxidant activity were dissolved in DMSO or ethanol and added in a volume of 5 μl to the incubation mixture. Stock solution of the compounds were diluted sequentially to obtain final concentration of 0.5, 1, 2, 5 and 5 μM. Oxidation was performed at 37°C for 2 hours and was stopped by the addition of 20 μl of a 2% ethanolic solution of BHT. The generated peroxides measured as malondialdehyde formation were quantitated according to the method of Yagi ("Lipid Peroxides in Biology and Medicine" p. 223-242, 1982, Ed. K. Yagi, Academic Press Inc.) using the Thiobaibituric Acid Reaction and with 1,1,3,3,-tetramethoxypropane as standard. Results are given as concentration in μmol/l which inhibits malondialdehyde formation by 50% (IC50).
All the tested compounds have IC50's between 0.5 and 5 μM and are more active man Probucol, vitamin E and Vitamin C. Butyl hydroxytoluene (BHT) has an IC50 of 3.3 μM in this assay. Compound of formula (I) are thus useful for the treatment of disease states in which oxygen reactive species are involved. 2) Copper Oxidation of human low density lipoproteins (LDL) Plasma was obtained after low speed centrifugation of blood from donors. LDL
(d= 1.006- 1.063 g/ml) were isolated by preparative ultracentrifugation in a salt solution (NaBr, KBr). The isolated LDL fraction was dialysed against phosphate buffer.
LDL oxidation was performed according to Esterbauer et al. (Continuous
Monitoring of in Vitro Oxidation of Human Low Density Lipoprotein, Free Rad. Res. Commun.6, 67-75, 1989). Briefly the LDL suspension (50-200μg protein/ml) was distributed in quartz cuvettes and kept at 37°C then a solution of CuCI2 was added at a final concentration of 5μM. The increase in optical density at 235 nm was recorded using a UV- visible spectrophotometer. The time course of oxidation was recorded over a period of 8 hours at 10 min intervals. Compounds to be tested were dissolved in ethanol and added at the final concentration of 0.1 μM. Controls received ethanol only. The lag phase is prolonged by the presence of antioxidants. This method was validated with Probucol and vitamin-E as reference antioxidants.
The prolongation of the lag phase was used to quantify the antioxidant activity of the compounds tested, this prolongation was expressed in percent of the value measured in absence of exogen antioxidant (controls).
The phosphonates of Formula (I) as noted in Table 3 prolong the lag phase compared to control. An inhibitory activity on LDL oxidation is thus demonstrated which is clearly superior to that of Probucol and vitamin E. Since these two antioxidants have been shown to be anti-atherosclerotic in animal models, the therapeutic potential of phosphonates of Formula (I) is obvious.
B. Inhibition of Cholesterol and Cholesteryl Esters Synthesis
The human intestinal cell line CaCo2 cells (ATCC HTB37) was used to study the effect of compounds of formula (I) on cholesterol synthesis. The cells were grown in 6 wells dishes (Falcon) in 2 ml of Dulbecco's modified Eagle culture medium
(DMEM) supplemented with 20% fetal calf serum (Flow). Cells were maintained at 37°C in a 5% CO2 atmosphere and the labelling experiment was done 8 days after cell plating. To the culture were added 10 μl of the eth anol solution of the compounds to be tested. Control wells received 10μl of ethanol alone. One hour later 0.7 μCi of 14-C-acetate 53.4 mCi/mmol was added, labelling was continued for 4 hours and was stopped by washing the cell layer with chilled PBS. The cells were collected in 2ml of 0.01 N NaOH and 1 ml of PBS. Lipids were extracted by the Folch method and separated on silica gel TLC plates developed in petroleum ether: diethyl ether: acetic acid (70:30: 0.5). After exposition to iodine vapors, the bands corresponding to cholesterol and cholesteryl esters were scrapped off and radioactivity was measured in a liquid scintillator counter.
The amount of radioactivity incorporated in cholesterol and cholesteryl esters in presence of compounds to be tested was compared to that of the control cells.
HMGCoA reductase inhibitors such as simvastatin (1μM) served to validate the measurement of 14C-acetate incorporation in cholesterol and cholesteryl esters.
All the compounds tested inhibited cholesterol and cholesteryl esters synthesis.
Most of the compounds inhibited cholesteryl esters synthesis by more than 50%
(Table 4). Phosphonates of formula (I) display an inhibitory activity on cholesterol and cholesteryl esters and can be considered as therapeutic agents in the treatment of hyperlipidemia and ath erosclerosis.
C. Calcium Entry Blocking activity of ketophosphonates
Experiments were performed on aortic rings from male Sprague -Dawley rats (280-350g body weight) which were killed by stunning and exsanguination.
Thoracic aortas were cleared of connective tissues and cut into rings of approximately 2mm in length. Each ring was mounted under a resting tension of 2g and was equilibrated for 1 hour at 37°C in a 10 ml organ bath containing a HEPES buffer Ringer solution (Buffer composition (mM): NaCl 139.0, KC15.0, MgCl23.7, D-Glucose 11.0, HEPES 5.0, pH 7.4) aerated with 95% O2:5% CO2.
Maximal contractions were produced within 5-10 min exposure to 10μM
Phenylephrine. The tissues were then washed with a Ca+2 free HEPES buffer. After 30 min the tissue was depolarised with KCl (60mM).One hundred μl of the vehicle (10% DMSO) or compound solution (1 μM) were added 5 min later. The final concentration of DMSO was 1%. The tissues (n=2 per compound) were further equilibrated for 15 min in the presence of compounds prior to cumulative addition of Ca+2 (0.1-30 mM). The contractions to each concentration of calcium are calculated as a percentage of the second phenylephrine contraction and the EC30 (concentration of Ca2+ producing a contraction 30% of the phenylephrine contraction) calculated. The potency index of each compound is expressed as the concentration ratio (calcium drug EC30/vehicle EC30), where a potency index >1 indicates a compound effect.
The compounds of formula (I) are thus potentially useful in the treatment of cardiovascular diseases via their calcium entry blocking activity. The primary indications of these compounds would be the treatment of atherosclerosis, angina pectoris, congestive heart failure and hypertension.
Table 5
Effect of compounds (I) on Ca+2 induced contraction of K+ depolarized rat aorta

Claims

1. A compound of formula (I)
where
- X1, X2 identical or different are straight or branched C1 to C6 alkyl groups,
- Y is O or S,
- Z1, Z2, identical or different, are: - OR where R is H, a straight or branched C1-C6 alkyl group,
- NR1R2 where R1, R2, identical or different are H or a straight or branched C1-C6 alkyl group,
- Z1, Z2 together may form a C2-C8 alkylidenedioxy group, - G is OH or a bioprecursor thereof;
D is a saturated or unsaturated C1-C11 alkylene chain in which one or more of the methylene groups can be replaced by a sulphur atom, an oxygen atom, a carbonyl group; optionally one or more methylene groups can be substituted by one or more halogen atoms (F, Cl or Br), C1-6 alkyl, phenyl, hydroxy or acyloxy groups, and salts, solvates and hydrates thereof.
2. A compound of formula (I) according to claim 1 where :
D is A-C(O)-B, A-CH(OH)-B, A-CH2-B, (CH2)t-(CH=CH)n-(CH2)t or S- (CH2)t, where - A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3, S-(CH2)t-(CH=CH)n, S-CX4X5,
(CH=CH)n-CH=CH-C(O)-CHX3, (CH2)p-CH=CH-C(O)-CHX3,
(CH2)t-C(O)-CHX3, S-(CH2)t-(CH=CH)n-C(O)-CΗX3, S-CX4X5-C(O)-CHX3, (CH=CH)n-CH=CH-CH(OH)-CHX3, (CH2)p-CH=CH-CH(OH)-CHX3,
(CH2)t-CH(OH)-CHX3, S-(CH2)t-(CH=CH)n-CH(OH)-CHX3,
S-CX4X5-CH(OH)-CHX3, where n is zero, 1 or 2, t is a number from 0 to 4, p is a number from 1 to 3,
- X3 is H, a straight or branched alkyl C1-C6 group, a substituted or unsubstituted phenyl group,
- X4, X5 identical or different are H, a straight or branched C1-C4 alkyl group,
- B is CH2, CH-X6, X6-C-X7, where X6 and X7 identical or different are halogen atoms (F,Cl, Br), straight or branched C1-C6 alkyl groups, a substituted or unsubstituted phenyl group; when A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHx3, S-(CH2)t-(CH=CH)n, S-CX4X5, then B is also CH=CH-(CH2)p, CH=CH-CHX6, CH=CH-CX6X7, where p and X6, X7 are defined as above.
3. A compound of formula (I) according to claim 1 in which D is A-C(O)-B in which
A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3, S-(CH2)t-(CH=CH)n,
S-CX4X5,
(CH=CH)n-CH=CH-C(O)-CHX3, (CH2)p-CH=CH-C(O)-CHX3,
(CH2)t-C(O)-CHX3, S-(CH2)t-(CH=CH)n-C(O)-CHX3, S-CX4X5-C(O)-CHX3, (CH=CH)n-CH=CH-CH(OH)-CHX3, (CH2)p-CH=CH-CH(OH)-CHX3,
(CH2)t-CH(OH)-CHX3, S-(CH2)t-(CH=CH)n-CH(OH)-CHX3,
S-CX4X5-CH(OH)-CHX3, and where n is zero, 1 or 2, t is a number from 0 to 4, p is a number from 1 to 3,
- X3 is H, a straight or branched alkyl C1-C6 group, a substituted or unsubstituted phenyl group, - X4, X5 identical or different are H, a straight or branched C1-C4 alkyl group, and
B is CH2, CH-X6, X6-C-X7, where X6 and X7 identical or different are halogen atoms (F,Cl, Br), straight or branched C1-C6 alkyl groups, a substituted or unsubstituted phenyl group; when A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3, S-(CH2)t-(CH=CH)n, S-CX4X5, then B is also CH=CH-(CH2)p, CH=CH-CHX6, CH=CH-CX6X7, where p and X6, X7 are as defined in claim 1.
4. A compound of formula (I) according to claim 1 in which D is -ACH(OH)-B- in which A and B are as described in claim 2.
5. A compound of formula (I) according to claim 1 in which D is
A'-CH(O-CO-X8)-B' where
A' is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3, S-(CH2)t-(CH=CH)n,
S-CX4X5, and
B' is CH2, CH-X6, X6-C-X7, CH=CH-(CH2)p, CH=CH-CHX6, CH=CH-CX6X7 where t, n, p, X3, X4, X5, X6 and X7 are as described in claim 2, and X8 is a saturated or unsaturated C1-C6alkyl or alkenyl chain.
6. A compound of formula (I) according to claim 1 selected from the group comprising: dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate, diisopropyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate, dibutyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-3-buten-1-yl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-3-buten-1-yl phosphonate, diisopropyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-methyl-2-oxo-3-buten-1-yl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-methyl-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methyl-2-oxo-3-buten-1-yl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methyl-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(n-butyl)-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(n-pentyl)-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-phenyl-3-buten-1-yl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-phenyl-3-buten-1-yl phosphonate, dimethyl 4- (3 ,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-butyl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-butyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl -2-oxo-1-butyl
phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl -2-oxo-1-butyl phosphonate, diethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3,5-hexadien-1-yl phosphonate dimethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1 -dimethyl-2-oxo-3,5-hexadien-1- yl phosphonate diethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethy l-2-oxo-3,5-hexadien-1-yl- phosphonate, dimethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-ethyl phosphonate,
N,N,N',N'-tetramethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonamide, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo- 1 -butyl phosphonate, dimethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-5-hexen-1-yl phosphonate, diethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-5-hexen-1-yl phosphonate, diethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-1-hexyl phosphonate, dimethyl 6-(3 ,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-hexyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl) 3-ethyl-2-oxo-3-buten-1-yl
phosphonate dimethyl 4-(3,5-di-sec-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate, diethyl 4-(3,5-di-sec-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3 ,5-di-tert-butyl-4-methoxyphenyl)-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl
thionophosphonate,
2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl](2-oxo-1,3,2- dioxaphosphorinan), dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxo-2-buten-1-yl phosphonate, diethyl 4-(3 ,5-di-tert-butyl-4-hydroxyphenyl)-4-oxo-2-buten-1-yl phosphonate, diethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-ethyl phosphonate, diisopropyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-edιyl phosphonate, dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio )-2-oxo-1-propyl phosphonate, diethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio)-2-oxo-1-propyl phosphonate, dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio)-3,3-dimethyl-2-oxo-1-propyl phosphonate diethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio)-3,3-dimethyl-2-oxo-1-propyl phosphonate dimethyl 5- (3 ,5-di-tert-butyl-4-hydrox yphenylthio)-2,4-dioxo-1-pentyl phosphonate, diethyl 5-(3,5-di-tert-butyl-4-hydroxyphenylthio)-2,4-dioxo-1-pentyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-hydroxy-3-buten-1-yl
phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-hydroxy-1-butyl phosphonate, dimethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-hydroxy-1-ethyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dihydroxy-1-butyl phosphonate, dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenylthio)-2-hydroxy 1-propyl
phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-butadien-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(acetyl oxy)-1 -butyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(hexanoyl oxy)-1 -butyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(4-pentenoyl oxy)-1-butyl phosphonate, dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio)-2-(acetyl oxy)-1-propyl phosphonate, dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio)-2-(hexanoyl oxy)-1-propyl phosphonate. A process for preparing compounds of formula (I) according to claim 3, where A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3, S-(CH2)t-(CH=CH)n,
S-CX4X5 where n, t, X3, X4 and X5 are as described in claim 1 which consists in reacting the alkylphosphonates III
where B is CH2, CHX6, CX6X7 and X6, X7, Y, Z1 and Z2 are as described in claim 1, with n-butyllithium or lithium diisopropylamide at a temperature between -78° and -40°, then reacting in situ the lithium anion of III thus formed with the ester II
where X1 , X2, G are as described in claim 1 and A is (CH2)t,
(CH=CH)n-CH=CX3, (CΗ2)t-CHX3 ,S-(CH2)t-(CH=CH)n or S-CX4X5 in tetrahydrofuran at a temperature between -78° C and 25°C.
8. A process for preparing compounds of formula (I) according to claim 3 where A is (CH=CH)n-CH=CX3 which consists in reacting an aldehyde of formula IV
where G, X1, X2, n are as described in claim 1,
with a ketophosphonate of formula V
where X3, B, Y, Z1, Z2 are as described in claim 1,
in tetrahydrofuran in presence of titanium tetrachloride and N-methyl morpholine at a temperature between -20°C and 66°C.
9. A process for preparing compounds of formula (I) according to claim 3 in which A is (CH2)t-CHX3, which consists in reacting the compound V
where X3, B, Y, Z1 and Z2 are as described in claim 1 first with sodium hydride and n-butyl lithium, men with the halide of formula VI
where G, X1, X2, t are as described in claim 1,
in tetrahydrofuran at a temperature between -30° and the boiling point of tetrahydrofuran (66°C).
10. A process for preparing compounds of formula (I) according to claim 3 where
A is (CH=CH)n-CH=CH-C(O)-CHX3, (CH2)p-CH=CH-C(O)-CHX3,
(CH2)t-C(O)-CHX3, S-(CH2)t-(CH=CH)n-C(O)-CHX3 or
S-CX4X5-C(O)-CHX3 where n, p, t, X3, X4 and X5 are as described in claim 1 which consists in reacting compound V
where X3, B, Y, Z1, Z2 are as described in claim 1, first with sodium hydride then with n-butyl lithium or lithium diisopropylamide at a temperature between -78° and 0°, then with ester VII
where E is (CH=CH)n-CH=CH, (CH2)p-CH=CH, (CH2)t or
S (CH2)t-(CH=CH)n, S-CX4X5, n, p, t, X4, X5 are as described in claim 1, in tetrahydrofuran at a temperature between -60° and 25°C°. 11. A process for preparing compounds of formula (I) according to claim 4 which consists in reducing the ketone functional group by a complex hydride, which is sodium borohydride or lithium borohydride in methanol, ethanol or isopropanol at a temperature between -20°C and the boiling point of the solvent.
12. A process for preparing compounds of formula (I) according to claim 5 which consists of esterification of the corresponding acyloxy-phosphonate compound, with an appropriate acid anhydride (X8CO)2O or acid chloride X8-CO'-Cl.
13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 in combination with a
pharmaceutically acceptable carrier.
14. A compound of formula (I) as claimed in claim 1 for use in therapy.
15. A compound of formula (I) as claimed in claim 1 for use in the treatment of
atherosclerosis.
EP94909033A 1993-02-19 1994-02-21 Substituted phosphonates, the processes for their preparation and pharmaceutical compositions containing them Withdrawn EP0638084A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CH521/93 1993-02-19
CH52193 1993-02-19
PCT/EP1994/000520 WO1994019358A1 (en) 1993-02-19 1994-02-21 Substituted phosphonates, the processes for their preparation and pharmaceutical compositions containing them

Publications (1)

Publication Number Publication Date
EP0638084A1 true EP0638084A1 (en) 1995-02-15

Family

ID=4188911

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94909033A Withdrawn EP0638084A1 (en) 1993-02-19 1994-02-21 Substituted phosphonates, the processes for their preparation and pharmaceutical compositions containing them

Country Status (8)

Country Link
EP (1) EP0638084A1 (en)
JP (1) JPH07506121A (en)
CN (1) CN1106611A (en)
AU (1) AU6205294A (en)
CA (1) CA2118409A1 (en)
MX (1) MX9401295A (en)
WO (1) WO1994019358A1 (en)
ZA (1) ZA941088B (en)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4433244A1 (en) * 1994-09-19 1996-03-28 Hoechst Ag Aminomethylphosphonic and aminomethylphosphinic acid derivatives and their use for the treatment of degenerative joint diseases
DE19502209A1 (en) * 1995-01-25 1996-08-01 Hoechst Ag Phosphonoacetic acid derivatives and their use for the treatment of degenerative joint diseases
JP3588734B2 (en) * 1996-07-26 2004-11-17 コニカミノルタホールディングス株式会社 Electrophotographic photoreceptor
AU2003272534A1 (en) * 2002-09-19 2004-04-08 Ilex Oncology Research, Sarl Therapeutic uses of linear ketophosphonates
WO2004026315A1 (en) * 2002-09-19 2004-04-01 Ilex Oncology Research, Sarl Substituted ketophosphonate compounds having bone anabolic activity
FR2876104B1 (en) * 2004-10-04 2007-02-23 Centre Nat Rech Scient FLUOROPHOSPHONOCINNAMIC COMPOUNDS, SYSTEM AND APLICATIONS
GB0613518D0 (en) * 2006-07-06 2006-08-16 Phytopharm Plc Chemical compounds
JP5559186B2 (en) * 2008-11-13 2014-07-23 ビーエーエスエフ ソシエタス・ヨーロピア Benzylidene compounds containing phosphono groups
EP2270021A1 (en) * 2009-06-18 2011-01-05 Centre National de la Recherche Scientifique Phosphonates synthons for the synthesis of phosphonates derivatives showing better bioavailability
WO2018227940A1 (en) * 2017-12-29 2018-12-20 邦泰生物工程(深圳)有限公司 Method for preparing ursodeoxycholic acid via chemical-enzymatic process
CN108794559A (en) * 2018-07-31 2018-11-13 重庆波克底科技开发有限责任公司 A method of using hyodesoxycholic acid as Material synthesis lithocholic acid

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2024030A1 (en) * 1970-05-16 1971-12-02 Deutsche Advance Produktion GmbH, 6141 Lautern 2,6-dialkyl phenols
JPS5921889B2 (en) * 1975-06-02 1984-05-23 帝人株式会社 Polyester manufacturing method
JPS5782828A (en) * 1980-11-11 1982-05-24 Canon Inc Heat developing photosensitive material
EP0106799B1 (en) * 1982-10-07 1986-03-19 Ciba-Geigy Ag Phenols and their preparation
CH675422A5 (en) * 1988-03-31 1990-09-28 Symphar Sa
JPH0377894A (en) * 1989-08-18 1991-04-03 Toray Ind Inc Methylene diphosphonic acid compound
US5300687A (en) * 1991-07-18 1994-04-05 Ortho Pharmaceutical Corporation Trifluoromethylbenzylphosphonates useful in treating osteoporosis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9419358A1 *

Also Published As

Publication number Publication date
CA2118409A1 (en) 1994-09-01
JPH07506121A (en) 1995-07-06
WO1994019358A1 (en) 1994-09-01
MX9401295A (en) 1994-08-31
ZA941088B (en) 1995-09-27
CN1106611A (en) 1995-08-09
AU6205294A (en) 1994-09-14

Similar Documents

Publication Publication Date Title
EP0339237B1 (en) Phenol substituted gem-diphosphonate derivatives, process for their preparation and pharmaceutical compositions containing them
FI77041C (en) FOERFARANDE FOER FRAMSTAELLNING AV NYA, TERAPEUTISKT ANVAENDBARA DIPHOSFONSYRADERIVAT.
US5202327A (en) Phosphorus-containing hmg-coa reductase inhibitors
EP0638084A1 (en) Substituted phosphonates, the processes for their preparation and pharmaceutical compositions containing them
EP0688325A1 (en) Phosphonic acid derivatives
Iyer et al. Synthesis of acyloxyalkyl acylphosphonates as potential prodrugs of the antiviral, trisodium phosphonoformate (foscarnet sodium)
NL7907568A (en) PHOSPHINYL ALKANOYLPROLINES.
US5354879A (en) Optically active intermediate and method for production thereof
EP0559079B1 (en) Substituted aminophosphonate derivatives, process for their preparation and pharmaceutical compositions containing them
KR100233986B1 (en) Novel methylenebisphosphonic acid derivatives
US5374628A (en) Aryl and heteroaryl(phosphinylmethyl)phosphonate squalene synthetase inhibitors and method
JP2007519625A (en) Method for preparing pyridine derivatives
US5563129A (en) Hydroquinone derivatives and intermediates for production thereof
FI83421B (en) FOERFARANDE FOER FRAMSTAELLNING AV FARMAKOLOGISKT ANVAENDBARA METYLENBISFOSFONSYRADERIVAT.
EP0671395A1 (en) 1,2-Dioxetane derivatives, intermediates for syntheses thereof and methods of producing the intermediates
US5177239A (en) Method for preparing a phosphonic acid ester
WO2004026245A2 (en) Substituted phosphonate compounds having bone anabolic activity
IE914417A1 (en) Bisphosphonic acid derivatives, their production and use
US6147244A (en) Preparations of thiophosphites and thiophosphonates
US5414133A (en) Protected phosphine oxides
Grison et al. New ketone homoenolate anion equivalents derived from (alkenyl) pentamethyl phosphoric triamides
FI89170C (en) FRAMEWORK FOR FRAMSTATION OF ALIFATHYLFOSPHINSYRADERIVAT
US4305891A (en) Method for preparing O-4-(hydroxyalkyl)-thiophenyl phosphates
US5166386A (en) Process of making isoprenoid phosphinylformic acid squalene synthetase inhibitors
US5210262A (en) Method for preparing a phosphonic acid ester

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19941010

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19960903