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WO1994019358A1 - Phosphonates substitues, procedes de preparation et compositions pharmaceutiques les contenant - Google Patents

Phosphonates substitues, procedes de preparation et compositions pharmaceutiques les contenant Download PDF

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Publication number
WO1994019358A1
WO1994019358A1 PCT/EP1994/000520 EP9400520W WO9419358A1 WO 1994019358 A1 WO1994019358 A1 WO 1994019358A1 EP 9400520 W EP9400520 W EP 9400520W WO 9419358 A1 WO9419358 A1 WO 9419358A1
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Prior art keywords
butyl
tert
phosphonate
hydroxyphenyl
dimethyl
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Ceased
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PCT/EP1994/000520
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English (en)
Inventor
Lân Nguyen
Eric Niesor
Craig L. Bentzen
Vinh Van Diep
Hieu Phan
Simon Floret
Raymond Azoulay
Yves Guyon-Gellin
Pierre Maechler
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Symphar SA
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Symphar SA
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Priority to EP94909033A priority Critical patent/EP0638084A1/fr
Priority to AU62052/94A priority patent/AU6205294A/en
Priority to JP6518667A priority patent/JPH07506121A/ja
Publication of WO1994019358A1 publication Critical patent/WO1994019358A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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.

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Abstract

L'invention concerne de nouveaux phosphonates substitués par un groupe dialkylphénol de formule (I), où G, X1, X2, D, Y, Z1 et Z2 sont définis dans la revendication 1, ainsi que leur préparation et les compositions pharmaceutiques les contenant.
PCT/EP1994/000520 1993-02-19 1994-02-21 Phosphonates substitues, procedes de preparation et compositions pharmaceutiques les contenant Ceased WO1994019358A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP94909033A EP0638084A1 (fr) 1993-02-19 1994-02-21 Phosphonates substitues, procedes de preparation et compositions pharmaceutiques les contenant
AU62052/94A AU6205294A (en) 1993-02-19 1994-02-21 Substituted phosphonates, the processes for their preparation and pharmaceutical compositions containing them
JP6518667A JPH07506121A (ja) 1993-02-19 1994-02-21 置換ホスホネート，その製法およびその化合物含有の医薬組成物

Applications Claiming Priority (2)

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CH52193 1993-02-19
CH521/93-1 1993-02-19

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WO1994019358A1 true WO1994019358A1 (fr) 1994-09-01

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JP (1) JPH07506121A (fr)
CN (1) CN1106611A (fr)
AU (1) AU6205294A (fr)
CA (1) CA2118409A1 (fr)
MX (1) MX9401295A (fr)
WO (1) WO1994019358A1 (fr)
ZA (1) ZA941088B (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0703239A1 (fr) * 1994-09-19 1996-03-27 Hoechst Aktiengesellschaft Dérivés d'acides aminomethylphosphoniques et aminomethylphosphiniques et leur utilisation dans le traitements de maladies articulaires dégénératives
EP0723969A1 (fr) * 1995-01-25 1996-07-31 Hoechst Aktiengesellschaft Dérivés de l'acide phosphonocarboxylique et leur utilisation dans le traitement de maladies dégénératives des articulations
WO2004026243A3 (fr) * 2002-09-19 2004-06-03 Ilex Oncology Res Sarl Utilisations therapeutiques de cetophosphonates lineaires
FR2876104A1 (fr) * 2004-10-04 2006-04-07 Centre Nat Rech Scient Composes fluorophosphonocinnamiques, systhese et aplications
EP1551418A4 (fr) * 2002-09-19 2006-05-03 Ilex Oncology Res Sarl Composes de cetophosphonates substitues ayant une activite anabolisante sur les os
GB2440034A (en) * 2006-07-06 2008-01-16 Phytopharm Plc Beta-Diketones and their use against conditions modulated by the TRPV1 receptor
WO2010054966A3 (fr) * 2008-11-13 2011-08-11 Basf Se Composés de benzylidène comprenant des groupes phosphono

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JP3588734B2 (ja) * 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 電子写真感光体
EP2270021A1 (fr) * 2009-06-18 2011-01-05 Centre National de la Recherche Scientifique Synthons de phosphonates pour la synthèse de dérivés de phosphonates démontrant une meilleure biodisponibilité
WO2018227940A1 (fr) * 2017-12-29 2018-12-20 邦泰生物工程(深圳)有限公司 Procédé de préparation d'acide ursodésoxycholique au moyen d'un procédé chimique-enzymatique
CN108794559A (zh) * 2018-07-31 2018-11-13 重庆波克底科技开发有限责任公司 一种以猪去氧胆酸为原料合成石胆酸的方法

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EP0703239A1 (fr) * 1994-09-19 1996-03-27 Hoechst Aktiengesellschaft Dérivés d'acides aminomethylphosphoniques et aminomethylphosphiniques et leur utilisation dans le traitements de maladies articulaires dégénératives
EP0723969A1 (fr) * 1995-01-25 1996-07-31 Hoechst Aktiengesellschaft Dérivés de l'acide phosphonocarboxylique et leur utilisation dans le traitement de maladies dégénératives des articulations
US5627173A (en) * 1995-01-25 1997-05-06 Hoechst Aktiengesellschaft Phosphonoacetic acid derivatives and their use for treating degenerative joint disorders
EP1551418A4 (fr) * 2002-09-19 2006-05-03 Ilex Oncology Res Sarl Composes de cetophosphonates substitues ayant une activite anabolisante sur les os
WO2004026243A3 (fr) * 2002-09-19 2004-06-03 Ilex Oncology Res Sarl Utilisations therapeutiques de cetophosphonates lineaires
WO2006037869A3 (fr) * 2004-10-04 2006-06-08 Centre Nat Rech Scient Composes fluorophosphonocinnamiques , synthese et applications dans le traitement des troubles causés par un stress oxydatif
FR2876104A1 (fr) * 2004-10-04 2006-04-07 Centre Nat Rech Scient Composes fluorophosphonocinnamiques, systhese et aplications
US7517869B2 (en) 2004-10-04 2009-04-14 Centre National De La Recherche Scientique (C.N.R.S.) Fluorophosphonocinnamic compounds, synthesis and uses for treating disorders caused by oxidative stress
GB2440034A (en) * 2006-07-06 2008-01-16 Phytopharm Plc Beta-Diketones and their use against conditions modulated by the TRPV1 receptor
US7589123B2 (en) 2006-07-06 2009-09-15 Phytopharm Plc Chemical compounds
GB2440034B (en) * 2006-07-06 2011-02-16 Phytopharm Plc Beta-Diketones and their use against conditions modulated by the TRPV1 receptor
WO2010054966A3 (fr) * 2008-11-13 2011-08-11 Basf Se Composés de benzylidène comprenant des groupes phosphono
US8529877B2 (en) 2008-11-13 2013-09-10 Basf Se Benzylidene compounds comprising phosphono-groups
KR101550085B1 (ko) 2008-11-13 2015-09-03 바스프 에스이 포스포노-기를 포함하는 벤질리덴 화합물

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JPH07506121A (ja) 1995-07-06
EP0638084A1 (fr) 1995-02-15

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