FR2596393A1 - Derivatives of 3-hydroxy-4-(dihydroxooxophosphorio)butanoic acid, process for their preparation, their application as medicament and the compositions which contain them - Google Patents

Abstract

Derivatives of 3-hydroxy-4-(dihydroxooxophosphorio)butanoic acid, a process for preparing them, their application as medicaments and the compositions which contain them. These derivatives correspond to the general formula: in which: - R1 can be hydrogen, a saturated or unsaturated, linear or branched, lower alkyl group, or an optionally substituted aralkyl group. - R2 can be hydrogen, a saturated or unsaturated, linear or branched, lower alkyl group, or an optionally substituted aralkyl group. - R3 and R4 can be, together or independently of each other, hydrogen or a saturated or unsaturated, linear or branched, lower alkyl group, or an optionally substituted aryl or aralkyl group or one of its stereoisomeric forms as well as the addition salts with pharmaceutically acceptable inorganic or organic bases. The invention also relates to their application as medicaments and to the compositions which contain them.

Description

dans laquelle - R1 peut être l'hydrogène, un groupe alcoyle inférieur, linéaire ou ramifié, un groupe aralcoyle éventuellement substitué.The invention relates to derivatives of 3-hydroxy-dihydroxyoxophosphorio-4-butanoic acid, to a process for preparing them, to their application as a medicament and to the compositions containing them,
These derivatives correspond to the general formula

in which - R1 may be hydrogen, a linear or branched lower alkyl group, an optionally substituted aralkyl group.

R2 may be hydrogen, a linear or branched lower alkyl group or an optionally substituted aralkyl group.

 R 3 and R 4 may be together or independently of each other hydrogen or a linear or branched lower alkyl group, an optionally substituted aryl or aralkyl group.

In the case where R 1, R 3 and R 4 are hydrogen, the invention also comprises addition salts with inorganic bases such as alkali hydroxides, in particular the hydroxides of sodium, potassium, calcium, magnesium or bases. pharmaceutically acceptable organic compounds.

By lower alkyl group is meant a saturated C 1 to C 6 hydrocarbon chain such as methyl, ethyl, isopropyl, isobutyl, tert-butyl, n-hexyl, butyryl-2, or unsaturated C 2 to C 6 such as vinyl, allyl, ethynyl, propargyl, crotyl, 2-methylcrotyl, 2-methylallyl.

By aralkyl group is meant a benzyl, phenethyl group.

By aryl group is meant alpha-naphthyl phenyl, beta-naphthyl.

The compounds of formula (I) above, comprising at least one asymmetric center may exist in the form of several stereoisomers (enantiomers, diastereoisomers). The invention relates to each stereoisomer as well as to their mixture.

Atherosclerosis and its complications is a growing problem in the field of public health. The discovery of cholesterol in the affected arteries and the experimental observation of the induction of atherosclerosis by cholesterol were the first indications on the role of this steroid in this type of pathology. The control or inhibition of endogenous cholesterol synthesis can be achieved by the inhibition of HMG-CoA reductase, a key enzyme catalyzing the main step, limiting the rate, in the biosynthesis of cholesterol in mammals (VW RODWELL and Adv Lipid, Res 1976, 14, 1). Inhibition of HMG-CoA reductase results in a decrease in the intracellular cholesterol pool and thus an increase in cellular cholesterol requirements. To meet these needs, cells synthesize LDL receptors to capture exogenous cholesterol; this results in a significant increase in LDL catabolism and a reduction in plasma cholesterol levels.

analogue non phosphonique des dérivés de l'invention, possède une activité hypocholestérolémiante (Z. BEG , P. LUPIEN, Biochem. Biophys.Thus, meglutol or 3-hydroxy-3-methylglutaric acid of formula

Nonphosphonic analogue of the derivatives of the invention, has a hypocholesterolemic activity (Z. BEG, P. LUPIEN, Biochem Biophys.

Acta 1972, 260, 439; Z. BEG, M. SIDDIQI, Experientia 1967, 23, 380; 1968, 24, 15), which would be related to the inhibition of HMGCoA reductase.

The compounds of the invention of formula (I) appear to be much better cholesterol-lowering drugs than meglutol at the plasma and tissue level.

en imidoesters de formule (III) que l'on hydrolyse sélectivement en esters de formule (la) selon le schéma réactionnel

The subject of the invention is also a process for the preparation of the compounds of formula (I) above, characterized in that the esters of formula (Ia) in which R 1 represents an alkyl radical, R2 represents hydrogen, are prepared. , an alkyl or aralkyl radical, R 3 and R have the same value and represent an alkyl, aryl or aralkyl radical, by conversion of the nitriles of general formula (II) in which
R2 represents hydrogen, an alkyl or aralkyl radical, R 3 and
R 4 have the same value and represent an alkyl, aryl or aralkyl radical

imidoesters of formula (III) which are selectively hydrolyzed to esters of formula (Ia) according to the reaction scheme

<tb><SEP> O / OR <SEP> 3 <SEP> R <SEP> OH <SEP> HN <SEP> R <SE> O <SEP> OR
<tb><SEP> R2 <SEP> II / <SEP> 1 <SEP> R <SEP> 12 <SEP> R, <SEP> y
<tb> NC <SEP> - <SEP> CH2 <SEP> - <SEP> C <SEP> - <SEP> CH <SEP> - <SEP> P <SEP> C-CH-C-CH <SEP> - P <SEP> HCl
<tb><SEP> 2 <SEP> OR <SEP> HCL <SEP> gas <SEP> R <SEP> C-CH2 <SEP> 21 <SEP> 2 <SEP> \ OR
<tb><SEP> OH <SEP> 4 <SEP> OH <SEP> 4
<tb><SEP> (11 <SEP>: <SEP> R3 <SEP> R4) <SEP> (III <SEP>: <SEP> R3 <SEP> = <SEP> R4)
<tb><SEP> hydrolysis
<tb><SEP> selective
<tb><SEP> R2 <SEP> 10 <SEP> I <SEP> n <SEP> OR
<tb><SEP> O <SEP> - <SEP> C-CH2-C-CH2 <SEP> P <SEP> OH
<tb><SEP> R <SEP> 1 <SEP> OH <SEP> 4
<Tb>
(Ia: R3 = R4)
This conversion of nitrile (II) to imidoester (III) is carried out in the presence of a large excess of a saturated solution of hydrochloric gas in alcohol R 1OH at temperatures between 0 and 50C for 5 to 18 hours. The hydrolysis of the imidoester (III) is carried out by pouring the reaction medium over ice water and leads to the esters of the invention (Ia).

The selective cleavage of the phosphonate function of the esters of formula (Ia) leads to the phosphonic acids of formula (Ib) in which R and R2 have the meanings described above, according to the reaction scheme below.

(Ib: R3 = R4 = H)
(1 9 H)
This selective hydrolysis is carried out by reaction with a trimethylsilyl halide Me 3 SiX, in which X is a halogen, in particular chlorine, bromine or iodine, in an inert, rigorously anhydrous solvent, such as dichloromethane, dimethylformamide, acetonitrile, at temperatures between 100 and 250C, for 2 to 15 hours. Hydrolysis of the intermediate silicon derivative (IV) is carried out by pouring the reaction medium over ice water and abandoning the reaction medium at room temperature for 2 to 5 hours under an inert atmosphere.

After neutralization, the saponification of the ester function of the compound (Ib) leads to the acids of the invention of formula (Ic) in which R2 has the values defined above.

<tb><SEP> O <SEP> R2 <SEP> O <SEP> O <SEP> P2 <SEP> O
<tb><SEP> It <SEP> i <SEP> It <SEP> OH <SEP> saponification <SEP> e <SEP> 12 <SEP> 8 <SEP> OH
<tb> R <SEP> 10C-CH2-C-CH2-P <SEP> X <SEP> M <SEP> OH
<tb><SEP> OH <SEP> HO-C-CH2-C1-CH2
<tb><SEP> OH <SEP> OH
<tb> (Ib: R3 = R4 = H (Ic: R1 = R3 = R4 = H)
This saponification is carried out in an H20 hydroalcoholic medium in which ROH is a lower alcohol such as ethanol, methanol or isopropanol, in the presence of three equivalents of an alkaline hydroxide such as sodium or potassium hydroxide. at room temperature (250C) under an inert atmosphere.

dans laquelle R2 a les valeurs définies ci-dessus et X est un halogène notamment le chlore, le brome ou l'iode, pour donner le phosphonate de formule (VII), selon le schéma réactionnel

The new nitriles of formula (II) are obtained by a process consisting of a) alkylating a phosphite of formula (V)
P (OR 3) 3 (v) in which R 3 represents an alkyl, aryl or aralkyl radical with an o-halooxirane of general formula (VI)

in which R2 has the values defined above and X is a halogen, in particular chlorine, bromine or iodine, to give the phosphonate of formula (VII), according to the reaction scheme

This condensation is carried out by heating the mixture of the two reagents (VI) and (V) to a temperature such that the halide R 3X (VIII) formed is removed as it is formed by distillation at ordinary pressure.

The halo-oxiranes (R 2 = H) are prepared according to a method described in the literature (Organic Synthesis, Vol.II, page 256, Ed N. RABJOHN,
John Wiley and Sons Inc. NY).

Halo-oxiranes (R + H) are prepared according to an adaptation of
2 processes described in the literature (EP ADAMS et al J. Chem., Soc., 1960, 2649, AK YAVROUIAN et al., Synthesis 1981, 791).

The phosphites P (OR 3) 3 in which R 3 may be a branched or unsubstituted, saturated or unsaturated lower alkyl group, an optionally substituted aryl or alkyl group are prepared according to the method of AH FORD-MOORE and BJ PERRY (Organic Synthesis, Vol. 4, 955, Ed N. RABJOHN, John
Wiley and Sons Inc. NY 1963).

dans laquelle R2 et R 3 ont les mêmes valeurs décrites ci-dessus.b) opening the epoxide of the compound (VII) by nucleophilic attack of the cyanide anion CN -, in the form of alkaline cyanide to give the nitrile of formula (II) according to the reaction scheme

wherein R2 and R3 have the same values as described above.

This reaction takes place in an inert atmosphere, in water in the presence of weak acid, especially acetic acid, at temperatures between 0 and 100C for 5 to 20 hours.

The nitriles of formula (II) in which R 2 represents hydrogen are prepared from the phosphonate of formula (VII) in which R 2 represents hydrogen by nucleophilic attack of the cyanide anion CNO on the epoxide, according to the process described above. Phosphonates of formula (VII) in which R 2 represents hydrogen are prepared according to a process described in the literature (C. E. GRIFFIN et al., J. Org Chem 1969, 34, 1532).

It is possible, by selective cleavage from the compounds of formula (Ia), to prepare the compounds of formula (Id) in which R3 different from R4, represents hydrogen according to the reaction scheme

This partial selective hydrolysis of the phosphonate function takes place in a hydro-organic medium, in particular the water-dioxane mixture, in the presence of an equivalent of alkaline hydroxide, in particular sodium or potassium hydroxide, in the presence of small amounts of potassium fluoride and a crown ether at temperatures between 150 and 400C for 10 to 12 hours. The saponification of the esters of formula (Id) according to the same process as that which made it possible to prepare the compound of formula (Ib) gives the acids of formula (Ie) according to the reaction scheme below.

The compounds of formula (Ic) (R 1 = R 3 = R 4 = H) are also prepared from the compounds of formula (Ie) according to the same process as the compounds of formula (Ib) or via a halide of trimethylsilyl if R 4 represents an alkyl or aralkyl radical, or by catalytic hydrogenation if R 4 represents an aryl radical.

The acids of formula (Ic) are obtained according to the reaction scheme

The following nonlimiting examples are given by way of illustration of the invention.

EXAMPLE 1 Bromo-1-epoxy-2,3-methyl-2 propane (VI: R 2 = CH 3, X = Br)
75 g (1.04 mol) of 2-methyl-2-propene-1-ol are dissolved in 200 ml of carbon disulphide, 180 g (1.132 mol) of bromine dissolved in 300 ml of bromine are added dropwise at -200c. carbon sulphide. The mixture is left at 0 ° C. for 24 hours. After evaporation of the carbon disulphide, the residue is taken up in dichloromethane. The organic phase is washed with 250 ml of a 5% aqueous solution of sodium bicarbonate, dried over dry sodium sulphate and evaporated to dryness. The oily residue obtained, consisting of 2,3-dibromethyl-2-propanol, is taken up in 200 ml of water. 85 g (1,147 moles) of calcium hydroxide are added in portions. The reaction medium is gradually heated and is distilled under reduced pressure (45 mm Hg).

The recovered distillate consists of two phases: the organic lower phase is recovered and dissolved in 500 ml of dichloromethane.

The organic phase obtained is dried over dry sodium sulphate and evaporated. A colorless oil is recovered. Yield: 76 X
1 H NMR in ppm (CDCl 3): 1.5 (s, 3H); 2.8 (s, 2H); 3.4 (s, 2H)
EXAMPLE 2 (2,3-Epoxy-2-methyl-1-propyl-1-phosphonate) (VII: R 2 = CH 3; R 3 = C 2 H 5)
A mixture of 40 g (0.264 mol) of bromo-1-epoxy-2,3-methyl-2 propane (Example 1) and 47.2 g (0.284 mol) of triethyl phosphite (V: R3 = CH) and distils as it is formed, the ethyl bromide, which is separated, at atmospheric pressure. The mixture is then refluxed for 4 hours. The reaction medium is then distilled under reduced pressure (3 mmHg). The product is recovered in the form of a colorless oil.Eb3 = 960C
Yield: 65%
IR (film): # P = O = 1250 cm-1
1 H NMR in ppm (CDCl 3): 1.35 (t, 6H); 1.45 (s, 3H); 2.0 (dd, 2H) 2.75 (q, 2H); 4.1 (m, 4H)
EXAMPLE 3 (Diethyl 2-cyano-2-hydroxy-methyl-2-propyl-1) phosphonate (II: R 2 = CH 3, R 3 = R 4 = C 2 H 5)
4 g (0.081 mol) of sodium cyanide are dissolved in 50 ml of water and 3.2 ml of glacial acetic acid are added dropwise to OOC under an inert atmosphere. To this solution is added 14 g (0.067 mol) of diethyl 2,3-epoxy-2-methylpropyl-1-phosphonate (Example 2), drop by drop.

The reaction medium is left at ambient temperature for 16 hours after the end of the addition. The reaction medium is poured into a mixture of 130 ml of 1N aqueous sodium hydroxide and 130 ml of dichloromethane. The organic phase is decanted and dried over dry sodium sulphate. Evaporation leaves an oily residue which is purified by chromatography on a silica bed (elution toluene-ethyl acetate 1/1). Colorless oil. Yield: 84%.

IR (film): # (C # N): 2250 cm -1; # (P = 0): 1225 cm -1; # (OH): 3350 cm
1 H NMR in ppm (CDCl 3): 1.35 (t, 6H); 1.55 (t, 3H); 2.2 (d, 2H) 2.75 (s, 2H); 4.15 (q, 4H); 4.75 (s, 1H)
EXAMPLE 4 (Diethyl 2-cyano-2-hydroxypropyl-1) phosphonate (II: R 2 = H; R 3 = R 4 = C 2 H 5)
Prepared according to the procedure described in Example 3 by nucleophilic addition of the cyanide anion to the diethyl (2,3-epoxypropyl-1) phosphonate (VII: R 2 = H; R 3 = C 2 H 5)
Colorless oil, Eb0.01 = 1350C, yield: 71.5%
IR (film): # (C # N): 2250 cm -1; # (P = 0): 1250 cm -1; # (OH): 3400 cm -1
1 H NMR in ppm (CDCl 3): 1.35 (t, 6H); 2.1 (dd, 2H); 2.65 (d, 2H); 4.0 (m, 1H); 4.1 (qd, 4H); 4.8 (s, 1H)
EXAMPLE 5 Diethyl 2-hydroxy-2 (methoxyiminomethyl) -3-methylpropyl-1-phosphonate (III: R = CH 3, R 2 = CH 3, R 3 = R 4 = C 2 H)
4 2 5
24 g (0.102 mol) of diethyl 2-cyano-2-hydroxy-2-methylpropyl-1-phosphonate (Example 3) are dissolved in 300 ml of dry methanol, which has been previously saturated with hydrochloric gas, at room temperature. OOC. OOC is left under an inert atmosphere, the reaction medium for 18 hours.

The solvent is evaporated without heating, and the expected imidoester hydrochloride is recovered, which is used without further purification in the next step. Yield: 90% (hydrochloride)
IR (film) (C: 1660 cm
1 H NMR in ppm (DMSO-d6): 1.25 (t, 3H); 1.35 (s, 3H); 2.15 (d, 2H) 2.60 (s, 2H); 3.5 (s, 3H); 3.95 (m, 4H)
EXAMPLE 6 Diethyl 2-hydroxy (methoxyiminomethyl) -3-propyl-9-phosphonate (III: R1 = CH3, R2 = H, R3 = R4 = C2H5)
Prepared according to the procedure described in Example 5 from diethyl (3-cyano-2-hydroxypropyl-1) phosphonate (Example 4).

Yield: 85% (hydrochloride)
IR (film): # (C = N): 1660 cm -1
1 H NMR in ppm (DMSO-d6): 1.25 (t, 3H); 2.15 (dd, 2H); 2.60 (d, 2H) 3.5 (s, 3H); 3.80 (m, 1H); 4.0 (qd, 4H)
EXAMPLE 7 Methyl 3-dietoxoxophosphorio-3-hydroxy-3-methyl butanoate (Ia: R 3 CH 3, R 2 CH 3, R = R 4 = C 2 H 5), derivative N 1
The tetrahydroxy-2-hydroxy (methoxyiminomethyl) -3-methyl-2-propyl-1-phosphonate diethyl ester (Example 5) is dissolved in 140 ml of water and left for 24 hours at room temperature. The reaction medium is extracted with dichloromethane. The organic extracts are dried over dry sodium sulphate and evaporated to dryness. An oily residue is recovered which is purified by chromatography on a silica bed (elution: ethyl acetate).
Colorless oil, yield: 90%.

IR (film): # (OH): 3400 cm -1; # (C = O): 1740 cm -1; # (P = O: 1230 cm-1
1 H NMR in ppm (CDCl 3): 1.35 (t, 6H); 1.40 (s, 3H); 2.25 (d, 2H); 2.75 (s, 2H); 3.75 (s, 3H); 4.20 (q, 4H); 4.45 (s, 1H)
EXAMPLE 8 Methyl 4-diethoxyoxophosphorio-3-hydroxybutanoate (Ia R1 = CH3: R2 = H; R3 = R4 = C2H5) N 2 derivative
Prepared according to the procedure described in Example 7 from diethyl [2-hydroxy-2-methoxyiminomethyl] propyl-1-phosphonate hydrochloride (Example 6).

Colorless oil, yield: 85%
IR (film): # (OH): 3400 cm -1; # (C = O): 1735 cm -1; # (P = O): 1225 cm-1
1 H NMR in ppm (CDCl 3): 1.35 (t, 6H); 2.15 (dd, 2H); 2.60 (d, 2H) 4.1 (m, 1H); 3.70 (s, 3H); 4,? 1 (q, 4H); 4.40 (s, 1H)
EXAMPLE 9 3-Hydroxy-3-dihydroxyoxophosphorio-4-methyl-3-butanoate (R 1 = CH 3, R 2 = CH 3, R 3 = R 4 = H) N 3
10.1 ml (0.0764 mol) of trimethylsilyl bromide are added under an inert atmosphere, keeping the temperature between 0 and 50C, to a solution of 5 g (0.0186 mol) of 4-diethoxyoxophosphorio-3-hydroxy-methyl 3 methyl butanoate (Example 7) dissolved in 100 ml of dry dichloromethane. The reaction medium is allowed to return to ambient temperature and the reaction medium is maintained at this temperature for 2 hours. The solvent is evaporated to dryness and the residue is taken up in 120 ml of water. The resulting aqueous solution is kept at room temperature for 30 minutes. This aqueous solution is washed with dichloromethane and then with ethyl ether. The aqueous phase is then lyophilized, a colorless oily compound is recovered. Yield: 97%
IR (film): # (C = O): 1715 cm -1; # (OH): 3400 cm -1
1 H NMR in ppm (D 2 O): 1.5 (s, 3H); 2.3 (d, 2H); 2.8 (s, 2H); 3.7 (s, 3H)
EXAMPLE 10 Methyl 3-hydroxy-4-dihydroxyoxophosphorio-4-butanoate (R 1 R 1 = CH 3, R 2 = H, R 3 = R 4 = H) N 4 derivative
Prepared according to the procedure described in Example 9 starting from diethoxyoxophosphorio-4-hydroxy-3-butanoate methyl (Example 8).

Colorless oil, yield: 96%
IR (film): # (C = O): 1740 cm -1; # (P = O): 1225 cm-1
in ppm (D 2 O): 2.25 (dd, 2H); 2.75 (d, 2H); 4.0 (m, 1H) 3.70 (s, 3H)
EXAMPLE 11 3-hydroxy-4-dihydroxyoxophosphorio-3-methyl-butanoic acid (Ic R1 = H, R2 = CH3, R3 = R4 = H) N 5 derivative
3.83 g (0.018 mol) of 3-dihydroxyoxophosphorio-3-hydroxy-3-methyl-3-butanoic acid methyl ester (Example 9) are dissolved in 55 ml (0.055 mol) of aqueous 1N sodium hydroxide solution, under an inert atmosphere, at room temperature. room temperature The reaction medium is maintained at room temperature overnight, the methanol is evaporated and the aqueous phase is freeze-dried The white crystals obtained are crystallized with isopropanol.

Trisodium salt, white crystals, F = 1030C (deliquescent), yield: 85%
IR (KBr): # (C = O): 1580 cm
1 H NMR in ppm (D 2 O): 1.4 (s, 3H); 1.8 (d, 2H); 2.45 (s, - 2H)
13 C NMR (ppm): 24.73 and 24.97; 35.23 and 41.36; 48.22 and 48.64 68.00; 178.21
Calcium salt formation
3.6 g of trisodium salt are dissolved in 5.75 ml of water and a solution of 4.7 g of calcium chloride in 7.2 ml of water is added.

The crystals which precipitate are filtered and dried in an oven.

Calcium salt, white crystals, F> 26O0C.

EXAMPLE 12 3-Hydroxydihydroxyoxophosphorio-4-butanoic acid (Ic R1 R1 = R2 = R3 = R4 = H) Derivative N 6
Prepared according to the procedure described in Example 11 from methyl 3-hydroxy-dihydroxyoxophosphorio-4-butanoate (Example 10).

Trisodium salt, white crystals, F (very hygroscopic), yield: 80% IR (KBr): # (C = O): 1580 cm-1
1 H NMR in ppm (D 2 O): 1.8 (d, 2H); 2.40 (s, 2H)
The results of pharmacological and toxicological studies reported below have demonstrated the interesting properties of the derivatives of the invention, both in terms of toxicity and tolerance as in terms of their lipid-lowering activity.

The invention therefore also relates to a medicament having, in particular, a lipid-lowering activity, characterized in that it contains, as active ingredient, a derivative of the formula (I) or one of its forms stereoisomers where they exist, as well as one of its addition salts of compounds Ib, Ic, Id and Ic, with pharmaceutically acceptable inorganic or organic bases.

TOXICOLOGICAL STUDY
The compounds of the invention benefit from good tolerance and low toxicity.

Trials conducted on different animal species on acute, subchronic and chronic toxicities did not reveal any local or general reaction, disturbance or abnormality in the biochemical, macroscopic and microscopic examinations carried out throughout the tests.

PHARMACOLOGICAL STUDY
The action of the compounds of the invention was studied on experimental dyslipo proteinasein in rats compared to meglutol.

1 - Material and methods
The animals are male rats weighing between 150 and 200 g divided into different lots (18 lots of 5 rats each).

The atherogenic diet is that described by NATH
hydrogenated coconut oil 24p100
cholesterol lplOO
cholic acid lplOO
casein 20plOO
4p100 mineral salts
corn oil ....................... 1p100
sucrose ............................. 48p100
vitamins lplOO
Dyslipemia was achieved by administration of the atherogenic diet for a period of 7 days (lots N07 to 18); control groups received a normal non-atherogenic diet (lots N 1 to 6).

The animals were then treated by gastric tubing. They received
50 mg meglutol / kg / day (lots N03, 4, 9, 10, 15 and 16)
50 mg of the calcium salt of the derivative N 5 / Kg / day (lots N05,
6, 11, 12, 17 and 18).

either distilled water (lots N 1, 2, 7, 8, 13 and 14)
This treatment was carried out for a period of 2 days (lots Nos. 1, 3, 5, 7, 9, 11, 13, 15 and 17) under a normal diet (lots N 1 to 12) or under an atherogenic diet (lots N 13 to 18).

2 - Pharmacological parameters
The animals were sacrificed 2 hours after the last administration of each product and the analyzes performed were as follows
. total, free, esterified cholesterol
. HDL cholesterol triglycerides
Phospholics 3 - Results
The results are shown in the following table

<tb><SEP> REGIME <SEP> ATHEROGENE <SEP> J1 <SEP> to <SEP> J9
<tb><SEP> TESTS <SEP> MEGLUTOL <SEP> Derived <SEP> N <SEP> 5
<tb><SEP> (batch <SEP> 13) <SEP> (batch <SEP> 15) <SEP> (batch <SEP> 17)
<tb> Cholesterol <SEP> total <SEP> 1.85 <SEP>#<SEP> 0.11 <SEP> 1.65 <SEP>#<SEP><SEP> 0.12 <SEP> 1.31 <SEP>#<SEP><SEP> 0.09
<tb> g / 1
<tb> Cholesterol <SEP> free <SEP> 0.60 <SEP>#<SEP><SEP> 0.07 <SEP> 0.62 <SEP>#<SEP><SEP> 0.12 <SEP> 0 , 39 <SEP>#<SEP><SEP> 0.04
<tb> g / 1
<tb> Cholesterol <SEP> HDL <SEP> 0.10 <SEP>#<SEP><SEP> 0.01 <SEP> 0.14 <SEP>#<SEP><SEP> 0.03 <SEP> 0 , 12 <SEP>#<SEP><SEP> 0.02
<tb> g / l
<tb> triglycerides <SEP> 0.46 <SEP>#<SEP><SEP> 0.10 <SEP> 0.49 <SEP>#<SEP><SEP> 0.06 <SEP> 0.40 <SEP >#<SEP> 0.05
<tb> g / l
<tb> phospholipids <SEP> 1.17 <SEP>#<SEP><SEP> 0.07 <SEP> 1.26 <SEP>#<SEP><SEP> 0.07 <SEP> 0.98 <SEP >#<SEP><SEP> 0.03
<tb> g / l
<Tb>
Examination of the results obtained shows that meglutol, after 2 days of treatment, does not modify any parameter significantly.

On the other hand, the NO 5 derivative causes, under the same conditions, a significant decrease in total cholesterol (-29 X) and phospholipids (-16%) in the animals subjected to the atherogenic diet.

The results of the toxicological and pharmacological tests that come
to be reported, have highlighted the good tolerance and interest
hypolipidemic properties of the compounds of the invention.

The medicament of the invention may be presented for oral administration in the form of tablets, coated tablets, capsules, drops, syrup or granules.

 It may also be presented for rectal administration in the form of suppositories and for parenteral administration as an injectable solution.

Each unit dose advantageously contains from 0.010 g to 0.500 g of active ingredient according to the patient's sage and the severity of the disease.
the treated condition.

Some examples will be given below as non-limiting examples
pharmaceutical compositions of the medicament of the invention.

1) tablets
derivative NO 4 0.250 g
excipient sucrose, polyvinylpyrrolidone,
magnesium stearate.

2) sugar-coated tablets
derivative NO 6 0.100 g
excipient sucrose, gum arabic, talc,
colloidal silica, polyvinylpyrro
lidone, new coccine.

3) capsules
derivative NO 3 0.125 g
lactose excipient, wheat starch, stearate
magnesium.

4) suppositories
derivative NO 5 0, 100 g
excipient semi-synthetic glycerides.

5) injectable solution
derivative N 6 0.050 g
isotonic solvent excipient qs 3 ml
For its interesting lipid-lowering properties, the drug of the invention is usefully administered both in adults and children in the treatment of isolated or associated endogenous hypercholesterolemia and hypertriglyceridemia.

Claims (8)

1- Compounds of formula

 in which - R1 may be hydrogen, a linear or branched lower alkyl group, an optionally substituted aralkyl group. R2 may be hydrogen, a linear or branched lower alkyl group, an optionally substituted aralkyl group, - R3 and R4 may be together or independently of each other hydrogen or a linear or branched lower alkyl group, an optionally substituted aryl or aralkyl group, as well as addition salts with pharmaceutically acceptable inorganic or organic bases. 2-hydroxy-3-hydroxy-4-dihydroxyoxophosphorio-3-butanoic acid.  Process for the preparation of the compounds of formula (I) according to Claims 1 and 2, characterized in that a) a phosphite of formula P (OR 3) 3 (V) in which R 3 represents an alkyl, aryl or aralkyl radical is alkylated by a G-halogeno-oxirane of formula (VI)

 wherein R2 has the defined values for formula (I) to form the phosphonate of formula (VII)

  b) The compound of formula (VII) is treated by nucleophilic attack of the cyanide anion CN - to form the nitrile of formula (II)

 in which R2 and R3 have the values described above. c) Under the action of the alcohol of formula R 1 OH wherein R 1 represents an alkyl radical, the nitrile of formula (II) is converted into imidoester of formula (III)

 d) By selective hydrolysis, the compounds of formula Ia in which R 1 represents an alkyl radical, R 2 represents hydrogen, an alkyl or aralkyl radical, the two identical R 3 radicals represent an alkyl, aryl or alkyl group;

 4-Process according to Claim 3, characterized in that, by selective cleavage of the phosphonate function of the esters of formula (Ia), the phosphonic acids of formula (Ib) in which R1 and R2 have the same values as in the formula ( Ia)

  5-Process according to Claim 3, characterized in that, by saponification of the ester function of the compound of formula (Ib), the acids of formula (Ic) in which R2 has the same values as in formula (Ib) are obtained

 6-Process according to claim 3 characterized in that by partial selective hydrolysis of the phosphonate function of the compounds (Ia) are obtained the compounds of formula (Id)

 wherein R1, R2 and R4 have the same values as in formula (Ia). 7-Process according to Claim 3, characterized in that, by saponification of the esters of formula (Id), the acids of formula (Ie) are obtained

 wherein R2 and R4 have the same meanings as in formula (Ia). 8A medicament characterized in that it contains as active ingredient a derivative of formula (I) according to claim 1 or 2. 9-Drug according to claim 8 characterized in that it contains as active ingredient 3-hydroxy-dihydroxyoxophosphorio-4-methyl-3-butanoic acid. 10-drug according to claims 8 or 9 characterized in that each unit dose contains from 0.010 g to 0.500 g of active ingredient.