MXPA98000189A - Compounds and pharmaceutical compositions that contains them - Google Patents

Abstract

Alpha aminophosphonates substituted by phenosyl groups of the formula (I) :( See Formula) have lipoprotein lowering activity (

Description

COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM FIELD OF THE INVENTION This invention relates to a new therapeutic use of aminophosphonate compounds to reduce the levels of lipoprotein (a) in plasma and tissue. In particular, this invention provides a novel use of aminophosphonate derivatives, for the preparation of pharmaceutical compositions useful in the treatment of diseases or disorders associated with high concentrations of lipoprotein (a) in plasma and tissue, such as, for example, atherosclerosis, thrombosis , restenosis after angioplasty and fulminating attack. This invention also provides a method for increasing troblisis and preventing thrombosis, and a method of treating restenosis after angioplasty, by administering to a patient in need thereof, an aminophosphonate compound at an effective dose to reduce lipoprotein levels. (a) in plasma and tissue. In addition, this i-pvention also provides a group of novel aminophosphonate compounds for use in the aforementioned applications and compositions.

BACKGROUND OF THE INVENTION Recent epidemiological studies have shown a strong association between elevated lipoprotein levels (a) CLp (a)] in plasma and the occurrence of coronary heart disease, fulminant attack and peripheral arterial disease. Lp (a) is now recognized as an independent risk factor for cardiovascular diseases; moreover, its role in the promotion of thrombosis is being increasingly recognized, reducing thrombolysis; see, for example: "Lipoprotein (a) as A Risk Factor for preclinical Atheroselosis", P. J. Schreiner. J.D. Morrisett, A.R. Sharrett, W. patsch, H.A. Tyroler K.Wu and G. Heiss; Arteriosclerosis and Thrombosis 13, p. 826-833 (1993); "Detection and Quantification of Lipoprotein (a) in the Arterial Wall of 107 Coronary Bypass Patients" M. Rath, A. Niendorf, T. Reblin, M. Dietel, H.J. Krebber and U. Beisiegel; Arteriosclerosis 9, p. 579-592 (1989); and "Lipoprotein (a): Structure, properties and possible lnvolvement in Thrombogenesis and Atherogenesis" A.D. MBewu and P.N. Durrington; Athe sprinkle rosis 85, p. 1-14 (1990). The potential for involvement of thrombosis in vessel occlusion and acute cardiovascular syndrome is becoming increasingly recognized. One of the mechanisms that mediate thrombosis associated with rupture of atheromatous plaque involves elevated lipoprotein (a) levels. The. structure of Lp (a) consists of a particle similar to a low density lipoprotein (LDB) with a glycoprotein, the apolipoprotein (a) Capo (a)] that is linked by a disulfide bridge to the entity apo B-100 of the LDB. Structurally there is a striking analogy between apo (a) and plasminogen, the plasmin precursor that breaks the fibrin to dissolve blood clots. However, unlike plasminogen, apo (a) is not a substrate for plasminogen activators. This structural similarity has led researchers to postulate and then demonstrate that apo (a) interferes with the normal physiological function of plasminogen, leading to a potential thrombogenic activity of Lp (a); see, for example: "Activation of Transforming Growth Factor-B is lnversely Correlated with Three Major Risk Factors for Coronary Artery Dissect: Lipoprotein (a), LDL-Cholesterol and plasminogen Activator lnhibitor-1", A. Chauhan, N.R. Williams, J.C. Metcalfe, A. Grace, A.C. Liu, R.M. Lawn, P.R. Kemp, P.M. Schofield and D.J. Grainger, Circulation, Vol 90, No, 4, part 2, p. 1-623 (1994): and "Influence of Human Apo (a) Expression on Fibrinolysis in vivo in Trangenic Mice" T.M. palabrica, A.C. Liu, M.J. Aronovitz, B. Furie, B.C. Furie and R. Lawn; Circulation, Vol 90, No. 4, part 2, p. 1-623 (1994). Based on its suspected thrombogenic activity, Lp (a) has also been implicated in peripheral arterial disease, in particular, fulminant attack. Recently, clinicians have shown that serum levels of Lp (a) were significantly higher in patients with fulminant attack than in a normal reference population. "Lp (a) Lipoprotein in patients with Acute Stroke" K.

Asplund, T. Olsson, M. Viitanen and G. Dahlen; Cerebrovasc. 1 p. 90-96 (1991). Restenosis after percutaneous transluminal angioplasty is a common complication that occurs in up to 40% of cases within 3 to 6 months of the intervention. It is believed that the main cause for restenosis is the abnormal activation and proliferation of vascular smooth muscle cells. The evidence that high levels of Lp (a) in plasma are associated with proliferation and activation of smooth muscle cells was established in vitro and in vivo by the following two studies: "Proliferation of Human Smooth Muscle Cells promoted by Lipoprotein (a ) "DJ Grainger, H. L. Kirschenlohr, J.C. Metcalfe, P.L. Weissberg, D.P. Wade and R.M. Lawn; Science, Vol 260, p.1655-1658 (1993); and "Activation of Transforming Growth Factor-B is Inhibited by Apolipoprotein (a) in vivo", D.J. Grainger, P.R. Kemp, A.C. Liu, R.M. Lawn and J.C. Metcalfe; Circulation, Vol 90, No. 4, part 2, p. 1-623 (1994). This observation has led to the hypothesis that high levels of plasma Lp (a) are associated with an increased incidence of restenosis. The hypothesis was confirmed by the results of a recent clinical study showing that, in patients with high levels of Lp (a) in plasma, a reduction in Lp (a) levels by more than 50% by LDH apheresis significantly reduced the proportion of restenosis; see, for example: "Effectiveness of LDL-Apheresis in preventing Restenosis After percutaneous Transluminal Coronary Angioplasty (PTCA): LDL-Apheresis Angioplasty Restenosis Trial (L-ART) "HYJ Lee, H. Daida, H. Yokoi, H. Miyano, T. Kanoh, S. lshiwata, K. Kato, H Nishikawa, F. Takatsu, Y. Kutsumi, H. Mokuno, N. Yamada and A. Noma, Chemistry and Physics of Lipids, Vol 67/68, pp. 399-403 (1994). reasoned for the reduction of Lp (a) in the plasma of patients at risk with high levels (> 20-30 mg / dL) .The concentration of Lp (a) in individuals seems to be highly determined by inheritance and is influenced Strongly by dietary regimes, various hormones (ie, steroid hormones, growth hormones, thyroid hormones) have been shown to regulate plasma levels of Lp (a) in man, of particular interest, drugs that effectively reduce LDB such as the bile acid sequestrant, cholestyramine or the inhibitors of HMGCoA reductase, lovastatin or provastatin, do not affect the levels of Lp (a). The drugs of the fibrate family: clofibrate or bezafibrate and the antioxidant drug probucol are equally ineffective. The only drug that has been reported to reduce Lp (a) is nicotinic acid. However, at the high doses necessary for its efficacy (4g / day), nicotinic acid has several serious side effects that prevent its wide use: embarrassment, vasodilation and hepatotoxicity. Therefore, the medical need to reduce elevated levels is still not met of Lp (a) in plasma, an independent risk factor for cardiovascular disease. In contrast to LDBs, Lp (a) exists only in higher mammals on the evolutionary scale (human and non-human primates) and is synthesized exclusively by liver cells. Cynomolgus monkeys possess a Lp (a) that is similar to human Lp (a), including possession of the unique apo (a) apolipoprotein. This primate offers an experimental opportunity to study the synthesis of Lp (a) and the role of Lp (a) in atherosclerosis and thrombosis. The primary cultures of cynomolgus monkey hepatocytes have been selected as the in vitro test to select aminophosphonate derivatives of formula (I) for their ability to modulate Lp (a) levels. Prior to selection, this test system has been validated by testing as reference products, nicotinic acid and steroid hormones, which are known to reduce Lp (a) in man. The present invention relates to the unexpected discovery that the aminophosphonate derivatives are effective in reducing lipoprotein (a) in plasma and tissue. Therefore, in a first aspect, the present invention provides the use of a compound of formula (I): in which: ?? and X2, which may be identical or different, are H, an alkyl or straight or branched alkoxy group having 1 to 8 carbon atoms, a hydroxyl group, or a nitro group, X3 is H, an alkyl group of 1 to 4 carbon atoms; X 0 and one of the other two substituents X 1 or X 2, can form a dioxyalkylidene ring having from 1 to 4 carbon atoms, R 1, R 2, identical or different are H, a straight or branched alkyl group having from 1 to 6 carbon atoms, B is CH2, CH2-CH2, or CH = CH, n is zero or 1 Z is H, a straight or branched alkyl group having from 1 to 8 carbon atoms, an acyl group R3-C0, wherein R3 is an alkyl group of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbon atoms, A is H, CH2-CH = CH2, a straight, branched or cyclic alkyl group having from 1 to 8 carbon atoms, or is selected from the following groups: -COO-R wherein k is an integer from 2 to 4, m is 0 or an integer from 1 to 5, X *, X5, X6, identical or different, are H, an alkyl or straight or branched alkoxy group of 1 to 8 carbon atoms; carbon, a hydroxyl group, trifluoromethyl, nitro, amino, dimethylamino, diethylamino, a halogen atom (F, Cl, Br, I), X * and X5 can form an alkylidenedioxy ring having the 4 carbon atoms, X7 is H or CH 3, R is a straight or branched alkyl group having from 1 to 6 carbon atoms, an aryl or arylalkyl group of 6 to 9 carbon atoms; or a pharmaceutically acceptable salt thereof; in the manufacture of a drug to reduce lipoprotein (a) in plasma and tissue. European Patent Application EP 0'559'079A (1993) [corresponding to the patent of E.U.A. 5 424 303], describes compounds of formula (I), as well as their use in the reduction of plasma cholesterol and peroxides in blood. Preferred compounds of formula (I) for use in the manufacture of a medicament for reduction of lipoprotein (a) in plasma and tissue are those of formula (la): in which B, Rl, R2, X *, X2, X3, X *, Z, n and m, they are as defined above; or a pharmaceutically acceptable salt thereof. Certain compounds within the scope of formula (la) are novel and are particularly useful in the reduction of lipoprotein (a) in plasma and tissue. Therefore, in a further aspect, this invention provides aminophosphonate derivatives of formula (la) in which: X 1 is H, Ci-β alkyl, or Ci-s alkoxy; X2 is Ci-β alkyl or Ci-β alkoxy; X3 is H, C1-4 alkyl, or X30 and one of the other two substituents X1 or X2 can form a dioxyalkylidene ring having from 1 to 4 carbon atoms; R1, R2, which may be identical or different, are H or C1-6 alkyl; B is CH2-CH2, or CH = CH, or CH2, n is zero or 1 Z is H or Ci-β alkyl; m is an integer from 0 to 5; X * is H, C1-8 alkyl, C1-8 alkoxy, or halogen; and the pyridyl ring is attached via the α- or β-carbon of the ring to the nitrogen (2-, or 3-pyridyl); or a salt, preferably, a pharmaceutically acceptable salt thereof; and excluding: diethyl a- (3,5-di-tert-Butyl-4-hydroxyphenyl) -N- (3-piperidyl) -aminomethylphosphonate; a- (3,5-di-tert-Butyl-4-hydroxyphenyl) -N- (2-picolyl) - diethyl aminomethylphosphonate; (3, 5-di-e-butyl-4-hydroxy-enyl) -N- (3-picolyl) -aminomethylphosphonate diethyl ester; a- (3, 5-di-e-butyl-4-hydroxy-phenyl) -N-methyl-N- (3-picolyl) aminomethylphosphonate diethyl ester; a- (3, 5-di-te-butyl-4-hydroxy-phenyl) -N- (2-pyridylethyl) -aminomethylphosphonate diethyl ester, and a- (3,5-di-te-butyl-4-) diethyl hydroxy phenyl) -N- (4-picolyl) -aminomethylphosphonate. Suitably, X 1 is H, C 1-4 alkyl or C 1- alkoxy, preferably C 1-3 alkyl or C 1-3 alkoxy, preferably hydrogen, methyl or methoxy. Suitably, X 2 is C 1-4 alkyl or C 1-4 alkoxy, preferably C 1-3 alkyl or C 1-3 alkoxy, preferably methyl or methoxy. Conveniently, X1 and X2 are both alkoxy or one of X1 and X2 is alkyl and the other is alkoxy, or one of X 1 and X 2 is C 1 - alkyl, and the other of X 1 and X 2 is C 1-3 alkyl. Suitable combinations of X1 and X2 include methoxy and methoxy, methoxy and methyl, n-propyl or iso-butyl, methyl and methyl or t-butyl, respectively. Preferably, X3 is hydrogen. Preferably, (B) n is a direct link. Preferably, R1 and R2 is each a C1-3 alkyl group, preferably an alkyl group of C2 or C3, in particular, R1 and R2 are ethyl or isopropyl.

Preferably, 1 is hydrogen. Preferably, X * is hydrogen or methyl which is preferably on the carbon of the ring adjacent to N. Preferably, the pyridyl ring is attached via the & -carbon to the nitrogen (3-pi-ridyl). When used herein the terms "alkyl" and "alkoxy" include both straight and branched groups, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, s-butyl, t-butyl , etc. Preferred compounds of formula (la) include: diisopropyl a- (4-hydroxy-3-methoxy-5-methylphenyl) -N- (3-piperidyl) -aminomethylphosphonate; a- (3, 5-dimethoxy-4-hydroxy-enyl) -N- (3-piyryl) -aminomethylphosphonate diisopropyl; a- (3-methyl-4-hydroxy-5-t-butylfyl) -N- (3-piyryl) -aminomethylphosphonate diethyl ester; a- (3, 5-dimethoxy-4-hydroxyl enyl-N- (3-pyridyl) -aminomethylphosphonate diethyl ester, and a- (3, 5-dimet i 1-4-hyd roxy phenyl) -N- ( Diethyl 3-pyridyl) -aminomethylphosphonate Regardless of the activity published above, the present invention relates to the unexpected discovery that the aminophosphonate derivatives of formula (I) are effective in reducing the production of Lp (a) from primary cultures. of monkey hepatocytes Cynomolgus. The Lp (a) of these primates is similar in immunological properties to human Lp (a) and occurs in an almost identical frequency distribution of plasma concentrations, see for example: "Plasma Lipoprotein (a) Concentration in Controlled by Apolipoprotein (a) protein Size and the Abundance of Hepatic Apo (a) mRNA in a Cynomolgus Monkey Model ", N. Azrolan, D.

Gavish and J. Breslow; J. Biol. Chem., Vol 266, p.13866-13872 (1991). Therefore, the compounds of this invention are potentially useful for reducing Lp (a) in man and thus provide a therapeutic benefit. In particular, this invention provides a new therapeutic use for aminophosphonate compounds of formula (I) as Lp (a) reducing agents. Diseases associated with elevated levels of lipoprotein (a) in plasma and tissue include, for example, coronary heart disease, peripheral arterial disease, intermittent claudication, thrombosis, restenosis after angioplasty, atherosclerosis of the extracranial carotid, fulminating attack and atherosclerosis that occurs after heart transplant. The newly discovered activity of reducing Lp (a) of the aminophosphonates of formula (I) is independent of its previously reported pharmacological properties of reducing plasma cholesterol and blood peroxides. Recent clinical studies have shown that neither the hypocholesterolemic drug provastatin nor the antioxidant drug probucol can reduce Lp (a) levels in man. See for example: "Serum Lp (a) Concentrations are Unaffected by Treatment with the HMG-CoA Reductase Inhibitor Pravastatin: Results of a 2-Year lnvestigation" H.G. Fieseler, V.W. Armstrong, E. Wieland, J. Thiery, E. Schutz, A.K. Walli and D. Seidel; Clinic Chimica Acta, Vol 204, p. 291-300 (1991) and "Lack of Effect of Probucol on Serum Lipoprotein (a) Levéis", A. Noma; Atherosclerosis 79, p. 267-269 (1989). For therapeutic use of the compounds of the present invention, they will generally be administered in a standard pharmaceutical composition obtained by mixing with a selected pharmaceutical carrier considering the intended route of administration and standard pharmaceutical practice. For example, they can be administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules, ovules or pellets, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring agents. or dyes. They can be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, salts or glucose in sufficient quantities to make the solution isotonic with the blood. The choice of administration form, as well as the effective dosages may vary depending, among other things, on the condition to be treated. The choice of mode of administration and dosage are within the abilities of the expert in the field. The compounds of structure (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example, syrups, suspensions or emulsions, or as solids, for example, tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier (s), for example, ethanol, glycerin, a non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative and flavored or coloring agents. A composition in tablet form can be prepared using any pharmaceutically acceptable carrier (s) customarily used to prepare solid formulations. Examples of such vehicles include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the capsule form can be prepared using the usual encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled with hard gelatin capsules; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier (s), for example, aqueous gums, celluloses, silicates or oils and then fill with the dispersion or suspension soft gelatin capsules. Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example, polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just prior to administration. A typical suppository formulation comprises a compound of structure (I) or a pharmaceutically acceptable salt thereof which is active when administered in this form, with a binder and / or lubricant such as polymeric glycols, gelatins or cocoa butter. other waxes or vegetable or synthetic fats of low melting point. Preferably, the composition is in a dosage form such as a tablet or capsule. Each unit dosed for oral administration preferably contains from 1 to 250 mg (and for parenteral administration it preferably contains 0.1 s 25 mg) of a compound of structure (I) or a pharmaceutically acceptable salt thereof, calculated as the base free. The pharmaceutically acceptable compounds of the invention will normally be administered to a subject in a daily dosage regimen. For an adult patient this it can be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 and 25 mg. mg, of the compound of structure (I) or a pharmaceutically acceptable salt thereof calculated as the free base, administering the compound 1 to 4 times a day. The compounds of formula (I) can be prepared in accordance with the process described in European Patent Application EP 0 559 079-A, 1993 [corresponding to the US Patent 424 303]. This procedure, which has two variants, is shown in the following general scheme: GENERAL SCHEME OF THE SYNTHESIS Variant 1 , 0R, 0R \ Na 'P ^ OR P-OR' Z is H Variant H Variant 1 is used when Z is H, that is, when the starting compound is a primary amine. Briefly, the aminophosphonates of formula (I) are prepared by means of nucleophilic addition of a dialkylphosphite, or its sodium salt obtained in situ by the reaction of dialkylphosphite and sodium hydride, on the imine obtained by condensation of the appropriate aldehyde and an amine primary. Variant 2 of use when Z is not H, that is, when the starting compound is a secondary amine. In this case, the aminophosphonates of formula (I) are prepared by reacting equimolar amounts of the appropriate aldehyde and the secondary amine and a dialkyl phosphite. The reaction is conveniently carried out in the presence of p-toluenesulfonic acid as a catalyst in a hydrocarbon solvent such as benzene or toluene with concomitant removal of water, for example, using a Dean-Stark apparatus. The novel compounds of formula (la) in which Z is hydrogen can be prepared by means of a process comprising treating an imine of formula (II): (p) in which B, X *, X2, X3, X *, m and n are as defined above; with a phosphite compound of formula (III): HP0 (0Ri) (0R2) (III) in which R1 and R2 are as defined above; or with a trialkylsilyl derivative thereof, preferably the trimethylsilyl phosphite, or a metal salt thereof, for example, the sodium salt formed in situ by treatment of the compound of formula (III) with a suitable base, for example , hydride, ethoxide or sodium methoxide. The reaction can be carried out in the presence or absence of a catalyst. Suitable catalysts include amines such as diethylamine or triethylamine. The reaction can be carried out in the absence or presence of a solvent. Suitable solvents include petroleum ether, benzene, toluene, diethyl ether, te rahydrofuran, 1,2-dimethoxy-ethane. Suitable reaction temperatures are in the range of 30 to 140"C. The imine compound of formula (II) can be obtained by condensing an aldehyde compound of formula (V): wherein B, X, X2, X3, and n are as defined above; with a primary amine of formula (VI): H2NA in which A is as defined above; under conditions of imine formation. Conveniently, the condensation can be carried out with or without a catalyst in a solvent such as ether, tetrahydrofuran, benzene, toluene or ethanol. Suitable catalysts include molecular sieve, an acid such as glacial acetic acid, p-toluenesulfonic acid, thionyl chloride, titanium tetrachloride, boron trifluoride etherate, or a base such as potassium carbonate. The reaction is conveniently carried out at a temperature on the 0 ° C scale up to the boiling point of the solvent used. For less reactive amines / aldehydes, the reaction can be advantageously carried out in a Dean-Stark apparatus. The novel compounds of formula can be prepared (la) in which Z is not hydrogen, by means of a process comprising treating equimolar amounts of an aldehyde of formula (V), a secondary amine of formula (VII): HNZA (VII) in which Z is a group C 1-8 alkyl and A is as defined above; and a phosphite of formula (III), conveniently in the presence of p-toluenesulfonic acid as catalyst, in a hydrocarbon solvent such as petroleum ether, benzene, toluene or xylene, at a temperature between room temperature and the boiling point of the solvent used, and with concomitant removal of water, for example, using a Dean-Stark device. Compounds of formula (la) in which m is non-zero can be prepared, by means of a process comprising treating a compound of formula (VIII): (V? D in which B, R1, R2, X1, X, X3 and n are as defined above, an aldehyde of formula (IX): (IX) wherein m is an integer from 1 to 5 and X * is as defined above; under conditions of reductive amination. These suitable conditions include carrying out the reaction in the presence of sodium cyanoborohydride in an alcohol solvent, preferably methanol, at a pH between 3 and 6 and at a temperature between 0 ° C and 25 ° C.

A compound of formula (VIII) can be obtained according to the process described above for a compound of formula (la), from an aldehyde of formula (V), a secondary amine of formula (VII) in which Z is a a protecting group which can be removed by hydrogenolysis, for example an a-substituted benzyl or benzyloxycarbonyl, and a phosphite of formula (III). This forms an intermediate that is then subjected to hydrogenolysis according to standard conditions, to give a compound of formula (VIII). Through its amino function, the aminophosphonate ester (I) can form salts of inorganic acids such as HCl, H2SO4 or with organic acids such as oxalic acid, maleic acid, sulfonic acids, etc. An example of aminophosphonate hydrochloride salt (I) is provided (example 5). All these salts are an integral part of this invention. The compounds of structure (I) are racemates, since they have at least one qui ral center which is the carbon atom in alpha position with respect to the phosphonate group. Therefore, the compounds (I) exist in the two enantiomeric forms. Racemic mixtures (50% of each enantiomer) and pure enantiomers are within the scope of this application. In certain cases, it may be convenient to separate the enantiomers. In a further aspect, the present invention provides a method for the enantiomeric synthesis of a derivative of formula (I); the procedure involves treating either the enantiome ro (+) or (-) of the aminometi l phosphonate oc-substi tuido of formula (X): (X) wherein B, R1, R2, X1, X2, X3, and n are as defined above; with an aldehyde of formula (XI): R3-CH0 (XI) in which R3 is as defined above; under conditions of reductive amination. These suitable conditions include carrying out the reaction in the presence of sodium cyanoborohydride in an alcohol solvent, preferably methanol, at a pH between 3 and 6, and at a temperature between 0 βC and 25 ° C. The primary ot-substituted primary aminomethylphosphonate (X) is obtained by treating an aldehyde of formula (V), as defined above, with (+) or (-) a-methylbenzylamine to form an intermediate imine which is then reacted with an ester of phosphite HPOÍOR1) (0R2) to give a mixture of diastereomers which can be resolved by conventional techniques, for example, fractional crystallization or chromatography. Then, hydrogenolysis can be used to remove the benzyl group from the nitrogen, to give the primary a-substituted aminomethylphosphonate (X). This aspect is illustrated by the preparation of the enantiomers of Compounds No. 7 and 15 of Table 1. Alternatively, the resolution of the aminophosphonate racemates can be effected by preparative, preparative chromatography, in particular, by quiral HPLC. The experimental conditions for the chromatographic separation of the enantiomers of compound No. 20 are provided. With any separation method, the final enantiomeric purity can be determined by measuring the specific rotations of the separated isomers. The structure of the compounds of formula was established by their elemental analysis and their IR (IR), mass (EM) and nuclear magnetic resonance (NMR) spectra. The purity of the compounds was analyzed by thin layer chromatography and gas-liquid and high-resolution liquid chromatographies. The invention is further described in the following examples which are intended to illustrate the invention, without limiting its scope. In the tables, n is normal, i is iso, s is secondary and t is tertiary. In the description of the NMR spectrum, respectively, s is singlet, d is doublet, t is triplet and m is multiplet. TsOH is p-toluenesulfonic acid monohydrate. The temperatures were recorded in degrees Celsius and the melting points are not corrected. In the measurement of optical activity, an enantiomer that rotates the plane of polarized light to the right is called dextrorotatory and is designated (+) or (D). Conversely, levorotatory defines an enantiomer that rotates the plane of polarized light to the left, designated (-) or (L). Unless indicated otherwise, the physical constants and biological data given for the aminophosphonates of formula (I) refer to the racemates.

EXAMPLE 1 a- (3,5-di-te-butyl-4-hydroxy-enyl) -N-Q-pi-ridyl) -dimethyl aminomethylphosphonate A mixture of 50 g (0.206 mole) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 20.3 g (2.16 mole) of 3-aminopyridine dissolved in 300 ml of toluene and a certain amount were refluxed for 17 hours. catalyst of p-toluenesulfonic acid (ca. 50 mg), contained in a flask connected to a Dean Stark apparatus. The solution was evaporated to dryness to give a solid which was purified by recrystallization of ligroin: m.p. = 125-130 °, IR (KBr): 1590 air *: CH = N. Dimethyl phosphite (63.8 g, 0.58 moles) was added to 60 g (0.19 moles) of the above-described imine dissolved in 230 ml of THF, and the mixture was refluxed for 6 hours. The solvent was evaporated and the residue was purified by column chromatography (SÍO2, 9/1 CHCl3 / Me0H). Recrystallization from a mixture of ethyl tert-butyl ether / petroleum ether gave a white solid, m.p. 168-170 ° C. IR (KBr) = 3300 cm-i; NH, 1240: P = 0, 1030: P-0-C NMR (CDCl 3): d = 8.06, 7.4 and 6.9 (4m, 1H each): aromatic H, 3-pyridyl, 7.2 (d, J PH = 2Hz , 2H): aromatic H, substituted phenyl, 5.24 (s, ÍH): OH, 4.66 (d, J PH = 22Hz, ÍH): CH-P03Me2, 4.75 -4.68 (m, ÍH): NH, 3.74 and 3.39 = (two d, J = 11Hz): P-0-CH3, 1.42 (s, 18H): ter-Bu. MS: m / e = 419: M + - 1.311 (100%): M + -P? 3Me2.

EXAMPLE 2 or - (diethyl 3,5-di-tert-butyl-4-hydroxyphenyl) -N- (2-pyridyl) -aminomethylphosphonate) The procedure described in example 1 was used using 2-aminopyridine as the amine and diethyl phosphite as the phosphonate reagent. The title compound was purified by column chromatography (95/5 CHCl 3 / MeOH) to yield a solid (61%). P.f. = 116-118Q (AcOEt-ligroin). MS (m / e) = 448: M + -P03Et2, 78 (100%): CSHAN, d = 8.09, 7.38 and 6.57 and 6.44 (4m, 1H each): aromatic H, 2-pyridyl, 7.28 (d, J PH = 2Hz, 2H): aromatic H, substituted phenyl, 5.46 (dd, J = 9 and 22 Hz, ÍH): CH-P03Et2, 5.3 (m, ÍH): NH, 4.14-3.66 (3m, 4H total): P-0-CH2-CH3, 1.42 (s, 18H): ter-Bu, 1.21 and 1.16 (2 t, 3H each): PO-CH2-CH3.

EXAMPLE 3 a- (3,5-di-tert-Butyl-4-hydroxyphenyl) -N-C5- (2-chloro-pyridyl)] - diethyl aminomethylphosphonate The procedure described in Example 1 was employed using 5-amino-2-chloro-pyrimine as the amine and diethyl phosphite as the phosphonate reagent. The title compound was obtained in 50% yield after chromatography on column (98/2 CHCl3 / MeOH) and trituration in petroleum ether; p.f. = 124-126 ° C. MS (m / e) = 483: M ++ 1.345 (100%), 347 (30%): M + -P03Et2. NMR (CDC13): d = 7.78. 7.05 and 6.09 (3H): aromatic H, 3-pyridyl, 7.18 (d, J = 2Hz, 2H): aromatic H, substituted phenyl, 5.22 (s, 1H): 0H, 4.83 (t, J = 8Hz): NH , 4.57 (dd, J = 7.5 and 22.5Hz): CH-P03-Et2, 4.1, 3.86 and 3.56 (3m, 4H): PO-CH2-CH3, 1.40 (s, 18H): t-Bu, 1.28 and 1.05 (2t, J = 7Hz): P-0-CH2 -CH3.

EXAMPLE 4 tt- (3,5-di-tert-Butyl-4-hydroxyphenyl) -N-acetyl-N- (4-picolyl) -aminomethyl phosphonate diethyl ester A mixture of acetic anhydride was refluxed (1.4 g, 14 mmol), cx- (3,5-di-tert-butyl-4-hydroxyphenyl) -N- (4-picolyl) -aminomethylphosphonate diethyl ester (6g, 13 mmol) and triethylamine (1.9 ml, 14 mmoles) in 20 ml of toluene. The reaction mixture was extracted with brine, dried and evaporated to dryness. The residue was recrystallized from a mixture of dichloromethane and petroleum ether to give 3.7 g (57% yield); p.f. = 160-162 ° C. MS (m / e): 504: M +, 461: M + - C0CH3, 367: M + -P03Et2, 325 (100%): M + + l-P03Et2 -C0CH3.

EXAMPLE 5 Diethyl tt- (3,5-di-tert-butyl-4-hydroxyphenyl) -N- (3-piperidyl) aminomethylphosphonate hydrochloride salt Diethyl (3,5-di-tert-butyl-4-hydroxyphenyl) -N- (3-pyridyl) aminomethylphosphonate (3 g, 6.7 mmol) was dissolved with light heating in 60 ml of toluene and the resulting solution was Saturated with gaseous hydrogen chloride. After 16 hours at 0 ° C, the mixture was evaporated to dryness and the residue was recrystallized from EtOH; p.f. = 193-194 ° C. Elemental Analysis: C24H38CIN2O4P% Cale. C 59.43 H 7.90 Cl 7.31 N 5.78 P 6.39% Jan. C 59.43 H 8.10 Cl 7.02 N 5.72 P 6.21 EXAMPLE 6 a- (3,4-Methylenedioxyphenyl) -N- (3-piperidyl) -aminomethylphosphonate diethyl ester The procedure described in Example 8 was followed. The title compound was purified by column chromatography (9/1 CHCl 3 / MeOH); 60% yield, P.f. = 98-99ßC, C17H21N2O5P. IR (KBr) = 1240 ci-r *: P = 0, 1030: P-O-C. MS (m / e) = 365 M ++ 1, 227 (100%): M + - P? 3Et2. NMR (CDCl 3) d = 8.1, 7.95, 7.05 and 6.95 (4m, 1H each): aromatic H, 3-pyridyl, 6.90, 6.85, 6.75 (3m, 3H): aromatic H, substituted phenyl, 5.95 (2H): = 0-CH2-0.4.86 (dxd, ÍH, J = 8 and 10Hz): NH, 4.63 (dxd, ÍH, J = 8 and 24 Hz): CH-P03Et2, 4.18-3.70 (3m, 4H total ): PO-CH2-CH3, 1.31 and 1.16: (2t, J = 7Hz): PO-CH2-CH3.

EXAMPLE 7 a- (4-Hydroxyphenyl) -N- (3-pyridyl) -aminomethylphosphonate diethyl ester 4-Hydroxybenzaldehyde (6 g, 49 mmol) was reacted at room temperature with 3-aminopyridine (4.5 g, 52 mmol) in 30 mL of THF at room temperature to give 9.9 g of a light brown solid. The imine thus obtained (5.9 g, 30 mmol) was dissolved in 50 ml of THF, diethyl phosphite was added in two portions, one at the beginning of the reaction and the other after 6 hours under reflux (total amount: 8.2 g, 60 mmol). The reaction mixture was refluxed overnight. Filtration of the ed precipitate produced 7.5 g (75%) of a tan solid, m.p. = 210-212 ° C (EtOH). MS (m / e) = 337: M + + 1, 199 (100%): M + -P03Et2. NMR (DMS0-d6): d = 9.35 (s, ÍH): OH, 8.15, 7.7, 7.1 and 7.0 (4m, 1H each): aromatic H, 3-pyridyl, 6.5 (dxd, 1H): NH, 7.3 and 6.7 (2m, 2H each): aromatic H, 4-hydroxyphenyl, 4.93 (dxd, ÍH): CH-P? 3Et2, 4.1-3.6 (3m, 4H total): PO-CH2-CH3, 1.15 and 1.02 ( 2t, 3H each): PO-CH3.

EXAMPLE 8 a- (3,5-Dimethoxy-4-hydroxyphenyl) -N- (3-piperidyl) -aminomethylphosphonate diethyl ester A mixture of 3 g (16.4 mmoles) of syringe-aldehyde and 1.63 g (17.3 mmoles) of 3-aminopyridine dissolved in 10 ml of toluene and a catalytic amount of p-toluenesulfonic acid (approx 5 g) were refluxed for 17 hours. mg), contained in a flask connected to a Dean Stark apparatus. The solution was evaporated to dryness to give 4.2 g (100%) of the crude imine. Dimethyl phosphite (4.8 g, 35 mmol) was added to 4.2 g (17.3 mmol) of the above-described imine dissolved in 10 mL of THF, and the mixture was refluxed for 7 hours. Another amount of diethyl phosphite (4.8 g, 35 mmol) was added and the mixture was refluxed overnight (total reaction time: 17 hours). The solvent and excess diethyl phosphite were evaporated and the residue was recrystallized from a mixture of ethanol and dichloromethane to give 4.2 g (61%) of a white solid, m.p. 181-183 ° C. IR (KBr) = 1240 air *: P = 0 and 1030: P-0-C.

MS (m / e) = 397: M + + 1.259 (100%): M + - P03Et2 - NMR (CDC13): d = 8.08, 7.04 and 6.84 (4m, 1H each): aromatic H, 3-pyridyl, 6.69 ( d, J = 2H): aromatic H, substituted phenyl, 5.8 (broad, ÍH): OH, 4.84 (dxd, ÍH, J = 7 and 10Hz): NH, 4.62 (dxd, ÍH, J = 7 and 23 Hz) : CH-P03Et2, 4.18- 3.65 (3m, 4H total): P-0-CH2-CH3, 3.86 (s, 6H): 0CH3, 1.16: (2t, J = 7Hz): P-O-CH2-CH3. Elemental Analysis: C18H25N2O6P% Cale. C 59.54 H 6.36 N 7.07 P 7.81% Jan. C 54.50 H 6.38 N 6.99 P 7.65 EXAMPLE 9 a- (3,4,5-T-rimethoxy f-enyl) -N- (3-piperidyl) -aminomethyl phosphinate diethyl ester A mixture of water was refluxed for 16 hours. 3,4,5-trimethoxy-benzaldehyde (10 g, 51 mmol) and 3-a inopyridine (4.8 g, 51 mmol) and a catalytic amount of TsOH in 50 ml of toluene, in a flask connected to a trap Dean-Stark 12.9 g (93%) was produced by evaporation of toluene of the raw imine that was used directly in the next reaction. A mixture was refluxed in 50 ml of THF containing the imine (6 g, 22 mmol) and diethyl phosphite (6.1 g introduced at the start and 6.1 g after 4 hours, total amount = 12.2 g, 88 mmol). The residue, after evaporation of the THF and excess HP 3 Et 2, was triturated in petroleum ether to give 7.12 g (79%) of a white solid, m.p. = 135-137 ° C. MS (m / e) = 410: M +, 273 (100%): M + -P03Et2. NMR (CDC13): d = 8.1.8.0, 7.05 and 6.85 (4m, 1H each): aromatic H, 3-pyridyl, 6.69 and 6.68: (d, J = 2Hz): aromatic H, substituted phenyl, 4.86 (dxd , ÍH, J = 8 and 10Hz): NH, 4.63 (dxd, ÍH, J = 7 and 23 Hz): CH-P03Et2, 4.18-3.70 (3m, 4H total): P-0-CH2-CH3, 3.86 ( two s, 9H): OCH3, 1.31 and 1.16: (2t, J = 7Hz): P-0-CH2-CH3.

EXAMPLE 10 a- (3-ethoxy-4-hydroxyphenyl) -N- (3-pyridyl) -aminomethylphosphonate diethyl ester The solution was refluxed for 4 hours. 50 ml of toluene containing 3-ethoxy-4-hydroxybenzaldehyde (10 g, 60 mmol), 3-aminopi-ridine (5.6 g, 60 mmol) and 50 mg of TsOH, placed in a flask connected to a Dean-Stark trap, to give 14.62 g (95%) of the corresponding imine. To a suspension of sodium hydride (1.19 g of a 60% mixture, 30 mmol) in 20 ml of dry THF, HP03 Et2 (9.12 g, 66 mmol) was added under nitrogen, and the resulting mixture was stirred until initial turbid suspension became completely clear. To this solution of NaP? 3Et2 was added the above imine (8 g, 33 mmol) dissolved in 10 ml of THF, and the resulting solution was refluxed for 2 hours. The THF was evaporated and the residue was partitioned between H2O and CH2Cl2. Evaporation of the dry organic phase gave 3.1 g of a white solid, m.p. = 184-187 ßC. MS: (m / e) = 380: M +, 243: M + - P03Et2. NMR (DMS0-d6): d = 8.9 (s, HH): OH, 8.15, 7.3, 7.0 and 6.9 (HH each): aromatic H, 3-pyridyl, 7.1 (m, 2H) and 6.68 (d, J) = 8 Hz, ÍH): aromatic H, phenyl, 6.5 (dxd, J = 6 and 10 Hz): NH, 4.92, J = 10 and 24 Hz): CH-P03Et2, 4.05-3.6 (4m, 6H total): P-0-CH2-CH3, 1.29 (t, J = 7Hz, 3H): 0-CH2-CH3, 1.16 and 1.04 (2t, J = 7Hz, 3H each): P-0-CH2-CH3.

EXAMPLE 11 a- (-hyd roxy -3-me toxi f eni l) -N- (3-pi ridyl) -aminomethyl phosphone or diethyl The procedure of Example 10 was followed, using 4-hydroxy-3-methoxybenzaldehyde as the starting material. The title compound is a white solid, MS (m / e) = 366: M +, 229: M + - P03Et2. NMR (DMS0-d6) d = 8.9 (s, ÍH): OH, 8.15, 7.75 and 6.9 (4m, 4H): aromatic H, 3-pyridyl, 7.1 (m, 2H) and 6.7 (d, J = 8 Hz, ÍH): aromatic H, phenyl, 6.5 (dxd, J = 6 and 10 Hz): NH , 4.92 (dxd, J = 10 and 24 Hz): CH-P03Et2, 4.05-3.6 (3m, 4 H total): PO-CH2-CH3, 3.72 (s, 3H): OCH3, 1.17 and 1.4 (2t, J = 7Hz, 6H): PO-CH2-CH3.

EXAMPLE 12 tt- (3,5-Dimethoxy-4-hydroxyphenyl) -N- (4-picolyl) -aminomethylphosphonate diethyl ester A solution of 2.5 g (13.7 mmoles) of syringe-aldehyde and 1.6 g (14.4 mmoles) of 4-picolyl-amine dissolved in 100 ml of toluene, contained in a flask connected to a Dean apparatus, was refluxed for 3 hours. Stark The toluene was evaporated under vacuum, then the residue was dissolved in 10 ml of THF and heated with 5.1 g (36.8 mmoles) of diethyl phosphite for 6 hours. The THF was evaporated and the residue was purified by column chromatography (SÍO2, 95/5 CHCl3 / Me0H). Recrystallization from a mixture of CH2Cl2-petroleum ether afforded 3.7 g (45%) of a solid, m.p. 124- 126 ° C. MS (m / e) = 410: M +, 273: M + -P? 3Et2. NMR (CDCl 3) d = 8.55 and 7.22 (2m, 4H): aromatic H, 4-picolyl, 6.75 (d, J = 2Hz, 2H): aromatic H, phenyl, 4.15-3.77 (several m, 5 H): PO -CH2-CH3 and CH-P03Et2, 3.89 (s, 6H): OCH3, 3. 82 and 3.62 (2d, J = 14 Hz): NH-CH2-py, 1.33 and 1.16 (2t, J = 7Hz, 6H): P-O-CH2-CH3.

EXAMPLE 13 tt- (3,5-Dimethoxy-4-hydroxyphenyl) -N- (3-picolyl) amino-methylphosphonate diethyl ester The procedure described in Example 12 was followed, using 3-picolyl-amine as the starting material. The title compound was purified by column chromatography (9/1 CHCl3 / MeOH) to give a thick yellow oil. Recrystallization from CH2Cl2-petroleum ether gave a tan solid, m.p. = 99-101 ° C. MS (m / e): 410: M +, 273 = M + -P03Et2. NMR (CDCl 3) d = 8.51, 8.50, 7.64 and 7.25 (4m, 4H): aromatic H, 3-picolyl, 6.65 (d, J = 2Hz, 2H): aromatic H, phenyl, 7.75 (broad, ÍH): OH , 4.15-3.75 (several m, 5H): P-0-CH2-CH3 and CH-P03Et2, 3.9 (s, 6H): 0CH3, 3.83 and 3.61 (2d, J = 14Hz, 2H): NH-CH2-py , 1.31 and 1.16 (2t, J = 7Hz, 6H): P-0-CH2-CH3.

EXAMPLE 14 or - (3,5-dimethoxy-4-hydroxyphenyl) -N- (2-piperidyl) amino-methylphosphonate diethyl ester A mixture of 3.64 g (20 mmoles) of syringe-aldehyde and 1.88 g (20 mmoles) of 2-amino-pyridine dissolved in 20 ml of toluene and a catalytic amount of TsOH contained in a flask was refluxed for 24 hours. connected to a Dean-Stark device. The solution was evaporated to dryness to give 5.2 g (100%) of the crude imine. Diethyl phosphite (5.8 g, 42 mmol) was added to 3.6 g (14 mmol) of the above-described imine dissolved in 25 mL of THF, and the mixture was refluxed for 20 hours. The solvent and excess diethyl phosphite were evaporated, and the residue was recrystallized from ethanol to give 4.2 g (76%) of a white solid, m.p. = 163-165 ° C. IR (KBr) = 1240 cm-1: P = 0 and 1030: P-O-C. MS (m / e) = 397: M + + 1259 (100%): M + - P03Et2. NMR (CDC13): d = 8.08, 6.60 and 6.41 (4m, ÍH each): Aromatic H, 2-pyridyl, 6.76 (d, J = 2Hz): aromatic H, phenyl substituted, 5.6 (s, ÍH): OH, 5.39 (m, ÍH): NH, 5.37 (dxd, ÍH, J = 9 and 28 Hz): CH-P03Et2, 4.18-3.69 (3m, 4H total): PO- CH2-CH3, 3.87 (s, 6H): OCH3, 1.24 and 1.15: (2t, J = 7Hz): PO-CH2-CH3.

EXAMPLE 15 tt- (3,5-dimethoxy-4-hydroxy-enyl) -N- (4-pi-di-methyl) -methyl-methyl-phosphonate diethyl ester The solution was refluxed for 48 hours ml of toluene, containing syringe-aldehyde (3.64 g, 20 mmol), 4-amino-pyridine (1.9 g, 20 mmol) and 5 mg of TsOH, placed in a flask connected to a Dean-Stark trap, to give 5.0 g (95%) of the corresponding imine. To a suspension of sodium hydride (0.87 g of a 60% mixture, 20 mmol) in 25 ml of dry THF, HP03 Et2 (4.14 g, 30 mmol) was added under nitrogen, and the resulting mixture was stirred until initial turbid suspension became completely clear. To this NaP03Et2 solution was added the above imine (2.6 g, 10 mmol) dissolved in 5 mL of THF, and the resulting solution was refluxed for 2 hours. hours. The THF was evaporated and the residue was partitioned between H2O and CH2Cl2. Evaporation of the dried organic phase gave a white solid which was recrystallized from EtOH (1.84 g, 45%); p.f. = 172-174 ° C. MS (m / e) = 396: M +, 259 (100%): M + - P03Et2. NMR (CDCl 3): d = 8.18, 8.16, 6.48 and 6.46 (4m, 1H each): aromatic H, 4-pyridyl, 6.67 (d, J = 2Hz, 2H): aromatic H, substituted phenyl, 5.27 (dxd, ÍH, J = 7 and 10Hz): NH, 4.66 (dxd, ÍH, J = 7 and 23 Hz): CH-P03Et2, 4.18-3.60 (3m, 4H total): P-0-CH2-CH3, 3.87 (s , 6H): 0CH3, 1.30 and 1.15: (2t, J = 7Hz): P-O-CH2-CH3.

EXAMPLE 16 Enantiomers of a- (3,5-di-tert-butyl-4-hydroxyphenyl) -N- (4-picolip-ammonium diethyl ethylphosphonate) a) 3,5-Di-tert-butyl-4-hydroxybenzaldehyde was stirred (30 g, 123.5 mmol) and (R) - (+) - l-phenyl-ethylamine (15.7 g, 129.7 mmol) in 100 mL of THF at room temperature for one day. The solution was dried over MgSO-4 and concentrated. The corresponding imine was recrystallized from ligroin (38 g, 88% performance; p.f. = 127-128 ° C). The imine (30 g, 89 mmol) and the diethyl phosphite (15.4 g, 111.3 mmol) in 80 ml of toluene were refluxed for 5 hours. The mixture was evaporated to dryness. HPLC analysis of the residue showed that one of the diastereomers is predominantly formed (84% against 3% of the reaction mixture). The major diastereomer of diethyl α- (3,5-di-tert-butyl-4-hydroxyphenyl) -N- (1-phenyl-ethyl) -aminomethylphosphonate was isolated by successive crystallizations (10 g); [a] o 27 + 8.33 ° (c = 1649, CHC13); p.f. = 105-106 ßC). Hydrogenated (+) - a- (3,5-di-tert-butyl-4-hydroxyphenyl) -N- (1-phenyl-ethyl) -aminomethylphosphonate diethyl ester (9.5 g, 20 mmol) in ethanol in the presence of 2.5 g of 10% Pd on carbon to give (-) - - (3,5-di-te r-butyl-4-hydroxyphenyl) -aminomethylphosphonate diethyl ester (5.6 g, 76% yield, mp = 143- 145 ° C (recrystallized from ligroin / CH2Cl2); [a-b22-12.12 ° (c = 1650, CHCl3). (-) - a- (3,5-di-tert-butyl-4-hydroxyphenyl) - diethyl aminomethylphosphonate (11 g, 29.6 mmol) and pyridine-4-carboxaldehyde (6.3 g, 59.3 mmol) in 125 mL of MeOH The mixture was acidified with concentrated HCl (bromophenol blue indicator). After stirring at room temperature, NaBH3CN (5.6 g, 89 mmol) dissolved in 30 ml of MeOH was added and the pH was again adjusted with HCl The reaction mixture was stirred at room temperature for 4 hours, then evaporated to room temperature. dryness and extracted with CH2Cl2 and Water. The organic phase was dried over MgSO¿ and evaporated. The residue was separated by column chromatography (silica gel, 95/5 CHCl3 / MeOH to give (-) - oc- (3,5-di-tert-butyl-4-hydroxyphenyl) -N- (4- diethyl picolyl) -aminomethylphosphonate [(11 g, 80% yield; mp = 66-69 ° C; [CX] D21-44.05 ° (c = 1.650, CHCl3)]. b) 3,5-Di-tert-butyl-4-hydroxybenzaldehyde (30 g, 123.5 mmol) and (S) - (-) - 1-phenylethylamine (15.7 g, 129.7 mmol) in 100 ml of THF were stirred. during one day to give the corresponding imine (36.5 g, 88% yield, mp = 127-128 ° C). The imine (20 g, 59.3 mmol) and diethyl phosphite (10.2 g, 74.2 mmol) were refluxed in 60 mL of toluene for 7 hours. The mixture was evaporated to dryness. HPLC analysis of the residue indicated that the diastereomeric ratio was 60 to 40% in addition to the starting materials. The latter was steam-entrained by column chromatography on silica gel (98/2 CH2Cl2 / MeOH). The fractions containing the mixture of diastereomers were evaporated to dryness and recrystallized three times from ligroin / MTBE to produce the main diastereomer of oc- (3,5-di-te r-butyl-4-hyd roxyphenyl) - N- (1-ethylhexyl) -aminomethylphosphonate diethyl [12 g; p.f. = 104-105 ° C; [OC] D28-10.53 ° (c = 1643, CHCl3)]. Hydrogenated (-) - ot- (3,5-di-tert-butyl-4-hydroxyphenyl) -N- (1-phenyl-ethyl) -aminomethylphosphonate diethyl ester (42 g, 88.4 mmoles) in ethanol in the presence of 6 g of 10% Pd on carbon to give diethyl (+) - cc- (3,5-di-tert-butyl-4-hydroxyphenyl) -aminomethylphosphonate (24.5 g, 75% performance; p.f. 143-144 ° C (recrystallized from ligroin / MTBE); [OC] D29 + 11.04 ° (c = 1.714, CHC13). Diethyl (+) - a- (3,5-di-tert-butyl-4-hydroxyphenyl) -aminomethylphosphonate (11 g, 29.6 mmol) and pi ridin-4-carboxaldehyde (6.35 g, 59.3 mmol) were reacted 125 ml of MeOH with NaBH 3 CN (5.6 g, 89 mmol) in the same manner described for the (-) enantiomer. By column chromatography on silica gel (95/5 CHCl 3 / MeOH), (+) - a- (3,5-di-te r-butyl-4-hydroxyfine) -N- (4-picolyl) was produced. diethylamine amomethylphosphonate [(12 g, 87% yield; mp = 67-70 ° C; [<X] D21 + 43.03 ° (c = 1984, CHCl3)].

EXAMPLE 17 Enantiomers of a- (3,5-di-tert-butyl-4-hydroxyphenyl) -N- (3- picoliD-ammonium ethylphosphonate diethyl ester a) In the same way as described in example 16, Reacted (+) - - (3,5-di-tert-butyl-4-hydroxyphenyl) -aminomethylphosphonate diethyl ester (1 g, 2.7 mmol) and pyridine-3-carboxaldehyde (0.43 g, 4 mmol) with NaBH3CN (0.34) g, 5.4 mmol) in MeOH for 5 hours at room temperature to produce, after trituration in petroleum ether, (+) -a- (3,5-di-tert-butyl-4-hydroxyphenyl) -N- (3 -picolyl) -aminomethylphosphonate diethyl (lg, 80% yield, mp = 116-119 ° C; [oc] D23 + 42.88 ° (c = 1.614, CHC13)] b) Respectively, it was reacted (-) - diethyl a- (3,5-di-tert-butyl-4-hydroxyphenyl) -aminomethylphosphonate (1 g, 2. 7 mmoles) and pi ridin-3-carboxaldehyde (0.43 g, 4 mmoles) with NaBH3CN (0.34 g, 5.4 mmoles) in MeOH to give (-) - a- (3,5-di-te r-bu ti 1 - 4-hydroxy-phenyl) -N- (3-pi-colyl) -aminomethyl-phosphonate diethyl ester (0.7 g, 56% yield, mp = 118-120 ° C).

EXAMPLE 18 Enantiomers of a- (3,5-di-methoxy-4-hydroxyphenyl) -N- (3-pyridyl) -amoni-ethylphosphon or diethyl ester The enantiomers of a racemic mixture were separated by preparative HPLC on Chiralcel OD and isocratic elution with he / ethanol (9: 1), UV detection at 254 nm. Separation of the baseline was achieved and the content of both peaks was evaporated until white solids were formed in which no other isomer could be detected by analytical HPLC. First peak: retention time 18 min. [OC] D20 -7.4 ° (c = 0.244 p / v, EtOH)]. Second peak: retention time 34 min. [OC] D20 + 8.3 ° (c = 0.255 p / v, EtOH)]. The structure of both enantiomers was confirmed by NMR and MS spectroscopy and elemental analysis. Elemental Analysis: C18H25N2O6P% Cale. C 54.54 H 6.36 N 7.07 Enantiomer (+): p.f. 153-157 ° C. % Jan. C 53.85 H 6.22 N 6.81 Enantióme ro (-): p. f. 155-158 ° C. % Jan . C 54 .25 H 6.24 N 6. 94 EXAMPLE 19 Enantiomers of a- (3,5-di-tert-butyl-4-hydroxyphenyl) -N- (3-phenylpropyl-ammonimethylphosphonate diethyl ester a) Diethyl (-) - a- (3,5-di-tert-butyl-4-hydroxyphenyl) -aminomethylphosphonate (1.7 g, 4.5 mmol) and 3-phenyl-propionaldehyde (0.6 g, 4.5 mmol) were stirred in 20 ml of absolute methanol, under nitrogen, at room temperature, for 30 minutes. NaBH3CN (0.3 g, 4.5 mmol) dissolved in mL of methanol, and the mixture was evaporated to dryness, and the residue was dissolved in CH2Cl2. The organic phase was washed with water, then dried over MgSO4. Column chromatography with 98/2 CHCl3 / MeOH as eluent gave diethyl (-) - a- (3,5-di-tert-butyl-4-hydroxyphenyl) -N- (3-phenylpropyl) -aminomethylphosphonate [1.2 g; 56% yield; [CC] D25 + 33.1 ° (c = 2.055, CHCI3)]. b) Diethyl (+) - (3,5-di-tert-butyl-4-hydroxyphenyl) -aminomethylphosphonate (1.2 g, 3.2 mmol) and 3-phenyl-propionaldehyde (0.4 g) were reacted in the same manner. , 3.2 mmol) in 20 ml of absolute methanol with NaBH3CN (0.2 g, 3.2 mmoles) in 10 ml of methanol to produce, after column chromatography, (+) - a- (3,5-di-tert-butyl-4-hydroxyphenyl) -N- (3-phenylpropyl) -aminomethylphosphonate diethyl ester [ 0.94 g; 61% yield; [OC] D25 + 31.1 ° (c = 1.930, CHCl3)]. c) The structures of both enantiomers was confirmed by IR, NMR and MS. They were separated by analytical HPLC on Chiralpak AD and isocratic elution with he / 2-propanol (9: 1 / v: v).

EXAMPLE 20 a- (3,5-dimethoxy-4-hydroxy-enyl) -N-O-pi-ridyl) -diisopropyl aminomethylphosphonate Diisopropyl phosphite (3.3 g, 20 mmol) was added to 2.58 g (10 mmol) of 3,5-dimethoxy-4-hydroxybenzaldehyde-N- (3-pyridyl) imine dissolved in 15 ml of toluene, and the mixture was placed at reflux for 17 hours. The solvent and the excess of diisopropyl phosphite were evaporated, and the residue was purified by column chromatography (9/1 CH2Cl2 / MeOH), and its recrystallization from a mixture of EtOH / AcOEt yielded 1.56 g. (37%) of a white solid, m.p. = 157-160 ° C. MS (m / e) = 424: M +, 259 (100%): M + - P03iPr2. NMR (CDC13): d = 8.08, 7.96, 7.03 and 6.84 (4m, 1H each): aromatic H, 3-pyridyl, 6.69 (d, J = 2Hz, 2H): aromatic phenyl, 5.8 (broad, ÍH): OH, 4.82 (dxd, ÍH, J = 7 and 10Hz): NH, 4.55 (d xd, J = 7 and 23Hz): CH-P03iPr2, 4.75-4.65 and 4.55-4.45 (2m, 2H total): P-0-CH- (CH3 2, 3.86 (s, 6H): OCH3 , 1.34, 1.28, 1.24 and 0.9: (4d, J = 7Hz): P-0-CH- (CH3) 2.

EXAMPLE 21 diisopropyl a- (4-hydroxy-3-methoxy-5-methylphenyl) -N- (3-pyridyl) -aminomethylphosphonate) A mixture was refluxed for 15 hours. 1. 9 g (11 mmol) of 4-hydroxy-3-methoxy-5-methyl-benzaldehyde (mp = 98-100 ° C) and 1.08 g (11 mmol) of 3-amino-iridine dissolved in 15 ml of toluene and one catalytic amount of p-toluenesulfonic acid (ca. 5 mg), contained in a flask connected to a Dean Stark apparatus. The solution was evaporated to dryness to give the crude imine.

Diisopropyl phosphite (5.48 g, 33 moles) was added to 2.77 g (11 mmol) of the above imine dissolved in 20 ml of THF, and the mixture was refluxed for 24 hours. The solvent and excess diisopropyl phosphite were evaporated and the residue was purified by column chromatography (95/5 CHCl 3 / MeOH); by recrystallization from a petroleum ether / CH2Cl2 mixture 1.9 g (43%) of a white solid, m.p. 123-124 ° C. MS (m / e) = 408: M +, 243 (100%): M + - P03Pr2. NMR (CDCl 3): d = 8.07, 7.95, 7.02 and 6.84 (4m, 1H each): aromatic H, 3-pyridyl, 6.83-6.81: (m, 2H): aromatic H, substituted phenyl, 5.8 (s, 1H) ): OH, 4.78 (dxd, ÍH, J = 7.5 and 10Hz): NH, 4.30 (d xd, ÍH, J = 7.5 and 23Hz): CH-P03ÍPr2, 4.73-4.65 and 4.48-4.40 (2m, 2H total) : P-0-CH- (CH3) 2, 3.85 (s, 3H): 0CH3, 2.22 (s, 3H): CH3, 1.33, 1.26, 1.24 and 0.96: (4d, J = 7Hz): P-0- CH- (CH3) 2.

EXAMPLE 22 a- (3-n-butyl-4-hydroxy-5-methoxyphenyl) -N- (3-pi-di-methyl) -aminopropylphosphonate diisopropyl A mixture of 6.1 g (30 mmol) of 3-n-butyl-4-hydroxy-5-methoxy-benzaldehyde and 2.76 g (30 mmol) of 3-aminopi-ridine dissolved in 50 ml of toluene was refluxed for 16 hours. and a catalytic amount of p-toluenesulfonic acid (ca. 5 mg), contained in a flask connected to an apparatus Dean Stark The solution was evaporated to dryness to give 7.8 g (94%) of the crude imine. Diisopropyl phosphite (4.20 g, 25 mol) was added to 2.4 g (8 mmol) of the above imine dissolved in 30 ml of THF, and the mixture was refluxed for 24 hours. The solvent and excess diisopropyl phosphite were evaporated and the residue was purified by column chromatography (95/5 CHCl 3 / MeOH); by recrystallization from a petroleum ether / CH2Cl2 mixture 1.9 g (43%) of a white solid, m.p. 142-144 ° C. MS (m / e) = 450: M +, 285 (100%): M + -P03iPr2. NMR (CDCl 3): d = 8.07, 7.94, 7.0 and 6.84 (4m, 1H each): aromatic H, 3-pyridyl, 6.83-6.80: (m, 2H): aromatic H, substituted phenyl, 5.8 (s, 1H) ): OH, 4.74 (dxd, and 4.50 -4.40 (2m, 2H total): P-0-CH- (CH3) 2, 3.85 (s, 3H): OCH3, 2.60 (t, 2H), 1.5 (m, 2H), 1.31 (m, 2H) and 0.90 (t, 3H): n-Bu 1.33, 1.26, 1.24 and 0.94: (4d, J = 7Hz): P-0-CH- ( CH3) 2.

EXAMPLE 23 tt- (3,5-dimethoxy-4-hydroxyphenyl) -N-methyl-N- (3-picolyl) -aminomethylphosphonate diethyl A mixture of 3.0 g (16.5 mmoles) of syringe-aldehyde, 2.03 g (16.6 mmoles) of N-methyl-3-picolylamine and 2.3 g (16.6 mmoles) of diethyl phosphite dissolved in 15 ml was refluxed for 2 hours. of toluene and a catalytic amount of p-toluenesulfonic acid (ca. 5 mg), contained in a flask connected to a Dean Stark apparatus. The solution was evaporated to dryness and the residue was purified by column chromatography (95/5 CHCl 3 / MeOH); to give 3.2 g (46%) of a yellow oil. MS (m / e) = 287: M + -P03Et2- NMR (CDC13): d = 8.55, 8.51, 7.72 and 7.27 (4m, 1H each): aromatic H, 3-picolyl, 6.73 (d, 2H): H aromatic, substituted phenyl, 5.8 (broad, ÍH): OH, 4.25, 3.94 and 3.7 (3m, 4H): PO-CH2-CH3, 3.89 (d, J = 23Hz, ÍH): CH-P03Et2, 3.9 and 3.4 ( 2d, 2H): N (CH3) -CH2 -Py, 3.91 (s, 6H): OCH3, 2.41 (s, 3H): N (CH3) -CH2-Py, 1.39 and 1.08 (2t, J = 7Hz, 6H): P-O-CH2-CH3.

EXAMPLE 24 tt- (dihydroxy-3-methoxy-5-methylphenyl) -N-methyl-N- (3-picolyl) aminomethylphosphonate diisopropyl A mixture of water was refluxed for 2 hours. 2. 0 g (12 mmol) of 4-hydroxy-3-methoxy-5-methylbenzaldehyde, 1.8 g (13.2 mmol) of N-methyl-3-picolylamine and 2.2 g (13.2 mmol) of diisopropyl phosphite dissolved in 15 ml of toluene and a catalytic amount of p-toluenesulfonic acid (ca. 2 mg), contained in a flask connected to a Dean Stark apparatus. The solution was evaporated to dryness and the residue was purified by column chromatography (95/5 CHCl3 / MeOH); to give 2. 1 g (40%) of a yellow oil. MS (m / e) = 271 (100%): M + -P03iPr2. NMR (CDCl 3): d = 8.54, 8.50, 7.72 and 7.24 (4m, 1H each): aromatic H, 3-picolyl, 6.97 and 6.77 (2m, 2H): aromatic H, substituted phenyl, 5.75 (broad, 1H) : OH, 4.86-4.78 and 4.51-4.42 (2m, 2H total): P-0-CH (CH3) 2, 3.84 (d, J = 24Hz, ÍH): CH-P03ÍPr2, 3.97 and 3.34 (2d, J = 13.5 Hz, 2H): N (CH3) -CH2 -Py, 3. 91 (s, 3H): OCH3, 2.36 (s, 3H): CH3, 2.26 (s, 3H): N (CH3) - CH2-Py, 1.39, 1.37, 1.21 and 0.83 (4d, J = 7Hz, 12 H): P-0-CH (CH3) 2. The following compounds can also be obtained in a manner analogous to Examples 1 to 24: diethyl a- (4-hydroxy-3-methoxy-5-n-propylphenyl) -N- (3-piperidyl) -aminomethylphosphonate. a- (4-hydroxy-3-methoxy-5-n-propylphenyl) -N- (3-piperidyl) -aminomethylphosphonate diisopropyl. a- (3-i-butyl-4-hydroxy-5-methoxyphenyl) -N- (3-pi-di-methyl) -aminomethylphosphonate diethyl, and a- (3-i-butyl-4-hydroxy-5-methoxyphenyl) -N- (3- pyridyl) -aminomethylphosphonate diisopropyl. Table 1 lists the physicochemical data of the compounds of formula (I) that were prepared by the methods illustrated in examples 1-24 of this application. These methods are described in EP 0 559 079A (corresponding to the Patent of the U.S.A. 5 424 303).

TABLE 1 FORMULA ftMTNOPHOSPHONATES (I) cont * Identified by NMR and MS spectroscopy ** Enantiomer (+) of compound 20 *** (-) Enantiomer of compound 20 * Identified by spectroscopy of NMR and MS Biological Data In vitro data. The compounds of the formula (I) were analyzed to determine the reduction of Lp (a) production in primary cultures of Cynomolgus hepatocytes according to the tests described below. Two incubation times were used: 4hr for Test 1 and 24 hours for Test 2. Protocol. Hepatocytes were isolated from livers of adult Cynomolgus monkeys by means of the two-step collagenase perfusion method in accordance with C. Guguen-Guillouzo and A. Guillouzo "Methods for preparation of adult and fetal hepatocytes" p. 1-12, in "Isolated and Cultured Hepatocytes", les editions Inser Paris and John Libbey Eurotext, London (1986). The viability of the cells was determined by Tryptan blue staining. The cells were then seeded at a density of 1.5-2 x 10 5 viable cells per 2 cm 2 in 24-well tissue culture plates in a volume of 500 μl per well of Williams E tissue culture medium containing 10% fetal serum. of calf. The cells were incubated for 4 to 6 hours at 37 ° C in a CO2 incubator (5% CO2) in the presence of 20 μM of the test compounds dissolved in ethanol. Four wells were used for each compound. Nicotinic acid and steroid hormones were used as references to validate the test system, since it is known that they reduce Lp (a) in man. Control cells were incubated in the presence of ethanol only. The amount of Lp (a) secreted in the culture medium was determined directly by means of ELISA using commercially available equipment. The cells were washed and lysed as described by A.L. White and others in Journal of Lipid Research vol.34, p. 509-517 (1993), and the content of Lp (a) was determined as described above. The changes in concentration of Lp (a) in the culture medium are given as the percentage of measured value for the control plates at 4 hours (Test 1) or 24 hours (Test 2). Results Test 1. It was found that compounds 2, 7, 11, , 16, 18 and 20 change the concentrations of Lp (a) in the culture medium on the scale of -12 to -34%. Test 2. It was found that compounds 1, 2, 3, 5, 7, 11, 13, 15, 17, 19, 20, 21, 26 to 29, 32, 34 to 52, 57 to 60, 65 and 66, change the concentrations of Lp (a) in the culture medium in the scale -7 to 37%. In vivo data. Study protocol. Male cynomolgus monkeys with weights between 3 and 7 kg were divided into groups of 3 to 4 animals each. Prior to treatment, their plasma Lp (a) levels were monitored for a period of two months to determine a constant baseline value. The test compounds were administered orally by forced feeding at a dose of 25 mg / kg / day for 4 weeks and Lp (a) was measured. on day 28. At the end of the dosing period, the animals were maintained for a treatment-free period of 4 weeks, after which their plasma Lp (a) levels returned to pretreatment levels. This control provides evidence that the reduction in measured Lp (a) was caused by the pharmacological activity of the pdb compounds. Results On days -7 and 28, after fasting during the night, blood samples were taken on EDTA and Lp (a) was determined by the highly sensitive and specific ELISA test. The results (average of the 3-4 values of each group) were expressed as% of predosis (day -7). Selected compounds of formula (I) were analyzed under the experimental conditions to investigate their pharmacological activity in vivo. Compounds No. 1, 2, 3, 7, 15, 17, 19, 20, 21, 27, 28, 32, 44 and 52 decreased plasma Lp (a) on the scale from -13% to -51% ( measured value on day 28,% change of predosis on day -7). Therefore, the compounds of formula (I) have a therapeutic potential for the treatment of the following diseases, in which Lp (a) is associated with accelerated atherosclerosis, abnormal proliferation of smooth muscle cells and increased thrombogenesis: heart disease coronary artery disease, peripheral arterial disease, intermittent claudication, atherosclerosis of the extracranial carotid, attack fulminating, restenosis after angioplasty and atherosclerosis that occurs after heart transplantation. The primary indications of these compounds would be the treatment of the diseases mentioned above.

Claims (16)

NOVELTY OF THE INVENTION
2. A compound of formula (la):
3. X1 is H, C1-3 alkyl, hydroxyl or C1-4 alkoxy; X2 is C1-3 alkyl or C1-4 alkoxy; X3 is H or C1-4 alkyl; R1, R2, which may be identical or different, are H or C1-3 alkyl; B is CH2CH2, CH = CH, or CH2; n is zero or 1; Z is H or an alkyl group of Ci-β; m is 0 or 1; X 4 is H, Ci-β alkyl, Ci-β alkoxy, or halogen; and the pyridyl ring is attached to the nitrogen by means of the carbon a- or (3> - of the ring (2-, or 3-pyridyl), or a pharmaceutically acceptable salt thereof 2.- A compound in accordance with claim 1, characterized in that, in the compound of formula (la), X1 is hydrogen, methyl or methoxy 3. A compound according to claim 1 or 2, characterized in that, in the compound of formula (Ia), X2 is methyl or methoxy.
4. 4. - A compound according to claim 1, characterized in that, in the compound of formula (la), X1 and X2 are both C1- alkoxy, or one of X1 and X2 is Ci-3 alkyl and the other is alkoxy of C1-4.
5. 5. A compound according to any of claims 1 to 4, characterized in that, in the compound of formula (Ia), X3 is hydrogen.
6. 6. A compound according to any of claims 1 to 5, characterized in that, in the compound of formula (Ia), (B) n is a direct link.
7. 7. A compound according to any of claims 1 to 6, characterized in that, in the compound of formula (Ia), R1 and R2 are each a straight or branched C1-3 alkyl group.
8. 8. A compound according to any of claims 1 to 7, characterized in that, in the compound of formula (Ia), Z is hydrogen.
9. 9. A compound according to any of claims 1 to 8, characterized in that, in the compound of formula (Ia), X * is hydrogen or methyl which are preferably on the carbon adjacent to the N in the ring.
10. 10. A compound according to any of claims 1 to 9, characterized in that, in the compound of formula (Ia), the pyridyl ring is attached by means of the β-carbon of the ring to nitrogen (3-pyridyl).
11. 11. A compound of formula (Ia) in accordance with Claim 1, selected from: oc- (4-hydroxyphenyl) -N- (3-pyridyl) -aminomethylphosphonate diethyl; diethyl a- (3,4-methylenedioxyphenyl) -N- (3-pyridyl) -aminophosphonate; a- (3,5-dimethoxy-4-hydroxyphenyl) -N- (3-piyryl) -aminomethylphosphonate diethyl ester; Dimethyl (3,5-dimethoxy-4-hydroxyphenyl) -N- (3-pyridyl) -aminomethylphosphonate; a- (3,5-dimethoxy-4-hydroxyphenyl) -N- (3-pyridyl) -aminomethylphosphonate isopropyl; a- (3,5-dimethoxy-4-hydroxy-phenyl) -N- (2-pi-di-methyl) -aminomethylphosphonate; diethyl; - (diethyl 3,5-dimethoxy-4-hydroxyphenyl) -N- (4-pyridyl) -aminomethylphosphonate; diethyl a- (3,5-dimethoxy-4-hydroxyphenyl) -N- (2-picolyl) -aminomethylphosphonate; oc- (3,5-dimethoxy-4-hydroxyphenyl) -N- (3-picolyl) -aminomethylphosphonate diethyl; a- (3,5-dimethoxy-4-hydroxyphenyl) -N- (4-picolyl) -aminomethylphosphonate diethyl; oc- (4-hydroxy-3-methoxyphenyl) -N- (3-pyridyl) -aminomethylphosphonate diethyl ester; diethyl a- (3-ethoxy-4-hydroxyphenyl) -N- (3-pyridyl) -aminomethylphosphonate; diethyl a- (3,4,5-trimethoxyphenyl) -N- (3-pyridyl) -aminomethylphosphonate; a- (3,5-Dimethyl-4-hydroxyphenyl) -N- (3-pyridyl) -amino-methylphosphonate diethyl ester; (+) - a- (3,5-dimethoxy-4-hydroxyphenyl) -N- (3-pyridyl) -aminomethylphosphonate diethyl ester; (-) - < x- (3,5-dimethoxy-4-hydroxyphenyl) -N- (3-pi-di-methyl) -aminomethylphosphonate diethyl ester; - (3, 5-dimethoxy-4-hi roxyphenyl) -N- [5- (2-methylpiperidyl) -aminomethylphosphonate diisopropyl; a- (4-hydroxy-3-methoxy-5-methylphenyl) -N- (3-pyridyl) -aminomethylphosphonate diethyl ester; a- (4-hydroxy-3-methoxy-5-methylphenyl) -N- (3-pyridyl) -aminomethylphosphonate diisopropyl; a- (4-hydroxy-3-methoxy-5-n- propylphenyl) -N- (3-pyridyl) -aminomethylphosphonate diethyl; and a- (4-hydroxy-3-methoxy-5-n-propyl phenyl) -N- (3-pyridyl) -aminomethylphosphonate diisopropyl ester.
12. 12. A pharmaceutical composition comprising a compound of formula (Ia) in accordance with the claim 1, and a pharmaceutically acceptable carrier or excipient.
13. 13. A compound of formula (Ia) according to claim 1, for use in therapy.
14. 14. The use of a compound of formula (Ia) according to claim 1, for the manufacture of a medicament for the treatment of: a) peripheral arterial disease, b) thrombosis, c) restenosis after angioplasty, or d) atherosclerosis; decreasing plasma lipoprotein (a) levels.
15. 15. A process for preparing a compound of formula (Ia) according to claim 1, said process comprises, a) when Z is hydrogen, treating an imine of formula (II): (ID in which B, X *, X2, X3 and n are as defined in claim 1, with a phosphite compound of formula (III): HP0 (0R *) (0R2) (III), in which R and R2 are as defined in claim 1; or a trialkylsilyl derivative or metal salt thereof; in the presence or absence of a catalyst, optionally in a solvent; b) for compounds of formula (la) in which Z is not hydrogen, treat equimolar amounts of an aldehyde of formula (V): wherein B, X1, X2, X3 and n are as defined in claim 1; with a secondary amine of formula (VII): HNZA (VII), wherein Z is an alkyl group of C? -8 and A is as defined hereinabove; and a phosphite of formula (III); c) in compounds of formula (I) in which m is not zero, treat a compound of formula (VIII): (VIII) wherein B, R1, R2, X *, X2, X3 and n are as defined in claim 1; with an aldehyde of formula (IX): (IX) wherein m is an integer from 1 to 5 and X4 is as defined hereinabove, under conditions of reductive amination.
16. 16. A process for preparing a single enantiomer of an aminophosphonate of formula (Ia) according to claim 1, said process comprises treating any of the two enantiomers, (+) or (-), of the a-substituted aminomethylphosphonate of formula (X): wherein B, R1, R2,? i, X2, X3 and n are as defined in claim 1; with an aldehyde of formula (XI): R3-CH0 (XI), in which R3 is an alkyl group of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbon atoms; under conditions of reductive amination.