WO1995029154A1 - Novel benzylamine derivatives, method for their preparation and pharmaceutical compositions containing same - Google Patents

Abstract

Novel compounds of general formula (I) wherein R1-R7 denote, in particular, a straight or branched hydrocarbon radical comprising 1-6 carbon atoms, Z is a straight or branched hydroxycarbon radical comprising 2-6 carbon atoms, a triple bond, a Z or E stereochemistry double bond (Z'CH=CHZ') in which Z' and Z', which are the same or different, are a hydrogen atom, a fluorine atom or a straight or branched hydrocarbon radical comprising 1-6 carbon atoms; n=0.1 or 2; X and X', which are the same or different, are O or NR'1, where R'1 is a hydrogen atom, a straight or branched hydroxycarbon radical comprising 1-5 carbon atoms, or a cycloalkyl radical comprising 3-7 carbon atoms; and Y = O,S.

Description

NOVEL BENZYLAMINE DERIVATIVES, THEIR MANUFACTURING PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The present invention relates to new benzylamine derivatives, their salts, their manufacturing process and the pharmaceutical compositions containing them.

^• έrosclerosis is a degenerative arterial disease considered as one of the important s of coronary and cerebral arterial diseases, which are parrr. ~ s leading causes of death today. Atherosclerosis begins with a deposit of lipid in the wall of the vessels and leads to clinical symptoms such as cardiac ischemia, myocardial infarction, angina pectoris or cerebral atherosclerosis. The interest in lipid-lowering therapy lies in the link between blood lipid levels and atherosclerosis. (The hypolipaemics Report, SCRIP, 1-9, 1989). In particular, numerous epidemiological and experimental studies have shown and confirms the continuous positive relationship between cholesterolemia and coronary risk. Therapeutic trials have shown that lowering cholesterol levels through diet or medication can lower this risk of coronary heart disease. The benefits exist in men and women, in the young and the elderly, in those who have a high coronary risk due to their LDL cholesterol and those who have a moderately high risk (B. Jacotot, F. Delahaye, Arch. Mal. Coeur, £ 5 (111), 83-86, 1992). It is generally accepted that, in humans, more than 50% of cholesterol comes from de novo biosynthesis. Today, inhibitors of the biosynthesis of cholesterol and, more specifically, of the enzyme HMGCo-A-reductase are used as therapeutic agents in humans (for example simvastatin, lovastatin or pravastatin; cf. PA Me Carthy , Med. Res. Rev. 12, 139-159, 1993; A. Endo, J. Lipid. Res. 21, 1569-1582, 1992).

However, as the enzyme HMGCo-A-reductase is located very early in the biosynthesis of cholesterol, inhibitors of this enzyme are also capable of inhibiting the formation of other important biological metabolites such as dolichol, ubiquinone, isopentenyl adenine or farnesylated or geranyl-geranyl proteins. Inhibitors of squalene epoxidase (an essential enzyme in the biosynthesis of cholesterol but located much further downstream than HMGCo-A-reductase) should make it possible to avoid these problems while keeping very good cholesterol-lowering activity. Some compounds have been described as inhibitors of squalene epoxidase of fungal origin such as certain allyl-benzylamines (naftifine or terbinafine, NS Ryder, Biochem. Soc. Trans., 12, 774-777, 1991) and of squalene epoxidase such as as squalene derivatives (Chemtracts-Org. Chem. 5_, 27-30, 1992, Prestwich et al. J. Am. Chem. Soc. 111, 9674-9675, 1991; W. Moore et al. J. Am. Chem. Soc. 114, 360-361, 1992, W. Von Sickle, Lipids, 22.157-160, 1992). or new benzyl-allylamines such as NB-598 (J. Biol. Chem., 2èl, 18075-18078, 1990) capable of modulating the biosynthesis of cholesterol in cells (J. Biol. Chem., 266. 13171- 13177, 1991) and exert a cholesterol-lowering effect in dogs (Atherosclérosis,, 183-192, 1991).

Recent progress in research on the prevention of atherosclerosis suggests that, if a high level of LDL (associated with a high cholesterol level) is a risk factor, the quality of these same LDL also intervenes in the formation of the atheromatous plaque. Thus it has been shown (D. Steinberg, New England J. Med. 12Q, 915-924, 1989) that the oxidation of LDL confers on them a certain number of characteristics which can initiate the formation of foam cells. , starting point for lesions of atherosclerosis (S. Parthasarathy, S. Rankin, Prog. Lipid. Res. 11, 127-143, 1992; S. Parthasarathy, D. Steinberg, J. Witztum, Ann. Rev. Med . 41, 219-225, 1992; Rengstrôm et al., Lancet, 112,1 183-1186, 1992; JL Witztum, D. Steinberg, J. Clin. Invest. & 8_, 1785-1792, 1991; UP Steinbrecher, Clin Cardiol. \ 4, 865-867, 1991; H. Hoff, J. O'Neil, Klin. Wochenschr., 1032-1038, 1991; M. Aviram, Atherosclerosis, 2 £, 1-9, 1993). Numerous studies with antioxidants such as vitamin C, vitamin E or β-carotene, or even probucol suggest that these derivatives can play a role in the prevention of atherosclerosis by decreasing the susceptibility of LDL for oxidation (WS Harris, Clin. Cardiol. 15, 636-640, 1992).

In addition, an alternative therapy for hypercholesterolemia is the use of inhibitors of the enzyme acetyl CoA: cholesterol acyltransferase (ACAT): ACAT inhibitors are likely to decrease the concentration of plasma cholesterol by inhibiting intestinal absorption. endogenous cholesterol and can also have a direct effect on the liver (by inhibiting the secretion of VLDL) and on the arterial wall.

Inhibition of ACAT from macrophages in the arterial wall probably slows the formation of foam cells, precursors of streaks. lipids and atherosclerotic lesions (O'Brien PM, Sliskovic DR Curr Opin. Thera. Patents, 2, 507, 1992; Sliskovic DR, White AD, Trends Pharmacol. Sci., 12, 194, 1990).

The compounds of the present invention are lipid-lowering / anti-atheromatous agents which act as inhibitors of squalene epoxidase, inhibitors of ACAT and / or antioxidants and which for some of them can combine these mechanisms of action within the same molecule.

The derivatives of the present invention alone or combined with other therapeutic agents find their utility as medicaments and more particularly for the treatment and prevention of hypercholesterolemia, hyperlipemia, atherosclerosis, diseases linked to deficiency or any LDL receptor abnormality, but also pathologies in which peroxidation or any other form of lipid oxidation play an initiating and / or aggravating role such as ischemic heart disease, reperfusion of organs, including transplanted patients, pathologies traumatic or degenerative ischemic attacks of the central or peripheral nervous system, acute or chronic inflammatory diseases, autoimmune diseases and metabolic diseases such as for example diabetes.

The present invention relates to benzylamine derivatives corresponding to formula (I)

(I)

(I)

in which,

Rj and R'i, identical or different, represent a hydrogen atom, a hydrocarbon radical containing from 1 to 5 carbon atoms in a straight or branched chain, or a cycloalkyl comprising from 3 to 7 carbon atoms. R2 represents a hydrocarbon radical containing from 1 to 6 carbon atoms in a straight or branched chain optionally substituted by a methoxy, ethoxy radical, or a trimethylsilylated or triethylsilylated residue.

R3 represents a hydrogen, fluorine, chlorine or bromine atom, a hydrocarbon radical comprising from 1 to 6 carbon atoms in a straight or branched chain, a hydroxy, thio, acyloxy (R'3CO2) alkoxy (R 'radical) 30) or alkylthio, in which R'3 is a linear or branched hydrocarbon radical comprising from 1 to 6 carbon atoms.

R4 represents an aromatic ring, a cycloalkyl, a heterocycle or a hydrocarbon radical containing from 1 to 6 carbon atoms in a straight or branched chain and which can itself be substituted by an aromatic ring (such as a variously substituted phenyl), a heterocyl, a cycloalkyl or a silylated residue in which the silicon is substituted by radicals R5, Rg and R7.

R5 and Rg, which are identical or different, each represent a branched or linear hydrocarbon radical containing from 1 to 6 carbon atoms or a cycloalkyl residue containing from 3 to 8 carbon atoms or an aryl residue such as a phenyl.

R7 represents a linear or branched hydrocarbon radical comprising from 1 to 6 carbon atoms, a cycloalkyl radical comprising from 3 to 8 carbon atoms, an aryl or alkylaryl radical in which the aryl group may be, for example phenyl, naphthyl, thiophene, furan , pyridine, optionally substituted by a linear or branched hydrocarbon radical comprising from 1 to 6 carbon atoms optionally a double bond, an alkoxy (R'ό), amino (NR'gR'g), alkylthio (^ R'g) radical [in which R'g is hydrogen or an alkyl radical], a halogen (fluorine, chlorine or bromine), a nitro radical or an aryl radical. Z represents a linear or branched hydrocarbon radical comprising from 2 to 6 carbon atoms, a triple bond, a double bond (Z'CH = CHZ ") of stereochemistry Z or E in which Z 'and Z" identical or different represent an atom hydrogen, a fluorine atom, or a linear or branched hydrocarbon radical comprising from 1 to 6 carbon atoms; n = 0, 1 or 2; X and X 'identical or different represent O or NR'i Y = O, S

The compounds of formula (I) containing one or more asymmetric centers have isomeric forms. The racemates and pure enantiomers of these compounds are also part of this invention.

The invention also includes the salts, solvates (for example hydrates) and bioprecursors of these compounds acceptable for therapeutic use.

Among the salts acceptable for the therapeutic use of benzylamines of formula (I), mention will be made of the salts formed by addition with organic or mineral acids, for example hydrochlorides, hydrobromides, sulfates, fumarates, tartrates and maleates. The expression "bioprecursors" as used in the present invention applies to compounds of formula (I) but which, when administered to an animal or to a human being, are converted in the body into a compound of formula (I). The prior art in this field is illustrated in particular by:

• French patent 2,349,566 and European patent 24,587 which respectively describe naftifine and terbinafine as antimycotic agents. . European patent applications 0318860, 0395768 and 0448078 and Japanese patent application JP 3251588 which relate to benzylamines as inhibitors of squalene epoxidase.

Patent application JP 05213923 which relates to thioamide derivatives as squalene epoxidase inhibitors / hypercholesterolemic agents.

French patent application F 9309025 which describes new silylated benzylamine derivatives as medicaments. The present invention describes a new class of benzylamine derivatives which are distinguished from the closest derivatives of the prior art, not only by their original chemical structure but also by their biological profile and their mechanism of action since these derivatives can be independently or simultaneously squalene epoxidase inhibitors, ACAT inhibitors and antioxidants. The present invention also relates to the process for the preparation of derivatives of general formula (I), characterized in that one condenses, a derivative of general formula (II)

in which R \, R2, R3, Z, n and X are described as above, and a derivative of general formula (III)

R4 - X - H (III)

in which R4 and X are described as above, with a derivative of general formula (IV)

in which Y is defined as above and Xj, X2, which are identical or different, each represent a leaving group such as a halogen (in particular chlorine), an O-alkyl group (in particular the OCCI3 group), a succinimyl, phthalyl group or imidazole. The method of the present invention also comprises the use of precursors or analogues well known to the reagents of general formula (IV). It is thus and by way of example that the condensation of intermediates (II) and (III) with phosgene (C1COC1) can also be advantageously carried out using diphosgene or triphosgene according to a procedure well known in the art. tradesman.

Among the reagents of formula (IV), phosgene (or triphosgene), thiophosgene, carbonyl diimidazole, thiocarbonyl diimidazole, trichloromethyl chloroformate or even N, N disuccinimidyl carbonate are more particularly appreciated without however limiting the definition of reagent ( IV) to these examples only.

The methods and techniques chosen for carrying out the preparation of the compounds of general formula (I) by condensation of the derivatives of general formulas (II) and (III) with (IV) such as the choice of the order of the reactants, reaction times, isolation or / and purification of intermediates, temperature at different stages of condensation, the nature of the solvent (s), the presence of co-reactants or catalysts and the choice of residues X \ and X2 will be determined by the nature of Ri, R2, R3, R4, X, X, Y , Z and n.

Thus a particularly preferred method for repairing derivatives of formula (I) in which Rj, R2, R3, R4, X, X, Z .1 are described as above and Y represents an oxygen consists in reacting a intermediate of formula (H) in which R \, R2, R3, X and Z are described as above with triphosgene in the presence of a base such as a tertiary amine (triethylamine for example) in an aprotic solvent such as for example a chlorinated solvent (dichloromethane or chloroform) or an oxygen solvent such as for example THF or dioxane at a temperature between 20 ° C. and the reflux temperature of the solvent used.

This first step leads to an intermediate which can be condensed directly with an intermediate of general formula (III), in the presence of a tertiary amine such as triethylamine at a temperature between 20 and 100 ° C. depending on the solvent used to conduct in one step or a product of general formula (I).

In certain cases, it is recommended to isolate the reaction intermediate resulting from the condensation of the derivative of general formula (II) with the reagent of general formula (IV), by filtration, evaporation or distillation and then to carry out the condensation of this intermediate with a derivative of general formula (III) in an anhydrous and aprotic solvent such as a chlorinated solvent (dichloromethane or dichloroketone), an oxygenated solvent (THF, dioxane or dimethoxyketone), toluene, DMF or DMSO , in the presence of a base such as a tertiary amine at a temperature between 20 and 100 ° C.

In the particular case of the products of general formula (I) in which R \, R2, R3, R4, X ', Z, and n are described as above and X represents NR'j while Y represents oxygen, a particularly variant preferred consists in condensing the amines of general formula (II) in which X represents NR'j with chloromethylchloroformate in dichloromethane in the presence of triethylamine at a temperature between 20 and 40 ° C, or with N, N-disuccinimidyl carbonate in toluene to yield an intermediate which is directly condensed with a derivative of general formula (III) in a solvent such as toluene, THF or dioxane, in the presence of a tertiary amine at a temperature between 25 and 80 ° C to yield the product of general formula (I) in which X represents NR'j and Y represents oxygen. A particularly preferred method forming part of the present invention consists in initially condensing a derivative of general formula (III) in which R4 and X 'are described as above with a reagent of general formula (IV) in which Y, X \ and X2 are described as previously followed by the reaction of the intermediate thus formed with a derivative of general formula (II) in which R \, R2, R3, X, Z and n are described as previously according to the methods and techniques well known by the invention. 'skilled in the art for this type of preparation of carbonates, thiocarbonates, carbonates, thiocarbonates, ureas and thioureas and which have been illustrated previously.

Part of this invention must also be considered as the methods for preparing the compounds of general formula (I) in which Rj, R2, R3, X, X ', Y, Z and n are described as above which use the condensation a derivative of general formula (II) with intermediates of general formula (V):

in which X, Y, X2 and R4 are described so that the intermediates (V) are derivatives well known to those skilled in the art because previously described or commercially accessible.

Likewise, the preparation of derivatives of general formula (I) in which R \,

R2, R3, R4, X, Y and n are described as above and X 'represents NH by condensation of the intermediates of formula (II) in which X represents NH with a derivative of general formula (VI):

R -N = C = Y _{(γ [)}

according to the methods and techniques well known for the preparation of amides, thioamides carbonates and thiocarbonates from isocyanates and isothiocyanates also forms part of the present invention.

The intermediates of general formula (II) can be prepared by condensation of the compounds of general formula (VII) in which la R3 and n are defined as in the general formula (I), Y 'is a leaving group such as a halogen (bromine, chlorine, iodine), a mesylate, triflate or tosylate and X' can be equivalent to X or X 'is a function which is a precursor of X and which can be transformed into X as defined in formula (I), during a subsequent step

with derivatives of general formula (VIII) in which R, R2 and Z are defined as above.

Thus, the preparation of intermediates of general formula (II) in which n = 1 and X = O is preferably carried out by condensation of a derivative of formula (VIII) with a benzyl bromide of formula (Vlla)

dans laquelle R3 est défini comme dans la formule I et R' est un radical hydrogénocarboné linéaire comprenant de 1 à 4 atomes de carbone (préférentiellement un radical méthyle) suivi de la réduction de la fonction ester avec un réducteur bien connu pour la transformation d'un ester en alcool primaire, tel que les hydrures de bore ou d'aluminium, une méthode préférée étant l'utilisation d'hydrures d'aluminium tels que l'hydrure de diisobutylaluminium ou L-AIH4. La préparation des intermédiaires de formule générale (II) dans lesquels R\,

in which R3 is defined as in formula I and R 'is a linear hydrogen-carbon radical comprising from 1 to 4 carbon atoms (preferably a methyl radical) followed by the reduction of the ester function with a reducing agent well known for the transformation of an ester of primary alcohol, such as boron or aluminum hydrides, a preferred method being the use of aluminum hydrides such as diisobutylaluminum hydride or L-AIH4. The preparation of intermediates of general formula (II) in which R \,

suivi de la réduction de la fonction nitrile dont le protocole peut être choisi en fonction de la nature du radical R7; c'est ainsi que pour préparer l'intermédiaire de formule (II) dans lequel R7 est un hydrogène, la fonction nitrile de l'intermédiaire obtenu précédemment est traitée par l'hydrure de lithium et aluminium dans un solvant anhydre tel que l'éther ou le THF, à une température comprise entre -10°C et 30°C. Pour préparer l'intermédiaire de formule (II) dans lequel R7 est un radical hydrocarboné (CH3, C2H5, C3H7...), la fonction nitrile de l'intermédiaire obtenu comme précédemment est traitée par l'hydrure de diisobutylaluminium dans un solvant aprotique tel que le toluène à une température comprise entre -78°C et 0°C suivi d'une hydrolyse en milieu acide (HC1 aqueux). L'aldéhyde ainsi obtenu est ensuite condensée avec une aminé aliphatique primaire en présence d'un réducteur, selon une méthode bien connue de l'homme de métier comme "amination réductrice" pour laquelle on utilise préférentiellement un réducteur tel que le borohydrure de sodium (éthanol, 0°C à 40°C).R2, R3, Z are defined as in the general formula (I) and in which n = 1 and X≈NR is preferably produced by condensation of an amine (VIII) with a benzyl bromide of formula (Vllb)

monitoring of the reduction of the nitrile function, the protocol of which can be chosen according to the nature of the radical R7; thus, to prepare the intermediate of formula (II) in which R7 is hydrogen, the nitrile function of the intermediate obtained previously is treated with lithium aluminum hydride in an anhydrous solvent such as ether or THF, at a temperature between -10 ° C and 30 ° C. To prepare the intermediate of formula (II) in which R7 is a hydrocarbon radical (CH3, C2H5, C3H7 ...), the nitrile function of the intermediate obtained as above is treated with diisobutylaluminum hydride in an aprotic solvent such as toluene at a temperature between -78 ° C and 0 ° C followed by hydrolysis in acidic medium (aqueous HC1). The aldehyde thus obtained is then condensed with a primary aliphatic amine in the presence of a reducing agent, according to a method well known to those skilled in the art as "reducing amination" for which a reducing agent such as sodium borohydride is preferably used ( ethanol, 0 ° C to 40 ° C).

The preparation of intermediates of general formula (II) in which R \, R2, R3 and Z are defined as above, n = zero and X = NCOR'7 is preferably carried out by condensation of an amine of formula (VIII) with a benzyl bromide of formula (VIIc)

suivi de la réduction de la fonction nitro en aminé [par des méthodes appropriées et compatibles avec la nature des substituants et, en particulier, en utilisant le chlorure d'étain hydraté dans l'éthanol ou l'isopropanol, à une température comprise entre 0° et 20°C] qui est ensuite acylée par les méthodes usuelles, c'est-à-dire en utilisant un chlorure d'acide (R^COCl) ou un anhydride ((R'7CO)2θ) dans lesquels R'7 est décrit comme précédemment, dans un solvant inerte tel que le dichloromethane, le chloroforme, l'acétonitrile ou le THF à une température comprise entre 0 et 25 °C en présence ou non d'une base aminée telle que la triéthylamine, la di- isopropyléthylamine ou la N-méthylmorpholine.

monitoring of the reduction of the nitro function to the amino [by methods suitable and compatible with the nature of the substituents and, in particular, by using tin chloride hydrated in ethanol or isopropanol, at a temperature between 0 ° and 20 ° C] which is then acylated by the usual methods, that is to say using an acid chloride (R ^ COCl) or an anhydride ((R'7CO) 2θ) in which R'7 is described as above, in an inert solvent such as dichloromethane, chloroform, acetonitrile or THF at a temperature between 0 and 25 ° C in the presence or not of an amino base such as triethylamine, di- isopropylethylamine or N-methylmorpholine.

The preparation of intermediates (II) in which n = zero and X is an oxygen atom is preferably carried out by condensation of an amine of formula (VIII) with a benzyl bromide of formula (VIId) (prepared as described in J. Med. Chem. 11, 3509, 1992)

suivi de la déprotection de l'éther silylé par les méthodes connues pour ce type de déprotection telles que l'utilisation du fluorure de césium ou de tétrabutylammonium dans le THF ou l'utilisation d'un milieu acide tel que l'acide citriα : dans un solvant polaire tel que l'éthanol. L-ii les cas particuliers où n=2, et X est un oxygène, les intermédiaires de formule générale (II) sont préparés par condensation d'une aminé de formule générale (VIII) avec un composé de formule générale (VII) dans lequel Y' est un bon groupe partant tel qu'un brome ou un mésylate, m > 2 et X' est une forme protégée d'un alcool tel qu'un éther silylé, un éther tritylé, ou un éther tétrahydropyrannique, suivi de la déprotection de la fonction alcool qui sera dépendante du groupe protecteur choisi (cf. T.W. Greene, Protective Groups in Organic Synthesis, John Wii.-y & Sons, N.Y., 1981).

monitoring of the deprotection of silylated ether by the methods known for this type of deprotection such as the use of cesium or tetrabutylammonium fluoride in THF or the use of an acid medium such as citriα acid: in a polar solvent such as ethanol. L-ii the special cases where n = 2, and X is an oxygen, the intermediates of general formula (II) are prepared by condensation of an amine of general formula (VIII) with a compound of general formula (VII) in which Y 'is a good leaving group such as a bromine or a mesylate, m> 2 and X' is a protected form of an alcohol such as a silyl ether, a trityl ether, or a tetrahydropyrannical ether, followed by deprotection of the alcohol function which will be dependent on the protective group chosen (cf. TW Greene, Protective Groups in Organic Synthesis, John Wii.-y & Sons, NY, 1981).

The preparation of intermediates of general formula (II) by condensation of the amines (VIII) with the benzylic derivatives of general formula (II) in which Y 'and R3 are described as above and where X' is a precursor of X in various ways such as illustrated above is generally carried out in a polar aprotic solvent such as DMSO, DMF, DME or THF, at a temperature between 0 ° and 50 ° C, in the presence of a base such as ^ uOK, K2CO3 , KHCO3, CS2CO3, KOH or NaOH, a preferred method being the use of K CO ₃ in DMF at 20 ° C.

The amines of general formula (VIII) are prepared by different methods well known to those skilled in the art and which are adapted from reactions used in the chemistry of acetylenes as described in Brandsma, L. Preparative acetylenic chemistry (studies in organic chemistry, vol. 34) 2 ^{n <} ^ Ed., Elsevier, Amsterdam, 1988.

Some examples of the methods used depending on the nature of Z are described here. In the particular cases where Z is a double bond, the amines of general formula (VIII) can be prepared by the methods and techniques described in J. Med. Chem. 22, 1539 (1984), Tetrahedron, 41, 5685 (1985), Tetrahedron Lett. 3145 (1989), Tetrahedron Lett. 22, 1509 (1989), J. Med. Chem. 14, 65-73 (1991) and Pestic. Sci. 3_L, 437 (1991) as well as in European patent application 0421 302 A2.

In the particular case where Z represents a triple bond, the amines of general formula (VIII) can be prepared by the well-known method which consists in condensing a terminal acetylene derivative with a bromo-1-acetylene in the presence copper (I) chloride or iodide and NH2OH [cf. Proc. Chem. Soc, 340 (1963), Tetrahedron Lett., 1953 (1965), Synthesis, 1, 230 (1984), CR Acad. Sci. 260. 215 (1965)] or in the presence of palladium and Cul in THF [cf. Synth. Common. 21, 977 (1991)]. Thus, the amines of general formula (VIII) in which Z is a triple bond are preferably prepared by condensation of an acetylene derivative of general formula (IX), according to the methods described above,

^{2 H} (IX)

with an acetylene bromide of general formula (X)

^{x "} (X) in which X" represents the NRj group but can also represent a hydroxyl radical, which, after condensation of (IX) with (X) can be transformed into NR7 by well-known methods for converting a propagyl alcohol into an amine propargyl [cf. Bull. Soc. Chim. Fr., 4368 (1971), Ang. Chem. £ 2, 357 (1975), Tetrahedron Lett. Ifi, 3967 (1989), Tetrahedron Lett. 2S, 2207 (1987)]. The amines of general formula (VIII) in which Z is an acetylene can also be prepared by the same type of methods and techniques but by condensing an acetylenic bromide of structure (XI) with a terminal acetylenic derivative of structure (XII)

R, = - Br H - ΞΞΞ (CH,) - X " ^{2 B} (XI) ^2} (XII)

in which R2 and X "are described and handled as above.

The amines of general formula (VIII) in which Z represents a linear or branched hydrogen-carbon radical comprising from 2 to 4 carbon atoms are generally prepared by transformation of an intermediate alcohol (XIII) in which

R, ^ Ξ≡- (CH _!, N.OH _(χm)

R2 is defined as above and n is between 2 and 4 to the desired amine, for example by nucleophilic substitution of the mesylate or of the alcohol-derived triflate with sodium azide or potassium phthalimide followed by a transformation of the intermediate (azide or phthalimide) in amine by the methods described above. An alternative method which is particularly appreciated for preparing the amines of general formula (VIII) in which Z = CH2-CH2 consists in treating an ester of formula (XIV) in which

GOLD'

° (XIV)

R 'is a phenyl or alkyk with propargyl bromide (R2C = C-CH 2 Br) wherein R2 is as described previously in ^NCLUSION sodium salt of hexamethyldisilazane [cf. Tetrahedron Asymm., 2, - 5 (1991), Tetrahedron Lett., 2433 (1973), Tetrahedron Lett. 4135 (1975)] followed by hydrolysis of the ester into acid, activation of the acid by thionyl chloride or oxalyl chloride in the presence of a base such as triethylamine or N- methyl-morpholine, condensation of the acid chloride thus formed with an amine (R1NH2 in which finished as above) and reduction of the amide thus formed by

It should be emphasized here that the amines of general formula (VIII) in which R2 and Z are defined as above and R \ is different from hydrogen can also be prepared from the amines of general formula (VIII) in which R2 and Z are defined as above and where Rj represents hydrogen by conventional methods of monoalkylation of primary amines (reaction with an alkyl halide (R \ X where X = Br, Cl)) and by conventional methods of forming an amide or a suitable carbamate followed by a reduction of the amide or carbamate by reaction with a reducing agent such as LiAlH ₄ . The derivatives of general formula (III) in which R4 represents a hydrocarbon radical substituted with a silylated residue are prepared by techniques and methods well known to those skilled in the art and which are described in "Silicon reagents in organic synthesis" (EW Colvin , Académie press, 1988), "The chemistry of organic silicon compounds" (S. Pataï, Z. Rappoport, John Wiley, 1989) and "Silicon reagents for organic synthesis" (WP Weber, Springer-verlag, 1983). The aminomethylsilanes were preferably prepared by the method described by JE Noll et al (J. Amer. Chem. Soc, 73, 3867, 1951) and a particularly preferred method for preparing the α-silanols was described in the patent application GB2174993. All the methods which make it possible to transform a derivative of general formula (I) into another derivative of general formula (I) should also be considered as an integral part of the present invention. Thus the thiocarbonates (I) in which Y represents a sulfur atom can also be prepared from the corresponding derivatives of general formula (I) in which Y represents an oxygen by reaction for example with the Lawesson reagent (cf. for example Synthesis, H, 936, 1983 Heterocycles, JL9-, 2283, 1982) P2S5, P4S10 (see for example Annalen der Chemie, 746, 92, 1971). By way of nonexclusive example, let us also cite the case of derivatives of general formula (I) in which R3 represents a hydroxyl group; these products can be prepared from other derivatives of general formula (I) in which R3 represents an acyloxy (R'3 CO2) or alkoxy (R ^ O) radical by the methods and techniques well known for this type of transformation. It will therefore be understood that in some of the above transformations, it may be necessary or desirable to protect possible sensitive groups of the molecule in question in order to avoid undesirable side reactions. This can be achieved by the use of conventional protecting groups such as those described in "Protective Groups in Organic Synthesis" ed. JF McOwie, Plenum Press, 1973 and in TW Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, 1981. Protective groups can be removed at any suitable later stage, using the methods and techniques also described in references cited above.

When it is desired to isolate a compound according to the invention in the form of a salt, for example in the form of a salt formed by addition with an acid, this can be achieved by treating the free base of general formula (I) with an appropriate acid, preferably in equivalent amount, or by creatinine sulfate in an appropriate solvent.

When the processes described above for preparing the compounds of the invention give mixtures of stereoisomers, these isomers can be separated by conventional methods such as preparative chromatography.

When the new compounds of general formula (I) have one or more asymmetric centers, they can be prepared in the form of a racemic mixture or in the form of enantiomers, either by enantioselective synthesis or by resolution. The compounds of formula (I) having at least one asymmetric center can for example be separated into their enantiomers by the usual techniques such as the formation of diastereomeric pairs by formation of a salt with an optically active acid such as the acid (- ) di-p-toluoyl-1- tartaric acid (+) di-p-toluoyl-tartaric acid (+) camphor sulfonic acid (-) camphor sulfonic, (+) phenylpropionic acid, (-) phenylpropionic acid, followed by fractional crystallization and regeneration of the free base.

In general, the compounds of formula (I) can be purified by the usual methods, for example by crystallization (in particular when the compounds of formula (I) are isolated in the form of salt), chromatography or extraction.

The following examples illustrate the invention without, however, limiting its scope.

General procedure applying to examples A to E

To a solution (1M) of amine or alcohol and of triphosgene (1/3 eq.) In dioxane is added triethylamine (1 eq.) Then the medium is stirred at room temperature or at reflux until the complete disappearance of the starting materials in thin layer chromatography (TLC).

The alcohol (1.2 eq.) Or the amine (1.2 eq.) In solution (1 M) in dioxane and triethylamine (1 eq.) Are then added to the reaction medium and the resulting solution is stirred at room temperature or at reflux until the isocyanate or the intermediate carbamoyl chloride (CCM) has completely disappeared.

The reaction medium is then diluted in ether and washed with water. The organic phase is dried over magnesium sulfate, filtered and evaporated. "Flash" purification of the crude oil obtained on a silica column makes it possible to obtain the compounds described in examples A to E.

Example A: Synthesis of l - [(phenyl-dimethyl-silyl) -methyl] -3 - [(E) -3-

{N-ethyl-N (6,6-dimethy l-2-hepten-4-ynyl) -aminomethyl} - benzyl] -carbamate 1 ^

Ce composé est obtenu à partir de la (E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4- ynyl)-3-(aminomethyl)-benzylamine (500mg; 1.75mmoles) et d' hydroxyméthyl- phényldiméthylsilane (350mg; 2.1mmoles; 1.2éq.) selon le mode opératoire général décrit précédemment. a) Formation de l'isocyanate: chauffage au reflux pendant 2 heures b) Formation de 1 ^ : température ambiante pendant 2 heures

This compound is obtained from (E) -N-ethyl-N- (6,6-dimethyl-2-hepten-4-ynyl) -3- (aminomethyl) -benzylamine (500mg; 1.75mmoles) and hydroxymethylphenyldimethylsilane (350mg; 2.1mmoles; 1.2éq.) according to the general procedure described above. a) Formation of the isocyanate: heating at reflux for 2 hours b) Formation of 1 ^: room temperature for 2 hours

"Flash" purification of the oil obtained on a silica column (90/10 Petroleum Ether / Ethyl Ether) allows the expected product to be obtained in the majority fraction in the form of a light yellow oil (450 mg; 54% ).

IR (Film, cm-1): 3335; 2980; 2190; 1714; 1539; 1255; 865

NMR (CDC1 ₃ , 200 MHz, ppm)

7.60-7.10; M; 9H;

6.10; td; 1H; 17.8 / 6.4Hz; 5.65; td; 1 H; 17.8 / 1.2Hz;

4.94; brs; 2H;

4.32; d; 2H; 6 Hz;

4.00; s; 2H;

3.56; s; 2H; 3.12; dd; 2H; 6.4Hz;

2.57; q; 2H; 7.2Hz;

1.25; s; 9H;

1.05; t; 3H; 7.2Hz;

0.05; s; 6H. Elementary Analysis for: C29H4 () N2θ2Si

C H N

Calculated 73.06 8.46 5.88 Found 74.13 8.72 5.79 Example B: Synthesis of l - [(phenyl-dimethyl-silyl) -methyl] -3 - [(E) -3-

{N-ethy 1-N (6,6-dimethy l-2-hepten-4-yny l) -aminomethy 1}

(N'-ethyl) -benzyl] -carbamate Ir- $

17

17

This compound is obtained from (E) -N-ethyl-N- (6,6-dimethyl-2-hepten-4-ynyl) -3- (N-ethyl-aminomethyl) -benzylamine (350mg; 1.12mmoles ) and hydroxymethyl-phenyldimethylsilane (225mg; 1.34mmoles; 1.2éq.) according to the general procedure described above. a) Formation of carbamoyl chloride: heating at reflux for 3 hours b) Formation of. : heating at reflux for 3 hours A "flash" purification of the oil obtained on a silica column (90/10 Petroleum Ether / Ethyl Ether) allows the expected product to be obtained in the majority fraction in the form of an oil light yellow (250mg, 45%). IR (Film, cm-1): 2980; 2190; 1700; 1255; 865

NMR (CDCI3, 200 MHz, ppm)

7.60.-6.95; M; 9H;

6O; td; 1H; 17.8 / 6.4Hz;

5. i; td; 1H; 17.8 / 1.2Hz; 4.42; brs; 2H;

4.00; brs; 2H;

3.55; s; 2H;

3.40-3.10; brm; 2H;

3.07; dd; 2H; 6.4Hz; 2.57; q; 2H; 7.2Hz;

1.25; s; 9H;

1.01; t; 3H; 7.2Hz;

0.45-0.25; m; 6H.

Elementary Analysis for: C3} H44N2θ2Si C H N

Calculated 73.76 8.79 5.55

Found 73.74 8.84 5.25

Example C: Synthesis of l - [(phenyl-dimethyl-silyl) -methyl] -3 - [(E) -3-

{N-ethyl-N (6,6-dimethy l-2-hepten-4-yny l) -aminomethy 1} - phenyl] -carbamate IQ

⁽ⁱc⁾ 18

⁽ⁱ c ⁾ 18

This compound is obtained from 3 - [(E) -N-ethyl-N- (6,6-dimethyl-2-hepten- 4-ynyl)] - aniline (300mg; 1.Oόmmoles) and hydroxymethyl-phenyldimethylsilane (210 mg; 1.27 mmol; 1.2 eq.) according to the general procedure described above. a) Formation of isocyanate: room temperature for 15 minutes b) Formation of IA: heating under reflux for 5 hours

"Flash" purification of the oil obtained on a silica column (95/5 Ether

Petroleum / Ethyl acetate) makes it possible to obtain, in the majority fraction, the expected product in the form of a light yellow oil (98 mg, 20%).

IR (Film, cm-1): 3330; 2970; 2190; 1711; 1539; 1210; 840.

NMR (CDC1 ₃ , 200 MHz, ppm)

7.63-6.95; m; 9H;

6.60; brs; 1H;

6.10; td; 1H; 16.1 / 6.2Hz;

5.68; d; 1H; 16.1Hz;

4.06; s; 2H;

3.55; s; 2H;

3.11; d; 2H; 6.2Hz;

2.52; q; 2H; 7.0Hz;

1.25; s; 9H;

1.01; t; 3H; 7.0Hz;

0.42; s; 6H.

Elementary Analysis for: C28H3çN2θ2Si

C H N

Calculated 72.68 8.28 6.05

Found 72.04 8.02 5.87

Example D: Synthesis of l - [(phenyl-dimethyl-silyl) -methyl] -3 - [(E) -3-

{N-ethyl-N (6,6-dimethyl-2-hepten-4-yny l) -aminomethyl} - phenyl] -uree Irj

This compound is obtained from 3 - [(E) -N-ethyl-N- (6,6-dimethyl-2-hepten- 4-ynyl)] -aniline (300mg; 1.Oόmmoles) and from ( phenyldimethylsilyl) -methyl-amine (210mg; 1.27mmoles; 1.2éq.) According to the general procedure described above. a) Isocyanate formation: room temperature for 15 minutes b) IA formation: heating at reflux for 4 hours A "flash" purification of the oil obtained on a silica column (70/30 Petroleum Ether / Acetate ethyl) makes it possible to obtain in the majority fraction the expected product in the form of a light yellow oil (230, 47%).

IR (Film, cm-1): 3330; 2970; 2190; 1650; 1255; 1115; 865

NMR (CDCI3, 200 MHz, ppm) 7.58-6.95; m; 9H;

6.60; brs; 1H;

6.10; td; 1H; 16.1 / 6.2Hz;

5.68; d; 1H; 16.1Hz;

4.73-4.63; m; 1H; 3.55; s; 2H;

3.11; d; 2H; 6.2Hz;

2.93; d; 2H; 5.2Hz;

2.52; q; 2H; 7.0Hz;

1.25; s; 9H; 1.01; t; 3H; 7.0Hz;

0.35; s; 6H.

Elementary Analysis for: C28H39N3θSi

C H N

Calculated 72.84 8.51 9.10 Found 73.29 8.53 9.07

Example E: Synthesis of l - [(methyl-2-phenyl-2-propyl] -3 - [(E) -3- {N- ethyl-N (6,6-dimethyl-2-hepten-4-yny l ) -aminomethy 1} - benzylj-carbamate Ijg

Ce composé est obtenu à partir de la (E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4- ynyl)-3-(aminomethyl)-benzylamine (500mg; 1.75mmoles) et du methyl-2-phenyl- 2-propanol (315mg; 2. Immoles; 1.2éq.) selon le mode opératoire général décrit précédemment. a) Formation de l'isocyanate: température ambiante pendant 15 minutes b) Formation de IA : chauffage au reflux pendant 15 heures avec 1 éq. de triéthylamine puis pendant 6 heures avec 1 éq. d'hydrure de sodium.

This compound is obtained from (E) -N-ethyl-N- (6,6-dimethyl-2-hepten-4-ynyl) -3- (aminomethyl) -benzylamine (500mg; 1.75mmoles) and methyl -2-phenyl- 2-propanol (315mg; 2. Immoles; 1.2éq.) According to the general procedure described above. a) Formation of isocyanate: room temperature for 15 minutes b) Formation of IA: heating at reflux for 15 hours with 1 eq. of triethylamine then for 6 hours with 1 eq. sodium hydride.

"Flash" purification of the oil obtained on a silica column (80/20 Petroleum Ether / Ethyl acetate) makes it possible to obtain, in the majority fraction, the expected product in the form of a light yellow oil (200 mg, 25%).

IR (Film, cm-1): 3317; 2980; 2190; 1722; 1522; 1255; 865

NMR (CDC1 ₃ , 200 MHz, ppm)

7.60-7.10; M; 9H;

6.10; td; 1H; 17.8 / 6.4Hz; 5.65; td; 1H; 17.8 / 1.2Hz;

4.94; brs; 2H;

4.32; d; 2H; 6 Hz;

4.00; s; 2H;

3.56; brs; 2H; 3.12; brd; 2H; 6.4Hz;

2.57; q; 2H; 7.2Hz;

1.33; s; 6H

1.20; s; 9H

1.05; t; 3H; 7.2Hz. Elementary Analysis for: C3OH40N2O2

C H N

Calculated 78.22 8.75 6.08

Found 77.09 8.55 6.05

Example F: Synthesis of the hydrochloride of l - [(E) -3- {N-ethyl-N (6,6-dimethyl-2-hepten-4-ynyl) -aminomethyl} phenyl] -3-

(benzyl) -carbamate Ip

A une solution de (E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-hydroxy- benzylamine (500mg; 1.84mmoles) et de benzylisocyanate (294mg; 2.21mmoles; 1.2éq) dans le dioxanne est additionnée de la triéthylamine (3.68mmoles, 2éq.). Le milieu résultant est alors agité 1 heure à la température ambiante puis il est dilué dans l'ether et lavé avec de l'eau. La phase organique est séchée sur sulfate de magnésium, filtrée et évaporée.

To a solution of (E) -N-ethyl-N- (6,6-dimethyl-2-hepten-4-ynyl) -3-hydroxybenzylamine (500mg; 1.84mmoles) and benzylisocyanate (294mg; 2.21mmoles; 1.2 eq) in dioxane is added triethylamine (3.68 mmol, 2 eq.). The resulting medium is then stirred for 1 hour at room temperature then it is diluted in ether and washed with water. The organic phase is dried over magnesium sulfate, filtered and evaporated.

"Flash" purification of the oil obtained on a silica column (80/20 Petroleum Ether / Ethyl acetate) makes it possible to obtain, in the majority fraction, the expected product in the form of a light yellow oil (350 mg, 47%). The hydrochloride salt is obtained by treatment with an ether solution saturated with hydrochloric acid. IR (KBr, cm-1): 3230; 2970; 2500; 2190; 1740; 1529; 1230; 700 NMR (CDC1 ₃ , 200 MHz, ppm) 12.8; brm, 1H 7.50-7.15; M; 9H; 6.35-6.15; brm; 1H; 5.80; brd; 1H; 16.1Hz; 5.50; brm; 1H 4.32; d; 2H; 6 Hz; 4.10; brm; 2H; 3.75-3.40; brm; 2H; 3.25-2.85; brm; 2H; 1.05; t; 3H; 7.2Hz; 1.23; s; 9H. Elementary Analysis for: C26H33CIN2O2

C H N

Calculated 70.81 7.54 6.35

Found 69.68 7.62 6.01

Example G: Synthesis of 1- [benzyl] -3 - [(E) -3- {N-ethyl-N (6,6-dimethyl-

2-hepten-4-ynyl)} - aminomethyl} benzyl] -carbamate lQ

To a solution of (E) -N-ethyl-N- (6,6-dimethyl-2-hepten-4-ynyl) -3-

(aminomethyl) -benzylamine (500mg; 1.75mmoles) and benzyl chloroformate (360mg; 2. Immoles; 1.2éq) in dioxane is added with triethylamine (3.5mmoles, 2 eq.). The resulting medium is then stirred for 2 hours at room temperature then it is diluted in ether and washed with water. The organic phase is dried over magnesium sulfate, filtered and evaporated.

"Flash" purification of the oil obtained on a silica column (80/20 Petroleum Ether / Ethyl acetate) makes it possible to obtain, in the majority fraction, the expected product in the form of a light yellow oil (212 mg, 29%).

IR (KBr, cm-1): 3330; 2990; 2190; 1705; 1522; 1259; 700

NMR (CDCI3, 200 MHz, ppm)

7.40-7.10; M; 9H; 6.10; td; 1H; 17.8 / 6.4Hz;

5.65; td; 1H; 17.8 / 1.2Hz;

5.14; s; 2H

5.10-5.00; brs; 1H

4.37; d; 2H; 6 Hz; 3.54; s; 2H;

3.12; brd; 2H; 6.4Hz;

2.57; q; 2H; 7.2Hz;

1.20; s; 9H;

1.05; t; 3H; 7.2Hz. Elemental Analysis for: C27H34N2O2

C H N

Calculated 77.48 8.19 6.69

Found 76.11 8.02 6.50

Pharmacological assessments 1 - In vitro inhibition study of pig squalene epoxidase:

The study was carried out according to the technique described by M. Bai and G.D. Prestwich (Arch. Biochem. Biophys., 221, 305-313, 1992).

Under these conditions and by way of example, the compounds 1 ^ and Ip were characterized as inhibitors of squalene epoxidase with IC50s of 0.2 and 0.1 μM respectively.

2 - Study of the oxidation of rat liver microsomes

The study was carried out according to the technique described in the reference "Antioxidative properties of harmane and carboline Alkaloids", Susanna Y.H. Tse, I-Tong Mak and Benjamin F. Dickens, Biochemical Pharmacology, Vol 42, N ° 3, pp. 459-464, 1991.

Principle

In the presence of Fe 3+ and ADP, dihydroxyfumaric acid (DHF) undergoes autoxidation which generates oxygenated free radicals. 23

These lead to the peroxidation of microsomal hepatic lipids. The latter is measured using the thiobarbituric acid technique (formation of TBARS, thiobarbituric acid reactant species, eg MDA or Malondialdehyde). Under these conditions and by way of example, the derivatives 1 ^ and Iβ have been shown to be antioxidants with an IC50 of 5 μM. 3 - Study of the inhibition of ACAT

The inhibitory activity of ACAT (acetylCoA-cholesterol-O-acyltransferase enzyme) of the compounds was evaluated in vitro according to the procedure of H-Chauton et al. (Analytical Biochemistry, 122 436-439, 1988). Under these conditions and by way of example, the compound Irj was characterized as an ACAT inhibitor with an IC50 of 7 μM.

The present invention also relates to medicaments consisting of at least one compound of formula (I) in the pure state or in the form of a composition in which it is associated with "; t other pharmaceutically compatible product, which may be inert or physiologically active. The medicaments according to the invention can be used orally, parenterally, rectally, topically or any other route of administration.

As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon. These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.

As liquid compositions for oral administration, there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol. vegetable oils or paraffin oil. These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.

The sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, esters can be used. injectable organic substances, for example ethyl oleate or other suitable organic solvents. These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.

The doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 0.001 g and 1 g (preferably between 0.005 g and 0.25 g) per day, preferably orally for an adult with unit doses ranging from 0.1 mg to 500 mg of active substance, preferably from 1 mg to 50 mg.

In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated. The following examples illustrate compositions according to the invention [in these examples, the term "active component designates one or more (generally one) of the compounds of formula (I) according to the present invention]: Tablets They can be prepared by direct compression or passing through granulation in the wet. The procedure by direct compression is preferred but it may not be suitable in all cases depending on the doses and the physical properties of the active component. A - By direct compression mg for 1 tablet active component 10, 0 microcrystalline cellulose PCB 89.5 magnesium stearate 0.5

100.0 The active component is passed through a "sieve with a mesh opening of 250 μm side, it is mixed with the excipients and it is compressed using 6.0 mm punches. Tablets can be prepared with other mechanical resistance by modifying the compression weight with the use of appropriate punches B - Wet granulation mg for one tablet active component 10.0 lactose Codex 74.5 starch Codex 10.0 pregelatinized corn starch Codex 5.0 magnesium stearate 0.5

Compression weight 100.0

The active component is passed through a sieve with a mesh opening of 250 μm and mixed with lactose, starch and pregelatinized starch. The mixed powders are moistened with purified water, they are granulated, dried, sieved and mixed with magnesium stearate. The lubricated granules are put into tablets as for the formulas by compress ^: <n direct. A coating film can be applied to the tablets using suitable film-forming materials, for example methylcellulose or hydroxy-propyl-methyl-cellulose, according to conventional techniques. Sugar tablets can also be coated. Mg capsules for one active component capsule 10.0

* starch 1500 89.5 magnesium stearate Codex 0_ _» 5_

Filling weight 100.0

* a form of directly compressible starch from the firm Colorcon Ltd, Orpington, Kent, United Kingdom. The active component is passed through a sieve with a mesh opening of 250 μm and mixed with the other substances. The mixture is introduced into hard gelatin capsules No. 2 on an appropriate filling machine. Other dosage units can be prepared by changing the filling weight and, if necessary, changing the size of the capsule. Syrup mg per 5 ml dose active ingredient 10.0 sucrose Codex 2750.0 glycerin Codex 500.0 buffer) flavor) color) qs preservative) distilled water 5.0

The active component, the buffer, the flavor, the color and the preservative are dissolved in part of the water and the glycerin is added. The remaining water is heated to

80 ° C and the sucrose is dissolved therein and then cooled. The two solutions are combined, the volume is adjusted and mixed. The syrup obtained is clarified by filtration. Suppositories

Active ingredient 10.0 mg

* Witepsol H15 supplement to 1.0 g

* Brand sold for Adeps Solidus of the European Pharmacopoeia.

A suspension of the active component in Witepsol H15 is prepared and introduced into a suitable machine with 1 g suppository molds.

Liquid for administration by intravenous injection g / 1 active component 2.0 water for injection Codex complement to 1000.0 Sodium chloride can be added to adjust the tone of the solution and adjust the pH to maximum stability and / or to facilitate dissolving the active component by means of a dilute acid or alkali or by adding appropriate buffer salts. The solution is prepared, clarified and introduced into ampoules of appropriate size which are sealed by melting the glass. The liquid for injection can also be sterilized by heating in an autoclave according to one of the acceptable cycles. The solution can also be sterilized by filtration and introduced into a sterile ampoule under aseptic conditions. The solution can be introduced into the ampoules in a gaseous atmosphere. Cartridges for inhalation g / cartridge active component mironized 1.0 lactose Codex 39.0 The active component is micronized in a fluid energy mill and brought to the state of fine particles before mixing with lactose for tablets in a high blender energy. The powder mixture is introduced into hard gelatin capsules No. 3 on an appropriate encapsulating machine. The contents of the cartridges are administered using a powder inhaler. Pressure aerosol with metering valve mg / dose for 1 can of micronized active ingredient 0.500 120 mg oleic acid Codex 0.050 12 mg ^τ richlorofluoromethane for pharmaceutical use 22.25 5.34 g

dichlorodifluoromethane for pharmaceutical use 60.90 14.62 g

The active component is micronized in a fluid energy mill and put into the state of fine particles. The oleic acid is mixed with the trichlorofluoromethane at a temperature of 10-15 ° C. and the micronized drug is introduced into the solution using a mixer with a high shearing effect. The suspension is introduced in measured quantity into aluminum aerosol cans on which are fixed appropriate metering valves delivering a dose of 85 mg of the suspension; dichlorodifluoromethane is introduced into the boxes by injection through the valves.

In general, the pharmaceutical compounds which are the subject of the present invention are useful for the treatment and prevention of mycoses and other infections of fungal origin, for example due to trichophyton quinckeanum, microsporum canis, aspergillus fumagitus, sporotrychium schenkii candida albicans.

Claims

Claims: 1. New compounds corresponding to the general formula (I) R.

(I) in which, R \ represents a hydrogen atom, a hydrocarbon radical containing from 1 to 5 carbon atoms in a straight or branched chain, or a cycloalkyl comprising from 3 to 7 carbon atoms. R2 represents a hydrocarbon radical containing from 1 to 6 carbon atoms in a straight or branched chain optionally substituted by a methoxy, ethoxy radical, or a trimethylsilylated or triethylsilylated residue. R3 represents a hydrogen, fluorine, chlorine or bromine atom, a hydrocarbon radical comprising from 1 to 6 carbon atoms in a straight or branched chain, a hydroxy, thio, acyloxy (R'3CO2) alkoxy (R 'radical) 30) or alkylthio, in which R'3 is a linear or branched hydrocarbon radical comprising from 1 to 6 carbon atoms. R4 represents an aromatic ring, a cycloalkyl, a heterocycle or a hydrocarbon radical containing from 1 to 6 carbon atoms in a straight or branched chain and which can itself be substituted by an aromatic ring (such as a variously substituted phenyl), a heterocyl, a cycloalkyl or a silylated residue in which the silicon is substituted by radicals R5, Rg and R7. R5 and R, which are identical or different, each represent a branched or linear hydrocarbon radical containing from 1 to 6 carbon atoms or a cycloalkyl residue containing from 3 to 8 carbon atoms or an aryl residue such as phenyl. R7 represents a linear or branched hydrocarbon radical comprising from 1 to 6 carbon atoms, a cycloalkyl radical comprising from 3 to 8 carbon atoms, an aryl or alkylaryl radical in which the aryl group may for example be phenyl, naphthyl, thiophene, furan , pyridine, optionally substituted with a linear or branched hydrocarbon radical comprising from 1 to 6 carbon atoms optionally a double bond, an alkoxy (R'όO), amino (NR'gR'ό), alkylthio (^ R'ό) radical [in which R'g is hydrogen or an alkyl radical], a halogen (fluorine, chlorine or bromine), a nitro radical or an aryl radical. Z represents a linear or branched hydrocarbon radical comprising from 2 to 6 carbon atoms, a triple bond, a double bond (Z'CH = CHZ ") of stereochemistry Z or E in which Z 'and Z" identical or different represent an atom hydrogen, a fluorine atom, or a linear or branched hydrocarbon radical comprising from 1 to 6 carbon atoms; n = 0, 1 or 2; X and X ', which are identical or different, represent O or NR' where R '\ represents a hydrogen atom, a cyclic or linear hydrocarbon radical comprising from 1 to 5 carbon atoms Y = O, S The compounds of formula (I) containing one or more asymmetric centers have isomeric forms. The racemates and pure enantiomers of these compounds are also part of this invention. The invention also includes the salts, solvates (for example hydrates) and bioprecursors of these compounds acceptable for therapeutic use. 2. Compounds according to claim 1, characterized in that X is oxygen or represents NH. 3. Compounds according to one of claims 1 or 2 characterized in that n represents 1 or zero. 4. Compounds according to one of claims 1 to 3 characterized in that Y represents an oxygen. 5. Compounds according to one of claims 1 to 4 characterized in that R3 represents a hydrogen and R2 represents a tbutyl. 6. Compounds according to one of claims 1 to 5 characterized in that R4 represents a linear or branched hydrocarbon radical substituted by a silyl group defined as Si R5R6R7. 7. Compounds according to one of claims 1 to 6 characterized in that Z represents a double bond of stereochemistry E. 8. Process for preparing the compounds of general formula (I) according to one of claims 1 to 7 characterized in that a derivative of general formula (II) is condensed

in which R \, R2, R3, Z, n and X are described as in the general formula (I) and a derivative of formula (III): R4 - X - H (III) in which X 'and R4 are described as in formula (I) with a derivative of general formula (IV) Xl - C - X ₂ (IV) in which Y is defined as above and X, X2, identical or different, each represent a pArtant group such as a halogen, an O-alkyl group (in particular the OCCI3 group), a succinimyl, phtatyl or imidazole group. 9. Pharmaceutical compositions containing, as active ingredient, a derivative of formula (I), according to one of claims 1 to 7, in combination with a pharmaceutical vehicle acceptable as a medicament. 10. Pharmaceutical compositions containing, as active ingredient, a derivative of formula (I) according to one of claims 1 to 7, in combination with a pharmaceutical vehicle acceptable for the preventive and curative treatment of atherosclerosis. 11. Pharmaceutical compositions containing, as active ingredient, a derivative of formula (I), according to one of claims 1 to 7, in combination with a pharmaceutical vehicle acceptable for the treatment and prevention of mycoses and other infections d 'fungal origins (for example due to trichophyton quinckeanum, microsporum canis, aspergillus fumagitus, sporotrychium schenkii or candida albicans).