EP0500713A1

EP0500713A1 - New derivatives of 3,3,5-trimethylcyclohexanol methyl-2 propionate, preparation method and therapeutical compositions containing them

Info

Publication number: EP0500713A1
Application number: EP90917206A
Authority: EP
Inventors: Claude Laruelle; Marcel Lepant
Original assignee: Panmedica SA
Current assignee: Panmedica SA
Priority date: 1989-11-13
Filing date: 1990-11-12
Publication date: 1992-09-02
Also published as: ES2052483T1; WO1991007373A1; JPH05501561A; KR927003506A; FR2654429B1; FR2654429A1; GR930300004T1; US5310757A

Abstract

Dérivés du méthyl-2 propionate de 3,3,5-triméthylcyclohexanol, leur procédé de préparation, ainsi que les compositions thérapeutiques les contenant. Ces dérivés répondent à la formule générale (I).Derivatives of 2, 3, 5-methyl-propionate trimethylcyclohexanol, process for their preparation, as well as the therapeutic compositions containing them. These derivatives correspond to the general formula (I).

Description

NOVEL DERIVATIVES OF METHYL-2 PROPIONATE OF 3,3,5-TRIMETHYLCYCLOHEXANOL, THEIR PREPARATION PROCESS AND THE THERAPEUTIC COMPOSITIONS CONTAINING THEM.

The present invention relates to new derivatives of 3,3,5-trimethylcyclohexanol 2-methyl propionate, to their process of preparation, as well as to the therapeutic compositions containing them.

Phenoxyisobutyric acids and their esters of the first terms have long been known as lipid-lowering agents and are used in therapy to correct lipidemia disorders. US Pat. No. 3,907,792 describes fenofibrate or (4-chloro-benzoyl) -4 phenoxy isobutyrate d ¹ isopropyl, and is used in therapy to treat hypercholesterolemias and hypertriglyceridemias. Other analogues, such as bezafibrate or acid ((4-chloro-benzamido) -2 ethyl) -4-2-phenoxy-2-methyl-propionic, described in US Patent 3,781,328, ciprofibrate or acid (2-dichloro , 2 cyclopropyl) -4 2-phenoxy-2-methyl-propionic acid described in the patent according to US 3,948,973 or even gemfibrozil described in patent US 3,674,836, are used as drugs and prescribed in lipidemia disorders.

Trimethyl-3,3,5 cyclohexanol, on the other hand, is known for its pharmacological properties, in particular vasodilators, and is used in cyclandelate, in the form of a mandelic ester. European Patent Application 157,151, for its part, teaches nicotinoyl-2 trimethyl-3,3,5 cyclohexanol mandelate, another vasodilator. Other simple esters have been described in this same field of activity. Mention may in particular be made of bis-phenoxyacetics (DE 2 326 061) and biphenylcarboxylic-4 (EP 57 141).

The object of the present invention is to provide new lipid-lowering compounds which unexpectedly exhibit lipid-lowering activity. very much higher than those of the corresponding 2-methylpropanoic acids or their esters on both triglycerides and cholesterol.

It is also an object of the invention to provide a process for the preparation of said compounds.

The subject of the present invention is derivatives of 3,3,5-trimethylcyclohexanol, characterized in that they correspond to the general formula:

in which ; n = 0,1,2,3,4 or 5

R ^ and R2 are identical or different and each tent représen¬ an atom ^'hydrogen or one of the following substi¬ tuants: 3 ^-H -OCH 3, -F, -CF _3, ethyl, propyl, hydroxy propyl, propionyl, acetyl-cyclopropyl, dichloro-2,2 cyclopropyl; a benzoyl-4 group in which the benzoyl ring can be substituted by one or more of the following units: Cl-, F-, Br-, CF3-, CH3-, CH3O-; a phenylacetyl-4 group; a phenyl group; a parachlorobenzoylamino-ethyl-4 group; or a group (3-phenoxy-propyl) -4 in which the phenyl ring can be substituted by one or more units chosen from Cl, Br, F, CF3, OCH3, CH ₃ .

The preferred compounds according to the invention are:

- (4-chloro-benzoyl) -4-2-phenoxy-2-methyl-3,3,5-trimethylcyclohexanol. - (2,2-dichloro-cyclopropyl) -4-2-phenoxy-2-methyl-2,3,5-trimethyl cyclohexanol pionate,

- (4-fluorophenoxy) -2 methyl-2-propion tri¬ methyl-3,3,5 cyclohexanol, - ((2,5-dimethylphenoxy) -3 propyl) -2 methyl-2 propio¬ nate trimethyl-3,3,5 cyclohexanol,

- ((4-chloro-benzamido) -2 ethyl) -4-2-phenoxy-2-methyl-3,3,5 trimethyl cyclohexanol.

Within the meaning of the present invention, the term 3,3,5-trimethyl cyclohexanol includes, as well the mixture of its CIS and TRANS isomers, as one of these isomers enriched CIS or TRANS or each of these iso¬ mothers in a pure state. Obviously, for each of these CIS or TRANS forms, we mean each optical isomer of configuration (R) or (S), having regard to the chirality of carbon in position 3 of the alcohol function or else of their racemic mixture.

The compounds according to the present invention have interesting lipid-lowering pharmacological properties and prove useful in the treatment of dysfunctions of lipidemia or cholesterolemia both in humans and in animals.

Indeed, the Applicant has found that the esters of trimethyl-3,3,5 cyclohexanol of 2-methylpropanoic acid substituted in 2 have antihypertriglyceridemic, hypocholesterolemic and lipid-lowering activities, much superior to those of methyl acids. -2 corresponding propanoics or their simple al yl esters. The products in accordance with the present invention have the advantage of exhibiting modulating activities of the enzymatic systems involved in the synthesis of cholesterol, giving them, by way of consequence, a particular interest in the treatment of atherosclerosis. The present invention also relates to a process for the preparation of esters in accordance with the invention, characterized in that the tri¬ methyl-3, 3, 5 cyclohexanol is reacted with a reactive form of an appropriate carboxylic acid, formula II, below:

in which n, R- ^ and R2 have the same meanings as above and R represents a halogen, an alkoxy group in which the alkyl group is in C - ^ - g, an O-CO- R 'group, in which R "is a C1-C6 alkyl group or a group

n, R- ^ and R2 having the same meanings as above, or an OH group, in the presence of an inert solvent and possibly a hydrogen acceptor.

When R is a halogen (bromine, chlorine, iodine in particular), the reactive derivative is an acid halide; when R is an alkoxy group, the reactive derivative is an alkanol ester; when R is an O-CO-R 'group, the reactive derivative is an acid anhydride.

According to an advantageous embodiment of the method, the trimethyl-3, 3, 5 cyclohexanol and the reagent derivative are in stoichiometric quantities.

According to another embodiment of the process, the trimethyl-3, 3, 5 cyclohexanol is in excess.

According to yet another advantageous embodiment of the process, when R is a halogen, the reaction temperature is between 0 ° and the boiling temperature of the solvent, preferably at the temperature of solvent boiling.

When trimethyl-3, 3-5 cyclohexanol is in excess, the excess alcohol can then be eliminated by vacuum distillation and recovered. The reaction is carried out in a solvent inert with respect to reagents such as dimethylformamide or haloalkanes such as chloroform, methylene chloride, dichloromethane. The presence of a hydrogen acceptor, which is not essential, however promotes the completion of the esterification. For this purpose, it is possible to use sparingly soluble mineral bases such as magnesia or preferably tertiary amines such as triethylamine or dimethylaminopyridine.

According to another advantageous embodiment of the process, when R is an alkoxy group, the reaction temperature is between 60 ° and 110 ° C, said reaction being carried out in the presence of an appropriate catalyst .

The catalyst is for example, represented by traces of alkali metals, their hydrides, or their alcoholates or even their carbonates. Sodium or sodium hydride will preferably be used. The reaction can be carried out in a large excess of 3,3,5-trimethyl cyclohexanol which serves as a solvent medium, or carried out with ratios of reagents close to stoichiometry but operating this time in a solvent chosen from aliphatic or aromatic hydrocarbons . It will preferably be chosen, capable of giving an azeotropic mixture with the alkanol of the starting ester, for example for a methyl ester, octane, toluene, benzene, cyclohexane for an ethyl ester will be chosen. ethylbutyl ether, heptane, hexane, toluene, benzene, cyclohexane. After isolation of the crude products with an immiscible solvent and washing with water, the products are purified by conventional methods, namely crystallization for products with a high melting point or absorption chromatography on silica or alumina for products today leux or low melting point.

According to still another implementation of the method, when R is OH, the reaction temperature is between 0 ^° C and the temperature of re-flow of solvent, preferably about 0 ° C to the top of the reaction then at ambient temperature thereafter and said reaction is carried out in the presence of a coupling agent, for example N, N'dicyclohexylcarbodiimide or N-ethyl N'- (dimethylaminopropyl) carbodiimide in an inert solvent.

The proportions of the reagents used are those of stoichiometry and the solvents chosen are dimethylformamide or halogenated derivatives such as chloroform or dichloromethane. The dicyclohexylurea formed is removed by filtration and then after a first evaporation, recovery with ethyl acetate allows the urea to be completely eliminated. The product is then purified by the usual techniques already mentioned for the previous tests. As a variant, when R is an OH group, the esterification reaction is carried out by direct reaction of the carboxylic acid and of trimethylcyclohexanol at a temperature slightly below the boiling point of trimethylcyclohexanol under the pressure conditions used.

This is done in particular when the chosen carboxylic acid has good thermal stability and a sufficiently low pKa. In this case, an excess of trimethylcyclohexanol is used ranging from 1 to 4 times the stoichiometry. If one operates spherical atmo¬ pressure, the reaction is carried between 100 ^β C and 190 ° C, preferably about 150 ^* C to remove the water formed in the reaction by stripping with hexanol triméthylcyclo¬. This temperature can be lowered if operating under reduced pressure. In addition to the foregoing provisions, the invention also comprises other provisions, which will emerge from the description which follows, which refers to examples of implementation of the method which is the subject of the present invention.

It should be understood, however, that these examples are given solely by way of illustration of the subject of the invention, of which they do not in any way constitute a limitation. EXAMPLE 1: ((4-CHLORO-BENZOYL) -4 PHENOXY) -2 METHYL-2-TRIMETHYL-3,3,5 CYCLOHEXANOL (TRANS) PROPIONATE BY REACTION OF ACID CHLORIDE.

To 50 ml of pure chloroform is added 5 g (35 mMole) of TRANS trimethyl-3.3.5 cyclohexanol then 3.5 g (35mMole) of triethylamine dissolved in 10 ml of chloroform. The solution is stirred cold and then added with 12 g (35 mMole) of ((4-chloro-benzoyl) -4 phenoxy) -2 methyl-2-propionic acid chloride diluted in 100 ml of chloroform. It is brought to the boil for three hours and then left to stand for 24 hours. Then washed successively with normal hydrochloric acid, then with a bicarbonate solution and finally with water. After drying over anhydrous sodium sulfate, the evaporated chloroform solution is recrystallized from ethanol; we obtain beautiful white crystals of ρF≈129 "C constituting the title derivative, presenting only one spot in TLC on Silica Kieselgel plate of Rf = 0.80 (for 0.40 for trimethyl-3,3,5 cyclohexanol) in the 85% petroleum solvent solvent system, ethyl acetate 15% The revelation can be made by exposure to UV light 254 nm or by spraying the plate with a sulfuric vanillin solution (blue-violet spot for tri¬ methyl- 3.3.5 cyclohexanol and its ester).

The IR spectrum (recorded in K Br) has the following characteristic bands: 2950 to 2850 cm-1. -CH ₂ - and -CH ₃ ; three strong bands at 1735, 1660 and 1600 cm-1 of the carboxylic esters.

EXAMPLE 2: ((CHLORO-4 BENZOYL) -4 PHENOXY) -2 METHYL-2 TRIMETHYL-3,3,5-CYCLOHEXANOL PROPIONATE (CIS). To 50 ml of pure chloroform is added 5 g of trimethyl-3,3,5-cyclohexanol CIS form and then 3.5 g of triethylamine dissolved in 10 ml of chloroform. The solution is then slowly added at low temperature with 12 g of acid chloride ((chloro-4-benzoyl) -4 phenoxy) -2 2-methylpropionic diluted in a few ml of chloroform. It is refluxed for three hours, then, after cooling, the organic layer is washed with successively a normal solution of hydrochloric acid, sodium hydroxide and then with distilled water. It is evaporated under reduced pressure and then chromatographed on a silica column with a mixture of petroleum ether and ethyl acetate and finally recrystallized from ethanol. The title derivative is obtained in the form of beautiful white crystals of pF = 65 "C having, in Chromatography on a Thin Layer in the solvent system described in example 1, a single spot of Rf = 0.45.

The I.R. spectrum recorded in the K Br has the same characteristic bands at 2950-2850, 1735, 1660, 1600 cm-1 as that of the previous example but shows significant differences between 1000 and 600 cm-1.

EXAMPLE 3: (((CHLORO-4 BENZAMIDO) -2 ETHYL) -4 PHENOXY) -2 METHYL-2 PROPIONATE OF TRIMETHYL-3,3,5 CYCLOHEXANOL (TRANS) 12.5 g (0.034 mole) of acid (( para-chlorobenzamido-2-ethyl) -4-phenoxy) -2-methyl-2-propionic acid in 100 ml of anhydrous dimethylforrαamide and add 4.8 g of trimethyl-3,3,5-cyclohexanol (trans form) (0.034 mole ) and 0.5 g of dimethylaminopyridine. After solubilization, slowly added at temperature close to 0 ° C. a solution of 7 g of dicyclohexylcarbidimide (0.034 mole) in 20 ml of dimethylformamide. The reaction medium is left to react for 24 hours at ordinary temperature and the precipitate of dicyclohexylurea is filtered, after evaporation of the filtrate under reduced pressure, chromatography on a column of silica in a mixture of petroleum ether and ethyl acetate. After evaporation of the solvent, the title derivative is obtained in the form of white crystals with a pF = 100 ^* C: the yield is 45%. This product chromatography under the conditions of Example 1 shows

'' a single spot of Rf ≈ 0.2. The I.R. spectrum recorded in the K Br has the following characteristic bands; a wide strip at 3250 cm-1 a set of fine strips at

3000-2840 cm-1, and two strong bands at 1750 cm-1 and 1640 cm-1.

EXAMPLE 4: (((CHLORO-4 BENZAMIDO) -2 ETHYL) -4 PHENOXY) -2 METHYL-2 PROPIONATE OF TRIMETHYL-3,3,5 CYCLOHEXANOL (CIS).

The operation is carried out under the same conditions as those of Example 3 and with the same proportions of reactants. After chromatography on a silica column, it can be recrystallized from ethyl acetate. The title derivative is thus obtained in the form of white crystals of pF = 122 "C (capillary). Chromatography on a thin layer under the conditions already described reveals a single spot whose Rf = 0.2 is identical to that of the product according to Example 3. The IR spectrum recorded in the K Br has the same main characteristic bands as in Example 3, on the other hand the fine bands between 1000 and 600 cm-1 are clearly different.

EXAMPLE 5: (2,5-DIMETHYL PHENOXY) -3 PROPYL-2 METHYL-2 TRIMETHYL-3,3,5-CYCLOHEXANOL PROPIONATE (CIS form).

25 g of (2,5-dimethylphenoxy) -3-propyl-2-methyl-2-propionic acid chloride are added to 14 g of trimethyl-3,3,5-cyclohexanol (cis) dissolved in 100ml of toluene. It is refluxed for three hours and then evaporated to dryness. The evaporation residue is chromatographed on a silica column with chloroform. The product according to the description, is obtained in an amorphous state, it has a single spot in thin layer chromatography under the preceding conditions, the characteristic bands of its IR spectrum recorded in the K Br are as follows: 3000-2850 cm-1, group of thin bands; 1730 cm-1 strong carbonyl band. EXAMPLE 6 (2,5-DIMETHYL-PHENOXY) -3 PROPYL-2 METHYL-2 TRIMETHYL-3,3,5-CYCLOHEXANOL PROPIONATE (TRANS form).

By operating under the conditions of the above example and with the same proportions of reactants but this time using trimethyl-3,3,5-cyclohexanol (TRANS form), the product according to the present example is obtained. amorphous state having the same physical and chromatographic characteristics as the product of the previous example. The IR spectrum has the same characteristic bands as the derivative according to example 5, differences are noted only at the level of 1000 to 600 cm - 1.

EXAMPLE 7 (PHENYL-4 PHENOXY) -2 METHYL-2 PROPIONATE OF TRIMETHYL-3,3,5 CYCLOHEXANOL (TRANS).

To 14.2 g of trimethyl-3,3,5 cyclohexanol (trans) (0.1 mole) dissolved in 500 ml of heptane are added 27 g of (4-phenylphenoxy) -2 methyl-2-methyl propionate ( 0.1 mole) and 0.3 g of 60% sodium hydride in oil. The stirred mixture is brought to the boil in a distillation apparatus, suitably equipped, to gradually separate the binary heptane / methanol mixture which boils at 59 ° C., the operation requires 4 to 5 hours, it is cooled and then washed thoroughly with water. alkaline water then acid finally with pure water. After chromatography on a silica column with a mixture of ethyl acetate and petroleum ether and recrystallization from isopropanol at 90% the title derivative is obtained in the form of silky crystals with pF = 96 ^* C. The TLC practiced under the preceding conditions gives a single spot of Rf

= 0.90. The I.R. spectrum shows the characteristic bands at 2950-2850, 1745, and 1640 cm-1.

EXAMPLE 8 (PHENYL-4 PHENOXY) -2 METHYL-2 PROPIONATE

TRIMETHYL-3,3,5 CYCLOHEXANOL (CIS).

The procedure of the previous example is used, this time using the cis isomer. The title derivative is obtained in the form of fatty crystals of pF of between 76 and 80 ° C. The spectrum I.R. is identical to that of the previous example with the exception of the fine bands around 1000 to 800 cm-1.

Using the conditions of the previous example with the appropriate methyl ester, the following derivatives are obtained.

EXAMPLE 9: (PROPIONYL-4 PHENOXY) -2 METHYL-2 PROPIONATE

OF TRIMETHYL-3,3,5 CYCLOHEXANOL (TRANS).

EXAMPLE 10: (PROPIONYL-4 PHENOXY) -2 METHYL-2 PROPIONATE OF TRIMETHYL-3,3,5 CYCLOHEXANOL (CIS).

EXAMPLE 11: (ACETYL-4 CHLORO-2 PHENOXY) -2 METHYL-2

TRIMETHYL-3,3,5 CYCLOHEXANOL PROPIONATE (TRANS).

EXAMPLE 12: (ACETYL-4 CHLORO-2 PHENOXY) -2 METHYL-2

TRIMETHYL-3,3,5 CYCLOHEXANOL PROPIONATE (CIS). EXAMPLE 13 (ACETYL) -3 PHENOXY-2 METHYL-2 PROPIONATE

TRIMETHYL-3,3,5 CYCLOHEXANOL (TRANS).

EXAMPLE 14 (ACETYL) -3 PHENOXY-2 METHYL-2 PROPIONATE

TRIMETHYL-3,3,5 CYCLOHEXANOL (CIS).

EXAMPLE 15: (ACETYL-4 PHENOXY) -2 METHYL-2 PROPIONATE OF TRIMETHYL-3,3,5 CYCLOHEXANOL (TRANS).

EXAMPLE 16 (ACETYL-4 PHENOXY) -2 METHYL-2 PROPIONATE

TRIMETHYL-3,3,5 CYCLOHEXANOL (CIS).

EXAMPLE 17: (PHENYLACETYL-4 PHENOXY) -2 METHYL-2

TRIMETHYL-3,3,5 CYCLOHEXANOL PROPIONATE (TRANS). EXAMPLE 18: (PHENYLACETYL-4 PHENOXY) -2 METHYL-2 PROPIONATE OF TRIMETHYL-3,3,5 CYCLOHEXANOL (CIS). EXAMPLE 19: (PHENOXY) -4 BUTYL-2 METHYL-2 PROPIONATE OF TRIMETHYL-3,3,5 CYCLOHEXANOL (TRANS). EXAMPLE 20: (PHENOXY) -4 BUTYL-2 METHYL-2 PROPIONATE OF TRIMETHYL-3,3,5 CYCLOHEXANOL (CIS).

EXAMPLE 21: ((2,4-DIMETHYL PHENOXY) -4 BUTYL) -2 METHYL-2 PROPIONATE OF TRIMETHYL-3,3,5 CYCLOHEXANOL (CIS). EXAMPLE 22: ((DIMETHYL-3,5 PHENOXY) -4 BUTYL) -2 METHYL-2 PROPIONATE OF TRIMETHYL-3,3,5 CYCLOHEXANOL (CIS).

The compounds according to the present invention were subjected to toxicity controls practiced in mice weighing 20 to 25 grams. The routes of administration were the oral route and the intraperitoneal route. The LD ₅₀ according to the Miller and Taister method are all greater than 2000 mg / Kg.

The lipid-lowering, antihypercholesterolemic, antihypertriglyceridemic and inhibitory activities of the enzyme systems synthesizing cholesterol were found to be superior to the reference products. The following table summarizes the results of the pharmacological studies carried out in particular by the hyperlipemia test caused by TRITON 1339. The experimental protocol was that published by JC FRUCHARD et al. (Gaz.Med. France 3rd inter-coll. 1982 Dijon 18-22). The tests are carried out on groups of 7 rats weighing from 280 to 290 g. After oral administration for six days at a rate of 0.5 millimole per kilo of body weight, the Triton test is carried out. The following lipid parameters are measured: total cholesterol, tri-glycerides, total lipids and HDL cholesterol The results are summarized in Table I below. TABLE I

The biosynthesis of cholesterol in an isolated enzymatic system or in a cell culture from organs taken from experimental animals is inhibited by the limitation of the activity of the enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase. These products in accordance with the invention prove to be active in the treatment of hypercholesterolemia in humans or animals and therefore also in the treatment of atherosclerosis.

The determination of the inhibitory activity of the products according to the present invention was carried out by the method of Kuroda et al. (Biochemica and Biophysica Acta Vol. 486 pp. 70-81 (1977)), modification of the method of Shapiro et al. (Analytical Biochemistry Vol. 31 pp. 383-390 (1969). The results are summarized in the Table II in which IC50 is the concentration of product in the experimental medium, necessary to obtain a 50% inhibition of the 3-hydroxy-3-methylglutarylCoA reductase activity expressed in nanomoles. TABLE II

Composed of the example: ^IC 50

2 37.2 3 39

4 25.6

5 30.1 7 42.5 10 37.6 12 21.9

13 35.7

16 45.9

18 32.9

20 40.5 22 30.2

In addition, chronic administration of the most active derivatives in vitro to rats intraperitoneally makes it possible to measure the HMG Co A activity.

Table III below shows the results obtained as regards the inhibition of the HMG CoA activity with respect to the product. of reference that is fenofibrate. The administration doses were 50 mg / kg for 6 days, six rats were used in each series, they are sacrificed without anesthesia and the liver microsomes are isolated for the assay, which is carried out according to the protocol cited above. 15 TABLE III

Product according to Mevalonate formed Inhibition%

Example 1 4.44 74 Example 2 7.3 57 Example 5 6.71 60 Example 6 6.01 65 Example 17 8.66 50 Example 19 5.2 70 Example 21 3.8 78 Fenofibrate 4.16 75 Control 17 0

Given these interesting pharmacological properties and the low toxicities recorded, these compounds can be used effectively in human or veterinary therapy for the treatment of lipidemia disorders, a frequent cause of atheromatous disease and consequently of vascular accidents. The products according to the invention can be administered alone or in combination with an emulsifier or a pharmaceutically acceptable solvent, they can also be prepared using a galenical device, making it possible to modulate their speed of assimilation. The pharmaceutical compositions containing these products can be administered by the oral, parenteral or rectal route or also by the transcutaneous route. The percentage of active ingredient in pharmaceutical compositions can vary within wide limits depending on the patient, the method of administration and the frequency of administration. The daily dosage can vary from 1 mg to 1000 mg / kg of body weight, preferably from 1 to 30 mg per kg of body weight. As is apparent from the above. The invention is in no way limited to those of its modes of implementation, embodiment and application which have just been described more explicitly; on the contrary, it embraces all the variants which may come to the mind of the technician in the matter, without departing from the framework, or the scope, of the present invention.

Claims

1) Derivatives of 3,3,5-trimethylcyclohexanol, characterized in that they correspond to the general formula:

in which ; n = 0,1,2,3,4 or 5

Rτ_ and R ₂ are identical or different and each represents a hydrogen atom or one of the following substituents:

-CH ₃ , -OCH3, -F, -CF ₃ , ethyl, propyl, hydroxypropyl, propionyl, acetyl-cyclopropyl, 2,2-dichloro cyclopropyl; a benzoyl-4 group in which the benzoyl ring can be substituted by one or more of the following units: Cl-, F-, Br-, CF3-, CH3-, CH3O-; a phenylacetyl-4 group; a phenyl group; a parachlorobenzoylaminoethyl-4 group; or a group (3-phenoxy-propyl) -4 in which the phenyl ring can be substituted by one or more units chosen from Cl, Br, F, CF ₃ , OCH3, CH ₃ .

2 ") Derivatives according to claim 1, characterized in that the 3,3,5-trimethyl cyclohexanol is in one of the pure cis or trans forms or in the form of a mixture more or less enriched in one of said forms.

3 °) Derivatives according to claim 2, characterized in that the 3,3,5-trimethyl cyclohexanol is in the form of one of its diastereoisomeres L or D or of the corresponding racemic product. 4 °) derivative according to any one of claims 1 to 3, characterized in that said derivative is (4-chloro-benzoyl) -4-2-phenoxy-2-methyl-3,3,5 trimethyl cyclohexanol, CIS or TRANS. 5 °) derivative according to any one of claims 1 to 3, characterized in that said derivative is (2,2-dichloro-cyclopropyl) -4-2-phenoxy-2-methyl-3,3,5 trimo-cyclohexanol, CIS or TRANS. 6 ^* ) Derivative according to any one of Claims 1 to 3, characterized in that the said derivative is (4-fluoro-phenoxy) -2-trimethyl-3,3,5-methyl-2,5,5-cyclohexanol, CIS or TRANS.

7 °) derivative according to any one of claims 1 to 3, characterized in that said derivative is (2,5-dimethyl benzoyl) 2-propyl-2-methyl-3,3,5 trimethyl cyclohexanol propionate, CIS or TRANS.

8 ^* ) Derivative according to any one of Claims 1 to 3, characterized in that the said derivative is ((4-chloro-benzamido) -2 ethyl) -4 phenoxy-2-methyl-2-trimethyl-3,3-propionate, 5 cyclohexanol, CIS or

TRANS.

9 ^* ) Process for the preparation of the derivatives according to claims 1 to 8, characterized in that the trimethyl-3,3,5 cyclohexanol is reacted with a reactive form of an appropriate carboxylic acid, of formula

II, below:

in which n, R- _j _ and R ₂ have the same meanings as above and R represents a halogen, an alkoxy group in which the alkyl group is C - ^ - g, an O-CO- R 'group, in which R 'is a C ^ -g alkyl group or a group

n, R ^ and R ₂ having the same meanings as above, or an OH group, in the presence of an inert solvent and optionally a hydrogen acceptor. 10 °) Method according to claim 9, characterized in that the trimethyl-3,3,5 cyclohexanol and the reactive derivative are in stoichiometric quantities.

11 °) Method according to claim 9, characterized in that the trimethyl-3,3,5 cyclohexanol is in excess.

12 °) Process according to any one of claims 9 to 11, characterized in that when R is a halogen, the reaction temperature is between 0 ° and the boiling point of the solvent, preferably at the temperature of solvent boiling.

13 °) Process according to any one of claims 9 to 11, characterized in that when R is an alkoxy group, the reaction temperature is between 60 ° and 110 ° C, said reaction being carried out in the presence of a catalyst appropriate.

14 °) Process according to any one of claims 9 to 11, characterized in that when R is an OH group, the reaction temperature is between 0 ° C and the reflux temperature of the solvent, preferably towards O'C at the start of the reaction then at room temperature thereafter and said reaction is carried out in the presence of a coupling agent, for example N, N'dicyclohexylcarbodiimide or N-ethyl N'- (dimethylaminopropyl) carbodiimide in an inert solvent. 15 °) Process according to any one of claims 9 to 11, characterized in that when R is an OH group, the esterification reaction is carried out by direct reaction of the carboxylic acid and of trimethylcyclohexanol at a temperature slightly below the point trimethylcyclohexanol under the pressure conditions used.

16 °) medicament containing at least one of the derivatives according to claims 1 to 8 used alone or with pharmacologically acceptable adjuvants or solvents intended for oral parenteral rectal or transdermal administration, capable of correcting the dysregulations of lipidemia in humans and l and prevent atheromatous disease.