FR2499559A1 - NOVEL DERIVATIVES OF 2-HYDROXY-5- (2 ', 4'-DIFLUOROPHENYL) -BENZOIC ACID, PROCESSES FOR THEIR PREPARATION, THEIR USE AS A PHARMACOLOGICALLY ACTIVE AGENT AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING SAME - Google Patents

Abstract

2-Hydroxy-5-(2',4'-difluorophenyl)benzoic acid derivatives of the general formula in which R can be hydrogen or an oxycarbonyl radical of the formula in which X is a linear or branched alkyl group having 1 to 6 carbon atoms, phenyl, benzyl, (C5-7) cycloalkyl, 2,2,2-tricholoroethyl or 2,2,2-tribromoethyl; process for the preparation of the compounds; use of the compounds as anti-inflammatories, antipyretics, analgesics and expectorants; and pharmaceutical formulations which contain these compounds.

Description

 The present invention relates to novel 2-hydroxy-5- (2 ', 4'-difluorophenyl) benzoic acid derivatives, processes for their preparation, use as a pharmacologically active agent and pharmaceutical compositions containing them.

dans laquelle R peut représenter l'hydrogène ou un radical oxycarbonyle de formule

dans laquelle X est choisi parmi un groupe alkyle linéaire ou ramifié contenant de 1 à 6 atomes de carbone, un groupe phényle, benzyle,(C5 7) cycloalkyle, 2,2,2-trichloroéthyle et 2,2,2-tribromoéthyle.More specifically, the present invention relates to the compounds of the following general formulas

in which R may represent hydrogen or an oxycarbonyl radical of formula

wherein X is selected from a linear or branched alkyl group containing from 1 to 6 carbon atoms, phenyl, benzyl, (C5 7) cycloalkyl, 2,2,2-trichloroethyl and 2,2,2-tribromoethyl.

 Examples of alkyl groups as defined herein are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n -pentyl, isopentyl, neopentyl, n-hexyl, 2, 3-dimethylbutyl, 2-methylpentyl and 3-methylpentyl.

 Examples of a (C5-7) cycloalkyl as defined herein are cyclopentyl, cyclohexyl and cycloheptyl.

 A group of preferred compounds includes the compounds of formula (I) wherein R is hydrogen or a group of formula (II) or X is a linear or branched alkyl group containing from 1 to 4 carbon atoms or benzyl group.

2-hydroxy-5- (2 ', 4'-difluorophenyl) -benzoic acid is a known substance; see, for example, British Patent No. 1,170,212; South African Patent No. 67 010 21; French Patent No. 1,522,570; German Patent No. 1,618,663 and German Publication No. 2,532,559; licences
EA Nos. 3,674,870 and 3,681,445.

Its biological properties are reported by J. Hannah et al.,
Brit. Day. Clin. Pharmacol., 75-135, 1977, and PQW. Major and others,
Brit. Day. Clin. Pharmacol., 4, 155-185, 1977, as well as by other authors.

 The compounds according to the invention can be prepared according to various methods which depend essentially on the final products which it is desired to obtain.

avec un halocarbonate organique de formule

dans laquelle Y est un atome dshaigène et X est tel que défini ci-dessus, pour obtenir ainsi un composé de formule

dans laquelle X est tel que défini ci-dessus, que l'on fait ensuite réagir avec le 2-méthoxy-phénol de formule(VI)pour obtenir des composés de formule(I) ci-dessus dans laquelle R est le groupe

Thus, for example, a general method for the synthesis of the compounds of formula (I) above comprises the reaction of 2-hydroxy-5 (2 ', 4'-difluorophenyl) -benzoic acid of formula

with an organic halocarbonate of formula

wherein Y is an oxygen atom and X is as defined above, to thereby obtain a compound of formula

wherein X is as defined above, which is then reacted with 2-methoxyphenol of formula (VI) to obtain compounds of formula (I) above wherein R is the group

Xposseding the same meaning as before.

The following reactions can be illustrated by the following diagram

<tb> cH <SEP> o
<tb><SEP> F- <SEP>) -X
<tb><SEP> (VI <SEP>) - <SEP> (VII) = <SEP> compounds <SEP> of <SEP> formula <SEP> I <SEP> in
<tb> which R

par un atome d'hydrogène ; on obtient ainsi le composé de formule(I)dans laquelle R est l'hydrogène.When X represents 2,2,2-trichloroethyl or 2,2,2-tribronoethyl, the compound of formula (VII) above can undergo selective hydrogenolysis, which allows the replacement of the group

by a hydrogen atom; the compound of formula (I) in which R is hydrogen is thus obtained.

 In practice, a molar proportion of the compound of formula (III) is reacted with about 2 to 4 molar equivalents of a compound of formula (IV), preferably a compound wherein Y is chlorine, at a temperature of about 100 C and about room temperature, for a period of time ranging from about 10 to about 40 minutes, preferably 15-30 minutes.On reaction is carried out in an anhydrous organic solvent, preferably selected from a lower aliphatic ketone such as for example, acetone, methyl ethyl ketone, diethyl ketone and the like and in the presence of a base containing a tertiary organic nitrogen such as, for example, trimethylamine, triethylamine, pyridine, picolines and the like in order to capture the acidity that forms during the reaction. A compound of formula (V) is obtained which can, if desired, be isolated and characterized, but it can also be used as such for the next step. As a result, this compound is brought into contact with a light molar excess [calculated relative to the starting material of formula (III)] of 2-methoxyphenol of formula (VI), at a temperature between about -100 ° C. and about room temperature, for a period of about 3 at about 8 hours, thereby obtaining a compound of formula (VII) which is isolated and characterized by techniques well known to those skilled in the art.

est remplacé par un atome d'hydrogène. On effectue cette hydro génolyse de maniée classique, comme par exemple au moyen de zinc et d'acide acétique dans du diéthyl éther ou par voie catalytique en utilisant PtO2 ou
Pd/charbon à titre de catalyseur.As stated above, the compounds of formula (VII) wherein X is 2,2,2-trichloroethyl or 2,2,2-tribromoethyl are also useful as intermediates to obtain the compound of the formula wherein
R is hydrogen via selective hydrogenolysis during which the group

is replaced by a hydrogen atom. This hydrolysis is carried out in a conventional manner, for example using zinc and acetic acid in diethyl ether or catalytically using PtO 2 or
Pd / coal as a catalyst.

 The compound of formula (I) in which R is hydrogen can be prepared by another process which comprises simply contacting a molar amount of the compound of formula (III) alrec from about 3 to about 7, and preferably about 5, molar equivalents of the compound of formula (VI) in the presence of catalytic amounts of a strong acid such as, for example, sulfuric acid or p-toluene sulfonic acid. The reaction is carried out under an inert atmosphere at the melting temperature of the reaction mixture and thus in the absence of any reaction solvent, and the continuous flow is carried out by means of thin layer chromatography (TLC) up to the reaction temperature. The compounds according to the invention are useful as pharmacologically active agents. More particularly, they possess remarkable anti-inflammatory, antipyretic, analgesic and expectorant properties. The anti-inflammatory, antipyretic and analgesic properties occur at doses which, when expressed in mg / kg, appear to be greater than those observed for the reference substance, the acid of 2-hydroxy-5- (2 ', 4-difluorophenyl) -benzoic but which when expressed more precisely in m. mole / kg are absolutely comparable with, or better than, the same level as those of the reference subStance mentioned above. In any case, apart from these facts, the substances of formula (I) according to the invention have a marked expectorant activity whereas this property does not exist in 2-hydroxy-5- (2 ', 4) acid. '-difluorophényl) benzoic acid. Finally, it should be noted that the compounds of the present invention are very low in toxicity (this is clearly shown in Table 1) so that the corresponding therapeutic indices, i.e., the ratios between effective doses and the toxic doses are more favorable than the already high therapeutic index of the reference compound. It should be noted that a high therapeutic index is a clear indication of the potential safety of a drug.

In the following table 1, the values of DL determined are indicated.
50 born on mice according to Lichtfield and Wilcoxon, Day. Pharm. Expt. Ther.,, 99, 1949, the physicochemical properties and the effective anti-inflammatory, antipyretic, analgesic and expectorant effective doses determined according to the tests illustrated below on the compounds of the present invention.

Thus, antiinflammatory properties are investigated by carageenine-induced edema in rats (730 male rats).
Sprague Dawley with an average weight of 150 g made practically as described by CA Winter et al., Proc. Soc. Exptl. Biol. Med., 111, 544, 1962.

 Table 2 shows the representative results obtained with the compound of Example 3 in comparison with 2-hydroxy-5- (2 ', 4'-difluorophenyl) benzoic acid.

The analgesic activity is sought by means of the Randall test and
Selitto, according to which a pressure is applied to the hind paw of the rat previously inflamed by an injection of brewer's yeast, and the pain threshold is measured. Table 3 shows the representative results. obtained with the compound of Example 6 in comparison with 2-hydroxy-5- (2 ''4'-difluorophenyl) benzoic acid.

Similarly, in hyperthermia induced in rats (165 mule rats
Sprague Dawley with an average weight of 200 g), by means of the intramuscular administration of brewer's yeast, the activity of the compounds of Examples 3, 5 and 6 is quite remarkable: in fact, the doses indicated in Table 1 causes an average reduction in body temperature, recorded 1.2, and 4 hours after administration, of about 1 degree centigrade.

The data reported in Table 4 relate to representative experiments performed on rats according to EM Boyd and GM Johnston,
Am. Day. Med. Sci., 199, 246, 1940 and 201, 810, 1941 in order to ascertain the expectorant properties of the compounds according to the invention. These data clearly indicate that the compounds according to Examples 3.5 and 6, unlike the reference compound. , 2-hydroxy-5- (2 ', 4'-diftuorophenyl) -benzoic acid, cause a marked increase in the water content of the upper respiratory tract, which confirms the stimulating activity of these compounds to the secretion of the respiratory system. Similarly, the compounds of Examples 1 (2) and 4 have the same property although to a lesser degree.

TABLE 1
Physico-chemical properties, LD50 value (mg / kg po) and minimum effective doses (mg / kg po) *
I -I
LD50 dot compound Effective doses Minima ss of fusion Mouse (rats) Example C
Activity Activity Activity Activity; ii
antiinfective-antipy-analgesic-expeclamatory toric reactive 1,2 105-6> 1300 **> 50 *** -> 50 ***> 400 *** 3 oil 1050 40 50 70 200 438 20 30 40> 400 4 103-6> 1350 **> 50 *** -> 50 ***> 400 *** 5 78-79 970 35 48 70 200 1 6 90-92 1200 35 50 70 200 ii I
* minimum doses capable of causing significant differences
(P <0.01) between the responses of the treated groups and the responses of
untreated groups (controls)
** Absence of any mortality at the indicated doses.

 *** No significant effects up to the indicated doses.

TABLE 2
Activity of the compound of Example 3 and 2-hydroxy-5- (2 ', 4'-difluorophenyl) benzoic acid in the carrageenin-induced edema test in rats (240 male Sprague Dawley rats , 30 rats per group in 8 experiments)
Dose% inhibition compound Meaning | the mg / kg example of statistical induced edema
per os in relation to
witnesses 3 20 -27 NS

40 -51 <0.01
60 -70 <0.01
80 -80 (u, 01 ------------------------------------------- --------------- acid 2-hy-10 -24 NS

droxy-5- (2 ', 4' -55 <0.01)
-difluorophenyl) 30 -68 (0.01
- - benzoic 40 -84 <0.01
NS = not significant
TABLE 3
Analgesic activity of the compound of Example 6 and 2-hydroxy-5 (2 ', 4'-difluorophenoxy) -benzoic acid in the Randall and Selitto test.

Dose Compound Number Threshold of sensitivity to o of increase of
example mg / kg pain (gram) pain threshold by
per os rats (*) inflamed paw (**) compared to controls
6 40 30 127.2 29.8
60 30 139.9 42.7 (***)
80, 155.8 58.9 (***) 2-hydroxy-124.8 27.5 t xy-5- (2 ', 4'-di), 30, 141, 44.08 (**) *) luorophenyl) - 40 30 152.7 55.8 (***) benzoic
Witnesses (#) 30 98 # 6.2
(#) the controls are administered orally with 10 mg / kg of oil
peanut
(*) average of 3 experiments
(**) average after 1 and 2 hours after the administration of the substances
(***) statistically significant (P <0.01) value compared with
witnesses.

TABLE 4
Moisture content (in mg) in the tracheas of Sprague Dawlcy rats treated orally with saline solution. the compounds according to the invention.

Reference Compounds: 2-hydroxy-5- (2 ', 4'-difluorophenyl) benzoic acid.

Dose Compound Number Percentage Increase% P Example mg / kg of mean water relative to rat oral controls (*) (mg)
1.2 400 40 93 # 8.5 10.9 ns

3,300 40,140 # 11.3 65.6 <0.01
4,400 40 98 # 11.6 11.5 ns

5 250 40 142 # 13.1 67.1 <0.01 6 300 40 135 # 15.3 58.8 <0.01 acid 2-hydroxy-5- (2 ', 4'- 400 40 86 + 9, Difluorophenyl) benzoic acid
Solution 10 ml 40 85 # 6.8 physiological
(*) Average of 4 experiments
ns = not significant.

 The use of the compounds according to the invention concerns all industrially applicable acts and aspects of this use, including their incorporation into pharmaceutical compositions.

Accordingly, in the method of using compounds of the present invention, the active ingredient can be administered directly or as an active component of pharmaceutical compositions suitable for oral, parenteral or rectal administration. To illustrate oral administration, the compounds may be, for example, in the form of tablets, sugar-coated tablet capsules, dispersible powders, lozenges, tblets, syrups, elixirs and the like. The compositions for oral administration may contain one or more conventional adjuvants such as, for example, sweetening, flavoring, coloring, coating and preserving agents in order to obtain an elegant and tasteful preparation. use parenterally, the compounds according to the invention are in the form of pharmaceutical preparations suitable for intravenous or intramuscular administration such as for example vials or ampoules. The active ingredient is thus formulated as injectable doses which are formulated as is known in the art and also contains suitable dispersing, wetting, suspending and buffering agents.
For rectal administration, the active ingredient is preferably in the form of suppositories. Likewise suppositories are formulated as is known in the art and have the active substance in admixture with generally acceptable carriers such as, for example paraffin, spermaceti, sesame oil, gelatin, peanut oil or mixtures thereof.

 Depending on the method of use of the compounds according to the invention, they are administered in daily doses ranging from about 5 to about 25 mg per kg of body weight. The pharmaceutical compositions contain the active ingredient in amounts varying from about 350 to about 1700 mg and they are suitable for administration once a day or several times a day.

 Representative but non-limiting pharmaceutical compositions and levels of administration are shown below by way of illustration.

 - Tablets: about 400 to 1000 mg of active ingredient, two or more per day.

 suppositories: about 700 to 1500 mg of active ingredient, two or more per day.

The following examples are given to better illustrate the present invention but it does not constitute a limitation of its scope.
Example 1 2-Hydroxy-5- (2 ', 4'-difluorophenyl) benzoate of 2 methoxyphenol (Formula I, R = H)
A mixture of 25 g (0.1 mole) of 2-hydroxy-5 (2 ', 4'-difluorophenyl) benzoic acid, 62 g (0.5 mole) of 2-methoxyphenol is prepared. and 0.5 -1 g of p-toluysulfonic acid in an inert atmosphere until a homogeneous and clear liquid is obtained. The course of the reaction is carried out by TLC (Merck silica gel plates F254, eluent system: anhydrous benzene, visualization: UV light, 254 nm). When the reaction is considered complete, the melt is cooled and it is passed through a column of silica gel (Merck silica gel 60 average particle size: 230 400 mesh) eluting with anhydrous benzene.

 The fractions characterized by a single spot with Rf = 0.70 are collected, the benzene is removed by evaporation in vacuo to leave an oily residue which after being left standing for a few hours, becomes solid and is recrystallized from diisopropyl ether.

Mp 102-103 C.

Elemental analysis for C20 H14 F2 O4 MW = 356.33
Calc. 67.41 3.97
Found 67.42 4.04
Infra-red spectrum (in CHCl3 solution): the characteristic absorption bands are observed at the following frequencies (cm-1) 3230, 1700, 1600-1620
Nuclear Magnetic Resonance Spectrum (in CDCl 3): the following 6 characteristic resonance peaks are observed (ppm, internal standard: TMS): 3.77 (s, 3H); 6.67-7.77 (m, 9H); 8.17-8.27 (m, 1H) 10.57 (s, 1H).

s = singlet; m = multiplet.

Example 2: 2-Methoxyphenol 2-hydroxy-5- (2 ', 4'-difluorophenyl) benzoate (Formula I, R = II)
5 grams (0.020 mole) of 2-hydroy-5- [2 ', 4-difluorophenyl] benzoic acid and 4 g (0.039 mole) of anhydrous triethylamine are dissolved in 58 ml of anhydrous methyl ethyl ketone, after cooling to below OOC. 8.4 g (0.039 mol) of 2,22-trichloroethyl-chlorocarbonate are added dropwise to the reaction solution, the temperature is maintained below 0 ° C. for 15-30 minutes, and thus a After the addition of a solution of 3.6 g (0.029 mol) of 2-methoxyphenol in 40 ml of the same anhydrous lower aliphatic ketone as above, the temperature is allowed to rise to 0.degree. rise to room temperature, then the reaction solution is stirred for a few hours and filtered to remove the insoluble parts.The resulting solution is brought to dryness under reduced pressure and the remaining oily residue is taken up with sodium chloride. methylene.We first wash the organic solution with 5% aqueous hydrochloric acid, then with 5% aqueous sodium hydroxide and finally with slurry, dried over sodium sulfate, filtered and evaporated to dryness in vacuo to obtain a residue. oily which according to CcM analysis (Merck F254 silica gel plates eluent system: anhydrous ethyl acetate; visualization of spots: UV light, 254 nm) shows a main spot and traces of the starting acid.

 The residue left at cold rest becomes solid; it is crystallized several times from a lower aliphatic alcohol, preferably absolute ethanol. m.p. C. The product corresponds to a compound of formula (I) in which R is the 2,2,2-trichloroethoxycarbonyl radical, specifically 2- (2,2,2-trichloroethoxycarbonyloxy) ) -5- (2 '- (2', 2 ', 4'-difluorophenyl) -benzoate of 2-methoxyphenol.

Elemental analysis for C23H15F2Cl3O6; PM = 530.71
@
% c
Calc. 51.95 2.84
Found 52.16 2.84
The hydrogenolysis of this compound is carried out according to the known procedures: for example either by dissolving the product in diethyl ether containing glacial acetic acid and adding zinc powder or by catalytic hydrogenation in the presence of platinum or palladium / charcoal.

 The final product is then isolated according to the known procedures. Accordingly, the resulting oily residue is allowed to stand until solidified and recrystallized from diisopropyl ether or diethyl ether / petroleum ether. m.p. C. The chemical-physical characteristics are identical to those of the compound prepared in Example 1.

Example 3 2- (Benzyloxycarbonyloxy) -5- (2 ', 4'-difluorophenyl) benzoate 2-methoxyphenol (Formula I,

A solution of 8 g (0.032 mole) of 2-hydroxy-5- (2 ', 4'-difluorophenyl) benzoic acid and 8 g (0.079 mole) of anhydrous triethylamine in 100 ml of water is cooled to below 0.degree. 1 ml of an anhydrous lower aliphatic ketone and a 50% solution of 26.9 g (0.079 mol) of benzyl-chlorocarbonate is added thereto over 15 minutes. After the addition is complete, the reaction mixture is stirred, always keeping the temperature below 0 ° C., and a solution of 4 g (0.032 mol) of 2-methoxy-phenol in 16 ml of the same anhydrous lower aliphatic ketone as above.

After stirring for a few hours at room temperature, continuously monitoring the progress of the reaction by TLC (silica gel plates)
Merck F254; eluent system: anhydrous ethyl acetate; stain visualization, UV light, 254 nm; Rf of the product: 0.82) the solvent is evaporated off under reduced pressure to give an oily residue which is passed through a column of silica gel (Merck silica gel 60, average particle size: 230.degree. 400 mesh) and eluted with a 1/1 (v / v) chloroform / n-hexane mixture.

 Fractions having a unit spot are collected, dried and a pure colorless oil is obtained as the residue.

Elemental analysis for C28H20F206; MW = 490.47
% C% H% F
Calc. 68.57 4.11 7.75
found 68.36 3.99 7.90
Infra-red spectrum (pure liquid compound): the characteristic absorption bands are observed at the following frequencies (cm-1): 1765.1700.

 Nuclear Magnetic Resonance Spectrum (in CDCl3): the characteristic resonance peaks at b are observed (p.p.m.

internal standard: TMS): 3.70 (s, 3H); 5.17 (s, 2H); 6.55-8.33 (m, 15H) s = singlet; m = multiplet
Example 4 2- (Methoxycarbonyloxy) -5- (2 ', 4'-difluorophenyl) benzoate of 2-methoxyphenol (Formula I

The compound stated above is prepared in the same way as in
Example 3, from 2-hydroxy-5- (2 ', 4'-difluorophenyl) -benzoic acid, methyl-chlorocarbonate and 2-methoxy-phenol. The desired final product is obtained in the form of a dense oil which it is not necessary to purify by chromatography because it solidifies at rest. It is recrystallized from diisopropyl ether (mp 102-1060 ° C.) to obtain a product with R f = 0.85 (same conditions as in Example 3).

Elemental analysis for C22H16F2; PM = 414.37
"c 96H% F
Calc. 63.77 3.89 9.14
Found 63.89 4.01 9.14
Infrared spectrum (nujol): the characteristic absorption bands are observed at the following frequencies (cm-1): 1760, 1740.

 Nuclear Magnetic Resonance Spectrum (in CDCl 3): The following characteristic resonance peaks are observed: (p.p.m., internal standard: T.M.S.): 3.77 (s, 3H); 3.83 (s, 3H); 6.5-8.4 (m, 10H).

s = singlet; m I multiplet
EXAMPLE 5 2- (Methylobutyloxycarbonyloxy) -5- (2'4'-difluorophenyl) -2-methoxyphenol benzoate (Formula I

The compound stated above is prepared in the same manner as in Example 3, starting from 2-hydroxy-5- (2 ', 4'-difluorophenyl) -benzoic acid, isobutyl-chlorocarbonate and 2 methoxy-phenol. The crude compound is purified by means of column chromatography as shown in Example 3, collecting the fractions characterized by a unit spot with Rf = 0.84.

The product solidifies at rest and is recrystallized from absolute ethanol. m.p. 76-780C

Elemental analysis for C25H22F206 MW = 456.46
"c 96H% F
Calc. 65.78 4.85 8.32
Found 65.62 5.06 8.34
Infrared spectrum (nujol): the characteristic absorption bands are observed at the following frequencies (cm-1): 1770, 1750.

 Nuclear Magnetic Resonance Spectrum (in CDCl30: the characteristic resonance peaks at the following # are observed (p.p.m.

internal standard: TMS): 0.88 (d, 6H); 1.50-2.30 (m, 1H); 3.77 (s, 3H) 3.98 (d, 2H); 6.67-7.90 (m, 9H); 8.27-8.43 (m, 1H) s = singlet; d = doublet; m = multiplet
Example 6 2- (Methoxycarbonyloxy) -5- (2 ', 4'-difluorophenyl) -benzoate of 2-methoxyphenol (Formula I

The compound stated above is prepared in the same manner as in the procedure of Example 3, starting from 2-hydroxy-5- (2 ', 4'-difluorophenyl) benzoic acid, ethyl-chlorocarbonate and 2-methoxy-phenol. After the usual washings, the compound becomes solid and is recrystallized from diisopropyl ether. p .f. 90-92 C. The TLC investigation performed according to Example 3 leads to a unit spot with R = 0.87.

f
Infrared spectrum (nujol): the characteristic absorption bands are observed at the following frequencies (cm-1): 1760, 1740.

 Nuclear Magnetic Resonance Spectrum (in CDCl 3): the characteristic resonance peaks at the following # are observed (p.p.m., internal standard: T..M.S.): 1.25 (3H, t); 3.75 (3H, s); 4.20 (2H, q); 53-7.77 (9H, m); 8.13-8.23 (1H, m).

s = singlet; t = triplet; q = quartet; m = multiplet
Finally, it should be noted that the derivatives which are the subject of the present application and the pharmaceutical compositions containing these derivatives as active ingredients, can be used in particular for the treatment of rheumatism,
febrile states, headaches, joint pain, flu, colds, tracheitis
bronchitis and inflammation of the respiratory tract.

Claims (11)

 1. Novel derivatives of 2-hydroxy-5- (2 ', 4'-difluorophenyl) benzoic acid corresponding to the general formula

 in which R may represent hydrogen or an oxycarbonyl radical of formula

 wherein X is selected from a linear or branched alkyl group containing from 1 to G carbon atoms; phenyl, benzyl, (C5 7) cycloalkyl, 2,2,2-trichloroethyl and 2,2,2-tribromoethyl.  2. Compound according to claim 1, characterized in that R denotes hydrogen or a group of formula (II) where X is an alkyl group  linear or branched containing 1 to 4 carbon atoms or group  benzyl  3. As a compound according to claim 1, 2-methoxy-phenol 2-hydroxy-5 (2Es4edifluorophenyl) -benzoate  4. As a compound according to claim 1, 2- (benzyloxycarbonyloxy) -5- (2 ', 4'-difluorophenyl) -benzoate of 2-methoxyphenol.  5. As a compound according to claim 1, 2- (methoxycarbonyloxy) -5- (2 ', 4'-difluorophenyl) -benzoate of 2-methoxyphenol.  6. As a compound according to claim 1, 2- (isobutyloxycarbonyloxy) -5- (2 ', 4'-difluorophenyl) -benzoate of 2-methoxyphenol.  7. As a compound according to claim 1, 2- (ethoxycarbonyloxy) -5- (2 ', 4'-difluorophenyl) -benzoate of 2-methoxyphenol.  8. Process for the preparation of compounds of formula

 wherein R is as defined in claim 1, which comprises reacting a molar amount of the compound of formula

 with about 2 to 4 molar equivalents of a compound of formula

 wherein Y is a halogen atom and X is as defined in claim 1, at a temperature of from about -10 ° C to about room temperature, for a period of time ranging from about 10 to about 40 minutes, in an anhydrous organic solvent and in the presence of a tertiary organic nitrogen-containing base, to thereby obtain a compound of formula

 wherein X is as defined in claim 1, which is reacted with a slight molar excess, # compound of formula III, 2-methoxyphenol of formula

 at a temperature between about -10 ° C and room temperature, for about 3 to about 8 hours, this process being further characterized in that when X is 2,2,2-trichloroethyl or 2,2,2-trichloroethyl -tribromoethyl, the compound of formula (V) may undergo selective hydrogenolysis to thereby obtain the compound of formula (I) wherein R is hydrogen.  9. Process for the preparation of compounds according to claim 1, wherein R represents hydrogen, characterized in that it consists in bringing into contact a molar amount of the compound of formula

 with about 3 to 7 molar equivalents of 2-methoxyphenol of formula

 in the presence of a catalytic amount of a strong acid, in an inert atmosphere, at the melting temperature of the reaction mixture.  10. Pharmaceutical composition having, in particular, antipyretic, analgesic, anti-inflammatory and expectorant properties, characterized in that it comprises, as active ingredient,  a compound as defined in claim 1, in admixture with a pharmaceutically acceptable carrier.  11. Pharmaceutical composition according to claim 10, characterized in that it comprises as active ingredient about 350 to about 1700 mg of a compound as defined in claim 2.