FR2528826A1 - Phenyl and naphthyl polyoxyethylene cpds. - anti:seborrhoea and antiinflammatories applied topically to skin, as lotions, creams, shampoo etc. - Google Patents

Abstract

Cpds. of formula (I) are new, (n is 4-24; R1 and R2 are each H, halo, nitro, opt. branched 2-12C alkyl, cycloalkyl, alkoxy, cycloalkoxy, acyl or opt. substd. phenyl; at least one being other than H or R1 and R2 together are -CH=CH-CH=CH- joined to 2 adjacent C atoms to form a naphthyl ring). (I) are anti-seborrhea and antiinflammatory cpds., which have low toxicity and are well tolerated by the skin. They may be used to treat smooth skin seborrhea (which may have acne complications), scalp seborrhea and seborrheic dermatitis. The products may be applied locally as lotions, creams, gels, shampoos, etc. Activity tests are described.

Description

New compounds derived from phenols, process for preparing said compounds and entiseborrheic and anti-inflammatory drugs containing as active substance at least one of said compounds.

 The present invention relates, as new industrial products, derivatives of phenols having an antiseborrheic and anti-inflammatory activity, a process for their preparation as well as the drugs containing these products.

More specifically, the invention relates to variously substituted derivatives of phenols, corresponding to the general formula

wherein n is an integer from 4 to 24;
R1 and R2 considered in isolation each represent a hydro atom
gene, a halogen atom, a nitro group, a straight alkyl group
or branched having from 2 to 12 carbon atoms, a cycloalkyl group,
an alkoxy or cycloalkyloxy group, an acyl group or a group
phenyl eventually substituted; R 1 and R 2 occupy one of the free positions of the phenyl ring of formula (I) and at least
one of them is different from hydrogen, R1 and R2 taken together may also constitute a group -CH = CH-CH-CH- -substituting 2 carbon atoms adjacent to the phenyl ring so as to form therewith a naphthyl nucleus.

The compounds (I) according to the invention are obtained
from the appropriately substituted phenols-corresponding (1) by action of a chlorinated drift (2).

 Compounds (1) are generally known or can be prepared by conventional methods of preparing phenols.

The chlorinated derivatives (2) are known up to m = 6 and it is thus possible to obtain the compounds (I) for which n = 4, 5 or 6.

 An alkaline salt, usually the sodium salt of the phenol to be substituted, is first prepared. This, taken up in an anhydrous inert solvent, such as toluene, is refluxed for 15 to 20 hours with an excess of 25 to 50% of the chlorinated derivative (2).

 After filtration of the formed sodium chloride, the solvent is evaporated and then the volatile products (excess of chlorine derivative 2) are removed by heating at 250 ° C. under high vacuum. The residue is purified by chromatography on silica gel.

 From the compounds (I) where n 3 4> 5, 6 thus obtained, the compounds can be prepared where n has a larger value by reacting on the first the chlorine derivative (2). The substitution taking place here on an alcoholic hydroxyl and not on a phenolic hydroxyl, it is necessary to avoid parasitic condensations to block the terminal hydroxyl of the chlorinated derivative (2).

In order to easily remove this protecting group, a tetrahydropyranyl group is usually used which is removed by simply heating in an acid medium.

The condensation is carried out by heating 600C reagents (3) and (4) in the presence of sodium hydroxide and a catalyst such as tetrabutylammonium acid sulfate,
After the end of the reaction, the tetrahydropyranyl group is removed by heating in acidic medium, and the product (6) is purified by chromatography on silica.

 By varying the values of m and P, it is possible to obtain all the products (I) having a value of n between 6 and 12. By repeating the new operation from the products (I) thus obtained, the compounds (I) where n varies from 12 to 18 and so on.

 The reagents (4) are easily obtained from the chlorine derivatives (2) by heating with 3,4-dihydro-2H-pyran in the presence of para-toluenesulphonic acid.

 The compounds (I) are most often under strong oil. They are characterized, on the one hand, by their refractive index and, on the other hand, by their retention time in HPLC chromatography.

The following examples, which are in no way limiting, will make it possible to better understand the scope of the invention. For each of the compounds according to the invention, the HPLC chromatogram was recorded under the following conditions:
silica column (Si 60) particle size 5
inner diameter 1/4 inch, length 15 cm
injection 10 μl, flow rate of the solvent 1 to 3 ml / min;
detection W at 280 or 254 nm.

Solvent systems used

<tb><SEP> Solvast <SEP> B <SEP> B <SEP> C <SEP> D
<tb> Ether <SEP> isopropyl ether <SEP> 700 <SEP> 700 <SEP> 700 <SEP> 700
<tb> Acetate <SEP> of ethyl <SEP> @ <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 100
<tb> Acetonitrile <SEP> 100 <SEP> 70 <SEP> 200 <SEP> 30
<tb> Isooctane <SEP> 800 <SEP> 800 <SEP> 800 <SEP> 800
<tb> Methanol <SEP> 160 <SEP> 130 <SEP> 320 <SEP> 80
<tb> Water <SEP> 8 <SEP> 6 <SEP> 16 <SEP> 5
<tb> Triethylamine <SEP> 2 <SEP> 2 <SEP> 22
<Tb>
In each case, the results are indicated by the retention time expressed in minutes and tenths followed by the indication in parentheses and, in the order of the solvent system used (A to D), the solvent flow rate used (1 to 3).

EXAMPLE 1 (4-Cyclohexylphenoxy) -17 pentaoxa-3,6,9,12,15-heptadecanol-1 (CM 40179)
[(I) R1 = cyclohexyl ~ 4; R2 = H; n - 6]
To the solution of 10 g of cyclohexyl-4-phenol in 100 ml of methanol is added in small portions, 1.3 g of sodium and then heated for 1 h under reflux.

 The methanol is evaporated to dryness and the sodium salt is taken up in 150 ml of anhydrous toluene. 18 g of chloro-17 pentaoxa-3,6,9,12,15 heptadecanol-1 are added and the mixture is refluxed for 20 hours. The precipitate of sodium chloride is filtered and the volatile products are distilled off by heating at 220 ° C. under high vacuum.

 The product is purified by chromatography on a silica column eluting with the chloroform-methanol mixture.

 A viscous hygroscopic liquid is obtained.

 HPLC: 3 min (C, 3).

EXAMPLES 2 to 17
By operating as in the previous example, but by varying the nature of the starting phenol, the compounds according to the invention, n = 6, are obtained in Table I below.

For each of the products are indicated:
- the code number of the product,
the nature of the substituents R1 and R2 as well as
their position on the benzene ring,
- the refractive index,
- the retention time in HPLC.

EXAMPLE 18 (4-Propyl-phenoxy) -ll trioxa-3,6,9 undecanol-1 (CM 7960)
[(I) R1 = propyl-4; R2 = H; n = 4 @
The procedure is as in Example 1 from 4-propylphenol and chloro-11 trioxa-3,6,9 undecanol-1.

 The isolated product as in Example 1 is finally distilled under high vacuum.

 Eb / 0.01 min: 160-175C.

a) (Chloro-17 pentaoxa-3,6,9,12,15 heptadécyloxy)-2tzétrahydropyranne
On chauffe sous agitation à 50 C, pendant 1 h, le mélange de 133 g de chloro-17 pentaoxa-1,6,9,12,15 heptadécanol-1, 45 g de dihydro-3,4 2H-pyranne et 0,2 g d'acide paratoluènesulfonique. EXAMPLE 19 [2,4-Difluoro-phenyl] -4-phenoxy] -35-undecanoxa-3,6,9,12,15,18,21,24,27,30,33 pentatriacontanol-1 (CM 40264)

a) (Chloro-17 pentaoxa-3,6,9,12,15 heptadecyloxy) -2-tetrahydropyran
The mixture of 133 g of chloro-17-pentaoxa-1,6,9,12,15-heptadecanol-45 g of 3,4-dihydro-2H-pyran and 0 is heated with stirring at 50 ° C. for 1 h. 2 g of para-toluenesulfonic acid.

 After cooling, the reaction mixture is taken up in 200 ml of ether and neutralized by addition of a 10% sodium hydroxide solution. The insoluble material is filtered and the solvent is evaporated to dryness.

 170 g of the expected product is obtained, characterized by the absence of an OH band in the infrared spectrum.

(b) CM 40264
An emulsion is formed by stirring the mixture of
25 g of t (2,4-difluorophenyl) -4-phenoxy] -17-pentaoxa-3,6,9,12,15-heptadecanol (CM 40263, Example 16),
25 g of chloro-17-pentaoxa-3,6,9,12,15-heptadecyloxy-2-tetrahydropyran,
20 g of an aqueous solution of 50% sodium hydroxide,
1.1 g of tetrabutylammonium bisulphate and then heated at 800 ° C. for 16 hours.

 After cooling, the residue is taken up in 200 ml of water and extracted 3 times with chloroform. The organic solution is washed with water, dried over sodium sulfate and the solvent is evaporated to dryness.

 The residue is taken up in 300 ml of methanol, 1 ml of concentrated hydrochloric acid is added and the mixture is heated at 600 ° C. for 1 hour. The solvent is evaporated and then the volatile products are removed by heating at 2400 ° C. under 0.05 mmHg.

 The residue is chromatographed on a silica column (15 g of silica per gram of product), glutinous with chloroform and then with a chloroform methanol 97/3 (vol / vol).

First 3 g of CM 40 263 starting material are recovered, then 8 g of the expected product are obtained in the form of a liquid; n21.5D: 1.5077
HPLC: 12 min (C-1).

EXAMPLES 20 to 32
Operating as in Example 18, but replacing CM40263 by the products obtained in Examples 1 to 16, the products are obtained in Table II below.

EXAMPLE 33

(Nonyl-4 phenoxy) -26-octaoxa-3,6,9,12,15,18,21,24 hexacosanol-1.

(CM 7948)
[(I) R1 = - (CH2) 8CH3 (4); R2 = H; n = 9]
The procedure is as in Example 19 using (4-nonyl-phenoxy) pentaoxa-3, 6, 9, 12, 15 beptadecanol-1 (Cm 40124, Example 4) and (8-chloro-3-dioxa). 6-octyloxy) -2 tetrahydropyran prepared according to the technique described in Example 19 a).

HPLC: 4.5 (C-1); nD = 1.4614
EXAMPLE 34

(Nonyl-4 phenoxy) -29 conaoxa-3,6,9,12,15,18,21,24,27 nonacosanol-1.

(GM 7949)
[* I) R1 = - (CH2) 8CH3 (4); R2 = H; n = 10]
The procedure is as in Example 33, replacing (8-chloro-3,6-dioxo-octyloxy) -2-tetrahydropyran with (chloro-11-trioxa-3,6,9-undecyloxy) -2-tetrahydropyran.

 HPLC; 4.2 (C-1); n21D = 1.4515.

EXAMPLE 35

(Nonyl-4-phenoxy) -53 heptadecaoxa-3,6,9,12,15,18,21,24,27,30,33,36, 39,42,45,48,51 tripentacontanol-1. (CM 40257)
L (I) R11OC9H19 (4); R2 ~ H; n - 18]
The mixture of 11 g of (nonyl-4-phenoxy) -35 undecaoxa-3,9,12,15,18,21,24,27,30,33 pentatria-1-butanol (CM 7887, Example 30) was stirred for 90 hours. ), 8.5 g of (17-chloro-3,9-pentaoxa, 12,15-heptadecyloxy) -2-tetrahydropyran, 6 g of sodium hydroxide solution and <50%, and 0.3 g of tetrabutylammonium bisulfate. 60 ml of methanol are then added and acidified to pH = 1 with concentrated hydrochloric acid. The mixture is heated for 1 hour at 600 ° C. and the solvent is evaporated to dryness.

 The residue is taken up in water and extracted with methylene chloride. The organic solution is dried over sodium sulphate and evaporated to dryness. Volatiles are removed by heating at 2600C under 0.5 mm Hg.

 The residue is purified by chromatography on a column of silica gel (350 g). Glutinating with chloroform-methanol to 97.3Z chloroform by volume, eluted unreacted starting material (CM 7887). With a chloroform-methanol mixture with 94.6% of chloroform by volume, the expected product is eluted.

 It is in the form of a solid. Fc:: 300C.

 The products according to the invention have been studied with regard to their therapeutic properties and in particular their antiseborrheic activity and their topical anti-inflammatory activity.

I ANTISEBORREIQUE ACTIVITY.

 A) Activity on Sebaceous Lipogenesis in vitro.

Method:
After male Spleen Chloroform Sacrifices Sprague
Dawley with an average weight of 210 g, the ears are cut with scissors following fixed anatomical references, then their ventral side is carefully shaved. After fixing with adhesive tapes on a glass plate, the ventral side of the ear is removed using a Castrovieto keratotome whose cutting thickness is set to No. 3. This sample is then cut into small squares of 1 u with a razor blade, and weighed before introduction into the tube for incubation.

 The incubation is carried out in 1.5 ml of buffered Krebs-Ringer & pH 7.4 (1/15 M Sorensen phosphate buffer) and containing 100 U / ml of penicillin, 1 mg / ml of streptomycin and 2 mM of non glucose. radioactive. The product, at the concentration to be studied, is previously dissolved in propylene glycol (final concentration equal to 0.5%), and then introduced into the incubation medium. The tubes for incubation are kept in an ice bath until all the samples are taken, then 2 μCi of U-14C glucose (2-4 mCi / mmol) is added to each tube.

 For each rat used, one of the orients serves to test the potential antiseborrheic product, while the other serves as a control.

 After 4 hours of incubation at 37 ° C., the incubation medium is removed, and then the incubate undergoes 4 washings for 3 minutes with stirring using non-radioactive glucose (2 g / l). Once the last wash water has been removed, 3 ml of N alcoholic potash is added to each tube containing the sebaceous glands of the ear skin. The tubes are plugged and brought to 700C overnight.

After this time, the tubes are cooled and 3 ml of 2N hydrochloric acid are introduced into each tube. The lipids present corresponding to the sebaceous glands of each ear are then extracted twice with 4 ml of hexane after stirring with 5.in. After separating the aqueous and benzoic phases, 3.25 ml of hexane at the first extraction and 4 ml at the second are taken and combined in a counting vial containing 10 ml of scintillant mixture liquid.

 The vials, after capping and stirring, are introduced into a pre-set liquid scintillation counter on channel C. The counting time of each vial is 4 minutes.

For each vial, the result expressed in counts / minute (cpm) is transformed according to the sampling weight in cpm / mg and the inhibition of lipid synthesis is given by the variation% (@%) of the incorporation into cpm / mg between the control ear and the "treated" ear.

 The Z average is taken and the statistical value of the results is determined by the calculation of the coefficient "t" (method of couples).

 From the values thus determined for different concentrations of the product studied, it is possible to calculate the inhibitory concentration 50 (IC 50), that is to say the concentration of the test substance which produces a 50% inhibition of sebaceous lipogenesis.

 The results obtained with various products (I) are summarized in Table III below. The results are given as IC 50 expressed in g / ml.

 The antiseborrheic activity can be confirmed by an in vivo study.

 B) Local antiseborrhea activity.

 Method.

 Golden Syrian female hamsters with an average weight of 110 g are shaved and shaved at the level of the flank organs, which appear as a dark spot about 2 mm in diameter on both sides of the body. spine. On one organ, 1.25 11 g of testosterone propionate are applied daily in a volume of 10 l of acetone, the other organ receiving the same amount of testosterone associated with the product to be studied. The treatment is carried out 5 days / 7 during 21 days.

 At the end of this period, the animals are sacrificed with chloroform and the diameters of the pigmented spots are measured using a graduated rule. Skin esc removed, fixed cte.épiderme down, on a wooden board. The palisier muscle and adipose tissue are then eliminated by planarization with Castroviejo keratotome (thickening of cut set on the nO 3) then a biopsy of 10 mm of diameter at the level of each organ is carried out using a trephine .

This biopsy is delivered in squares of 1 mm, then weighed (# 0.1 mg).

 The rest of the manipulation: incubation, saponification, extraction is identical to that performed in the "in vitro" lipogenesis test above.

 The results obtained with various compounds (I) are shown in Table IV below.

 The results represent the inhibition of sebaceous lipogenesis as a percentage relative to the controls after treatment with a dose of 2,000 μg per day of each of the products.

II ANTIINPLAMMATORY EFFECT: inflammation in croton oil
rat.

 The method used is that of Tonelli et al. as described by Le Douarec and Visalli (J. Pharmacol., Paris, 1970, 1 (3), 395-405).

 The results obtained with various products (I) are shown in Table V below. They are expressed as IC 50.

III TOLERANCE - TOXICITY.

 In addition, the products (I) have low general toxicity. They also have good local cutaneous tolerance.

 As a result, the products (I) have all the qualities required for their use in human therapy and in particular for the treatment of all the pathological conditions related to an excessive production of sebum.

 The products of the invention may be used in the case of seborrhea of the glabrous skin complicated or not acne, in the seborrhea of the scalp and seborrheic dermatitis.

 The products (I) can be presented in any form suitable for external application such as, for example: lotion, cream, gel, shampoo, etc.

By way of example, the following formulations may be indicated
Hydroalcoholic solution.

CM 7887 10 g
Ethyl alcohol 60 qs 100 g
Aqueous gel.

CM 40264 5 g
Carbopol 934 lg
Soda qs gel formation
Purified water 100 g
Shampoo.

CM 7887 15 g
Dihydroxymethylneuramide 5 g
Essence of lavender 0.2 g
Soda qsp pH 7.5
Purified water qs 100 g
TABLE I

<tb><SEP> e <SEP> of <SEP> code <SEP> R1 <SEP> (position) <SEP> R2 <SEP> (position) <SEP> Index <SEP> of <SEP> Time <SEP> of <SEP> reten
<tb><SEP> tion <SEP> tion <SEP> HPLC
<tb><SEP> (conditions)
<tb><SEP> 21
<tb><SEP> 7951 <SEP> CH3CH2CH2 <SEP> (4) <SEP> H <SEP>"D<SEP>:<SEQ> 1.4963 <SEP> 4.1 <SEP> (C-1)
<tb><SEP> 40122 <SEP><9 ~ <SEP> (4) <SEP> R <SEP> nDl '<SEP> 5 <SEP>: <SEP> 1.5437 <SEP> 2.5 <SEP > (B-2.5)
<tb><SEP> 40124 <SEP> CH3 <SEP> (CH2) 8 <SEP> (4) <SEP> H <SEP> n22 <SEP> i <SEP> 4891 <SEP> 7.0 <SEP> ( B-2)
<tb><SEP>J>
<tb><SEP> 40126 <SEP> (CH3) 3 <SEP> (3) <SEP> (CH3) 3 <SEP>(<SEP>)<SEP> n2l <SEP>: <SEP> 1.4912 <SEP> 3.66 <SEP> (B-2)
<tb><SEP> 40127 <SEP> Dv <SEP> (4) <SEP> H <SEP> nD <SEP>: <SEP> 1.5053 <SEP> 3.4 <SEP> (B-2.5 )
<tb><SEP>J>
<tb><SEP> 40128 <SEP> -NO2 * <SEP> (4) <SEP> H <SEP> n22 <SEP>: <SEP> 1.5246 <SEP> 5.4 <SEP> (B-2) , 5)
<tb><SEP> 22
<tb><SEP> 40129 <SEP> -CH = CH-CH = CH- <SEP> (3-4) <SEP> nD <SEP>: <SEP> 1.5388 <SEP> 4.56 <SEP> (B-2)
<tb><SEP> 40131 <SEQ> Cl <SEP> (4) <SEP> R <SEP> n22 <SEP>: <SEP> 1.5038 <SEP> 4.3 <SEP> (B-2)
<tb><SEP> D
<tb> 40152 <SEP> F <SEP> (4) <SEP> R <SEP>n21'5<SEP>:<SEP> 1.4881 <SEP> 8.84 <SEP> (C-1)
<tb><SEP>J>
<tb><SEP> 40179 <SEP> 0 <SEP> (4) <SEP> H <SEP>n2D1> 5 <SEP>: <SEP> 1.4928 <SEP> 8.0 <SEP> (C-3 )
<tb><SEP>?'3<SEP>? i3 <SEP> 22
<tb><SEP> 40181 <SEQ> H3C-C-CH2-C <SEP> (4) <SEP> N <SEP> 1.4931 <SEP> 6.8 <SEP> (C-2)
<tb><SEP> CH3 <SEP> CH3
<tb><SEP> ai
<tb><SEP> 3 <SEP> H3C '(4) <SEP> H <SEP> 22
<tb><SEP> 40200 <SEP> H3C-C, <SEP> 3 <SEP> (4) <SEP> H <SEP> nD2 <SEP>: <SEP> 1.4938 <SEP> 4.0 <SEP > (CI1)
<tb><SEP> cH3
<tb><SEP> 21
<tb><SEP> 40256 <SEP> -C9R19 <SEP> (4) <SEP> H <SEP> nD <SEP>: <SEP> 1.4938 <SEP> 7.8 <SEP> (D-2)
<tb><SEP> o
<tb> 40262 <SEP> CH3 (CH2) 7-C- <SEP> (4) <SEP> nD1 <SEP>: <SEP> 1.4962 <SEP> 11.4 <SEP> (B-1)
<tb><SEP> CR3 (-CN) 7-C- <SEP> (4) <SEP>"D<SEP> n <SEP> 4962
<tb><SEP> F
<tb> 40263 <SEP> P- (<SEP> (4) <SEP> - <SEP> H <SEP> Nose <SEP>: <SEP>1> 5077 <SEP> 5 <SEP> (Cl)
<tb><SEP> 40367 <SEP>{><SEP> (4) <SEP> Cl <SEP> (3) <SEP> oD2 <SEP>: <SEP> 1.5149
<Tb>
TABLE II

<tb><SEP> Point <SEP> of <SEP> Merge <SEP> Time <SEP> of <SEP> Reten
<tb> n0 <SEP> of <SEP> code <SEP> R1 <SEP> (position) <SEP> N <SEP> (position) <SEP> or <SEP> index <SEP> of <SEP> tion <SEP > HPLC
<tb><SEP> refraction <SEP> 1 <SEP>(conditions>
<tb><SEP> 7966 <SEP> ~ <SEP> ~ <SEP> ~ <SEP> ~ <SEP> ~ <SEP> (4) <SEP> 21 <SEP> 1.4930 <SEP> 2.5 <SEP> (Cl)
<tb> nD
<tb><SEP> 40123 <SEP> O <SEP> (4) <SEP> H <SEP> Fc <SEP>: <SEP> 350C <SEP> 22.2 <SEP> (B-2.5)
<tb><SEP> 7886 <SEP> C, - (CB2) <SEP> H <SEP> Fc <SEP>: <SEP> 30 C <SEP> 2,4 <SEP> (ce3)
<tb><SEP> 40125 <SEP> (cli <SEP>) <SEP> c- <SEP> (3) <SEP> (cii3) 3c- <SEP> nD <SEP>: <SEP>: <SEP> 1.4846 <SEP> 21
<tb> 33 <SEP> nD <SEP>1> 4846 <SEP> 13 <SEP> (1-2)
<tb><SEP> 40130 <SEP>><SEP> (4) <SEP> H <SEP> nD <SEP>'5<SEP>:<SEQ> 1.4939 <SEP> 23.3 <SEP> B-2)
<tb><SEP> 40151 <SEP> -CR = -CIa <SEP> (3-4) <SEP> Fc <SEP>: <SEP> 25-270C <SEP>: <SEP> 5.2 <SEP> (C-3)
<tb><SEP>21> 5
<tb><SEP> 40132 <SEQ> Cl- <SEP> (4) <SEP> H <SEP>oDl'5<SEP>:<SEQ> 1.4917 <SEP> 26.2 <SEP> (B- 2)
<tb><SEP> 21.5
<tb><SEP> 40153 <SEQ> F- <SEP> (4) <SEP> R <SEP>1> 4804 <SEP> 5.2 <SEP> (C-3)
<tb><SEP> 40180 <SEP> o <SEP> (4) <SEP> B <SEP> nD <SEP>: <SEP> 14a95 <SEP> 4 <SEP> (C-2)
<tb><SEP> oe
<tb><SEP> C, H3 <SEP> C, H3 <SEP> 22
<tb><SEP> 40182 <SEP> a <SEP> cc <SEP> - <SEP> 4-c- <SEP> - <SEP> H <SEP> nD <SEP>: <SEQ> 1.4851 <SEP > 3.4 <SEP> (C-2)
<tb><SEP> ai <SEP> CH
<tb><SEP> 3 <SEP> 3
<tb><SEP> 22
<tb><SEP> 7887 <SEQ> C9H19 <SEP> (4) <SEP> H <SEP> n, <SEP>: <SEQ> 1.4853 <SEQ> 13.2 <SEP> (A-2)
<tb><SEP> 40270 <SEP> Cff3 <SEP>% <SEP>) 7-C; (4) <SEP> H <SEP><SEP>:<SEP>:<SEP> 260C <SEP> 10 <SEP> (Ci)
<tb><SEP> 40297 <SEP> o <SEP> (4) <SEP> Cl <SEP> (3) <SEP> 21 <SEP>: <SEQ> 1,5003 <SEP> 8 <SEP> (Cl )
<tb><SEP> CH3
<tb><SEP> I <SEP> I <SEP> 1 <SEP> 21
<tb><SEP> 40351 <SEP> HIC-C- <SEP> (4) <SEP> R <SEP> nD <SEP>: <SEQ> 1.4843 <SEQ> 4.2 <SEP> (C- 2)
<tb><SEP> CH3
<tb><SEP> 3
<Tb>
TABLE III
Activity on sebaceous lipogenesis in vitto.

<Tb>

<SEP> Product <SEP> CI <SEP> 50
<tb> n- <SEP> of <SEP> code <SEP> R1 <SEP> (position) <SEP> R2 <SEP> (position) <SEP> n <SEP> pglml
<tb><SEP> 40179 <SE> O <SEP> (4) <SEP> H <SEP> 6 <SEP> 46
<tb><SEP> 40180 <SEP> 9 <SEP> (4) <SEP> H <SEP> 12 <SEP> 38
<tb><SEP> CH3 <SEP> CH3
<tb><SEP> .3 <SEP> 1
<SEQUENCE NOTIFICATION>
<tb><SEP> 3 <SEP> CR3
<tb><SEP> 40182 <SEP> u <SEP> .. <SEP>., <SEP> H <SEP> 12 <SEP> 13
<tb><SEP> 40124 <SEP> CK3 = (CH2) 8 <SEP>(<SEP> H <SEP> 6 <SEP> 70
<tb><SEP> 7948 <SEP> CR3 <SEP> (ai2) 8- <SEP> (4) <SEP> H <SEP> 9 <SEP> 39
<tb><SEP> 7886 <SEP>(<SEP> tr <SEP> I '<SEP> H <SEP> 12 <SEP> 11
<tb><SEP> 7887 <SEQ> C99 <SEP> (4) <SEP> H <SEP> 12 <SEP> 11
<tb><SEP> 40122 <SE> O <SEP> (4) <SEP> H <SEP> 6 <SEP> 36
<tb> 40123 <SEP> cr <SEP> tr <SEP> H <SEP> 12 <SEP> 10
<tb><SEP> 40130 <SEP>) <SEP> O- <SEP> (4) <SEP> H <SEP> 12 <SEP> 70
<tb><SEP> CH3 <SEP> CH
<tb><SEP> .3 <SEP> 13
<tb><SEP> 40126 <SEP> 83C "(s) <SEP> (3) <SEP> H3C-C- <SEP> (5) <SEP> 6 <SEP> 77
<tb><SEP> 3 <SEP> CH3
<tb><SEP> 40151 <SEP> -CH-CH-CH-CH- <SEP> (3-4) <SEP> 12 <SEP> 33
<tb><SEP> 40270 <SEP> CR3- (CH2) 7α- <SEP> (4) <SEP> H <SEP> 12 <SEP> 6
<tb><SEP> 40264 <SEP><SEP><SEP> (4) <SEP> H <SEP> 12 <SEP> 5
<Tb>
TABLE IV

<tb><SEP> Product <SEP> Inbibition <SEP> of <SEP><SEP> Lipogenesis
<tb> (n <SEP> of <SEP> code) <SEP> sewn <SEP> (A% / witnesses)
<tb><SEP> 7886 <SEP> 100
<tb><SEP> 40123 <SEP> 100
<tb><SEP> 40151 <SEP> 51
<tb><SEP> 40179 <SEP> 43
<Tb>
TABLE V

<tb><SEP> Product <SEP> | <SEP> activity <SEP> antiinflax
<tb><SEP> matory <SEP> topical
<tb> n0 <SEP> of <SEP> code <SEP> \ <SEP> 1 <SEP> | <SEP> n <SEP> CI <SEP> SOZ
<tb> Ca <SEP> Ca
<tb><SEP> t3 <SEP> t3
<tb><SEP> 40182 <SEQ> li3CrCS <SEP> I-2- <SEP> li <SEP> a <SEP> 12 <SEP>3> 2
<tb> CR3 <SEP> 40182 <SEP> H <SEP> \ C <SEP> (4) <SEP> | <SEP> E
<tb><SEP> CX3 <SEP> CS
<tb><SEP> 7886 <SEP> 7886 <SEP> | <SEP> C113 (C112) 8 <SEP> (4) 1 <SEP> H <SEP> 1 <SEP> | <SEP> 3,7
<tb><SEP> 7887 <SE> Ic9El9 <SEP> (4) 1 <SEP> H <SEP> 12
<tb><SEP> 40257 <SEP> H <SEP> 8 <SEP> 18 <SEP> 2.1
<tb><SEP> 40123 <SEP>401; L3 <SEP> o <SEP> CF <SEP> t4) <SEP> | <SEP> R <SEP> 12 <SEP> 5.7 <SEP> 9
<tb><SEP> 40130 <SEP>(&gt;<SEP> a <SEP> 112 <SEP> 1 <SEP> 5.7
<tb><SEP> 40132 <SEQ> Ci <SEP> (4) 1 <SEP> R <SEP> 112 <SEP> I <SEP> 9.5
<tb><SEP> ca
<tb><SEP> .3
<tb><SEP>4> 125 <SEP> Ca3-C- <SEP> (3) <SEP> 3-C <SEP> (5) <SEP> 112 <SEP> 1 <SEP> 6
<tb><SEP> cR3 <SEP> 013
<Tb>

Claims (4)

 R 1 and R 2 taken together may also constitute a -CH-CH-CH-CH-group substituting 2 carbon atoms adjacent to the phenyl ring so as to form therewith a naphthyl ring.  R 1 and R 2 occupy one of the free positions of the phenyl ring of formula (I) and at least one of them is different from hydrogen;  R1 and R2 taken alone each represent a hydrogen atom, a halogen atom, a nitro group, a straight or branched allyl group having 2 to 12 carbon atoms, a cycloalkyl group, an aoxy or cycloalkyloxy group, a group acyl or an optionally substituted phenyl group;  wherein n denotes an integer from 4 to 24;

 CLAIMS 1. New industrial products characterized in that they correspond to the general formula 2. Process for the preparation of industrial products according to claim 1, characterized in that an alkaline salt of a phenol of formula

 in which R1 and R2 have the above meaning, with a chlorinated derivative of formula:  Cl (CH2-CH2-O) mH wherein m is an integer less than 6 and when ob is desired; A product of formula (I) wherein n is greater than 6, a novel chloro derivative of the formula is reacted with a product obtained in the preceding stage;

 p being selected-such that m + p is equal to n, said reaction being carried out by heating the reagent in the presence of a base and a catalyst such as tetrabutylammonifum acid sulfate, and then eliminating the tetrahydropyranyl group by heating the product obtained in acidic medium. Medicaments characterized in that they contain as active product at least one new product according to claim 1. 4. Medicaments according to claim 3, characterized in that they are packaged, for external application, in the form of lotion, cream, gel or shampoo.