FR2913685A1 - New unsaturated fatty amino acid derivatives useful e.g. to prepare dermocosmetologic antiradical, anti-inflammatory, anti-pruritic or anticollagenase compositions and to treat skin aging, keratinization and pigmentation disorders - Google Patents

Abstract

Unsaturated fatty amino acid derivatives (I) and their acid addition salts, as drugs, are new. Unsaturated fatty amino acid derivatives of formula (R a)(R b)N-CH 2-(CH(R n)) n-CH=C(R 1)-C(O)-OR (I) and their acid addition salts, as drugs, are new. X : O or NH; R nH or 1-6C alkyl (optionally substituted by halo), preferably H; R 1H, F, Cl or Br, CF 3, CHF 2 or 1-6C alkyl, 1-6C alkenyl or 1-6C alkynyl (optionally substituted by halo), preferably H or F; R : H, 1-6C alkyl or 3-6C cycloalkyl (optionally substituted by halo), preferably H; R a, R bH, 1-6C alkyl or 1-6C acyl, preferably H, or 4-6C hydrocarbon ring; and n : 2-14, preferably 3. Provided that as a new compound (I) is excluded from 6-amino-hex-2-enoic acid, its hydrochloride and trifluoroacetate, 8-amino-oct-2-enoic acid trifluoroacetate, 8-(dimethylamino)-oct-2-enoic acid, 12-(dimethylamino)-dodec-2-enoic acid, 6-(isopropylamino)-2-methyl-hex-2-enoate, ethyl-6-(tert-butylamino)-2-methyl-hex-2-enoate, 6-amino-2-methyl-hex-2-enoate, 7-amino-hept-2-enoate, 7-amino-2-methyl-hept-2-enoate and 7-amino-4-methyl-hept-2-enoate. Independent claims are included for: (1) the preparation of (I); and (2) an ester compound of formula PG-N(R d)-CH 2-(CHR 1)-C(O)-OR c (VIII). R cH or 1-6C alkyl; R 1H, F, Cl, Br, -CF 3 or -CHF 2, or 1-6C alkyl, alkenyl or alkynyl (optionally substituted by halo, preferably F); PG : a protecting group forming a carbamate group, preferably tert. butyl carbamate or benzyl carbamate, and R dH or PG, provided that (VIII) is excluded from tert-butyl-(E)-6-(N,N-di-tert-butoxycarbonylamino)-hex-2-tert-enoate, ethyl (E)-6-(N-tert-butoxy-carbonylamino)-hex-2-enoate, methyl-(E)-7-(E-tert-butoxy-carbonylamino)-hept-2-enoate and (E)-7-(E-tert-butoxy-carbonylamino)-hept-2-enoic acid. ACTIVITY : Dermatological; Antiinflammatory; Antipruritic; Vulnerary. MECHANISM OF ACTION : Melanogenesis modulator.

Description

The subject of the present invention is novel fatty amino acids

  unsaturated, as well as their dermocosmetological use. More particularly, the subject of the present invention is unsaturated fatty amino acid derivatives corresponding to the general formula (I): ## STR3 ## and their pharmaceutically acceptable acid addition salts, in which: independently of one another represent a hydrogen atom or an alkyl group, linear or branched, comprising 1 to 6 carbon atoms, and being optionally substituted by a halogen atom, in particular fluorine; R1 represents a hydrogen, fluorine, chlorine or bromine atom, or a -CF3 group or a linear or branched alkyl group comprising 1 to 6 carbon atoms; R represents a hydrogen atom or a linear or branched alkyl group comprising 1 to 6 carbon atoms, and being optionally substituted by a halogen atom, in particular fluorine; and • n is an integer from 2 to 14; with the exception of 6-amino-2-hexenoic acid, its hydrochloride and trifluoroacetate and 8-amino-2-octenoic acid trifluoroacetate. According to one particular characteristic of the invention, the unsaturated fatty amino acid derivatives of general formula (I) fulfill the following criteria: • Rn represent a hydrogen atom on all the carbon atoms of the carbon chain except on one where Rn represents a linear or branched alkyl group comprising 1 to 6 carbon atoms, and being optionally substituted by a halogen atom, in particular fluorine; R represents a hydrogen atom or a linear or branched alkyl group comprising 1 to 6 carbon atoms, and being optionally substituted by a halogen atom, in particular fluorine; R is preferably hydrogen; and • n and R1 are as defined above. According to one particular characteristic of the invention, the unsaturated fatty amino acid derivatives of general formula (I) fulfill the following criteria: • Rn and R represent a hydrogen atom; and • n and R1 are as defined above. According to one particular characteristic of the invention, the unsaturated fatty amino acid derivatives of general formula (I) fulfill the following criteria: • Rn and R represent a hydrogen atom; • n is as defined previously; and • R1 represents a hydrogen or fluorine atom. According to one particular characteristic of the invention, the unsaturated fatty amino acid derivatives of general formula (I) fulfill the following criteria: • Rn and R represent a hydrogen atom; R1 represents a hydrogen or fluorine atom; and n is from 2 to 10.

  According to one particular characteristic of the invention, the unsaturated fatty amino acid derivatives of general formula (I) fulfill the following criteria: • Rn and R represent a hydrogen atom; R1 represents a hydrogen or fluorine atom; and • n is between 3 and 10.

  According to one particular characteristic of the invention, the unsaturated fatty amino acid derivatives of general formula (I) fulfill the following criteria: R 1 and R 2 represent a hydrogen atom; R1 represents a hydrogen or fluorine atom; and • n is between 3 and 5.

  According to one particular characteristic of the invention, the unsaturated fatty amino acid derivatives of general formula (I) fulfill the following criteria: • Rn and R represent a hydrogen atom; • RI represents a hydrogen or fluorine atom; and • n is between 9 and 14.

  According to one particular characteristic of the invention, the unsaturated fatty amino acid derivatives of general formula (I) fulfill the following criteria: • Rn and R represent a hydrogen atom; • RI represents a hydrogen or fluorine atom; and • n is equal to 3.

  The unsaturated fatty amino acid derivatives of general formula (I), as defined above, may be in the form of Z or E isomers, or a mixture of Z isomers and E isomers, in all quantities. Within the meaning of the present invention, the "pharmaceutically acceptable acid addition salts" means the salts formed by addition of an acid to the compound, which are non-toxic and which possess the pharmacological activity of the parent compound. The acid addition salts can be formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or from organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, acid gluconic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzol-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, acid trimethylacetic acid or trifluoroacetic acid. Preferred pharmaceutically acceptable salts are salts formed from hydrochloric acid.

  The compounds which are the subject of the present invention are preferably in the form of hydrochloride salts. The subject of the present invention is also the unsaturated fatty amino acid derivatives of general formula (I): ## STR1 ## as well as their pharmaceutically acceptable acid addition salts, in which: Rn represent independently each other a hydrogen atom or an alkyl group, linear or branched, comprising 1 to 6 carbon atoms, and being optionally substituted by a halogen atom, in particular fluorine; R1 represents a hydrogen, fluorine, chlorine or bromine atom, or a -CF3 group or a linear or branched alkyl group comprising 1 to 6 carbon atoms; R represents a hydrogen atom or a linear or branched alkyl group comprising 1 to 6 carbon atoms, and being optionally substituted by a halogen atom, in particular fluorine; and • n is an integer from 2 to 14; as drugs. The present invention also relates to dermatological compositions comprising as active ingredient at least one fatty acid amino derivative of general formula (I), as defined above, in combination with a dermocosmetologically acceptable excipient. The subject of the present invention is also the use of the unsaturated fatty amino acid derivatives of general formula (I) as defined above for the preparation of an antiradical, anti-inflammatory, anti-puriginous and / or anti-aging dermatological composition intended for the treatment of aging. cutaneous, and / or intended to treat disorders of keratinization and pigmentation and / or to improve healing. The unsaturated fatty amino acid derivatives of general formula (I) are more particularly intended for compositions intended for the treatment of psoriasis, pruritus and / or atopic dermatitis, as well as for the repigmentation of hair or skin, in particular white age spots. According to the present invention, the unsaturated fatty amino acid derivatives of general formula (I) are more particularly intended for compositions intended to cause a lightening of the skin or to treat brown age spots.

  Because of their anti-radical activity, the unsaturated fatty amino acid derivatives of general formula (I) are also useful for preventing or limiting cutaneous photocarcinogenesis at early stages and therefore can be used in the prevention and treatment of various tumoral diseases of the skin.

  The unsaturated fatty amino acids that are the subject of the present invention can be prepared by using Wittig-Hôrner-type reactions from a phosphonate (fluorinated or non-fluorinated) or Wittig type from a triphenyl phosphonium on cyclized alpha hydroxy amine from the corresponding lactam whose amine function will be protected beforehand (see synthesis scheme developed below).

  A saponification reaction of the protected amino ester optionally follows to obtain an amino acid which will be deprotected by acid hydrolysis to give the unsaturated fatty amino acid of general formula: ## STR1 ## and R 1 = H, halogen, or alkyl. The Wittig-Hörner reaction is a reaction described in the document Modem Synthetic Reaction, Second Edition, Herbet O.House, Wittig Hot Reaction p.682-709, and any experimental condition described in the state of the art can be used in the context of the present invention. For example, the Wittig-Hôrner reaction can be carried out in the presence of triethylphosphonoacetate and potassium carbonate in an ethanolic medium. The method for protecting the amine function is a conventional method commonly used for its advantage of not being hydrolysable under the basic conditions (deprotection conditions of the ester function) and inert with respect to other nucleophilic reagents. (References: T. Kunieda, T. Higuchi, Y.Abe, and M. Hirobe, Chem Pharm Bull, 32, 2174, 1984, I. Grapsas, YJCho, and S.Mobashery, J. Org. 59, 1918, 1994).

  The partial lactam reduction step is carried out in the presence of a reducing agent such as diisobutyl aluminum hydride. At the end of the reaction, the aluminum salts are removed by formation of a water-soluble complex in the presence of Rozen salts (Reagents for organic synthesis, VoI, Louis Fieser and Mary Fieser, p.36).

  ## STR1 ## BocHN BocHN i OH O BocHN WhereO O

  An example of a derivative synthesis in which Rn = methyl can be illustrated by a sequence of protection, deprotection, Wittig-Hôrner and Gabriel reactions starting from a hydroxy ketone. After protection of the alcohol function, a succession of reactions of Wittig Hôrner is carried out. Deprotection of the alcohol function in an acid medium followed by a Gabriel reaction will generate the amine function.

  The present invention will be illustrated in the context of the synthesis examples given below:

  1) Synthesis of the compounds according to the invention 1.1) Compound No. 12 H3N Cl O OH 12

  Stage 1 In a three-neck stream under nitrogen flow, 10.0 g of Caprylolactam (70.8 mmol) are solubilized in 150 ml of tetrahydrofuran. 10.06 ml (1.01 eq) of triethylamine are added together with 8.74 g (1.01 eq) of 4-dimethylaminopyridine and finally 30.91 g (2 eq) of dibutyl di-carbonate. The reaction medium is stirred overnight at room temperature. A follow-up CCM makes it possible to control the end of the reaction. The reaction medium is concentrated, taken up in water and ethyl acetate. The mixture is extracted three times with ethyl acetate, the combined organic phases are washed with a 5% hydrochloric acid solution and then with a saturated solution of NaCl. The organic phases are dried over Na2SO4, filtered and concentrated in vacuo to yield a red oil. Characterizations: m = 24.0 g 100% Rf = 0.8 (DCM / MeOH 99/1) NMR (H, CDCl3): 1.50 (s, 9H); 1.53 (m, 6H); 1.67 (m, 2H); 1.82 (m, 2H); 2.87 (m, 2H), 2.78 (t, 2H).

  Stage 2 In a three-neck stream under nitrogen flow, 17.1 g of Caprylolactam protected with a Boc group (70.8 mmol) are solubilized in 170 ml of toluene. The medium is cooled to -78 ° C. and 59.2 ml of a 20% solution of Dibal-H in toluene (1.01 eq) are run dropwise over 1 hour, keeping the temperature of the medium between -80.degree. -75 C. A follow-up CCM makes it possible to control the end of the reaction. At -78 ° C, 480 ml of a saturated solution of double tartrate are slowly poured and the medium is stirred vigorously overnight. The organic phase is extracted. The aqueous phase is extracted with ethyl acetate three times. The combined organic phases are washed with saturated NaCl solution, dried over MgSO 4, filtered and concentrated in vacuo to yield an orange solid.

  Characterizations: m = 20.0 g 99% Rf = 0.1 (Heptane / ethyl acetate 7/3) NMR (1H, CDCl3): 1.40-1.80 (m, 20H); 2.85-2.89 (m, 2H); 3.75-3.79 (m, 2H).

  Stage 3 In a three-necked flowing stream of nitrogen, 2.0 g (8.22 mmol) of stage 2 compound are solubilized in 20 ml of ethanol. 1.70g (1.5eq) of potassium carbonate are added to the medium and 1.96m1 (1.2eq) of Triethylphosphonoacetate are slowly poured. The mixture is then heated at 45 ° C. for one night. A follow-up CCM makes it possible to control the end of the reaction. The reaction medium is concentrated and the residue is taken up in ethyl acetate and water. The aqueous phase is extracted with ethyl acetate three times. The combined organic phases are washed with a saturated solution of NaCl, dried over MgSO 4, filtered and concentrated in vacuo. The crude product obtained is purified by chromatography on silica gel (heptane / AcOEt gradient) to give a yellow oil.

  Characterizations: m = 1.60 g 62% Rf = 0.4 (Heptane / ethyl acetate 7/3) NMR (H, CDCl3, 300 MHz): δ 1.28-1.46 (m, 22H); 2.16-2.19 (m, 2H); 3.10 (m, 2H); 4.20 (q, 2H); 5.82 (dt, 1H, J = 15.6Hz); 6.97 (dt, 1H, J = 15.6Hz).

  Stage 4 In a flask, 1.60 g (5.10 mmol) of compound of stage 3 are dissolved in 16 ml of THF. 6.40m1 (2.5eq) of a solution of 2M NaOH are added and the reaction medium is heated at 65 ° C overnight. A follow-up CCM makes it possible to control the end of the reaction. The pH of the mixture is then adjusted to 4 by adding hydrochloric acid. The medium is concentrated, taken up by AcOEt / water. The aqueous phase is extracted with ethyl acetate (three times); the combined organic phases are washed with saturated NaCl solution, dried over Na 2 SO 4, filtered and concentrated in vacuo to yield a beige solid. Characterizations: m = 1.2g 82% Rf = 0.2 (Heptane / ethyl acetate 7/3) NMR (1H, CDCl3, 300 MHz): δ 1.30-1.46 (m, 19H); 2.20-2.27 (m, 2H); 3.13 (m, 2H); 5.80-5.86 (dt, 1H, J = 15.6Hz); 7.0 (dt, 1H, J = 15.6Hz).

  Stage 5 In a nitrogen balloon, 1.2 g (4.28 mmol) of compound of stage 4 are solubilized in 7.5 ml (3.5 eq) of a solution of HC1 in 2M ether. The medium is stirred overnight at 35 C. The TLC monitoring makes it possible to control the end of the reaction. The medium is concentrated under vacuum, taken up in dichloromethane, filtered and washed with dichloromethane, dried under vacuum to give a white solid. This solid is recrystallized several times in ethanol. Characterizations m = 0.59 g 82% Rf = 0.1 (Heptane / ethyl acetate 5/5) NMR (1H, MeOD, 300 MHz): δ 1.50-1.69 (m, 10H); 2.21-2.28 (q, 2H); 2.93 (t, 2H); 5.80 (d, 1H, J = 15.6Hz); 6.95 (dt, 1H, J = 15.6 Hz) Mass spectrometry: [M + H] + = 186 (calculated 185) 10 .2) Compound No. 13 OH 13

  Stages 1 and 2 are conducted in the same manner as previously, on Caprylolactam.

  Stage 3 In a three-necked flowing stream of nitrogen, 2.0 g (8.22 mmol) of stage 2 compound are solubilized in 20 ml of ethanol. 1.70g (1.5eq) of potassium carbonate are added to the medium and 2.06g (1.leq) of Triethylphosphonofluoroacetate are slowly poured. The mixture is then heated at 45 ° C. for one night. A follow-up CCM makes it possible to control the end of the reaction. The reaction medium is concentrated and the residue is taken up in ethyl acetate and water. The aqueous phase is extracted with ethyl acetate three times. The combined organic phases are washed with a saturated solution of NaCl, dried over MgSO 4, filtered and concentrated in vacuo. The crude product obtained is purified by chromatography on silica gel (heptane / AcOEt gradient) to give a pale yellow oil. Characterizations: m = 1.70 g 65% Rf = 0.5 (Heptane / ethyl acetate 7/3) NMR (1H, CDCl3, 300MHz): δ 1.32-1.39 (m, 22H); 2.21 (m, 2H); 3.11 (m, 2H); 4.30 (q, 2H); 5.89-5.96 (dt, 0.5H, J = 21.9 Hz, E form); 6.06-6.18 (dt, 0.5H, J = 33.3Hz, Z form).

  Stages 4 and 5 are carried out as above and lead to the following characterizations: Characterizations Stage 4: m = 1.4g 87% Rf = 0.2 (Heptane / ethyl acetate 7/3) NMR (1H, CDCl 3): 1.23- 1.46 (m, 19H); 2.26-2.55 (m, 2H); 3.12 (m, 2H), 5.98-6.32 (ddt, 1H, E and Z form). Characterizations Stage 5: m = 0.9g 95% Rf = 0.1 (Heptane / ethyl acetate 5/5) NMR (1H, MeOD): δ 1.41-1.53 (m, 8H); 1.65-1.70 (m, 2H), 2.24-2.29 (m, 1H Z-form); 2.53-2.56 (m, 1H, form E); 2.91-2.96 (t, 2H), 5.90-6.03 (dt, 0.5H, J = 21.6 Hz, form E); 6.08-6.25 (dt, 0.5H, J = 33.3Hz, Z form). Mass spectrometry: [M + H] + = 204 (calculated 203)

  1.3) Compound No. 7 The general procedure is applied to α-caprolactam to yield (E) -8-amino-oct-2-enoic acid. Rf = 0.1 (Heptane / ethyl acetate 5/5) NMR (1H, MeOD): 81.41-1.57 (m, 4H); 1.67-1.75 (m, 2H); 2.24-2.31 (m, 2H); 2.93-2.98 (m, 2H); 5.86 (dd, 1H); 6.98 (dt, 1H). Mass spectrometry: [M + H] + = 158 (calculated 157) 1.4) Compound No. 8 ## STR3 ## The general protocol is applied to oenantholactam to yield (E) -9-amino acid -non-2-enoic acid. Rf = 0.1 (Heptane / ethyl acetate 5/5) NMR (1H, DMSO-d6): δ 1.29-1.54 (m, 8H) 2.16-2.23 (m, 2H); 2.71-2.76 (m, 2H); 5.77 (dd, 1H, J = 18Hz); 6.81 (dt, 1H, J = 18Hz). Mass spectrometry: [M + H] + = 172 (calculated 171) Melting point: 104 C

1.5) Compound No. 9 Cl H3N OH 9

  The general protocol is applied to oenantholactam to yield 9-amino-2-fluoro-non-2-enoic acid. Rf = 0.1 (Heptane / ethyl acetate 5/5) NMR (HH, MeOD): 5151.40-1.71 (m, 8H); 2.30-2.35 (m, 2H); 2.91-2.96 (m, 2H); 5.92-6.05 (dt, 0.5H, J = 21.9 Hz, E form); 6.09-6.26 (dt, 0.5H, J = 33.3Hz, Z form). Mass Spectrometry: [M-H] - = 188 (calculated 189) mp: 120 ° C

1.6) Compound n 11 OH 25 11

  The general procedure is applied to azacyclodecanone to yield (E) -14-amino-tetradec-2-eneic acid.

  Rf = 0.1 (Heptane / ethyl acetate 5/5) NMR (HH, MeOD): δ 51.31-1.69 (m, 18H); 2.20-2.27 (m, 2H); 2.90-2.95 (m, 2H); 5.80 (dd, 1H, J = 15.6Hz); 6.96 (dt, 1H, J = 15.6Hz). Mass Spectrometry: [M + H] + = 242 (calc. 241) Melting Point: 153 ° C

1.7) Compound No. 10 OH 25 10

  The general procedure is applied to azacyclodecanone to yield 14-amino-2-fluoro-tetradec-2-enoic acid. Rf = 0.1 (Heptane / ethyl acetate 5/5) NMR (H, MeOD): 1.34-1.67 (m, 18H); 2.21-2. 26 (m, 1H form Z); 2.48-2.54 (m, 1H, form E); 2.92 (t, 2H), 5.91-6.04 (dt, 0.5H, J = 21.9 Hz, form E); 6.09-6.25 (dt, 0.5H, J = 33.3Hz, Z form). Mass spectrometry: [M + H] + = 260 (calculated 259) Melting point: 148.5 C 1.8) Compound No. 1 1 The general procedure is applied to 2-pyrrolidone to yield (E) -6- amino-hex-2-enoic acid. Rf = 0.1 (Heptane / ethyl acetate 5/5). NMR (1H, MeOD): b 1.81-1.91 (m, 2H); 2.32-2.40 (m, 2H); 2.95-3.00 (m, 2H); 5.90 (dd, 1H, J 15.6Hz); 6.96 (dt, 1H, J = 15.6Hz). Mass spectrometry: [M + H] + = 130 (calculated 129) 1.9) Compound No. 2 and Compound No. 3 F OH 2 3 The general procedure is applied to 2-pyrrolidone to yield (Z) -6 acid -amino-2-fluoro-hex-2-enoic acid (n 3) and (E) -6-amino-2-fluoro-hex-2-enoic acid (n 2), which were in this case separated . Form Z Rf = 0.1 (Heptane / ethyl acetate 5/5) NMR (H, MeOD): b 1.80-1.90 (m, 2H); 2.33-2.42 (m, 2H); 2.95-3.00 (m, 2H); 6.12-6.28 (dt, 1H, J = 32.7 Hz, form Z). Mass Spectrometry: [M + H] + = 148 (Calc'd 147) Form E Rf = 0.1 (Heptane / ethyl acetate 5/5) NMR (1H, MeOD): δ 1.77-1.89 (m, 2H); 2.60-2.68 (m, 2H); 2.94-2.99 (m, 2H); 5.96-6.08 (dt, 1H, J = 21.0Hz, form E). Mass spectrometry: [M + H] + = 148 (calculated 147)

  1.10) Compound No. 4 OH O 4 The general procedure is applied to 8-Valerolactone to yield (E) -7-amino-hept-2-eneic acid. Rf = 0.1 (Heptane / ethyl acetate 5/5) NMR (1H, MeOD): 8. 1.56-1.74 (m, 4H); 2.28-2.34 (m, 2H); 2.94-2.99 (m, 2H); 5.84 (dd, 1H, J = 15.6Hz); 6.97 (dt, 1H, J = 15.6Hz). Mass spectrometry: [M + H] + = 144 (calculated 143)

  1.11) Compound n 5 and Compound n 6 O O Cl OH H3N Cl H3N F OH 5 6

  The general protocol is applied to 8-Valerolactone to yield (Z) -7-15 amino-2-fluoro-hept-2-eneic acid (No. 6) and the acid mixture (Z + E). 7-amino-2-fluorohept-2-enenoic acid (n 5). Form Z Rf = 0.1 (Heptane / ethyl acetate 5/5) NMR (1H, MeOD): a. 1.55-1.71 (m, 4H); 2.32-2.35 (m, 2H); 2.93-2.98 (m, 2H); 6.11-6.28 (dt, 1H, J = 33.3Hz, Z form). Mass spectrometry: [M + H] + = 162 (calculated 161) Form E + Z Rf = 0.1 (Heptane / ethyl acetate 5/5) NMR (1H, MeOD): b 1.54-1.75 (m, 4H) ; 2.30-2.41 (m, 0.6H); 2.56-2.64 (m, 1.4H, E-form); 2.94-2.99 (m, 2H); 5.95-6.08 (dt, 0.7H, J = 21.6 Hz, E form); 6.12-6.28 (dt, 0.3H, J = 33.3 Hz, form Z). Mass spectrometry: [M + H] + = 162 (calculated 161). 2) Anti-Inflammatory Effect Analyzed at the Level of Lipid Mediators of Inflammation The keratinocyte, the most represented cell at the level of the epidermis, releases, in response to numerous extracellular factors present in its environment, biologically active mediators, in particular, prostaglandins and leukotrienes, which play an important role in the initiation and modulation of inflammatory skin reactions and which are also involved in the regulation of the immune response. Prostaglandin PG6KFlalpha, is one of the major metabolites produced by the stimulated keratinocyte, and representative of the modulation of the production of metabolites of arachidonic acid metabolism from the cyclooxygenase pathway.

  2.1) PROTOCOL: The suspension of keratinocytes in the DMEM 10% FCS is distributed in 6-well plates (1.2 × 10 6 cells / well), and incubated for 16 hours at 37 ° C. in a 5% CO 2 atmosphere. The keratinocytes are then rinsed with PBS to remove the non-adherent cells and then exposed to the test products included in DMEM without FCS (which could interfere in the assay). The concentration tested in culture is 3 g / ml. It was selected after a preliminary evaluation of cytotoxicity (neutral red) and is not cytotoxic.

  For each treatment, 3 wells are made. The cells are pre-incubated for 60 minutes with the test products and then a stimulating agent of the arachidonic acid cascade, the calcium ionophore, is added for 5 hours: the calcium ionophore A23187 is used at a concentration of 1 M. After these 5 hours of culture, the culture media of each of the wells are recovered, centrifuged at 3000 rpm and stored at -80 C. The production of prostaglandin 6KFla for each of the tests is measured by Kit Elisa EUROMEDEX.

  2.2) RESULTS: The results are summarized in Table 1 and are expressed as percentage of activity / stimulated control.

  Table 1 Compounds of formula I% inhibitory activity of the molecules evaluated on the production of PG6KFla N n R R R 1 Salt 1 2 HHH HCl + 2 2 HHF HC1 3 2 HHF HC1 22 4 3 HHH HC1 18 3 HHF HC1 41 6 3 HHF HCl 25 7 4 HHH HC1 36 8 5 HHH HC1 8 9 5 HHF HC1 17 10 HHF HCl 38 11 10 HHH HC1 40 The synthesis of the data obtained makes it possible to demonstrate the anti-inflammatory potential, in particular of the compounds n 11, 5 , 7 and 10, with an effective dose (DE45) for compound No. 11 of 10 g / ml and 25 g / ml for compound No. 5. 3) Anti-inflammatory property: inhibition of cytokine synthesis The skin barrier function provides protection against the external environment, and the epidermal keratinocytes can directly respond to a wide variety of irritants or allergens and participate actively in the skin. inflammatory and immune skin processes, particularly at t reverse the generation of pro-inflammatory cytokines, mediators of protein origin. Among these biologically active molecules, ILlu (Interleukin 1a) and TNFa (Tumor Necrosis Factor a) are considered as primary cytokines, their release being sufficient to induce inflammation by virtue of their induction of adhesion molecules. level of endothelial cells and their induction of chemotactic factors such as chemokines. The chemokine system controls leukocyte trafficking during the inflammatory response and is necessary for the interactions of innate and adaptive immune responses. In the present study, we are more specifically interested in the chemokine - Interleukin 8 - which is strongly involved in the amplification of the inflammatory response and whose main function is to recruit and activate neutrophils, in particular by stimulating their release of molecules. proinflammatory. In this study, carried out on 96-well plates, we evaluated the activity of amino alkenes on the production of interleukin-8 induced at the level of the keratinocyte by phorbol ester PMA and calcium ionophore A23187. 3.1) PROTOCOL: The keratinocyte suspension in complemented KSFM is distributed in 96-well plates (3.104 cells / well), and incubated for 16 hours at 37 ° C. in a 5% CO2 atmosphere. The keratinocytes are then rinsed with PBS to remove the non-adherent cells and then exposed to the test products included in uncomplemented KSFM (which could interfere in the assay). The concentration tested in culture is 3 g / ml. It was selected after a preliminary evaluation of cytotoxicity (neutral red) and is not cytotoxic. For each treatment, 3 wells are made. The cells are pre-incubated for 60 min with the test products and then stimulated, along with negative controls without stimulant: Phorbol Myristate Acetate (PMA) 1 M + calcium ionophore (A23187) 0.1 gM. Incubation for 6 hours at 37 ° C. in a humid atmosphere of air containing 5% of CO2. The culture media of each of the wells are recovered, centrifuged at 3000 rpm and stored at -80.degree. C. Cytokine assay: IL8 is assayed by an immunoenzymatic method in ELISA kit (Immunotech). 3.2) RESULTS: The results are collated in Table 2 and are expressed as percentage of activity / stimulated control. Table 2 Compounds of formula I% inhibitory activity of molecules evaluated on IL8 production N n R R R 1 Sel 1 2 HHH HC1 2 2 HHF HCl 3 2 HHF HC1 4 3 HHH HC1 3 HHF HCl + 6 3 HHF HC1 + 7 4 HHH HC1 8 5 HHH HC1 14 9 5 HHF HC1 20 10 HHF HC1 8 11 10 HHH HC1 22 The synthesis of the data obtained makes it possible to demonstrate the anti-inflammatory potential, in particular of compound 11 and 9, with effective dose 50 (DE 50) of 11 gg / ml for compound No. 11. 4) Study of the anti-radical effect on active species of oxygen (EAO) During normal cellular metabolism, during occasional exposure of the skin with stressors or during dermatological pathologies, reactive oxygen species also called Activated Oxygen Species (OAA) are generated (YMW Janssen et al, 1993). These EAOs, described as highly reactive metabolites, play an important role in many processes such as inflammation, aging and tumor promotion. EAOs are considered as second messengers in cellular signaling of oxidative stress and thus as early mediators of inflammation (A. Van Der Vliet and A. Bast, 1992).

  Their overproduction induces significant damage within the cell. Some cellular constituents are then the main targets of such oxidative stress: the lipid components of the plasma membrane (lipoperoxidation), the proteins (denaturation and degradation) and the genetic material or DNA (mutations) can be altered. Cells are able to limit this oxidative damage through various antiradical defense systems (enzymatic and non-enzymatic antioxidants) (B.P. Yu, 1994, H. Steiling et al, 1999). However, under certain conditions, EAOs are produced in such quantity that cellular antioxidant activity is insufficient; these EAOs then become inducing factors of inflammatory pathologies and tissue aging (Y.

  Miyachi et al, 1986; M. Kress et al, 1995). There are different chemical (eg H202) or physical (eg UVA) agents that can generate oxidative stress in vitro. Thus the produced EAO will alter various cellular targets (Membranes, DNA or Proteins) whose alteration can be analyzed by widely used biochemical methodologies such as the TBARS assay for lipid lipoperoxidation, or the in vitro assay of intracellular EAOs. using the H2DCF-DA probe.

  We have set up a model for in vitro study of H2O2 / Fer, H2O2 induced oxidative stress which massively generates intracellular EAO by a chain reaction triggered by the oxidation of membrane lipids. This technique is based on the use of a fluorescent probe, 6-carboxy-2 ', 7'-dichlorodihydro fluorescein diacetate, di (acetoxymethyl ester) (H2DCF-DA), which, once it has entered the cell is deacetylated by the intracellular esterases then forming H2DCF. This product is oxidized by intracellular EAO to a highly fluorescent compound: 2 ', 7'-dichlorofluorescein (DCF) (Suematsu M et al., 1996, Free Radical Pratical Approach, Punchard ed., P83-99).

  The materials and methods used for the in vitro assay of intracellular EAO are indicated below.

  a) Cellular tool: L929 mouse murine fibroblast cell line. b) Material: - 96 well plate microplate - Cytofluor II Cytofluorimeter: Ref. PERSEPTIVE BIOSYSTEMS c) Reagents: Cell Culture Reagents: Dulbecco's Modified Eagle Medium (DMEM) Fetal Calf Serum (FBS) PBS Phosphate Buffer pH 7, 4 Trypsin EDTA (1X) Fluorescent Probe: -6-carboxy-2 ' , 7'-dichlorodihydrofluorescein diacetate, di (acetoxymethyl ester) (MW 675.43) Cell stimulation products: Hydrogen Peroxide (H2O2) 3%: Ref. GIFRER (Gifrer Barbezat Laboratory) Ferrous Ammonium Sulfate (Fe2 +) Ferric Ammonium Sulfate (Fe3 +) d) Products Tested: The concentrations tested are non-cytotoxic concentrations. Cytotoxicity was performed by the neutral red method after incubation of the product for 3 hours.

  The reference anti-radical product is vitamin E or α-tocopherol (MW: 430.7) (SIGMA, ref: T-1539). The stock solution is prepared at 400 mg / ml in DMSO and stored at -20 ° C. The pretreatment solution is prepared extemporaneously at 400 g / ml in culture medium without FCS.

  For the evaluation of the unsaturated fatty amino acid derivatives, the dilutions are prepared in culture medium extemporaneously, for a concentration range of 0.02, 0.2, 2 and 20 ng / ml. e) Protocol: Seeding of the cells: The cells of the fibroblast line L929 are seeded in microplates of 96 wells with a flat bottom in 100 μl of DMEM supplemented with 10% of FCS, and then they are incubated overnight at 37 ° C. in a humid atmosphere. at 5% CO2. The cell-free plate blank is evaluated on 6 wells. Pretreatment of the cells: The dilutions of the test products and reference molecule are carried out in the culture medium without FCS and then deposited in 7 wells at a rate of 100 l per well. The cells are then incubated for 3 hours at 37 ° C. in a humid atmosphere at 5% CO 2. Control cells (natural fluorescence of the cells), Control 25 (basal production of EAO) and Stimulates (production of EAO after oxidative treatment) are covered with 100 l of DMEM. Control cells are incubated with the probe but are neither pre-treated nor treated. Stimulated cells are incubated with the probe and treated but not pretreated. The control cells are neither pre-treated, nor incubated with the probe, nor treated. Incubation of the cells with the probe and oxidative stress: The cells are rinsed with 1X PBS at a rate of 100 per well. Then they are incubated for 30 minutes at 37 ° C. in a humid atmosphere at 5% CO 2 with 50 μl of 5 M H2DCF-DA probe.

  After 30 minutes in contact with the probe alone, the cells are incubated for 30 minutes at 37 ° C. in a humid atmosphere at 5% CO2 with the addition of 25111 of 800 M H2O2 and 25 liters of ferrous and ferric iron solution. at 8mM, to have final concentrations of 200M H2O2 and 2mM ferrous and ferric iron. The cells are then rinsed with 1X PBS at a rate of 100 l per well and then incubated for 30 minutes at 37 ° C. in a humid atmosphere at 5% CO2 with 100 μl of 1 × PBS. These 1 h 30 minutes of incubation at 37 C allow intracellular esterases to deacetylate the H2DCF probe, oxidizable by intracellular EAO DCF: fluorescent compound whose formation is proportional to the amount of intracellular EAO. The fluorescence intensity is read with excitation cytofluorimeter = 485 nm and Remission = 530 nm. It reflects the amount of intracellular EAO produced.

  Scheme of the study protocol: Incorporation probe Stress Incubation Pretreatment product H2DCF-DA H2O2 / Iron PBS I I I 1 1

  3h 30 min 30 min 30 min to = 0 to + 3h to + 3h30min to + 4h to + 4h30min Reading Calculation of the% protection against the production of intracellular EAO: The report below makes it possible to calculate for each concentration of tested product the% protection against the production of intracellular EAO (since the Fluorescence Intensity or IF expresses the intracellular release of EAO). [IF Oxidant (H2O2 / Iron) - IF (Oxidizer + Product)] x 100 IF Oxidizer (H2O2 / Iron) - IF Control

  The values shown in Table 3 are the percentages of inhibition of intracellular EAO production following exogenous oxidative stress, relative to control (100%) and stimulated (0%) cells. The average percentages of protection for the 13 molecules tested at 4 concentrations on the L929 line are shown in Table 3 below.

  Table 3 Compounds of formula (I) Doses N n R Rn Rl Salt 0.02 0.2 2 20 ng / ml ng / ml ng / ml ng / ml 1 2 HHH HC1 12 13 5 1 2 2 HHF HC1 14 19 14 -13 3 2 HHF HCl 15 11 5 1 4 3 HHH HC1 13 12 8 -14 3 HHF HC1 18 23 26 23 6 3 HHF HC1 31 30 21 26 7 4 HHH HC1 31 33 26 32 8 5 HHH HC1 22 25 20 19 9 5 HHF HC1 18 20 23 18 10 HHF HC1 20 25 18 15 11 10 HHH HC1 20 19 22 19 Reference antiradical product Dose = 400 g / ml Vitamin E 31 Conclusion: In vitro, at the cellular level, stress Exogenous H2O2 / Fe2 + -Fe3 + is capable of inducing intracellular EAO production detected using the fluorescent probe. 5 - Vitamin E (reference anti-free radical molecule) has an average protection of 31% at 400 g / ml. The unsaturated fatty amino acid derivatives according to the short-chain (C7-C9) invention, in particular compounds 8, 7 and 6, exhibit anti-radical properties (activity> 25%).

  5) Study of the anti-radical effect. Lipid peroxidation analysis Moreover, during normal cellular metabolism, during occasional exposure of the skin to stressors or during dermatological pathologies, reactive oxygen species also called Oxygen Free Radicals (RLO) are generated (YMW Janssen et al., 1993). These RLOs, described as highly reactive metabolites, play an important role in many processes such as inflammation, aging and tumor promotion.

  RLOs are considered as second messengers in cellular signaling of oxidative stress and therefore as early mediators of inflammation (A. Van Der Vliet and A. Bast, 1992). Their overproduction induces significant damage within the cell. Some cellular constituents are then the main targets of such oxidative stress: the lipid components of the plasma membrane (lipoperoxidation), the proteins (denaturation and degradation) and the genetic material or DNA (mutations) can be altered. Cells are able to limit this oxidative damage through various antiradical defense systems (enzymatic and non-enzymatic antioxidants) (B.P. Yu, 1994, H. Steiling et al, 1999).

  However, under certain conditions, the RLOs are produced in such quantity that the cellular antioxidant activity is insufficient; these RLOs then become factors inducing inflammatory pathologies and tissue aging (Y. Miyachi et al, 1986, M. Kress et al, 1995). In order to enhance the anti-radical activity of the various derivatives according to the invention, we have analyzed their protective effect with respect to cell membrane damage induced by oxidative stress (chemical), in comparison with a reference antioxidant, vitamin E.

  The plasma membrane is the main and the first target of RLOs and, being rich in lipids, is the site of increased peroxidation (A. W. Girotti, 1985). The peroxides generated during this lipid oxidation are also very reactive and capable of degrading the protein and genomic material.

  To evaluate membrane damage, we measured lipid peroxidation by an in vitro assay of complexes between lipid oxidation products and thiobarbituric acid. These complexes are called TBARS (for Thiobarbituric Acid Reactive Substances) and give the name to the test: TBARS test. In order to mimic a chemical oxidative stress, we treated the fibroblast line, L929, with a complex composed of hydrogen peroxide (H2O2) and iron (Fe2 + / Fe3 +), thus reconstituting the Fenton reaction, source of RLO and more particularly hydroxyl radical (OH) (DA Vessey et al, 1992): H2O2 + Fe2 + 4 OH + OH- + Fe3 + The products were evaluated on the line of murine fibroblasts L929. The cells are pretreated with the different product concentrations for 16 hours and are then stimulated with the H2O2-Fe2 + / Fe3 + complex (200 M-1mM) for 1 hour. Stock solutions: 100 mg / ml, ethanol, 4 C. Final solutions: 0.02 ng / ml.

  The peroxidation of membrane lipids is analyzed by measuring TBARS (Protocol Ref PLN 2, according to Morliere et al, 1991). Principle of the test: In an acid environment, at 95 ° C., complexes are formed, labeled TBARS for Thio Barbituric Acid Reactive Substance, between lipid oxidation products (malondialdehyde or MDA) and thiobarbituric acid (TBA) which can be assayed. in fluorescence compared to a standard range with MDA. The TBARS assay is then expressed in pmol / g protein. Proteins and TBARS are assayed in the intracellular medium. Calculation of the percentage of protection of cell membranes: From the calculation of TBARS in pmol / g proteins, we calculated the protective efficacy of the different products against the oxidation of membrane lipids. % of protection: fTBARS Control] - FTBARS (+ products)] x 100 TBARS Control

  Seven independent experiments were conducted. During these experiments, various compounds were evaluated (the test does not make it possible to evaluate more than 10 molecules at the same time). The compounds evaluated several times were chosen according to the results obtained in the other test also measuring an anti-radical activity (assay of the active oxygen species, EAO). The model used in this experiment (Fenton reaction) induces significant lipid peroxidation in L929 fibroblasts. This massive discharge of hydroxyl radical OH- therefore generates oxidative stress at the cellular level and in particular at the level of the membranes. However, in this type of oxidative reaction, the products resulting from lipid peroxidation are internalized in the cells and the TBARS are then assayed in the intracellular medium.

  Vitamin E at 400 g / ml decreases the lipid peroxidation induced by the H2O2-Fe2 + / Fe3 + complex, and very effectively protects cell membranes. In Table 4, the results of the 7 experiments are presented.

  Table 4 Compounds according to the invention% protection of membrane lipids Dose = 0.02 ng / ml N n R R R R 1 Salt N ° Average Experiments 1 2 HHH HC1 3 13.41 2 2 HHF HC1 3 7.63 3 2 HHF HC1 3 - 4.00 4 3 HHH HC1 3 8.75 5 3 HHF HC1 3 36.27 6 3 HHF HC1 5 49.82 7 4 HHH HC1 4 48.30 8 5 HHH HC1 5 56.61 9 5 HHF HC1 3 27.49 10 10 HHF HC1 3 23.91 11 10 HHH HC1 2 - 26.31 Conclusion: The in vitro module presented in this study reflects the consequences of major oxidative stress on the main cellular target which is the plasma membrane.

  Thus, the lipid peroxidation assay is a good marker of oxidative stress and allows the evaluation of the antioxidant action, with respect to the hydroxyl radical, of active principles at the level of the cell membrane. In our experimental conditions, we observe that compounds 8, 9, 10, 7, 5 and 6 exhibit significant antiradical activity and very effectively protect cell membranes. Compounds Nos. 8, 7 and 6 exhibit the antiradical activity and the protection of the most important membranes.

  6) Effect of Unsaturated Fatty Acid Amino Acid Derivatives According to the Invention on In Vitro Melanin Synthesis Melanocytes are star-shaped cells, present as a minority in the basal layer of the epidermis. Their main function is to ensure melanogenesis, a process by which melanin is synthesized in specialized organelles, melanosomes, and then transported and distributed to neighboring keratinocytes via their dendritic extensions. This contact with keratinocytes allows cutaneous pigmentation, a protective mechanism of the epidermis against the mutagenic effects of ultraviolet rays. Each melanocyte is related to approximately thirty-six keratinocytes, thus forming an epidermal unit of melanization. Melanogenesis consists of a series of enzymatic and spontaneous reactions, the precursor of which is tyrosine. Three main enzymes participate in this process: tyrosinase, and tyrosinase-related protein 1 and 2 (TRP 1 and 2) (Jimbow et al., 2000). Tyrosinase catalyzes the transformation of tyrosine into dopaquinone. From there, two synthetic routes are possible: eumelanogenesis and pheomelanogenesis. The conversion of dopaquinone to eumelanin is through a series of successive reactions of oxidation involving TRP-1 and TRP-2. Eumelanin is the dark brown, low sulfur pigment and provides photoprotective power.

  In pheomelanogenesis, high-sulfur molecules are incorporated into dopaquinone to give the yellow-orange pheomelanin found in the skin of redheads. The physiological stimulus of melanin synthesis is the sun, which leads to an increase in the number of melanocytes, a melanin neosynthesis, and morphological changes in melanocytes, associating an increase in their dendricity with an increase in the transfer of melanosomes to keratinocytes. At the molecular level, sun exposure stimulates the synthesis and secretion of alpha melanocyte stimulating hormone. Α-MSH increases the intramelanocyte concentration of cAMP, activating the transcription factor, Mitf, which in turn stimulates the transcriptional activity of genes encoding tyrosinase, TRP-1 and TRP-2. Some exogenous molecules are also known to negatively regulate melanogenesis. Hydroquinone inhibits melanin synthesis by presenting itself as a tyrosinase substrate in order to divert its activity (Curto et al., 1999). Vitamin C inhibits tyrosinase but also does not have a strong reducing effect by inhibiting melanin staining by oxidation.

  6.1) The modulatory effect of unsaturated fatty amino acid derivatives on melanogenesis was analyzed. For this purpose, a measurement of the melanin synthesis by colorimetric assay is performed on a murine melanoma cell line: the B 16 -F 10 line. The effect of the products is investigated in the basal situation and after stimulation of the melanogenesis by MSH. determine the depigmenting power. Determination of melanin: The extracellular and intracellular melanin level is then measured spectrophotometrically at a wavelength of 405 nm according to the protocol (Meun, Y.J. et al.). The amount of pigment is determined by a standard range of melanin and analysis on Microwin software (Berthold Biotechnologies). A total protein assay is performed for intracellular melanin samples by the BCA-Copper method at 540nm. The standard range is made with a standard protein, BSA (Serum Albumin Bovine). 6.2) RESULTS: In the basal situation, the alpha MSH at 1 M increases by more than 100% the production of melanin compared with the control cells. This melanin increase is countered by depigmenting agents, such as 1 g / ml hydroquinone or 40 g / ml vitamin C, which inhibit melanogenesis by almost 60%. • Depigmenting molecule: At 30 g / ml, molecule No. 11 weakly inhibits the amount of intra- and extracellular melanin at approximately 45% and 30%, respectively. However, molecule No. 11 has no effect on the synthesis of melanin at 10 g / ml. Pigmenting Molecules: At 3, 10 and 30 μg / ml, molecule No. 6 increases the amount of intracellular melanin to about 100%. The molecule n 5 also seems to have a pigmenting effect, but it is weaker than that of the molecule n 6.

  Bibliography: - Janssen Y, M, W, et al (1993) Lab, Invest, 69: 261-74 - Van Der Vliet A, and Bast A, (1992) Chem, Biol, Interactions 85: 95-116 - Yu B, P, (1994) Physiol, Rev., 74: 139-62 - Steiling H, et al (1999) Exp. Cell, Res., 247: 484-94. Miyachi Y, et al (1986) J, Clin, Lab, Immunol, 19: 11-4-Kress M, et al. (1995) Bread 62: 87-94 - Girotti A , W, (1985) J, Free Radic, Biol, Med, 1: 87-95 - Vessey D, A et al (1992) J, Invest, Dermatol, 99: 859-63 - Morliere P, et al, (1991). Biochim, Biophys, Acta, 1084: 261-268; Emonet E et al (1997) J. Photochem. Photobiol 40: 84-90 - Meun, Y.J. et al. (2004) Biol. Pharm. Bull. June, 27 (No. 6): 806 - 809 - Curto EV., Kwong C., Hermersdorfer H., Glatt H., Santis C., Virador V., Hearing VJ., Dooley TP. Inhibitors of mammalian melanocyte tyrosinase: in vitro comparisons of alkyl esters of gentisic acid with others putative inhibitors (1999) Biochemical Pharmacology 57: 663-672 -Jimbow K., Hua C., Gomez P., Hirosaki K., Shinoda K., Salopek T., Matsusaka H., Jin H., Yamashita T. Intracellular vesicular trafficking of tyrosinase gene family protein in 5 eu- and pheomelanosome biogenesis (2000) Pigment cell res. 13: 110-117

Claims (15)

  1. unsaturated fatty amino acid derivatives corresponding to the general formula (I): ## STR2 ## and their pharmaceutically acceptable acid addition salts, in which: Rn represent independently of each other a hydrogen atom or a linear or branched alkyl group comprising 1 to 6 carbon atoms, and being optionally substituted by a halogen atom, in particular fluorine; R1 represents a hydrogen, fluorine, chlorine or bromine atom, or a -CF3 group or a linear or branched alkyl group comprising 1 to 6 carbon atoms; R represents a hydrogen atom or a linear or branched alkyl group comprising 1 to 6 carbon atoms, and being optionally substituted by a halogen atom, in particular fluorine; and • n is an integer from 2 to 14; with the exception of 6-amino-2-hexenoic acid, its hydrochloride and trifluoroacetate and 8-amino-2-octenoic acid trifluoroacetate. 20   2. unsaturated fatty amino acid derivatives according to claim 1, characterized in that • Rn and R represent a hydrogen atom; and • n and RI are as defined in claim 1. 25   3. unsaturated fatty amino acid derivatives according to claim 2, characterized in that R1 represents a hydrogen or fluorine atom.   4. unsaturated fatty amino acid derivatives according to claim 3, characterized in that n is between 2 and 10.   5. unsaturated fatty amino acid derivatives according to claim 3, characterized in that n is between 3 and 5.   6. unsaturated fatty amino acid derivatives according to claim 3, characterized in that n is between 9 and 14.   7. unsaturated fatty amino acid derivatives according to claim 3, characterized in that n is equal to 3.   8. Unsaturated fatty amino acid derivatives according to any one of the preceding claims, characterized in that they are in the form of Z or E isomers, or a mixture of Z isomers and E isomers , in all quantities. 15   9. unsaturated fatty amino acid derivatives according to any one of the preceding claims, characterized in that they present in the form of salts of pharmaceutically acceptable acid formed from hydrochloric acid, hydrobromic acid, l sulfuric acid, nitric acid, phosphoric acid, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzol-L-tartaric acid, tartaric acid p-toluenesulfonic acid, trimethylacetite acid or trifluoroacetic acid.   10. Unsaturated fatty amino acid derivatives of the general formula (I): ## STR1 ## and their pharmaceutically acceptable acid addition salts, wherein: Rn independently represent the others a hydrogen atom or a linear or branched alkyl group comprising 1 to 6 carbon atoms, and being optionally substituted by a halogen atom, in particular fluorine; R1 represents a hydrogen, fluorine, chlorine or bromine atom, or a -CF3 group or a linear or branched alkyl group comprising 1 to 6 carbon atoms; R represents a hydrogen atom or a linear or branched alkyl group comprising 1 to 6 carbon atoms, and being optionally substituted by a halogen atom, in particular fluorine; and • n is an integer from 2 to 14; as drugs.   11. Dermatological compositions comprising as active ingredient at least one unsaturated fatty amino acid derivative according to claim 10 in association with a dermatologically acceptable excipient.   12. Use of an unsaturated fatty amino acid derivative according to claim 10, for the preparation of a dermocosmetological antiradical composition, anti-inflammatory, anti-pruriginous, and / or for the treatment of skin aging, and / or or for the treatment of disorders of keratinization and pigmentation, and / or to improve healing.   13. Use according to claim 12, characterized in that said composition is intended for the treatment of psoriasis, pruritus and / or atopic dermatitis.   14. Use according to claim 12, characterized in that said composition is intended to repigment the hair or skin, including white age spots. 30   15. Use according to claim 12, characterized in that said composition is intended to cause lightening of the skin or to treat brown age spots. 25