Use of ester derivative of tryptophan as deodorant and/or perfume agent

Abstract

This invention relates to the use of at least one following compound having formula (I), as well as the salts thereof, the optical and geometric isomers thereof, and the solvates thereof, as deodorant agent for treating body odor, preferably underarm odor: ##STR00001##

Claims

1. A method for treating body odor which comprises applying to human keratin material at least one compound having formula (I), a salt thereof, an optical isomer thereof, a geometric isomer thereof, a solvate thereof, or mixture thereof, as a deodorant agent: ##STR00089## wherein R represents one of the following radicals: ##STR00090##

2. The method according to claim 1, where the at least one compound having formula (I) is selected from the group consisting of the following compounds: Tryptophan ethyl ester hydrochloride of the following structure: ##STR00091## Tryptophan cis-3-hexenyl ester of the following structure: ##STR00092## Tryptophan cis-3-hexenyl ester hydrochloride of the following structure: ##STR00093## Tryptophan benzyl ester of structure: ##STR00094##

3. The method according to claim 1, where the at least one compound selected from the group consisting of the following compounds: Tryptophan cis-3-hexenyl ester of the following structure: ##STR00095## Tryptophan cis-3-hexenyl ester hydrochloride of the following structure: ##STR00096## Tryptophan benzyl ester of structure: ##STR00097##

4. The method according to claim 1, wherein R is ##STR00098##

5. The method according to claim 1, wherein R is —CH.sub.2—CH.sub.3.

6. The method according to claim 1, wherein R is —CH.sub.2—CH.sub.2—CH═CH—CH.sub.2—CH.sub.3.

Description

EXAMPLES

(1) A. Preparing the Compounds

Example A-1

Preparing the Compound 1

(2) ##STR00081##
L-tryptophan ethyl ester chlorhydride (compound 1) was obtained as described in Synthesis of substituted dipeptide GB-115 as a potential selective anxiolytic Kir'yanova, E. P. et al Pharmaceutical Chemistry Journal, 45(2), 103-106; 2011. It can be obtained by treatment of the L-tryptophan with thionyl chloride at −10° C. in ethanol, cold stirring for 2 hours and at ambient temperature (about 25° C.) for 48 hours. After adding ether, the salt crystallizes.

Example A-2

Preparing the Compound 2 Described in WO 2006/119283

(3) ##STR00082##

(4) The ethyl N-Acetyl-L-tryptophanate (compound 2) can be obtained as described in patent CN 102351775 by acetylation of the compound 1. The acetylation can be carried out in ethyl acetate by treatment with triethylamine at 5° C. then stirring at ambient temperature for 1 hour.

Example A-3

Preparing the Compound 3 (Tryptophan cis-3-hexenyl ester)

(5) ##STR00083##

(6) To a solution of commercial Fmoc-Trp-OH (50 g) in dichloromethane (1 l) are added cis-hexenol (13.1 ml), dimethylaminopyridine (1.42 g) and N,N′-dicyclohexylcarbodiimide (24.6 g) heated beforehand using a hot water bath. The medium is stirred during the night at ambient temperature. A CCM control as well as an LCMS conducted using an aliquote show the presence of the product desired and the absence of alcohol. The mixture is filtered over celite. After rinsing with dichloromethane, the filtrate is dry concentrated to result in a gross product (68.3 g). The product is co-evaporated with methanol (150 ml) in order to eliminate the residual dichloromethane then the solution is dry concentrated (65.8 g). a purification via silica gel chromatography is carried out (deposit and eluent DCM 100%). The product obtained is solubilized in ethyl acetate. After concentration of the solution, the yellow oil obtained is crushed in pentane (2 l). The suspension is filtered and the solid is rinsed with pentane then dried in a vacuum twice to result in the product B desired: white solid—30 g—yield 50%.

(7) ##STR00084##

(8) To a solution of the compound B (30 g) in acetonitrile (450 ml) piperidine (58 ml) is added in 3 minutes. After 10 minutes of stirring, the formation of a white precipitate is observed. A CCM control (heptane/AcOEt 7/3) shows that the reaction is complete. The mixture is filtered. The filtrate is dry concentrated then co-evaporated 3 times using toluene to result in a gross product: beige solid—32 g. After several purifications via silica gel chromatography (DCM deposit, DCM/MeOH gradient), the desired product containing traces of dichloromethane and hexanol is obtained (batch 356-150-C2C2, 11.56 g). Several successive co-evaporations in a vacuum (0.6-1 mbar) with dichloromethane and pentane are carried out in order to eliminate the residual hexanol. The desired compound 3 is obtained: oil that crystallizes—5.94 g—yield 35%.

(9) Analyses: .sup.1H-RMN (MeOD, 300 MHz), .sup.13C-RMN (MeOD, 75 MHZ), LCMS, elemental analysis and CPG confirm the obtaining of the desired compound.

Example A-4

Preparing the Compound 4 (Tryptophan cis-3-hexenyl ester) hydrochloride

(10) ##STR00085##

(11) To a solution of the compound 3 (5.24 g) in dioxane (15 ml) cooled by a chilled water bath is added a solution of 4M hydrochloric acid in the dioxane (4.48 ml) resulting in the formation of a precipitate. Pentane (75 ml) is added and the mixture is crushed for 10 minutes the filtered. The filtrate is concentrated in a vacuum then water is added. The suspension is subjected to ultrasound then freeze dried to result in the compound 4 desired: white solid—5.6 g—yield 95%.

(12) Analyses: .sup.1H-RMN (MeOD, 300 MHz), .sup.13C-RMN (MeOD, 75 MHZ), LCMS and elemental analysis confirm the obtaining of the desired compound.

Example A-5

Preparing the Compound 5 (Tryptophan dihydromyrcenyl ester)

(13) ##STR00086##

(14) To a solution of commercial Fmoc-Trp-OH (38 g) in pyridine (190 ml) is added dihydromyrcenol (27.8 g). The medium is cooled by a chilled water bath before adding 1-propylphosphonic cyclic anhydride (113 g). Exothermicity is observed during the adding (Tmedium=10° C.). After return to ambient temperature, the medium is stirred during the night in nitrogen. The soluble yellow mixture becomes red. An LCMS carried out using an aliquote shows the presence of 3 products. The medium is concentrated at 38° C. to result in a gross product (149.5 g). A CCM control (heptane/AcOEt 9/1) shows the presence of the desired product, initial alcohol and pyridine. A purification via silica gel chromatography (DCM deposit, heptane/AcOEt gradient) followed by a co-evaporation with acetonitrile in order to eliminate the residual ethyl acetate resulting in the product A desired: white solid—43.5 g—yield 86%.

(15) Analyses: .sup.1H-RMN (MeOD, 300 MHz) confirms the obtaining of the expected compound.

(16) ##STR00087##

(17) To a solution of the compound A (43.5 g) in acetonitrile (650 ml) piperidine (76 ml) is added. The stirring is maintained for 10 minutes. The medium, initially soluble of yellow color, precipitates out little by little. A CCM control (heptane/AcOEt 7/3) shows that the reaction is complete. The medium is filtered and the filtrate is concentrated then co-evaporated with toluene to result in a gross product (48.4 g). A purification via silica gel chromatography (DCM deposit, DCM/MeOH gradient) to result in the product 5 desired: orange oil—10.5 g—yield 76%.

(18) Analyses: .sup.1H-RMN (MeOD, 300 MHz), .sup.13C-RMN (MeOD, 75 MHZ), LCMS and elemental analysis confirm the obtaining of the desired compound.

Example A-6

Compounds 6, 7 and 8

(19) These compounds are commercial. Compound 6 and 8 are available at SANTA CRUZ BIOTECHNOLOGY and compounds 7 and 8 are available at Sigma Aldrich.

(20) Compound 7 can be obtained as described in J. Org. Chem., 1983, 48 (1), pp 121-123

(21) ##STR00088##

(22) B. Activities of the Compounds

Example B-1

Study of the Anti-Microbial/Bactericidal Effects

(23) The anti-microbial activity of Tryptophan ethyl ester hydrochloride (compound 1) was valuated in vitro on Corynebacterium xerosis (killing test, quantity of micro-organisms killed).

(24) Purpose of test: Quantitative determination of the activity of a cosmetic starting material with respect to Corynebacterium xerosis, a micro-organism involved in the phenomena linked to underarm odor. This micro-organism is placed in optimum growth conditions.

(25) Protocol: The model strain used is: Corynebacterium xerosis CIP 5216 (bacteria)

(26) The strain is placed into contact with the starting material to be tested in a suitable liquid culture medium. The dilutions of the compounds under evaluation are performed in agar at 1:1000, making it possible, for dispersible compounds under evaluation, to do away with the use of a solvent which could introduce bias in the evaluation of the compounds. In parallel, a growth control, in which the starting material to be tested is replaced with diluent, is prepared in the same conditions.

(27) The samples are placed in a rotating incubator at 35° C. and maintained under stirring for the entire duration of the test.

(28) After 2, 6 and 24 hours of contact, the number of viable micro-organisms remaining in the mixture is evaluated.

(29) The results are expressed as a logarithm of the number of micro-organisms per milliliter of mixture.

(30) Results: The results (change in the number of viable micro-organisms per milliliter of sample, in log) are presented in the table hereinbelow:

(31) TABLE-US-00001 Inoculum (T0M/TA) CFU/g of CFU/g of preparation GERMS preparation 2 hours 6 hours 24 hours CORYNEBACTERIUM 1.4E7 4.6E3 4.0E1 <20 XEROSIS

(32) In terms of the growth control, Tryptophan ethyl ester hydrochloride at 0.5%, has excellent anti-microbial activity on C. xerosis. A reduction of 3.3 Log Units after 2 h of contact, of 5.4 Log after 6 h is noted. After 24 h of contact, the reduction is greater than or equal to 6.6 Log.

Example B-2

Study of the Anti-Odor Effects (on Incubated Sweat) of Compound 1

(33) The deodorant activity was evaluated in the ex-vivo olfactory evaluation test, on incubated sweat.

(34) Tryptophan ethyl ester hydrochloride (compound 1 of the example A-1) was evaluated at various concentrations in a pool of fresh sweat.

(35) The samples were prepared in 10-ml headspace screw bottles, they are incubated at 35° C. for 24 h under stirring. A sample of sweat with 1 mg of anhydrous aluminum hydroxychloride (ACH) in 1 ml of sweat (i.e. 0.1%) is incubated in order to serve as a positive reference (little odor) and a sample of sweat alone is incubated to serve as a negative reference (unpleasant odor).

(36) The samples after incubation are evaluated olfactively by a panel of several people in a blind test on the headspace bottles. The incubated samples of sweat containing ACH and sweat alone are evaluated at the same time in order to be used respectively as negative and positive references.

(37) 3 parameters are evaluated on a scale from 0 to 10: The residual of the unpleasant odor with 0 for not very unpleasant (positive reference) and 10 for very unpleasant odor (negative reference). The total power of the odor with 0 for little power and 10 for very powerful. The pleasantness of the odor with 0 for not very pleasant and 10 for very pleasant.

(38) Table 1 hereinbelow provides the results of the evaluations carried out by a panel of 6 people.

(39) TABLE-US-00002 TABLE 1 Residual Sample Power unpleasant odor Incubated sweat 9 10 Incubated sweat + ACH 1.6 0.5 Tryptophan ethyl ester 3.2 3.4 hydrochloride 0.1% Tryptophan ethyl ester 2.8 3.2 hydrochloride 0.5% Tryptophan ethyl ester 1.4 0.6 hydrochloride 1%

(40) A clear decrease in the unpleasant odor was observed with Tryptophan ethyl ester hydrochloride (compound 1 of the example A-1) with respect to the negative reference.

Example B-3

Comparative Study of the Anti-Odor Effects (on Incubated Sweat)

(41) The action of the compound 1 was compared with that of ethyl N-acetyl-L-tryptophanate (compound 2 outside the invention) in incubated sweat. The results show the superiority of the compound 1 with respect to ethyl N-acetyl-L-tryptophanate at several concentrations on the inhibition of the formation of the unpleasant odor in the olfactive evaluation test ex-vivo, on incubated sweat.

(42) The activities of the Tryptophan ethyl ester hydrochloride and of ethyl N-acetyl-L-tryptophanate in incubated sweat were gather together in the following table 2 indicating the results of the evaluations carried out by a panel of 6 people.

(43) TABLE-US-00003 TABLE 2 Residual Sample Power unpleasant odor Incubated sweat 9 10 Incubated sweat + ACH 1.6 0.5 Tryptophan ethyl ester 3.2 3.4 hydrochloride 0.1% Tryptophan ethyl ester 2.8 3.2 hydrochloride 0.5% Tryptophan ethyl ester 1.4 0.6 hydrochloride 1% Ethyl N-acetyl-L- 6.2 6.8 tryptophanate 0.1% Ethyl N-acetyl-L- 6.8 7.5 tryptophanate 0.5% Ethyl N-acetyl-L- 6.6 7 tryptophanate 1%

(44) At an equivalent dose, the Ethyl N-acetyl-L-tryptophanate was not as effective as Tryptophan ethyl ester hydrochloride. Tryptophan ester hydrochloride advantageously has better anti-odor activity than the Ethyl N-acetyl-L-tryptophanate.

Example B-3

Study of the Anti-Odor Effects (on Incubated Sweat) of Compounds 3, 4, 5, 6, 7, and 8

(45) The anti-odor activity was evaluated for Tryptophan cis-3-hexenyl ester (compound 3: example A-3), Tryptophan cis-3-hexenyl ester hydrochloride (compound 4, example A-4) and of tryptophan dihydromyrcenyl ester (compound 5: example A-5) at 0.5% in incubated sweat, as well as for the compound 6 at 0.3% in incubated sweat. Furthermore, the Tryptophan benzyl ester and Tryptophan tertiobutyl ester hydrochloride (compounds 7 and 8: example A-6) were evaluated at 0.5% in the incubated sweat.

(46) Table no. 3 hereinbelow indicates the results of the evaluations carried out by a panel of 6 people on the tryptophan cis-3-hexenyl ester (compound 3), of the Tryptophan cis-3-hexenyl hydrochloride (compound 4) and of the tryptophan dihydromyrcenyl ester (compound 5) at 0.5% in the incubated sweat.

(47) TABLE-US-00004 TABLE 3 Residual Pleasantness Sample Power unpleasant odor of the odor Incubated sweat 7 9.8 0.3 Incubated sweat + ACH 0.8 0.3 4 Tryptophan cis-3-hexenyl 6.8 1 7.8 0.5% Tryptophan cis-3-hexenyl 7 2.5 6 hydrochloride 0.5% Tryptophan dihydromycenyl 5.5 2.5 5.8 ester 0.5%

(48) Compounds 3, 4 and 5 have an effect of reducing the unpleasant odor compared to the negative control. Moreover, they advantageously contribute to the pleasantness of the odor through the release of odorous volatile molecules.

(49) Table no. 4 hereinbelow indicates the results of the evaluations of the compound 6 at 0.3% in the incubated sweat.

(50) TABLE-US-00005 TABLE 4 Residual Pleasantness Sample Power unpleasant odor of the odor Incubated sweat 7.7 8 1 Incubated sweat + ACH 2.7 2.7 3.7 Tryptophan ethyl ester 3 1.7 5.3 hydrochloride 0.3% Tryptophan octyl ester 7 0.3 7 hydrochloride 0.3%

(51) Table no. 5 hereinbelow indicates the results of the valuations of Tryptophan benzyl ester and Tryptophan tertiobutyl ester hydrochloride at 0.5% in the incubated sweat compared with the Tryptophan ethyl ester hydrochloride 1 and Tryptophan ethyl octyl hydrochloride at 0.5% in the incubated sweat.

(52) TABLE-US-00006 TABLE 5 Residual Pleasantness Sample Power unpleasant odor of the odor Incubated sweat 9.3 9.7 0.3 Incubated sweat + ACH 2 1.7 5 Tryptophan ethyl ester 3.3 1.3 5.7 hydrochloride 0.5% Tryptophan octyl ester 6.3 0.3 7.7 hydrochloride 0.5% Tryptophan benzyl ester 4.3 3 3.7 0.5% Tryptophan tertio butyl 4 1.7 5.7 ester hydrochloride 0.5%

(53) Tryptophan octyl ester hydrochloride has an effect of reducing the unpleasant odor compared to the negative control. Furthermore, it also generates a pleasant odor due to the release of odorous volatile molecules.

(54) Tryptophane benzyl ester and Tryptophan tertio butyl ester hydrochloride have an effect on the reduction of the unpleasant odor compared to the negative control and generate a pleasant odor due to the release of odorous volatile molecules.

(55) C. Formulations

(56) The following formulations were prepared:

(57) Formulation 1:

(58) TABLE-US-00007 % by weight compared to the Ingredients total weight of the composition Cross-linked 0.3 Poly(acrylic acid) (Carbomer) Preservatives 1 Compound 1 0.1 Water qsp qsp: in sufficient quantities

(59) The formulation produces a deodorant effect.

(60) Formulation 2:

(61) TABLE-US-00008 % by weight compared to the Ingredients total weight of the composition Cross-linked 0.3 Poly(acrylic acid) (Carbomer) Preservatives 1 Compound 1 5 Water qs 100

(62) The formulation produces a deodorant effect.

(63) Formulation 3 (with an Additional Antiperspirant Agent):

(64) TABLE-US-00009 % by weight compared to the Ingredients total weight of the composition Cross-linked 0.3 Poly(acrylic acid) (Carbomer) Preservatives 1 Aluminum 18 chlorhydroxide 50% Aluminum chloride 6 hexahydrate 50% Compound 1 0.1 Water qs 100

(65) The product formulation produces a deodorant and antiperspirant effect.

(66) Formulation 4 (with an Additional Antiperspirant Agent):

(67) TABLE-US-00010 % by weight compared to the Ingredients total weight of the composition Cross-linked 0.3 Poly(acrylic acid) (Carbomer) Preservatives 1 Aluminum 15 chlorhydroxide 50% Aluminum chloride 8 hexahydrate 50% Compound 1 5 Water qs 100

(68) The product formulation produces a deodorant and antiperspirant effect.

(69) Formulation 5 (Anydrous Formula):

(70) TABLE-US-00011 % by weight compared to the Ingredients total weight of the composition DIMETHICONE DIMETHICONOL 11 MODIFIED HECTORITE 2.66 PROPYLENE CARBONATE 0.89 ISOPROPYL PALMITATE 6 Compound 1 5 ISODODECANE 20 DIMETHICONE Qs 100

(71) The formulation produces a deodorant effect.