Monosubstituted urea derivatives as a self-tanning substance

Abstract

The present invention relates to the use of monosubstiuted urea derivatives of the formula I as self-tanning substance, for increasing melanin synthesis, for improving melanin transport and/or improving the distribution of melanin in suprabasal layers, and to preparations comprising these urea derivatives.

Claims

1. A tanning method comprising: adding one of more compounds of formula I, ##STR00013## where R.sup.1 and R.sup.2 stand, independently of one another, for —H, —OH, -straight-chain or branched O—(C.sub.1- to C.sub.6-alkyl), where R.sup.1 and R.sup.2 may also together form an unsubstituted or substituted five-membered ring, in which one or two non-adjacent CH.sub.2 groups may be replaced by O and which may be substituted by at least one straight-chain or branched alkyl group having 1 to 6 C atoms, and/or salts, conformers and/or solvates thereof, including mixtures thereof in all ratios, as a self-tanning substance to a composition to be applied topically, and topically applying said composition to skin of a human, wherein said composition is a face and/or body emulsion, face and/or body oil, powder make-up, emulsion make-up, wax make-up, sunscreen, pre-sun preparation or after-sun preparation.

2. A method comprising topically applying a face and/or body emulsion, face and/or body oil, powder make-up, emulsion make-up, wax make-up, sunscreen, pre-sun preparation or after-sun preparation comprising one or more compounds of formula I to skin of a human, ##STR00014## where R.sup.1 and R.sup.2 stand, independently of one another, for —H, —OH, -straight-chain or branched O—(C.sub.1- to C.sub.6-alkyl), where R.sup.1 and R.sup.2 may also together form an unsubstituted or substituted five-membered ring, in which one or two non-adjacent CH.sub.2 groups may be replaced by O and which may be substituted by at least one straight-chain or branched alkyl group having 1 to 6 C atoms, and/or salts, conformers and/or solvates thereof, including mixtures thereof in all ratios, in an amount sufficient for increasing melanin synthesis, for improving melanin transport and/or for improving distribution of melanin in suprabasal layers.

3. The method according to claim 1, wherein R.sup.1 in compounds of formula I stands for H, OH or a straight-chain or branched alkoxy group having 1 to 4 C atoms.

4. The method according to claim 1, wherein R.sup.2 in compounds of formula I stands for H, OH or a straight-chain or branched alkoxy group having 1 to 4 C atoms.

5. The method according to claim 1, wherein R.sup.1 and R.sup.2 in compounds of formula I together form a five-membered ring containing two O atoms, which may be substituted by one or two straight-chain or branched alkyl group(s) having 1 to 6 C atoms.

6. The method according to claim 1, wherein the compound of formula 1 is selected from the compounds of formula Ia to Ie ##STR00015##

7. A preparation comprising a vehicle which is suitable for topical application to skin of a human and at least one compound of formula I in an amount of 0.01 to 10% by weight, ##STR00016## where R.sup.1 and R.sup.2 stand, independently of one another, for —H, —OH, -straight-chain or branched O—(C.sub.1- to C.sub.6-alkyl), where R.sup.1 and R.sup.2 may also together form an unsubstituted or substituted five-membered ring, in which one or two non-adjacent CH.sub.2 groups may be replaced by O and which may be substituted by at least one straight-chain or branched alkyl group having 1 to 6 C atoms, subject to a proviso that R.sup.1 and R.sup.2 cannot both be H, and/or salts, conformers and/or solvates thereof, including mixtures thereof in all ratios, wherein said preparation is a face and/or body emulsion, face and/or body oil, lipstick, lip-care stick, powder make-up, emulsion make-up, wax make-up, sunscreen, pre-sun preparation or after-sun preparation.

8. The preparation according to claim 7, wherein at least one further self-tanning substance is present.

9. The method according to claim 2, wherein R.sup.1 in compounds of formula I stands for H, OH or a straight-chain or branched alkoxy group having 1 to 4 C atoms.

10. The method according to claim 2, wherein R.sup.2 in A compounds of formula I stands for H, OH or a straight-chain or branched alkoxy group having 1 to 4 C atoms.

11. The method according to claim 2, wherein R.sup.1 and R.sup.2 in compounds of formula I together form a five-membered ring containing two O atoms, which may be substituted by one or two straight-chain or branched alkyl group(s) having 1 to 6 C atoms.

12. The method according to claim 2, wherein the compound of formula 1 is selected from the compounds of formula Ia to Ie ##STR00017##

13. The method of claim 2 comprising topically applying a face and/or body emulsion, face and/or body oil, powder make-up, emulsion make-up, wax make-up, sunscreen, pre-sun preparation or after-sun preparation comprising a compound of formula Ic to skin of a human, ##STR00018## and/or salts, conformers and/or solvates thereof, including mixtures thereof in all ratios, in an amount sufficient for increasing melanin synthesis, for improving melanin transport and/or for improving the distribution of melanin in suprabasal layers.

14. A preparation comprising a vehicle which is suitable for topical application and at least one compound of formula Ic in an amount of 0.01 to 10% by weight, ##STR00019## and/or salts, conformers and/or solvates thereof, including mixtures thereof in all ratios, wherein said preparation is a face and/or body emulsion, face and/or body oil, lipstick, lip-care stick, powder make-up, emulsion make-up, wax make-up, A sunscreen, pre-sun preparation or after-sun preparation.

15. The preparation according to claim 14, wherein at least one further self-tanning substance is present.

16. The preparation according to claim 14, in the form of an emulsion.

17. The preparation according to claim 14, which additionally comprises one or more of a preservative, stabilizer, solubilizer, colorant, odour improver, thickener, plasticiser, humectant, interface-active agent, emulsifier, preservative, antifoaming agent, perfume or propellant.

18. The preparation according to claim 14, wherein the vehicle comprises a vegetable fat, vegetable oil, wax, paraffin, paraffin oil, lanolin oil, starch, tragacanth, fatty acid ester, animal fat, fatty alcohol, cellulose derivative, polyethylene glycol, silicone, silicone oil, bentonite, silica, talc, zinc oxide, or a mixture thereof.

Description

EXAMPLES

Example 1

Synthesis of Benzylurea (Ia)

(1) 6.00 g of benzylamine (56 mmol) and 13.45 g of urea (224 mmol) are weighed out successively into a 50 mL round-bottomed flask. 25 mL of water are subsequently added via a volumetric flask. The reaction solution is stirred for 5 minutes, 0.1-0.5 mL of concentrated hydrochloric acid are added, and the mixture is boiled under reflux for 3 hours.

(2) The reaction mixture is then cooled, and the product crystallises out at room temperature. 50 mL of water are added to the reaction mixture, and the precipitate is filtered off and washed with 4×15 mL of water and 3×10 mL of EtOH. The crude product is dried at 40° C. in a vacuum drying cabinet (50 mbar).

(3) Yield: 6.81 g (82% of theory).

(4) 1H-NMR (500 MHz, DMSO) δ[ppm]=4.19 (d, 2H, CH.sub.2—NH); 5.51 (s, 2H, NH.sub.2); 6.41 (t, 1H, NH); 7.28 (ddt, 5H, aromatic).

Example 2

Synthesis of (4-methoxybenzyl)urea (Ib)

(5) 1.50 g of 4-methoxybenzylamine (10.72 mmol) and 2.57 g of urea (42.86 mmol) are reacted analogously to Example 1. The crude product is recrystallised from ethanol in the ratio 1:6 (substance: solvent).

(6) Yield: 0.72 g (37% of theory).

(7) 1H-NMR (500 MHz, DMSO) δ[ppm]=3.72 (s, 3H, CH.sub.3−O); 4.10 (d, 2H, CH.sub.2—NH); 5.46 (s, 2H, NH.sub.2); 6.30 (t, 1H, NH) 6.86 (d, 2H, aromatic); 7.17 (d, 2H, aromatic).

Example 3

Synthesis of benzo[1,3]dioxol-5ylmethylurea (Ic)

(8) 2.50 g of piperonylamine (16.04 mmol) and 3.85 g of urea (64.17 mmol) are reacted analogously to Example 1.

(9) Yield: 2.87 g (88% of theory).

(10) 1H-NMR (500 MHz, DMSO) δ[ppm]=4.09 (d, 2H, CH.sub.2−NH); 5.98 (s, 2H, O—CH.sub.2—O); 5.48 (s, 2H, NH.sub.2); 6.33 (t, 1H, NH) 6.72 (d, 1H, aromatic); 6.84 (dt, 2H, aromatic).z

Example 4

Synthesis of (4-hydroxy-3-methoxybenzyl)urea (Id)

(11) 2.00 g of 4-(aminomethyl)-2-methoxyphenol (10.44 mmol) and 2.00 g of urea (33.30 mmol) are reacted analogously to Example 1.

(12) Yield: 1.56 g (76% of theory).

(13) 1H-NMR (500 MHz, DMSO) δ[ppm]=3.75 (s, 3H, CH.sub.3−O); 4.07 (s, 2H, CH.sub.2−NH); 5.48 (s, 2H, NH.sub.2); 8.75 (s, 1H, NH); 6.65 (d, 1H, aromatic) 6.72 (d, 1H, aromatic); 6.82 (s, 1H, aromatic); 12.5 (s, 1H, OH-aromatic)

Example 5

Synthesis of (3,4-dimethoxybenzyl)urea (Ie)

(14) 2.50 g of 3,4-dimethoxybenzylamine (14.50 mmol) and 3.48 g of urea (58 mmol) are reacted analogously to Example 1.

(15) Yield: 2.15 g (71% of theory).

(16) 1H-NMR (500 MHz, DMSO) δ[ppm]=3.73 (2s, 6H, CH.sub.3−O); 4.10 (d, 2H, CH.sub.2—NH); 5.47 (s, 2H, NH.sub.2); 6.30 (t, 1H, NH) 6.75-6.90 (2d, 1s, 3H, aromatic).

Example 6

Evaluation of the Synthesis of Melanin in a Cell Culture Model Containing Two Cell Types (Co-Culture), Firstly Normal Human Epidermal KeratinoCytes (NHEK) and Secondly Normal Human Epidermal Melanocytes, Lightly Pigmented (NHEM-LP)

(17) The two cell types NHEK and NHEM-LP (NHEK:NHEM-LP) are employed in a ratio of 2:1.

(18) The culture medium consists of the media keratinocyte-SFM (2 parts by volume) and medium M254 (1 part by volume).

(19) Keratinocyte-SFM contains 0.25 ng/ml of epidermal growth factor (EGF), 25 μg/ml of pituitary extract (PE) and 25 μg/ml of gentamycin and was purchased from Thermo Fisher Scientific.

(20) M254 contains PMA-free HMGS-2, 5 μg/ml of insulin, 50 U/ml of penicillin, 50 μg/ml of streptomycin and 25 μg/ml of gentamycin and was purchased from Thermo Fisher Scientific.

(21) IBMX denotes the compound 3-isobutyl-1-methylxanthine.

Cell Culture and Treatment

(22) NHEK and NHEM-LP were incubated in the culture medium in microtitre plates (24-well plates) for 24 hours (37° C., 5% CO.sub.2). The culture medium was removed and replaced by an assay medium which contained the culture medium and compounds Ia, Ib and Ic to be tested or alternatively no test substance, the reference L-tyrosine (1 mM), 200 μM of IBMX or the solvent control 0.1% of THF, 0.15% of THF. Compounds Ia, Ib and Ic are added as solution (0.15% in THF). After replacement of the assay medium, the cells were incubated again for 240 hours (10 days). On days 3 and 7, assay medium was again added. All experimental investigations were carried out using a triple determination. After the end of the incubation, the melanin was extracted by cell lysis with 0.5 N NaOH. The optical density (OD) of each sample was measured at 405 nm. The melanin quantity was calculated from melanin standards (standard curve 0.39 to 100 μg/ml of melanin).

Result

(23) None of the solvent controls exhibited an influence on the melanin synthesis. Compound Ia, which was tested at 45 μM, stimulates melanin synthesis by 17%.

(24) Compound Ib, which was tested at 45 μM, stimulates melanin synthesis by 18%.

(25) Compound Ic, which was tested at 20 μM and 30 μM, exhibits a concentration-dependent stimulating effect on melanin synthesis by 23% or 44%.

Example 7

Evaluation of the Tanning Properties In Vitro on Reconstructed Epidermis

(26) In this study, the tanning properties of compound Ic are investigated in vitro on 3D melanized reconstructed human epidermis (RHEs-MEL). The compound IBMX (3-isobutyl-1-methylxanthine) 100 μM is employed as positive control. Compound Ic is employed 25 μM and 12.5 M. Untreated reconstructed skin is used as negative control. The in vitro skin is treated systemically with the compounds to be investigated in a culture medium for 10 days and then analysed.

Result

(27) Compound Ic has comparably good properties as IBMX at 100 μM. This is evident for both concentrations, both in the reduction of the ITA value (ITA=individual typology angle), the visual colour difference and the increased amount of melanin.

Example 8

O/W Formulation

(28) TABLE-US-00001 Constituents/trade Source of [% by name supply INCI wt.] A Marlipal 1618/11 (1) CETEARETH-11 3 Lanette O (2) CETEARYLALCOHOL 7 Luvitol EHO (3) CETEARYLOCTANOATE 5 Tegosoft TN (4) C12-15 2.5 ALKYLBENZOATE Miglyol 812 N (1) CAPRYLIC/CAPRIC 2.5 TRIGLYCERIDE Propyl (5) PROPYLPARABEN 0.05 4-hydroxybenzoate Compound Ia, Ib, 0.5 Ic, Id or Ie B 1,2-Propanediol (5) PROPYLENE GLYCOL 4 Methyl (5) METHYLPARABEN 0.15 4-hydroxybenzoate Water, demineralised AQUA (WATER) to 100 Water, demineralised 10 Total 100.00

Preparation Process

(29) Firstly, phase A is warmed to 75° C. and phase B to 80° C. Phase B is then slowly added to phase A with stirring and stirred until a homogeneous mixture forms.

Sources of Supply

(30) TABLE-US-00002 (1) Sasol Germany GmbH (2) Cognis GmbH (3) BASF SE (4) Evonik Goldschmidt (5) Merck KGaA/Rona ® GmbH

Example 9

O/W Formulation

(31) TABLE-US-00003 Source of Constituents/trade name supply INCI [% by wt.] A Tego Care 150 (1) GLYCERYL 8 STEARATE, STEARETH-25, CETETH-20, STEARYL ALCOHOL Lanette O (2) CETEARYL ALCOHOL 1.5 Luvitol EHO (3) CETEARYL 5 OCTANOATE Miglyol 812 N (4) CAPRYLIC/CAPRIC 5 TRIGLYCERIDE Paraffin liquid (5) PARAFFINUM 3 LIQUIDUM (MINERAL OIL) AbilWax 2434 (1) STEAROXY 1.6 DIMETHICONE Dow Corning 200 Fluid (350 cs) (6) DIMETHICONE 0.5 Propyl 4-hydroxybenzoate (5) PROPYLLPARABEN 0.05 5,7-Dihydroxy-2-methyl- (5) 0.2 chromone B 1,2-Propanediol (5) PROPYLENE 3 GLYCOL Methyl 4-hydroxybenzoate (5) METHYLPARABEN 0.15 Water, demineralised AQUA (WATER) to 100 C Probiol L 05018 (empty (7) AQUA, ALCOHOL 5 liposomes) DENAT, LECITHIN, GLYCERINE, DISODIUM PHOSPHATE Water, demineralised AQUA (WATER) 10.00 Compound Ia, Ib, Ic, Id or Ie 0.2 Total 100.00

Preparation Process

(32) Firstly, phases A and B are warmed to 80° C. Phase B is then slowly added to phase A with stirring and homogenised. The mixture is then cooled, and phase C is added at 40° C.

Sources of Supply

(33) (1) Evonik Goldschmidt GmbH, (2) Cognis GmbH, (3) BASF SE, (4) Sasol Germany GmbH, (5) Merck KGaA/Rona®, (6) Dow Corning, (7) Kuhs GmbH & Co. KG

Example 10

W/O Formulation

(34) TABLE-US-00004 Source [% Constituents/trade name of supply INCI by wt.] A Dow Corning 3225 C (1) CYCLOMETHICONE, 23.6 DIMETHICONE COPOLYOL Propyl (2) PROPYLPARABEN 0.05 4-hydroxybenzoate Compound Ia, Ib, Ic, 0.1 Id or Ie B Methyl (2) METHYLPARABEN 0.15 4-hydroxybenzoate 1,2-Propanediol (2) PROPYLENE GLYCOL 35.9 Water, demineralised AQUA (WATER) to 100 Total 100.00

Preparation Process

(35) Firstly, phase B is dissolved and then added to phase A. The pH is adjusted to the value pH=6.0 using sodium hydroxide solution or citric acid.

Sources of Supply

(36) (1) Dow Corning (2) Merck KGaA/Rona®

Example 11

O/W Anti-Ageing Cream with UV A/B Protection

(37) TABLE-US-00005 Source of Constituents/trade name supply INCI [% by wt.] A Eusolex ® 2292 (1) ETHYLHEXYL 3 METHOXYCINNAMATE, BHT Eusolex ® 4360 (1) BENZOPHENONE-3 0.5 Tego Care 150 (2) GLYCERYL STEARATE, 8 STEARETH-25, CETETH- 20, STEARYL ALCOHOL Lanette O (3) CETEARYL ALCOHOL 1.5 Luvitol EHO (4) CETEARYL 5 OCTANOATE Miglyol 812 N (5) CAPRYLIC/CAPRIC 5 TRIGLYCERIDE Paraffin liquid (1) PARAFFINUM LIQUIDUM 3 (MINERAL OIL) Abil-Wax 2434 (2) STEAROXY 1.6 DIMETHICONE Dow Corning 200 Fluid (350 (6) DIMETHICONE 0.5 cs) Propyl 4-hydroxybenzoate (1) PROPYLPARABEN 0.05 Compound Ia, Ib, Ic, Id or Ie 1 B 1,2-Propanediol (1) PROPYLENE GLYCOL 3 Methyl 4-hydroxybenzoate (1) SODIUM 0.17 sodium salt METHYLPARABEN Water, demineralised AQUA (WATER) to 100 Total 100.00

Preparation Process

(38) Firstly, phases A and B are mixed separately and warmed to 80° C. Phase B is then slowly added to phase A with stirring. The mixture is homogenised cooled to room temperature.

(39) Sources of supply: (1) Merck KGaA/Rona®, (2) Evonik Goldschmidt GmbH, (3) Cognis GmbH, (4) BASF AG, (5) Sasol Germany GmbH, (6)