BARBITURIC ACID DERIVATIVES AS SELF-TANNING SUBSTANCES

Abstract

The present invention relates to the use of barbituric acid 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 superbasal layers, to preparations comprising these barbituric acid derivatives, and to specific barbituric acid derivatives.

Claims

1. A method for self-tanning, or a method for increasing melanin synthesis, for improving melanin transport and/or for improving the distribution of melanin in suprabasal layers, comprising applying to a surface to be tanned or to the skin a compound of formula I, ##STR00016## where R.sup.1 stands for H, straight-chain or branched C.sub.1- to C.sub.20-alkyl or for straight-chain or branched C.sub.2- to C.sub.20-alkenyl, R.sup.2 and R.sup.3 stand, independently of one another, for H, OH, straight-chain or branched C.sub.1- to C.sub.6-alkyl, straight-chain or branched O(C.sub.1- to C.sub.6-alkyl), where R.sup.2 and R.sup.3 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, tautomers, conformers and/or solvates thereof, including mixtures thereof in all ratios.

2. The method according to claim 1, which is for increasing melanin synthesis, for improving melanin transport and/or for improving the distribution of melanin in suprabasal layers, comprising applying to the skin a compound of formula I, ##STR00017## where R.sup.1 stands for H, straight-chain or branched C.sub.1- to C.sub.20-alkyl or for straight-chain or branched C.sub.2- to C.sub.20-alkenyl, R.sup.2 and R.sup.3 stand, independently of one another, for H, OH, straight-chain or branched C.sub.1- to C.sub.6-alkyl, straight-chain or branched O(C.sub.1- to C.sub.6-alkyl), where R.sup.2 and R.sup.3 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 0 and which may be substituted by at least one straight-chain or branched alkyl group having 1 to 6 C atoms, and/or salts, tautomers, conformers and/or solvates thereof, including mixtures thereof in all ratios.

3. The method according to claim 1, wherein R.sup.1 in compounds of the formula I stands for H or for a straight-chain or branched alkyl group having 1 to 6 C atoms.

4. The method according to claim 1, wherein R.sup.2 and R.sup.3 in compounds of the formula I each stand, independently of one another, for H, OH, a straight-chain or branched alkyl group having 1 to 4 C atoms or for a straight-chain or branched alkoxy group having 1 to 4 C atoms.

5. The method according to claim 1, characterised in that the compound of the formula I is selected from the compounds of the formula Ia to If ##STR00018##

6. Preparation comprising a vehicle which is suitable for topical applications and at least one compound of the formula I, ##STR00019## where R.sup.1 stands for H, straight-chain or branched C.sub.1- to C.sub.20-alkyl or for straight-chain or branched C.sub.2- to C.sub.20-alkenyl, R.sup.2 and R.sup.3 stand, independently of one another, for H, OH, straight-chain or branched C.sub.1- to C.sub.6-alkyl, straight-chain or branched O(C.sub.1- to C.sub.6-alkyl), where R.sup.2 and R.sup.3 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, tautomers, conformers and/or solvates thereof.

7. Preparation according to claim 6, characterised in that the compound of the formula I is present in an amount of 0.01 to 10% by weight.

8. Preparation according to claim 6, characterised in that at least one further self-tanning substances is present.

9. Process for the preparation of a preparation according to claim 6, characterised in that at least one compound of the formula I is mixed with a vehicle which is suitable for topical applications and optionally with other active substances or assistants.

10. Compounds of the formula I, ##STR00020## where R.sup.1 stands for straight-chain or branched C.sub.2- to C.sub.20-alkyl or for straight-chain or branched C.sub.2- to C.sub.20-alkenyl, R.sup.2 and R.sup.3 stand, independently of one another, for H, OH, straight-chain or branched C.sub.1- to C.sub.6-alkyl, straight-chain or branched O(C.sub.1- to C.sub.6-alkyl), where R.sup.2 and R.sup.3 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, tautomers, conformers and/or solvates thereof.

11. Process for the preparation of compounds of the formula I according to claim 10, characterised in that a compound of the formula II, ##STR00021## where R.sup.1 has a meaning indicated for the compound of formula I, is reacted with a compound of the formula III, ##STR00022## where R.sup.2 and R.sup.3 have a meaning indicated for the compound of formula I, and is subsequently hydrogenated.

12. The method according to claim 1, wherein the surface to be tanned is skin.

13. The method according to claim 1, which is for self-tanning, comprising applying to a surface to be tanned a compound of formula I, ##STR00023## where R.sup.1 stands for H, straight-chain or branched C.sub.1- to C.sub.20-alkyl or for straight-chain or branched C.sub.2- to C.sub.20-alkenyl, R.sup.2 and R.sup.3 stand, independently of one another, for H, OH, straight-chain or branched C.sub.1- to C.sub.6-alkyl, straight-chain or branched O(C.sub.1- to C.sub.6-alkyl), where R.sup.2 and R.sup.3 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, tautomers, conformers and/or solvates thereof, including mixtures thereof in all ratios.

14. The preparation according to claim 6, wherein the compound of the formula I is selected from the compounds of formula Ia to If ##STR00024##

15. The compound according to claim 10, which is of formula Ie or If ##STR00025##

Description

EXAMPLES

Example 1

Synthesis of 5-benzylpyrimidin-2,4,6-trione (Ia)

[0226] 2.00 g of barbituric acid (15.61 mmol) are dissolved in 50.0 mL of hot (70-80 C.) deionised water in a 100 mL two-necked round-bottomed flask. A solution of 1.49 g of benzaldehyde (14.05 mmol) in 10 mL of ethanol (EtOH) is subsequently metered in via a syringe. The reaction mixture is boiled under reflux for 30 min., during which a solid precipitates out. The reaction mixture is then cooled and filtered. The residue can be purified by recrystallisation (1 g of substance: 15 g of deionised water). 5-Benzylidenepyrimidine-2,4,6-trione is washed with EtOH in order to separate off further impurities. 5-Benzylidenepyrimidine-2,4,6-trione is then dissolved in THF (1 g in 10 mL) and hydrogenated by means of a palladium/carbon catalyst (1 g, 5% Pd/C) at 0.2 bar of H.sub.2 for 16.25 h. The catalyst is filtered off, and the reaction mixture is evaporated in a rotary evaporator. Substance Ia is obtained in high purity.

[0227] 1H-NMR (500 MHz, DMSO) [ppm]=3.24 (d, 2H, CHCH.sub.2-aromatic); 3.90 (t, 1H, CHCH.sub.2); 7.09 (d, 2H, aromatic); 7.25 (d, 2H, aromatic); 7.22 (s, 1H, aromatic); 11.14 (s, 2H, NH).

Example 2

Synthesis of 5-(4-methoxybenzyl)pyrimidine-2,4,6-trione (Ib)

[0228] Analogously to Example 1, 2.00 g of barbituric acid (15.61 mmol) are reacted with a solution of 2.16 g of anisaldehyde (14.05 mmol) in 10 mL of EtOH. After filtration, the residue is washed with 38 mL of cold EtOH, and 310 mL of deionised water and dried in a vacuum drying cabinet.

Intermediate 5-(4-methoxybenzylidene)pyrimidine-2,4,6-trione

[0229] 1H-NMR (500 MHz, DMSO) [ppm]=3.88 (s, 3H, CH.sub.3O); 7.07 (d, 2H, aromatic); 8.25 (s, 1H, CHC); 8.37 (d, 2H, aromatic); 11.16 (s, 1H, NH); 11.28 (s, 1H, NH).

[0230] The intermediate is then hydrogenated analogously to Example 1, giving substance Ib in high purity.

[0231] 1H-NMR (500 MHz, DMSO) [ppm]=3.20 (d, 2H, CH.sub.2-aromatic); 3.71 (s, 3H, CH.sub.3O); 3.82 (t, 1H, CHCH.sub.2); 6.81 (d, 2H, aromatic); 6.99 (d, 2H, aromatic); 11.16 (s, 2H, NH).

Example 3

Synthesis of 5-(4-hydroxy-3-methoxybenzyl)pyrimidine-2,4,6-trione (Ic)

[0232] Analogously to Example 1, 2.00 g of barbituric acid (15.61 mmol) are reacted with a solution of 2.16 g of vanillin (14.05 mmol) in 10 mL of EtOH. After filtration, the residue is washed with 510 mL of cold EtOH and dried in a vacuum drying cabinet.

Intermediate 5-(4-hydroxy-3-methoxybenzylidene)pyrimidine-2,4,6-trione

[0233] 1H-NMR (500 MHz, DMSO) [ppm]=3.82 (s, 3H, CH.sub.3O); 6.91 (s, 1H, aromatic); 7.81 (d, 1H, aromatic); 8.23 (d, 1H, CHC); 8.47 (d, 1H, aromatic); 11.11 (s, 1H, NH); 11.21 (s, 1H, NH).

[0234] The intermediate is then hydrogenated analogously to Example 1, giving substance Ic in purity.

[0235] 1H-NMR (500 MHz, DMSO) [ppm]=3.16 (d, 2H, CH.sub.2CH); 3.69 (s, 3H, CH.sub.3O); 3.75 (t, 1H, CHCH.sub.2); 6.45 (dd, 1H, aromatic); 6.61 (d, 1H, aromatic); 6.62 (s, 1H, aromatic); 11.12 (s, 2H, NH).

Example 4

Synthesis of 5-benzyl-1-butylpyrimidine-2,4,6-trione (Id)

[0236] 1.40 g of N-butylbarbituric acid (7.07 mmol) in 4.0 mL of EtOH are initially introduced in a 25 mL two-necked round-bottomed flask and heated to the reflux temperature. A solution of 0.90 g of benzaldehyde (8.48 mmol) in 3 mL of EtOH is subsequently metered in via a syringe. The reaction mixture is boiled under reflux for 30 min. A yellow clear solution forms. The reaction mixture is then cooled for a few hours. The crystals formed are filtered off and washed with a few mL of EtOH and MTBE in order to dissolve out impurities. The residue is dried on a vacuum pump at 0.02 mbar.

[0237] The crude product is then dissolved in THF and hydrogenated by means of a palladium/carbon catalyst analogously to Example 1. The reaction mixture is evaporated in a rotary evaporator to give substance Id in high purity.

[0238] 1H-NMR (500 MHz, DMSO) [ppm]=0.82 (t, 3H, CH.sub.3CH.sub.2); 1.10 (s, 2H, CH.sub.3CH.sub.2CH.sub.2); 1.32 (p, 2H, CH2-CH2-CH2); 3.28 (d, 2H, CHCH.sub.2-aromatic); 3.58 (multiplet, 2H, CH.sub.2CH.sub.2); 3.98 (t, 1H, CHCH2); 7.05 (d, 2H, aromatic); 7.25 (multiplet, 3H, aromatic); 11.38 (s, 1H, NH).

[0239] LC-MS: 99.8 area percent.

Example 5

Synthesis of 1-butyl-5-(4-methoxybenzyl)pyrimidine-2,4,6-trione (Ie)

[0240] Analogously to Example 4, 1.40 g of N-butylbarbituric acid (7.07 mmol) are reacted with a solution of 0.90 g of 4-methoxybenzaldehyde (8.48 mmol) in 3 mL of EtOH.

Intermediate 1-butyl-5-(4-methoxybenzylidene)pyrimidine-2.4,6-trione

[0241] 1H-NMR (500 MHz, DMSO) [ppm]=0.90 (t, 3H, CH.sub.3CH.sub.2); 1.31 (sextet, 2H, CH.sub.3CH.sub.2CH.sub.2); 1.50 (quintet, 2H, CH.sub.2CH.sub.2CH.sub.2); 3.79 (quartet, 2H, CH.sub.2CH.sub.2NH); 3.89 (s, 3H, OCH.sub.3); 7.08 (d, 2H); 8.35 (d, 3H).

[0242] The intermediate is then hydrogenated analogously to Example 1, giving substance Ie in high purity.

[0243] 1H-NMR (500 MHz, DMSO) [ppm]=0.85 (t, 3H, CH.sub.3CH.sub.2); 1.31 (sextet, 2H, CH.sub.3CH.sub.2CH.sub.2); 1.30 (quintet, 2H, CH.sub.2CH.sub.2CH.sub.2); 3.23 (d, 2H, CH2-aromatic); 3.59 (multiplet, 2H, CH.sub.2CH.sub.2); 3.70 (s, 3H, OCH.sub.3); 3.89 (t, 1H, CHCH.sub.2-aromatic); 6.80 (d, 2H, aromatic); 6.97 (d, 2H, aromatic); 11.35 (s, 1H, NH).

[0244] GC-MS: 91.3 area percent.

Example 6

Synthesis of 1-butyl-5-(4-hydroxy-3-methoxybenzyl)pyrimidine-2,4,6-trione (If)

[0245] Analogously to Example 4, 1.79 g of N-butylbarbituric acid (8.89 mmol) are reacted with a solution of 1.23 g of vanillin (8.00 mmol) in 3 mL of EtOH.

Intermediate 1-butyl-5-(4-hydroxy-3methoxybenzylidene)pyrimidine-2,4,6-trione

[0246] 1H-NMR (500 MHz, DMSO) [ppm]=0.90 (t, 3H, CH.sub.3CH.sub.2); 1.31 (sextet, 2H, CH.sub.3CH.sub.2CH.sub.2); 1.50 (quintet, 2H, CH.sub.2CH.sub.2CH.sub.2); 3.79 (quartet, 2H, CH.sub.2CH.sub.2NH); 3.89 (s, 3H, OCH.sub.3); 7.08 (d, 2H); 8.35 (d, 3H)(

[0247] The intermediate is then hydrogenated analogously to Example 1, giving substance If.

[0248] 1H-NMR (500 MHz, DMSO) [ppm]=0.84 (t, 3H, CH.sub.3CH.sub.2); 1.11 (sextet, 2H, CH.sub.3CH.sub.2CH.sub.2); 1.30 (quintet, 2H, CH.sub.2CH.sub.2CH.sub.2); 3.19 (d, 2H, CH2-aromatic); 3.59 (multiplet, 2H, CH.sub.2CH.sub.2); 3.70 (s, 3H, OCH.sub.3); 3.86 (t, 1H, CHCH.sub.2-aromatic); 6.43 (dd, 1H, aromatic); 6.57 (dd, 1H, aromatic); 6.62 (d, 1H, aromatic); 11.35 (s, 1H, NH).

[0249] LC-MS: 60% area percent.

Example 7

[0250] 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)

[0251] The two cell types NHEK and NHEM-LP (NHEK:NHEM-LP) are employed in a ratio of 2:1.

[0252] The culture medium consists of the media keratinocyte-SFM (2 parts by volume) and medium M254 (1 part by volume).

[0253] Keratinocyte-SFM contains 0.25 ng/ml of epidermal growth factor (EGF), 25 g/ml of pituitary extract (PE) and 25 g/ml of gentamycin and was purchased from Thermo Fisher Scientific.

[0254] M254 contains PMA-free HMGS-2, 5 g/ml of insulin, 50 U/ml of penicillin, 50 g/ml of streptomycin and 25 g/ml of gentamycin and was purchased from Thermo Fisher Scientific.

[0255] IBMX denotes the compound 3-isobutyl-1-methylxanthine.

[0256] Cell Culture and Treatment

[0257] 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 Ib and Id to be tested or alternatively no test substance, the reference L-tyrosine (1 mM), 200 M of IBMX or the solvent control 0.1% of THF, 0.15% of THF, 0.1% of DMSO, 0.15% of DMSO, 0.17% of DMSO. Compound Ib was added as solution (0.15% in DMSO). Compound Id was 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 g/ml of melanin).

[0258] Result:

[0259] None of the solvent controls exhibited an influence on the melanin synthesis.

[0260] Compound Ib, which was tested at 45 M, stimulates melanin synthesis by 20%.

[0261] Compound Id, which was tested at 20 M and 45 M, stimulates melanin synthesis by 17% and 25%.

Example 8

[0262] Evaluation of the Tanning Properties In Vitro on Reconstructed Epidermis

[0263] In this study, the tanning properties of compound Id are investigated in vitro on 3D melanized reconstructed human epidermis (RHEs-MEL). The compound IBMX (3-isobutyl-1-methylxanthine) 100 M is employed as positive control. Compound Id is employed 20 M and 10M. 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.

[0264] Result:

[0265] Compound Id has comparably good properties as IBMX at 100 M. This is evident for both concentrations, both in the reduction of the ITA value (ITA=individual typology angle) and in the visual colour difference.

Example 9: O/W Formulation

[0266]

TABLE-US-00001 Constituents/trade Source of name supply INCI [% by 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 4- (5) PROPYLPARABEN 0.05 hydroxybenzoate Compound Ia, Ib, 0.5 Ic, Id, Ie or If 5,7-Dihydroxy-2- (5) 0.2 methyl-chromone B 1,2-Propanediol (5) PROPYLENE GLYCOL 4 Methyl 4- (5) METHYLPARABEN 0.15 hydroxybenzoate Water, AQUA (WATER) to 100 demineralised Water, 10 demineralised Total 100.00

[0267] Preparation Process:

[0268] 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.

[0269] Sources of Supply:

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

Example 10: O/W Formulation

[0270]

TABLE-US-00003 Constituents/trade Source of 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 (6) DIMETHICONE 0.5 Fluid (350 cs) Propyl 4- (5) PROPYLLPARABEN 0.05 hydroxybenzoate B 1,2-Propanediol (5) PROPYLENE 3 GLYCOL Methyl 4- (5) METHYLPARABEN 0.15 hydroxybenzoate Water, AQUA (WATER) to 100 demineralised C Probiol L 05018 (7) AQUA, ALCOHOL 5 (empty liposomes) DENAT, LECITHIN, GLYCERINE, DISODIUM PHOSPHATE Water, AQUA (WATER) 10.00 demineralised Compound Ia, Ib, 0.2 Ic, Id, Ie or If Total 100.00

[0271] Preparation Process:

[0272] 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.

[0273] Sources of Supply:

[0274] (1) Evonik Goldschmidt GmbH, (2) Cognis GmbH, (3) BASF SE, (4) Sasol Germany GmbH, (5) Merck KGaA/Rona, (6) Dow Cornin, (7) Kuhs GmbH & Co. KG

Example 11: W/O Formulation

[0275]

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

[0276] Preparation Process:

[0277] 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.

[0278] Sources of Supply:

TABLE-US-00005 (1) Dow Corning (2) Merck KGaA/Rona

Example 12: O/W Anti-Ageing Cream with UV A/B Protection

[0279]

TABLE-US-00006 Constituents/trade Source of 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 (6) DIMETHICONE 0.5 Fluid (350 cs) Propyl 4- (1) PROPYLPARABEN 0.05 hydroxybenzoate Compound Ia, Ib, 1 Ic, Id, Ie or If B 1,2-Propanediol (1) PROPYLENE GLYCOL 3 Methyl 4- (1) SODIUM 0.17 hydroxybenzoate METHYLPARABEN sodium salt Water, AQUA (WATER) to 100 demineralised Total 100.00

[0280] Preparation Process:

[0281] 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.

[0282] Sources of Supply:

[0283] (1) Merck KGaA/Rona, (2) Evonik Goldschmidt GmbH, (3) Cognis GmbH, (4) BASF SE, (5) Sasol Germany GmbH, (6)