DE4033567A1 - Use of di:carboxylic acid mono:ester(s) - Google Patents

Abstract

Use of dicarboxylic acid monoesters of formula R1-O-C(O)-X-C(O)-O-R2 (I) as antiseborrhoeic agents in the prodn. of topical, pharmaceutical and cosmetic prepns. with sebosuppressive activity, e.g. for treatment of psoriasis, acne or dandruff, is new. In (I) one of R1, R2 = H and the other is: (a) alkyl (opt. branched, opt. mono- or polyunsatd., and opt. substd. by an aryl, alkaryl or cycloalkyl residue totalling up to 20C); or (b) up to 20C mono-, bi- or tricyclic residue (opt. mono- or polyunsatd., opt. substd. by a cycloalkkyl, aryl or opt. branched, opt. mono- or polyunsatd. alkyl). X = 1-12C alkylene, (CH2)n-(O)m-C6H4 or CH=CH; n = 1-5; m = 0 or 1.

Description

The invention relates to the use of dicarboxylic monoesters more specifically Structure as antiseborrheic agents for the preparation of topical, pharmaceutical or cosmetic preparations with sebosuppressive Effect.

Excessive secretions of the sebaceous glands of the epidermis can cause pathological Skin conditions lead. In more common, easier cases It is a cosmetic problem characterized by greasy appearance of Hair or a shiny, oily appearance of the skin manifests. The modern Cosmetics are therefore endeavored by suitable topically applicable preparations normalize the secretion of the sebaceous glands and the hair and give the skin an attractive appearance again.

It has been found that the dicarboxylic acid monoesters of the general formula I valuable new antisecretorrhoids with good inhibitory effects are.

The invention therefore relates to the use of dicarboxylic acid monoesters the general formula I

where:

• - One of R¹ or R² is a hydrogen atom and the other
  • a) a linear or branched, saturated or mono- or polyunsaturated, optionally substituted by an aryl, alkaryl or cycloalkyl radical alkyl radical having a maximum of 20 carbon atoms or
  • b) a mono-, bi- or tri-unsaturated radical optionally substituted by a cycloalkyl, aryl or a linear or branched, saturated or mono- or polyunsaturated alkyl radical having a total of not more than 20 C atoms,
• - X is an alkylene group having 1-12 C atoms or a group - (CH₂) _n - (O) _m -C₆H₄-, where n is a number from 1 to 5 and m is the number 0 or 1, or a group -CH = CH-,

as antiseborrheic agents for the preparation of topical, pharmaceutical and cosmetic preparations having sebosuppressive activity.

Dicarboxylic acid monoesters of general formula I are already partially known from the literature. For example, terephthalic acid monooctadecyl ester is in French Patent FR 14 53 972 (see Chem. Abstr. 95 821t) and terephthalic acid monooctyl ester in the European patent specification EP 1 53 826 A2 (compare Chem. Abstr. 104: 139 431a).

Terephthalsäuremonoalkylester can generally z. B. by implementation of terephthalic acid monomethyl ester chloride with the corresponding long chain Alcohol and subsequent transformation of the methyl ester into a Carboxylic acid group obtained.

The Dicarbonsäuremonoester of formula I have a pronounced sebosuppressive Effect, whereby many products already at very low application concentrations a noticeable sebostatic or antiseborrheic Unfold effect on the skin. They also have good skin and skin Mucous membrane compatibility. Another object of the invention are therefore antiseborrheic preparations for topical use on the hair or on the skin, consisting of antiseborrheic agents in one dermatologically acceptable cosmetic or pharmaceutical carrier, characterized in that at least as antiseborrheic active ingredient a compound of general formula I in an amount of 0.005 to 1.0 Wt .-% based on the total preparation is included. They let themselves  easily incorporate into various pharmaceutical and cosmetic carriers. Such preparations can also be used in the treatment of various Forms of skin disorders such as acne, psoriasis or dandruff with Use advantage.

As carriers are all suitable for application to the hair or the Skin suitable preparations. For the skin treatment are particularly suitable aqueous or alcoholic solutions, surfactant lotions, oils, Ointments, emulsions, creams, gels and stick preparations. For the hair treatment Hair lotions, hair shampoos, hair treatments, hair conditioners are particularly suitable and hairsprays. Because of the special cosmetic problems that caused by greasy hair, make up the hair cosmetic preparations particularly preferred embodiments of the invention.

The most important components of common pharmaceutical and cosmetic Carriers are:

• a) oil components, eg. B. Paraffin oil, vegetable oils, fatty acid esters, squalane, Fatty alcohols, 2-octyldodecanol,
• b) fats and waxes, e.g. Spermaceti, beeswax, montan wax, paraffin, cetyl stearyl alcohol,
• c) emulsifiers, for. B. fatty acid partial glycerides, fatty acid sorbitan partial esters and their ethoxylates, soaps, fatty alcohol sulfates, fatty alcohol polyglycol ethers, alkyl phosphates,
• d) washing raw materials, in particular anionic surfactants, for. B. fatty alcohol polyglycol ether sulfates, Fatty alcohol sulfates, alphaolefin sulfonates, alkanesulfonates, Sulfosuccinic acid esters, acyl taurides, acyl isethionates and acylsarcosides, ampholytic surfactants, e.g. N-alkylglycine, N-alkylaminopropionic acid, N-alkylaminobutyric acid having 8 to 18 C atoms in the alkyl group, zwitterionic surfactants, e.g. N-alkyl- (C₈-C₁₈) -N, N-dimethylammonio glycinate or N-cocoacylaminopropyl-N, N-dimethylammonium glycinate and nonionic surfactants, e.g. B. fatty alcohol polyglycol ethers, alkylphenol polyglycol ethers, Fatty acid polyglycol esters, amino oxide surfactants, fatty acid alkanolamides and their ethoxylates and cationic surfactants, e.g. B. Alkyl (C₁₂-C₁₈) trimethylammonium chloride, lauryldimethylbenzylammonium chloride, Cetylpyridinium chloride, distearyldimethylammonium chloride,
• e) lower alcohols such. For example, ethanol, isopropanol,  
• f) polyhydric alcohols such. As ethylene glycol, propylene glycol, glycerol,
• g) water and auxiliaries such. Fragrances, preservatives, buffer substances, Thickeners, dyes and opacifiers.

The following examples are intended to explain the subject matter of the invention in more detail without limiting it to it.  

Examples

structures

2. Syntheses Example 2-1 Terephthalic acid monoisotridecyl ester (1)

The mixture of 20 g (0.1 mol) of terephthalic acid methyl ester chloride, 20 g (0.1 mol) of isotridecyl alcohol, 200 ml of toluene and 11.1 g (0.11 mol) of triethylamine was heated to boiling for 3.5 hours , then filtered, the solution was evaporated, the residue taken up in tert-butyl methyl ether, the solution washed with highly dilute hydrochloric acid and water, dried with sodium sulfate, evaporated, the residue taken up in petroleum ether, the solution was filtered and the evaporation residue on silica gel (Merck) Chromatograph. The eluant used was methylene chloride / toluene (8: 2). 24.8 g (81% of theory) of terephthalic acid isotridecyl methyl ester (1a) of refractive index n _D (20) = 1.4968 were obtained.

To the stirred mixture of 1.32 g (33.1 mmol) of powdered sodium hydroxide, 100 ml of 1,2-diethoxyethane and 20 ml of water was added 12 g (33.1 mmol) of terephthalic acid isotridecyl methyl ester (1a) in as little as 1 , 2-dimethoxyethane. The mixture was stirred for 5 hours at 10 ° C, evaporated, the residue washed in methylene chloride, the cloudy solution washed with dilute hydrochloric acid, filtered, dried with sodium sulfate, evaporated and chromatographed twice on silica gel (Merck) (eluent: 1. methylene chloride, 2 Methylene chloride / methanol (9: 1).
Yield: 6.8 g (59% of theory) of the ester (1), as a cloudy-white pasty mass, which becomes clear at 59.degree.

example 2-2 Terephthalic acid mono-isononyl ester (2)

Preparation: analogously to Example 2-1, wherein isononyl alcohol was used as the alcohol.
Melting point: 115-121 ° C

example 2-3 Terephthalic acid mono-dodecyl esters (3)

Preparation: analogously to Example 2-1, wherein n-dodecanol was used as the alcohol.
Melting point: 109-112 ° C

example 2-4 Terephthalic acid monofarnesyl ester (4)

Preparation: analogously to Example 2-1, wherein as an alcohol farnesol (3,7,11-trimethyl-2,6,10-dodecatrien-1-ol) was used.
Appearance: cloudy, white, pasty mass that became clear at 36 ° C.

example 2-5 Terephthalic acid mono-4- (1,1,3-trimethyl-2-cyclohexyl) - 2-butyl ester (5)

Preparation: analogously to Example 2-1, using 4- (1,1,3-trimethyl-2-cyclohexyl) -butan-2-ol as the alcohol.
Melting point: 97-100 ° C

example 2-6 Fumaric acid mono-phytyl ester (6)

Preparation: analogously to Example 2-1, wherein fumaric acid methyl ester chloride and phytol was used as the acid component.
Refractive index: n _D (20) = 1.4782

example 2-7 Maleic acid mono-phytyl ester (7)

The mixture of 10 g (102 mmol) of maleic anhydride and 30.3 g (102 mmol) of phytol (32% cis, 68% trans) was heated with a spatula tip of p-toluenesulfonic acid under nitrogen for 2 hours at 70 ° C, in petroleum ether taken, filtered, treated with charcoal and dried under oil pump vacuum.
Yield: 30.3 g (75% of theory) of the ester (7)
Refractive index: n _D (20) = 1.4742

example 2-8 Maleic acid monoisotridecyl ester (8)

Preparation: analogously to Example 2-7, wherein isotridecanol was used as the alcohol.
Refractive index: n _D (20) = 1.4652

example 2-9 Maleic acid mono-farnesyl ester (9)

Preparation: analogous to Example 2-7, wherein as alcohol farnesol was used. The product was chromatographed on silica gel (Merck). The eluent was methylene chloride / methanol (85:15).
Refractive index: n _D (20) = 1.5016

example 2-10 Succinic acid monophytyl ester (10)

Preparation: analogously to Example 2-7, wherein succinic anhydride was used as the anhydride.
Refractive index: n _D (20) = 1.4660

example 2-11 4-carboxymethoxy-benzoic acid isononyl ester (11)

A mixture of 30 g (113 mmol) of isononyl 4-hydroxybenzoate (by esterification of 4-hydroxybenzoic acid with isononyl alcohol with sulfuric acid as catalyst, mp 93-96 ° C), 19 g (124 mmol) of methyl bromoacetate, 15.7 g (113 mmol) of potassium carbonate, 0.25 g of tetrabutylammonium iodide and 200 ml of butanone was heated to boiling for 12 hours. The precipitate was filtered off, the solution was concentrated first in a water-jet, then in an oil pump vacuum at 120 ° C (15 minutes) and the residue was chromatographed on silica gel with methylene chloride. The product was dried for 1 hour at 60 ° C in an oil pump vacuum. There were obtained 33.7 g (88% of theory) of 4-methoxycarbonylmethoxybenzoic acid isononyl ester as a liquid with a refractive index of n _D (20) = 1.5008, which was obtained by hydrolysis as in Example 2-1 in the half-ester ( 11) was transferred.
Melting point: 127-131 ° C

example 2-12 4-Carboxymethoxybenzoic acid isotridecyl ester (12)

Preparation: analogously to Example 2-11, the alcohol used being isotridecanol.
Refractive index: n _D (25) = 1.5132

example 2-13 Glutaric acid (1,1,4,4-tetramethyltetralin-6-ylmethyl) - ester (13)

Preparation: analogously to Example 2-7, wherein 1,1,4,4-tetramethyltetralin-6-yl-methanol was used as the alcohol and glutaric anhydride as the anhydride.
Melting point: 59-62 ° C

example 2-14 Terephthalic acid mono- (1,1,4,4-tetramethyltetralin-6- ylmethyl) ester (14)

Preparation: analogously to Example 2-1, alcohol being 1,1,4,4- Tetramethyltetralin-6-yl-methanol was used.

3. Testing and evaluation of the antiseborrheic effect 3.1 Kutan visual rat test 3.1.1 Basis

The test is based on the observation that male rats enter secrete brownish skin fat, so that the more or less strong Greasiness of the skin can be assessed visually well as a skin tanning can. That the tanning is skin surface fat, It can be seen from the fact that young female rats as well as male Rats after washing with surfactant solutions or with lipid solvents or even male rats that are systematically treated with estrogen were just the normal bright, pink skin after the Have scissors. In parallel, are from the cut hair to extract only very small quantities of lipid (cf. J. Soc. Cosmet. Chem. 1983 (34) 127).

3.1.2. Implementation and evaluation

The experimental animals used were male Wistar rats with a body weight from 220 to 230 g at the start of the experiment.

To assess the efficacy, the test substances were used in the in Table 1 indicated concentrations of ethanol / acetone (1: 1) respectively 6 rats half-side painted on the back of the coat. The other Page was treated only with the solvent.

During the trial period of 14 days was a total of 9 days once applied. For further control served a group of 6 Rats treated on both sides only with the solvent. At the At the end of the experiment, the animals were shorn on the back and on the flanks and by a panel of appraisers (6 people) independently below Double blind visually patterned. The degree of browning was thereby  on the back of the rats as a measure of the Hautfettbelag assessed visually.

• A) As a selection test for the determination of effective compounds of the Difference between right and left side scored, with pro Judge and animal in each case 1 point was to be assigned, in the way that the darker side with 1 point, the brighter side with 0 points and if equal, both sides with 0.5 points were graded. Significant differences between only with the Solvent treated and treated with test solution side according to this evaluation method show the local effectiveness of a Substance on.
• B) For the quantitative estimation of the antiseborrheic effect, the intensity differences of the brown shades were evaluated according to the following scale:
  • 3 points: strong brown
  • 2 points: medium brown
  • 1 point: slightly brown
  • 0 points: no browning.

After this evaluation method, the point differences were between the only treated with the solvent control animals and in each case the treated and untreated sides (ΔP) of the experimental animals formed, in turn, significant differences between Control animals and the treated side of the experimental animals the effect make a substance clear.

The sebum reduction is calculated from the point difference in such a way that one forms the quotient of the point difference ΔP and the number of points for the control group P _k and indicates the value obtained in%.

3.2. Enzyme Inhibition Assay 3.2.1 Basis

About the biochemical mechanism of action of substances with sebostatic Effect is little known, apart from the hormones. 2-pyrrolidone 5-carboxylic acid hexadecyl ester should z. B. by influencing the surface tension exert a sebum regulating effect (See DE-OS 21 02 172 and DE-OS 21 02 173). A conceivable way of working sebostatic substances could be that they inhibit important pathways that lead to the formation of lipids. It is known from the literature that the enzyme activity of some enzymes of the Sebaceous gland, directly or indirectly involved in the synthesis of skin lipids are involved, compared to the epidermis increased to a multiple (See M.J.C. Inn, J.E. Hoopes, J. Invest. Derm. 1974 (62) 153 and Table 1).  

Table 1

The inhibitory effect of a test substance on the enzymes GDH, G6-PDH and GPT can therefore be used as a measure of the sebostatic efficacy of a Substance are considered.

3.2.2 Implementation and evaluation 3.2.2.1 Reagents

The following reagents were purchased from Boehringer / Mannhein, Germany: GDH, G6-PDH, GPT, tris (hydroxymethyl) aminomethane, triethanolamine hydrochloride, Dihydroxyacetone phosphate dimethylketal, β-nicotonamidadenine dinucleotide (NADH), β-nicotinamide adenine dinucleotide phosphate (NADP).

The ion exchanger used was: DOWEX 50 WX8, from Serva / Heidelberg

3.2.2.2 GPT test

a) Buffer: 3.03 g of TRIS- (hydroxymethyl) -aminomethane were dissolved in about 400 ml dissolved bidistilled water and the pH with NaOH or HCl adjusted to 7.6. It was then diluted to 500 ml with water filled in (TRIS buffer, 50 mmol, pH 7.6).

b) Substrate: As substrate, ready-mixed reagents from Electro Nucleonics / Stuttgart used; the concentrations of the substrates in the solutions amounted to:

100 mmol / l phosphate buffer (pH 7.4)
1 mmol / L L-alanine
1.5 units / ml lactate dehydrogenase
0.23 mmol / l NADH
450 mmol / l oxyglutarate

After mixing, portions were added to 1.58 ml in test tubes Pipette and incubate in the refrigerator at 4 ° C until incubation stored.

c) Enzyme: 20 μl of GPT suspension were diluted to 50 ml with TRIS buffer diluted and this enzyme dilution in portions to 990 .mu.l in Test tubes pipetted. The enzyme dilution was until incubation stored at 4 ° C in the refrigerator.

d) Incubation: For incubation, 6 test tubes with enzyme dilution prepared as follows:

Glass 1: addition of 10 μl of substance buffer (blank)
Glass 2-5: addition of 10 μl sample solution (test substance)
Glass 6: addition of 10 μl of substance buffer (blank)

The test tubes were well mixed on a shaker and in a water bath at 37 ° C for 30 minutes. 5 minutes before At the end of the incubation, 6 glasses of substrate batch were obtained Tempered at 37 ° C. After incubation, each enzyme mix was mixed and 100 .mu.l pipetted to the substrate batch, mixed and transferred to 1.5 ml disposable cuvettes.

e) Measurement: The measurement of the extinctions was carried out using a spectrophotometer DU 64 from Beckmann with integrated 6-fold sample changer at a temperature of 37 ° C. and a wavelength of 340 nm. The decrease of the enzyme activity results from the measured extinction values of the samples with test substance (E _test ) compared to the blank sample (E _blind ) by _forming the quotient of ΔE = E _test -E _blind and E _blind and indicating the obtained value in% ,

If the values for ΔE are too small, the enzyme suspension is diluted differently and the measurement is carried out again.

The extinction measurements were evaluated electronically by a microcomputer (Labtop T 3200 from Toshiba) via a serial Interface was connected to the photometer.

3.2.2.3 GDH test

a) Buffer: 4.65 g of triethanolamine hydrochloride were dissolved in 400 ml of double-distilled water Dissolved water and the pH by adding NaOH or HCl adjusted to 7.6. It was then watered up 500 ml (triethanolamine buffer, 50 mmol, pH 7.6).

b) Substrate: The dihydroxyacetone phosphate was prepared as dimethylketal had to be hydrolyzed before use. DOWEX Ion Exchange was double-distilled in a beaker Slurried water and the separated ion exchanger separated. 30 mg of the ketal were dissolved in 3 ml bidistilled water and after addition of 0.6 ml of ion exchanger, the mixture became Shaken for 1 minute. The pH was 2 and became optional adjusted by adding DOWEX. About a micro Glass filter suction was sucked off, and with bidistilled Rinsed with water. The filtrate was made up to 10 ml, and in reaction tubes in 1 ml portions for 6 hours at 37 ° C incubated. Subsequently, the solutions were added until use -60 ° C stored.

As substrate were

760 μl NADH solution (10 mg / ml) and
960 μl dihydroxyacetone phosphate solution (see above)

dissolved in 30 ml triethanolamine buffer. In test tubes were Portions of 1.58 ml pipetted and this until incubation in Refrigerator stored at 4 ° C.

c) Enzyme: 30 μl of GDH suspension was mixed with 100 ml of triethanolamine buffer diluted and this enzyme dilution in portions to 990 .mu.l in Test tubes pipetted. The enzyme dilution was until incubation stored at 4 ° C in the refrigerator.

d) Incubation: as in 3.2.2.2 d

e) Measurement: as in 3.2.2.2 e

3.2.2.4 G6-PDH test

a) Buffer: 3.45 g of sodium dihydrogen phosphate were dissolved in about 400 ml dissolved bidistilled water and the pH with NaOH or HCl set to 7.6. It was then diluted to 500 ml with water filled in (phosphate buffer, 50 mmol, pH 7.6).

b) Substrate: As substrate

34.5 mg of glucose-6-phosphate
34.5 mg NAOP and
140.2 mg MgCl₂ · 6 H₂O

dissolved in 100 ml triethanolamine buffer. Become in test tubes Portions of 1.58 ml pipetted and this until incubation in Refrigerator stored at 4 ° C.

c) Enzyme: 24 μl G6-PDH suspension was diluted to 100 ml with phosphate buffer diluted and this enzyme dilution in portions to 990 .mu.l in Test tubes pipetted. The enzyme dilution was until incubation stored at 4 ° C in the refrigerator.

d) Incubation: as in 3.2.2.2 d

e) Measurement: as in 3.2.2.2 e

3.3 Results:

The measurement results for the substances (1) to (14) with respect to rat test and enzyme inhibition test are shown in Tables 2 and 3.  

Table 2

Table 3

4. Preparations according to the invention 4.1 Shampoo for greasy hair Texapon®N 25 (4-1) 40.0% by weight Comperlan®KD (4-2) 3.0% by weight Product according to Example 2-7 0.5% by weight Bronidox®L (4-3) 0.2% by weight Water, ad 100% by weight

4.2 Fast Hair Cure Emulsion cetyl alcohol 3.0% by weight Dehyquart®A (4-4) 2.0% by weight Product according to Example 2-9 0.5% by weight citric acid 1.0% by weight Water, ad 100% by weight

4.3 hair cure, clear Cetiol®HE (4-5) 20.0% by weight cetylpyridinium 5.0% by weight glycerin 5.0% by weight Product according to Example 2-2 0.6% by weight Isopropanol, ad 100% by weight

4.4 Hair tonic Cetiol®HE (4-5) 2.0% by weight birch extract 1.0% by weight Product according to Example 2-1 0.1% by weight isopropanol 30.0% by weight Water, ad 100% by weight

4.5 Skin emulsion O / W Cutina®MD (4-6) 7.0% by weight Eumulgin®B1 (4-7) 3.0% by weight Cetiol®SN (4-8) 10.0% by weight Myritol®318 (4-9) 10.0% by weight Product according to Example 2-9 0.2% by weight Water, ad 100% by weight

4.6 Skin cream O / W Cutina®MD (4-6) 17.0% by weight Eumulgin®B1 (4-7) 3.0% by weight Eutanol®G (4-10) 11.0% by weight Myritol®318 (4-9) 6.0% by weight Carrot oil CLR 3.0% by weight Product according to Example 2-1 0.1% by weight Water, ad 100% by weight

The trade names used in the recipe examples have the following Meaning:

(4-1) Texapon®N 25:
28% aqueous solution of alkyl (C₁₂-C₁₄) poly (2 EO) glycol ether sulfate Na salt (Henkel KGaA)

(4-2) Comperlan® KD:
Coconut fatty acid diethanolamide (Henkel KGaA)

(4-3) Bronidox®L:
5-Bromo-5-nitro-1,3-dioxane (10% solution in 1,2-propylene glycol) (Henkel KGaA)

(4-4) Dehyquart®A:
Cetyltrimethylammonium chloride (25% solution in water) (Henkel KGaA)

(4-5) Cetiol® HE:
Polyol fatty acid ester (CTFA name: PEG-7-glyceryl-cocoate) (Henkel KGaA)

(4-6) Cutina® MD:
Palmitin / stearic acid mono / diglyceride (Henkel KGaA)

(4-7) Eumulgin® B1:
Cetyl / stearyl alcohol + 12 moles of ethylene oxide (Henkel KGaA)

(4-8) Cetiol®SN:
Cetyl / stearyl isononanoate (Henkel KGaA)

(4-9) Myritol®318:
Caprylic / capric acid triglyceride (Henkel KGaA)

(4-10) Eutanol®G:
2-octyldodecanol) Henkel KGaA)

Claims (3)

1. Use of dicarboxylic acid monoesters of the general formula I. where:

• - One of R¹ or R² is a hydrogen atom and the other
  • a) a linear or branched, saturated or mono- or polyunsaturated, optionally substituted by an aryl, alkaryl or cycloalkyl radical alkyl radical having a maximum of 20 carbon atoms or
  • b) a mono-, bi- or tri-unsaturated radical optionally substituted by a cycloalkyl, aryl or a linear or branched, saturated or mono- or polyunsaturated alkyl radical having a total of not more than 20 C atoms,
• - X is an alkylene group having 1-12 C atoms or a group - (CH₂) _n - (O) _m -C₆H₄-, where n is a number from 1 to 5 and m is the number 0 or 1, or a group -CH = CH-

as antiseborrheic agents for the preparation of topical, pharmaceutical and cosmetic preparations having sebosuppressive activity, z. B. for the treatment of skin disorders such as acne, psoriasis and dandruff. 2. Antiseborrhoeic preparations for topical application on the hair or on the skin, consisting of antiseborrheic agents in one dermatologically acceptable cosmetic or pharmaceutical Support, characterized in that as antiseborrheic active ingredient at least one compound of general formula I according to claim 1 in in an amount of 0.005 to 1.0 wt .-% based on the total preparation is included.