EP0969790A2

EP0969790A2 - Compositions for treating acne rosacea

Info

Publication number: EP0969790A2
Application number: EP98913571A
Authority: EP
Inventors: Walter Diembeck; Udo Hoppe; Birgit Salzer; Gerhard Sauermann; Volker Steinkraus
Original assignee: Beiersdorf AG
Current assignee: Beiersdorf AG
Priority date: 1997-02-21
Filing date: 1998-02-20
Publication date: 2000-01-12
Also published as: WO1998036730A3; JP2001512471A; WO1998036730A2

Abstract

The invention concerns the use, in particular the topical use, of one or several compounds selected from the group of the NO-synthase inhibitors and their derivatives for the prevention and/or treatment of rosacea and acne rosacea.

Description

description

Preparations for the treatment of rosacea

The invention relates to topical cosmetic or dermatological preparations which are suitable for the treatment of rosacea. Rosacea also includes the manifestations of cuperose.

Rosacea is an inflammatory disease, preferably of the face, which is accompanied by pronounced erythema, papules and pustules of varying duration. Telangiectasias and elastosis are common, and intrafollicular accumulation of neutrophils can also be observed. Rosacea patients have exceptionally sensitive skin to chemical toxins and physical stress factors (UV light). The pathogenesis is unclear.

Rosacea is not curable, but can be treated with antibiotics, isotretinoin, fungal agents such as metronidazole or beta blockers.

In contrast to many skin diseases that are associated with massive influx of leukocytes, the leukocyte infiltrate near the blood vessels and sebaceous glands is moderate. It has also been questioned in the literature as to whether this could be difficult to back out ^'of rosacea patients erythema to be treated with nitric oxide synthase inhibitors (Qureshi, AA et al; Arch Dermatol Vol 132, August 1996... 889-893). However, no answer was given.

It is only in the advanced state of rosacea that apart from the differently developed erythema, there are also telangiectasias, papules, pustules and growths such as the rhinophyma. These phenomena are treated surgically.

Overall, the success of the pharmacological treatment of rosacea is unsatisfactory.

The object of the invention was therefore to remedy this and in particular to provide active substances and preparations with which rosacea, in particular the early forms of this disease, can be treated safely and free of side effects.

These tasks are solved according to the invention.

The invention relates to the use, in particular topical use, of one or more compounds selected from the group of NO synthase inhibitors and their derivatives for the prophylaxis and / or treatment of rosacea and cuperose.

The invention also relates to the use of cosmetic or dermatological topical preparations containing one or more compounds selected from the group of NO synthase inhibitors and their derivatives for the prophylaxis and / or treatment of rosacea and cuperose. The invention furthermore relates to cosmetic or dermatological topical preparations containing one or more compounds selected from the group of NO synthase inhibitors and their derivatives.

Suitable NO synthase inhibitors are, for example, 2-iminobiotin,

LN ⁵ - (1-aminoethyl) -ornithine (L-NOK),

S-methylisothiourea

S-methylisothiourea sulfate (SMT),

S-methyl-L-thiocitrulline,

LN ^G - (1-aminoethyl) lysine (L-NIL),

7-nitroindazole (7-Ni),

S, S'-1,3-phenylene-bis- (1,2-ethane-di-yl) bis-isothiourea (PBITU)

L-thiocitruliin (2-thioureido-L-norvaline) and their derivatives and in particular the arginine derivatives.

NO synthase inhibitors which contain a guanidine group are preferred.

Suitable derivatives are, for example, the compounds of the invention monoalkylated or dialkylated on the imino groups or amino groups.

In each case, the alkyl radicals of the monoalkyl groups or dialkyl groups can have 1 to 10, preferably 1 to 6, but in particular 1, 2 or 3, carbon atoms and can be straight-chain or branched.

Derivatives, especially arginine, whose amino groups are fully or partially acylated are also very suitable. These are in particular the amino groups of the amino acid residue and in particular the amino groups bound to the alpha-C atom. The are preferred mono-acyl compounds of the active ingredient according to the invention, in particular an arginine derivative.

The preferred acyl radical is alkylcarbonyl, which is used in acylations with carboxylic acids or their derivatives, e.g. Acid chlorides or anhydrides is obtained. The acyl radical or alkylcarbonyl radical can have 2-12, in particular 2-6, carbon atoms and is particularly preferably acetyl.

The compound alpha-N-acetyl-N -nitro-L-arginine-methyl ester (alpha-N-acetyl-

L-NAME), in which the amino group of the alpha-C atom of the amino acid function is mono-acetylated, is particularly preferred.

With good effectiveness, the acyl derivatives are notable for their storage stability and their stability in the preparations.

Suitable derivatives of the compounds according to the invention are in particular the salts and acid addition salts. Esters of carboxylic acid groups of the compounds according to the invention with alcohols are also preferred.

Preferred salts are water soluble salts, e.g. Sodium, potassium and ammonium salts. This also applies to the acid addition salts. Suitable acid addition salts are e.g. obtained with inorganic and organic acids. The hydrochlorides, phosphates, sulfates, acetates, caprylates, citrates, lactates, malates or tartrates are preferred.

Suitable esters are, for example, those which are formed with short-chain or medium-chain alcohols, preferably with mono-alcohols. They can be straight-chain or branched and have, for example, 1 to 12, preferably 1 to 6, carbon atoms. Methanol, ethanol, n-propanol and iso-propanol are preferred. The esters are particularly preferred derivatives. They are also characterized by better penetration.

The compounds according to the invention are known per se, are commercially available or can be obtained by known processes. Their action as NO synthase inhibitors is described in the literature. The acylated compounds can be obtained by the known acylation process.

NO synthase inhibitors according to the invention which contain an arginine residue and their derivatives, in particular as described below, are particularly preferred.

The invention therefore relates in particular to the use, in particular topical use, of one or more compounds

Compounds selected from the group of N -monoalkyl-L-arginine, N,

N -dialkyl-L-arginine, N, N -dialkyl-L-arginine and N -nitro-L-arginine and their derivatives for the prophylaxis and / or treatment of rosacea and cuperose.

The invention also relates in particular to the use of cosmetic or dermatological topical preparations containing one or more compounds selected from the

Group of N -monoalkyl-L-arginine, N, N -dialkyl-L-arginine,

C C

N, N -dialkyl-L-arginine and N -nitro-L-arginine and their derivatives for the prophylaxis and / or treatment of rosacea and cuperose.

The invention furthermore relates to cosmetic or dermatological topical preparations containing one or more compounds C c ^*

Compounds selected from the group of N -monoalkyl-L-arginine, N, c c c c

N -dialkyl-L-arginine, N, N -dialkyl-L-arginine and N -nitro-L-arginine and their derivatives.

Suitable derivatives of the compounds according to the invention are in particular the salts and acid addition salts. Esters of the carboxylic acid group of arginine with alcohols are also particularly preferred.

Suitable esters are e.g. those formed with short-chain or medium-chain alcohols, preferably with mono-alcohols. They can be straight or branched and e.g. 1 to 12, preferably 1 to 6 carbon atoms. Methanol, ethanol, n-propanol and iso-propanol are preferred.

The esters are particularly preferred derivatives. They are also characterized by better penetration.

These compounds according to the invention are also known, commercially available or can be obtained by known processes. Their action as NO synthase inhibitors is described in the literature. The following compounds are preferred: N -monomethyl-L-arginine,

N -monoethyl-L-arginine, f ~.

N -nitro-L-arginine,

N -nitro-L-arginine methyl ester,

N -nitro-L-arginine ethyl ester,

N -monomethyl-L-arginine-methyl ester, N -monoethyl-L-arginine-methyl ester, N -monomethyl-L-arginine-ethyl ester

N -monoethyl-L-arginine ethyl ester and c c N, N -dimethyl-L-arginine,

N, N -dimethyl-arginine

N, N -dimethyl-L-arginine dihydrochloride,

N, N -dimethyl-L-arginine dihydrochloride

The following compounds are particularly preferred:

N -monomethyl-L-arginine monoacetate (L-NMMA), N -monoethyl-L-arginine monoacetate (L-MEA),

N -nitro-L-arginine (L-NNA) and

N -Nitro-L-arginine methyl ester hydrochloride (L-NAME).

N -Nitro-L-arginine methyl ester or L-NAME is very particularly preferred.

The dermatological and cosmetic topical preparations according to the invention can contain, as active ingredient, one or more NO synthase inhibitors, for example one, two or three compounds. If preparations contain two or more of the active compounds according to the invention, those preparations are particularly preferred which contain at least one NO synthase inhibitor with an arginine residue, in particular one of the above-mentioned active compounds with an arginine residue.

Active ingredient combinations and preparations containing L-NAME and / or L-NMMA are particularly preferred.

The active ingredients containing an arginine residue can be used in the combinations e.g. in amounts of 10-90% by weight, in particular 30-70% by weight, based in each case on the total weight of the active ingredients.

The compounds according to the invention and the dermatological and cosmetic topical preparations therewith are outstandingly suitable for the treatment and prophylactic treatment of cuprose and rosacea, in particular stages I or II.

Surprisingly, the active substances and preparations according to the invention have a long-lasting, continuous action during use. Even after the end of treatment, the skin remains symptom-free or significantly improved for a long time, such as several weeks.

The cosmetic or dermatological topical preparations according to the invention can be based on conventional formulation bases and can be used to treat the skin in the sense of a dermatological treatment or a treatment in the sense of cosmetics.

The use, in particular topical, of the NO synthase inhibitors according to the invention surprisingly leads to a reduction in the cutaneous blood flow and thus the erythema. The resulting increased infiltration of leukocytes and other immune cells leads to better healing of the inflamed tissue.

This will solve the tasks.

The active compounds according to the invention and / or their derivatives are preferably in amounts of 0.001 to 20% by weight, particularly preferably 0.01 to 10% by weight, but in particular 0.1 to 5% by weight, in each case based on the total Preparation, contained in the topical cosmetic and dermatological preparations according to the invention.

The symptoms of rosacea, in particular erythema, are surprisingly alleviated or avoided.

Particularly advantageous preparations are also obtained if the active compounds according to the invention are combined with antioxidants.

The antioxidants according to the invention can advantageously be selected from the group of customary cosmetic and dermatological antioxidants, in particular from the group consisting of tocopherols and their derivatives, in particular tocopherol or α-tocopheryl esters, in particular α-tocopheryl acetate, furthermore sesamol, bile acid derivatives such as methyl, Ethyl, propyl, amyl, butyl and lauryl gallate, the konyferyl benzoate of benzoic resin, nordihydroguajakarzarzäure, nordihydroguajaretic acid, butylhydroxy-anisole, butylhydroxytoluene, ascorbic acid, citric acid, phosphoric acid, lecithin, tri-hydroxynate, trihydonroxybenxin, trihydonroxy in particular retinyl palmitate, ascorbic acid, ascorbyl palmitate, dilauryl thiodipropionate, distearyl thiodipropionate, monoisopropyl citrate, thiodipropionic acid, EDTA as well as EDTA derivatives, cysteine, glutathione and ester, uric acid, lipoic acid and esters, carotenes and heavy metal complexing acid acid and desferral (Ciba-Geigy) and

Flavonoids, e.g. 4-alpha-glucopyranosyl-rutin.

The cosmetic or dermatological preparations according to the invention preferably contain 0.01 to 10% by weight, but in particular 0.1 to 6% by weight, based on the total weight of the preparations, on one or more substances from the group of antioxidants.

It is preferred to choose the antioxidants according to the invention from the group of flavonoids or tocopherols and their derivatives.

For use, the preparations are applied to the skin in a sufficient amount once or more times a day in the manner customary for cosmetics or dermatics.

Skin care preparations and sun protection preparations are particularly preferred.

Dermatological and cosmetic preparations according to the invention can be in various forms. For example, aqueous, alcoholic or aqueous-alcoholic solutions, oil-in-water (O / W) type emulsions, water-in-oil (W / O) type emulsions, multiple emulsions e.g. of the type water-in-oil-in-water (W / O / W), gels, hydrodispersions, solid sticks or aerosols the above Combinations of active ingredients included. Low-water or water-free ointments and preparations are also preferred.

The topical preparations according to the invention can contain the customary auxiliaries such as emulsifiers and preservatives.

Those cosmetic and dermatological preparations which are in the form of a sunscreen are also preferred. These advantageously additionally contain at least one UVA filter and / or at least one UVB filter and / or at least one inorganic pigment. Preparations with one or more UVA filters are particularly preferred. UVA filters with strong absorption at 340 nm are particularly preferred.

However, those preparations which are applied to the skin after exposure to light, ie apres-soleil products, are also advantageous. In the case of such preparations, it is at the discretion of the person skilled in the art whether additional UV filter substances should be used or not. Cosmetic preparations according to the invention for protecting the skin from UV rays can be in various forms, such as are usually used for this type of preparation. For example, they can be an aqueous, alcoholic or aqueous alcoholic solution, an emulsion of the water-in-oil (W / O) or oil-in-water (O / W) type, or multiple emulsions, for example of the water type in oil-in-water (w / o / w), a gel, a hydrodispersion, an oil, a solid stick or an aerosol.

The topical preparations according to the invention can contain dermatological and cosmetic auxiliaries as are usually used in such preparations, e.g. Preservatives, bactericides, perfumes, anti-foaming agents, dyes, pigments that have a coloring effect, thickeners, surface-active substances, emulsifiers, softening substances, moisturizing and / or moisturizing substances, fats, oils, waxes or other conventional components of a cosmetic Formulation such as alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents or silicone derivatives.

If the cosmetic or dermatological preparation is a solution or lotion, the following can be used as solvents:

Water or aqueous solutions;

Oils, such as triglycerides of capric or caprylic acid, but preferably castor oil;

Fats, waxes and other natural and synthetic fat bodies, preferably esters of fatty acids with alcohols of low C number, e.g. with isopropanol, propylene glycol or glycerin, or esters of fatty alcohols with low C number alkanoic acids or with fatty acids;

Alcohols, diols or polyols of low C number, and their ethers, preferably ethanol, isopropanol, propylene glycol, glycerin, ethylene glycol, ethylene glycol monoethyl or monobutyl ether, propylene glycol monomethyl, monoethyl or monobutyl ether, Diethylene glycol monomethyl or monoethyl ether and analog products.

Mixtures of the abovementioned solvents are used in particular. Water can also be a component of alcoholic solvents.

Oils or emulsions according to the invention e.g. in the form of a sunscreen cream, a sunscreen lotion or a sunscreen milk are advantageous and contain e.g. the fats, oils, waxes and other fat bodies mentioned, as well as water and an emulsifier, as is usually used for such a type of formulation.

Cosmetic and dermatological preparations for the treatment and care of the skin can be in the form of gels which, in addition to the active ingredients and the solvents usually used for them, also contain organic thickeners, e.g. Gum arabic, xanthan gum, sodium alginate, cellulose derivatives, preferably methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or inorganic thickeners, e.g. B. aluminum silicates such as bentonite, or a mixture of polyethylene glycol and polyethylene glycol stearate or distearate. The thickener is in the gel e.g. in an amount between 0.1 and 30% by weight, preferably between 0.5 and 15% by weight.

Gels according to the invention usually contain low C number alcohols, e.g. Ethanol, isopropanol, 1, 2-propanediol, glycerol and water or an oil mentioned above in the presence of a thickener which is preferably silicon dioxide or an aluminum silicate in the case of oleo-alcoholic gels, and is preferably a polyacrylate in the case of aqueous-alcoholic or alcoholic gels.

Hydrodispersions are dispersions of a liquid, semi-solid or solid inner (discontinuous) lipid phase in an outer aqueous (continuous) phase. In contrast to O / W emulsions, which are characterized by a similar phase arrangement, hydrodispersions are essentially free of emulsifiers. Hydrodispersions, like the rest of emulsions, are metastable systems and tend to transition into a state of two interrelated discrete phases. In emulsions, the choice of a suitable emulsifier prevents phase separation.

In the case of hydrodispersions of a liquid lipid phase in an outer aqueous phase, the stability of such a system can be ensured, for example, by building a gel structure in the aqueous phase in which the lipid droplets are stably suspended.

Fixed pins according to the invention can e.g. contain natural or synthetic waxes, fatty alcohols or fatty acid esters. Lip care sticks are preferred.

Suitable blowing agents for cosmetic or dermatological preparations according to the invention which can be sprayed from aerosol containers are the customary known volatile, liquefied blowing agents, for example hydrocarbons (propane, butane, isobutane), which can be used alone or in a mixture with one another. Compressed air can also be used advantageously.

Of course, the person skilled in the art knows that there are non-toxic propellant gases per se which would in principle be suitable for the present invention, but which should nevertheless be dispensed with, in particular fluorocarbons and chlorofluorocarbons (CFCs), because of their harmful effects on the environment or other associated circumstances.

The preparations according to the invention can preferably also contain substances which absorb UV radiation in the UVB range, the total amount of the filter substances being, for example, 0.1% by weight to 30% by weight, preferably 0.5 to 10% by weight, is in particular 1 to 6% by weight, based on the total weight of the preparation, in order to provide preparations which protect the skin from the entire range of ultraviolet radiation. They can also serve as sunscreens. The UVB filters can be oil-soluble or water-soluble. Examples of oil-soluble substances are:

- 3-benzylidene camphor derivatives, preferably 3- (4-methylbenzylidene) camphor, 3-benzylidene camphor;

- 4-aminobenzoic acid derivatives, preferably 4- (dimethylamino) benzoic acid (2-ethylhexyl) ester, 4- (dimethylamino) benzoic acid amyl ester;

Esters of cinnamic acid, preferably 4-methoxycinnamic acid (2-ethylhexyl) ester, 4-methoxycinnamic acid isopentyl ester;

Esters of salicylic acid, preferably salicylic acid (2-ethylhexyl) ester, salicylic acid (4-isopropylbenzyl) ester, salicylic acid homomethyl ester;

- Derivatives of benzophenone, preferably 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4'-methylbenzophenone, 2,2'-dihydroxy-4-methoxybenzophenone;

- Esters of benzalmalonic acid, preferably 4-methoxybenzalmalonic acid di (2-ethylhexyl) ester;

- 2,4,6-trianiiino- (p-carbo-2'-ethyl-1'-hexyloxy) -1, 3,5-triazine.

As water-soluble substances e.g. to call:

- Salts of 2-phenylbenzimidazole-5-sulfonic acid such as its sodium, potassium or triethanolammonium salt, and the sulfonic acid itself;

- Sulfonic acid derivatives of benzophenones, preferably 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid and its salts;

- Sulfonic acid derivatives of 3-benzylidene camphor, e.g. 4- (2-oxo-3-bomylidene methyl) benzenesulfonic acid, 2-methyl-5- (2-oxo-3-bomylidene methyl) sulfonic acid and their salts.

The invention also relates to the combination of active ingredients according to the invention with one or more UVA and / or UVB filters or cosmetic or dermatological preparations according to the invention which also contain one or more UVA and / or UVB filters.

It can also be particularly advantageous to combine the active ingredients with UVA filters, which are also usually contained in cosmetic and / or dermatological preparations. These substances are preferably derivatives of dibenzoylmethane, in particular 1- (4'-tert-butylphenyl) -3- (4'-methoxyphenyl) propane-1, 3-dione and 1-phenyl-3- (4 '-isopropylphenyl) propane-1,3-dione. These combinations or preparations containing these combinations are also the subject of the invention. The quantities specified for the UVB combination can be used.

Advantageous preparations are also obtained if the active compounds according to the invention are combined with UVA and UVB filters.

Combinations of the active compounds according to the invention with one or more antioxidants and one or more UVA filters and / or one or more UVB filters are also particularly advantageous according to the invention.

The cosmetic or dermatological preparations can also contain inorganic pigments, which are usually used in cosmetics to protect the skin from UV rays. These are oxides of titanium, zinc, iron, zirconium, silicon, manganese, aluminum, cerium and mixtures thereof, as well as modifications in which the oxides are the active agents. It is particularly preferred to use pigments based on titanium dioxide. The invention also relates to the process for the preparation of the topical preparations according to the invention, which is characterized in that the active ingredients are incorporated into cosmetic or dermatological formulations in a manner known per se.

Unless otherwise stated, all quantities, parts and percentages are based on the weight and the total amount or on the total weight of the preparations.

The following examples are intended to illustrate the present invention without restricting it.

The following compounds are used in the examples: rs

N -monomethyl-L-arginine monoacetate (L-NMMA),

N -monoethyl-L-arginine monoacetate (L-MEA),

N ^G nitro-L-arginine (L-NNA),

N -Nitro-L-arginine methyl ester hydrochloride (L-NAME).

example 1

Sun angel (transparent)

% By weight

L-NAME 1

Benzophenone-4 0.5

Phenylbenzimidazole sulfonic acid 1, 3

Acrylamide / sodium acrylate copolymer 1, 6

Ethanol 5.0

Glycerin 15.0

NaOH (15%) q.s.

Perfume, preservative q.s.

Water, VES (fully desalinated) ad 100.0

Example 2

Hydrodispersion

% By weight

L-NMMA 5.0

Phenyltrimethicone 1.0

Carbomer (Carbopol 981) 1.0

Hydroxypropyl methyl cellulose 0.2

Butylene glycol 3.0

Tromethamine q.s.

EDTA solution (14%) 0.5

Ethanol 5.0

Perfume, preservative q.s.

Water, VES ad 100.0 Example 3

Sun milk O / W

% By weight

L-MEA 2.5

Urea 5.0

Octyl methoxycinnamate 5.0

Butyl methoxydibenzoyl methane 1.0

Cetearyl alcohol + PEG-40 castor oil

+ Sodium cetearyl sulfate 2.5

Glyceryl alcoholate 1.0

Laurylmethicone copolyol 0.5

Mineral oil (DAB 9) 5.0

Caprylic / capric triglycerides 5.0

Acrylamide / sodium acrylate copolymer 0.3

Cyclomethicone 2.0

TiO ₂ 1.0

Glycerin 3.0

EDTA solution (14%) 0.5

Ethanol 5.0

Perfume, preservative q.s.

Water, VES ad 100.0

Example 4

Care lotion W / O

% By weight

L-NNA, HCI 2.5

Cyclomethicone 3.0

PEG-1 glycerol sorbitan oleostearate 1,7

PEG-7 hydrogenated castor oil 6.3

Mineral oil (DAB 9) 13.0

Caprylic / capric triglycerides 13.0

Glycerin 4.0

MgSO ₄ 0.7 Perfume, preservative qs

Water, VES ad 100.0

Example 5

Nourishing face cream O / W

% By weight

L-NMMA 2.5

PEG-5 glyceryl stearate 2.00

Glyceryl stearate 3.00

Cyclomethicone 3.00

Caprylic / capric triglycerides 3.00

Cetyl alcohol 3.00

Ethanol 1.00

Hyaluronic acid 0.05

Tocopheryl acetate 0.50

Glycerin 4.00

Perfume, preservative q.s. Water, VES ad 100.00

Example 6

W / O cream

% By weight

L-NMMA 2.5

PEG-22 dodecyl glycol copolymer 3.0

Cetyl Dimethicone Copolyol 2.0

Cyclomethicone 4.0

Mineral oil (DAB 9) 4.0

Caprylic / capric triglycerides 4.0

Glycerin 4.00

Perfume, preservative qs water, VES ad 100.00 Example 7

After sun lotion

% By weight

L-NAME 5.0

Cetearyl alcohol + PEG-40 castor oil

+ Sodium cetearyl sulfate 2.50

Glyceryl stearate SE 0.60

Mineral oil (DAB 9) 4.00

Caprylic / capric triglycerides 2.00

Ski butter 2.00

Avocado oil 2.00

Tocopheryl acetate 3.00

Acrylamide / sodium acrylate copolymer 0.30

Glycerin 4.00

Hyaluronic acid 0.05

Bisabolol 0.05

Perfume, preservative q.s.

Water, VES ad 100.00

Example 8

Shower milk

% By weight

L-MEA 5.0

Sodium Laureth Sulfate 11

Cocamidopropyl betaine 5

Cocamide DEA 1 PEG-8 1

Soybean Oil 1

Citric acid 0.1

Sodium chloride 0.2

Fragrance 0.1 water, demin. ad 100.00 Example 9

Care stick

% By weight

1,2-propylene glycol 11,0

Oleyl alcohol 14.0

Eosin dyes 3.0 stearamide MEA

(Rewomid S 280) 10.0

Beeswax 10.0

Glycerol monostearate 10.0

Cetyl alcohol 10.0

Ceresin 8.0 stearyl heptanoate

(CL-solid) 6.0

Lanolin anhydr. 6.0

Pigments and color varnishes 6.0

Perfume oil 1, 0

L-NAME 5.0

Example 10

pen

% By weight

Castor Oil (and) Glyceryl Ricinoleate (and)

Octyldodecanol (and) carnauba (and)

Candelilla Wax (and) Microcrystalline (and)

Cetyl Alcohol (and) Beeswax (and) Mineral Oil

Cutina LM (Henkel) 65

Caprylic / Capric triglycerides

(Myristol 318) 20

Pigment colors 3.0

Titanium dioxide 7.0

L-NMMA 4.0

L-NOK 1, 0 Example 11

pen

% By weight

Castor Oil (and) Glyceryl Ricinoleate 78.0

(and) octyldodecanol (and) carnauba

(and) Candelilla Wax (and) Microcrystalline Wax

(and) Cetyl Alcohol (and) Beeswax (and)

Mineral Oil

Cutina LM (Henkel)

Octyldodecalol 15.0

(Eutanol G)

Color pigments 2.0

L-NMMA 4.0

L-NIL 1.0

Example 12

Care lotion W / O

% By weight

2-iminobiotin 2.5

Cyclomethicone 3.0

PEG-1 glycerol sorbitan oleostearate 1,7

PEG-7 hydrogenated castor oil 6.3

Mineral oil (DAB 9) 13.0

Caprylic / capric triglycerides 13.0

Glycerin 4.0 MgSO ₄ 0.7

Perfume, preservative qs water, VES ad 100.0 Example 13

Care lotion W / O

% By weight

L-NOK-HCI 2.5

Cyclomethicone 3.0

PEG-1 glycerol sorbitan oleostearate 1.7

PEG-7 hydrogenated castor oil 6.3

Mineral oil (DAB 9) 13.0

Caprylic / capric triglycerides 13.0

Glycerin 4.0 MgSO ₄ 0.7

Perfume, preservative q.s.

Water, VES ad 100.0

Example 14

Care lotion W / O

% By weight

S-methylisothiourea sulfate 2.5

Cyclomethicone 3.0

PEG-1 glycerol sorbitan oleostearate 1,7

PEG-7 hydrogenated castor oil 6.3

Mineral oil (DAB 9) 13.0

Caprylic / capric triglycerides 13.0

Glycerin 4.0 MgSO ₄ 0.7

Perfume, preservative q.s.

Water, VES ad 100.0 Example 15

Care lotion W / O

% By weight

S-methyl-L-thiocitrulline-2HCI 2.5

Cyclomethicone 3.0

PEG-1 glycerol sorbitan oleostearate 1,7

PEG-7 hydrogenated castor oil 6.3

Mineral oil (DAB 9) 13.0

Caprylic / capric triglycerides 13.0

Glycerin 4.0 MgSO ₄ 0.7

Perfume, preservative q.s.

Water, VES ad 100.0

Example 16

Care lotion W / O

% By weight

L-NIL-2HCI 2.5

Cyclomethicone 3.0

PEG-1 glycerol sorbitan oleostearate 1,7

PEG-7 hydrogenated castor oil 6.3

Mineral oil (DAB 9) 13.0

Caprylic / capric triglycerides 13.0

Glycerin 4.0 MgSO ₄ 0.7

Perfume, preservative q.s.

Water, VES ad 100.0 Example 17

Care lotion W / O

% By weight

7-nitroindazole 2.5

Cyclomethicone 3.0

PEG-1 glycerol sorbitan oleostearate 1.7

PEG-7 hydrogenated castor oil 6.3

Mineral oil (DAB 9) 13.0

Caprylic / capric triglycerides 13.0

Glycerin 4.0 MgSO ₄ 0.7

Perfume, preservative q.s.

Water, VES ad 100.0

Example 18

Care lotion W / O

% By weight

PBITU-2HBr 2.5

Cyclomethicone 3.0

PEG-1 glycerol sorbitan oleostearate 1,7

PEG-7 hydrogenated castor oil 6.3

Mineral oil (DAB 9) 13.0

Caprylic / capric triglycerides 13.0

Glycerin 4.0 MgSO ₄ 0.7

Perfume, preservative q.s.

Water, VES ad 100.0 Example 19

Care lotion W / O

% By weight

L-thiocitrulline-2HCI 2.5

Cyclomethicone 3.0

PEG-1 glycerol sorbitan oleostearate 1,7

PEG-7 hydrogenated castor oil 6.3

Mineral oil (DAB 9) 13.0

Caprylic / capric triglycerides 13.0

Glycerin 4.0

MgSO ₄ 0.7

Perfume, preservative q.s.

Water, VES ad 100.0

Example 20

Sun angel (transparent)

% By weight

Alpha-N-Acetyl-L name

(with monoacetylated amino group of the alpha-C atom of L-Name) 1

Benzophenone-4 0.5

Phenylbenzimidazole sulfonic acid 1, 3

Acrylamide / sodium acrylate copolymer 1.6

Ethanol 5.0

Glycerin 15.0

NaOH (15%) q.s.

Perfume, preservative q.s.

Water, VES (fully desalinated) ad 100.0 Example 21

Preparation of alpha-N-acetyl-L-NAME (according to Example 20)

1 equivalent of L-NAME hydrochloride is dissolved under nitrogen in methanol / Na-methanolate (1 equivalent, 8 ml of methanol / mmol) and stirred with 1.5 equivalents of acetic anhydride for 2 hours. It is then worked up, as usual, in water and mixed with saturated NaCl solution and extracted with ethyl acetate and dried with Mg sulfate. After stripping off the solvent, pure alpha-N-acetyl-L-NAME is obtained, yield 71%.

H-NMR spectrum: 1, 60, multiple, 4 H; 1, 90, singlet, 3 H; 3.15, triplet, 2 H; 3.60, singlet, 3 H of the Acetyl-Me group; 4.35, triplet, 1 H.

Become analog

G alpha-N-acetyl-N-monomethyl-L-arginine monoacetate (alpha-N-acetyl-L-NMMA)

G alpha-N-acetyl-N-monoethyl-L-arginine monoacetate (alpha-N-acetyl-L-MEA),

G alpha-N-acetyl-N -nitro-L-arginine (alpha-N-acetyl-L-NNA),

G obtained alpha-N-acetyl-N -nitro-L-arginine methyl ester (alpha-N-acetyl-L-NAME).

The N-acyl compounds according to the invention of the NO synthase inhibitors which optionally carry one or more amino groups or a guanidine group are new, in particular the acetyl compounds e.g. the mono-acetyl compounds, especially those acyl compounds or acetyl compounds of amino groups or alpha-C-amino groups of amino acids. Further preferred acyl radicals are aromatically substituted carbonyl, for example benzoyl.

Acyl compounds according to the invention are obtained by the customary acylation processes, for example by reaction with acid halides or acid anhydrides, if appropriate with the addition of solvents and bases, for example triethylamine or Alcoholates. For the mono-acyl compounds, equivalent amounts of NO synthase inhibitors and acylating agents are preferred. For multiple acylated compounds

e.g. correspondingly higher equivalent quantities are used, e.g. if necessary, further amino groups and the guanidino group can be reacted.

Claims

claims

1. Use of one or more compounds selected from the group of NO synthase inhibitors and their derivatives for the prophylaxis and / or treatment of rosacea and cuperose.

2. Use of cosmetic or dermatological topical preparations containing one or more compounds selected from the group of NO synthase inhibitors and their derivatives for the prophylaxis and / or treatment of rosacea and cuperose.

3. Cosmetic or dermatological topical preparations containing one or more compounds selected from the group of NO synthase inhibitors and their derivatives.

4. Use according to claim 2, characterized in that the preparations contain at least one antioxidant.

5. Use according to claim 2, characterized in that the preparations contain at least one UVA filter and / or at least one UVB filter and / or at least one inorganic pigment.

6. Use according to claim 2, characterized in that the preparations contain at least one antioxidant and at least one UVA filter and / or at least one UVB filter and / or at least one inorganic pigment.

7. Use of one or more compounds according to claim 1, selected from the group of N -monoalkyl-L-arginine, N, N -

O C C

Dialkyl-L-arginine, N, N -dialkyl-L-arginine and N -nitro-L-arginine and their derivatives for the prophylaxis and / or treatment of rosacea and cuperose.

8. Use of cosmetic or dermatological topical preparations according to claim 2 containing a compound or several compounds selected from the group of N -monoalkyl-L-arginine, N, N -dialkyl-L-arginine, N, N -dialkyl-L-arginine and N -nitro-L-arginine and their derivatives for prophylaxis and / or treating rosacea and cuperose.

9. Cosmetic or dermatological topical preparations according to claim 3 containing a compound _^ or more

Compounds selected from the group of N ^{^} -monoalkyl-L-arginine, N,

C C C "

10. Use or preparation according to claims 7-9, characterized in that N -nitro-L-arginine methyl ester or N -nitro-L-arginine methyl ester hydrochloride is used.

11. Use according to claim 8, characterized in that the preparations contain at least one antioxidant.

12. Use according to claim 8, characterized in that the preparations contain at least one UVA filter and / or at least one UVB filter and / or at least one inorganic pigment.

13. Use according to claim 8, characterized in that the preparations contain at least one antioxidant and at least one UVA filter and / or at least one UVB filter and / or at least one inorganic pigment.

14. Use of one or more compounds selected from the group of NO synthase inhibitors which contain an arginine residue and their derivatives for the prophylaxis and / or treatment of rosacea and cuperose.

15. Use of cosmetic or dermatological topical preparations containing one or more compounds selected from the group of NO synthase inhibitors which contain an arginine residue contain, and their derivatives for the prophylaxis and / or treatment of rosacea and cuperose.

16. Cosmetic or dermatological topical preparations containing one or more compounds selected from the group of NO synthase inhibitors containing an arginine residue and their derivatives.

17. NO synthase inhibitors with one or more acylated amino groups, in particular mono-acylated amino groups.