DE2817133C2 - - Google Patents

Description

The invention relates to agents for the treatment of hyperpigmentary Dermatoses or of skin hyperpigmentation with at least an active ingredient in a pharmaceutically acceptable Carrier.

Dermatoses, such as skin hyperpigmentation, are common disfiguring, as in the case of chloasma on the face, pose not only an aesthetic problem, but also a therapeutic problem. A basic solution this problem has not yet been identified. So far only have hydroquinone and its derivatives in vivo the treatment of skin hyperpigmentation a certain Effectiveness shown. However, they bring as a side effect the development of long-lasting hypopigmented zones with themselves that can sometimes no longer be eliminated.

The field of hyperpigmental dermatoses covers, however with much more serious points of view and consequences, certain pathological conditions that under the generic Term precancerous and cancerous dermatoses (e.g. premelanoma states and melanomas). There is currently no effective therapy for these dermatoses.

Biochemistry 1972, 11 (7), 1304 to 1306 describes the use of amino acids as substrates and sub-competitive inhibitors of bacterial glutamate decarboxylase. In Can. J. Microbiol. 1976, 22 (8), 1198 to 1201 it is described that α, ω- alkanedicarboxylic acids and their dimethyl esters have antifungal properties.

The object of the invention is to provide pharmaceuticals, which are useful for the above purposes. they especially the color of those suffering from hyperpigmentation Normalize skin and the appearance of certain shapes prevent precancerous and cancerous dermatoses and cause their regression.

According to the invention, it is possible to hyperpigmentary dermatoses to treat, taking a therapeutically effective amount of the drug mentioned.

The dicarboxylic acids used according to the invention are in particular selected from: pimelic acid, Suberic acid, azelaic acid, sebacic acid, 1,9-nonandicarboxylic acid, 1,10-decanedicarboxylic acid, 1,11-undecanedicarboxylic acid, and 1,12-dodecanedicarboxylic acid. To the The sodium salts belong to pharmaceutically acceptable salts.

In a preferred embodiment it is the dicarboxylic acid is azelaic acid or 1,12-dedecanedicarboxylic acid. The medicaments according to the invention can be administered orally, by subcutaneous Injection or topical application, for example in Forms of creams, ointments, pastes or lotions administered will.

It has been found that the medicament according to the invention is particularly capable of forming the main pigment To inhibit (melanin) by causing a reaction that The dopatyrosinase reaction proceeds according to a kind of competitive mechanism blocked. The exact mechanism of this Effect has not yet been elucidated. According to registration however, a mechanism has been identified that is compatible with that through the active component of the drug exercised mechanism matches or is related.

Although these observations help to better understand the Invention brought, they must not be considered definitive Explanation of the mechanism in progress nor are they intended in any way to be within the scope of the present Limit invention.

When investigating the behavior of a fungus pityrosporum orbicular, which is the cause of dermatoses, which is characterized by the appearance of achromatic or whitish Speckles or spots manifested (Pitiriasis versicolor) observations in vitro and in vivo have reasonable clues supplied for the fact that the fungus is usually on of the skin and for survival and diffusion required fatty acids are metabolized and to form Dicarboxylic acids, which then has an inhibitory influence have melanogenesis.

In this context, an investigation by Cultures of Pityrosporum orbiculare, which include technical Oleic acid was added as a lipid supplement after the saponification found that also pimelic acid, azelaic acid and 1,9-nonandicarboxylic acid (C₁₁). These were through Gas chromatography and mass spectrometry identified. The C₉ and C₁₁ representatives of the dicarboxylic acids have in vitro demonstrated significant anti-tyrosinase activity, which also with dicarboxylic acids with 8, 10 and 12 carbon atoms was found.

The mercapto derivatives also have an inhibitory effect on the Dopa tyrosinase reaction.

The production of mercapto-substituted derivatives of dicarboxylic acids done by one the Dicarboxylic acid is brominated to contain as many bromine atoms in the acid introduce how to be replaced by mercapto groups, the bromo derivative with thiourea in a solvent reacted to form the corresponding thiouronium salt and then saponified the salt thus formed to the appropriate Get mercapto derivatives.

The bromination of the bicarboxylic acid can be achieved by the dicarboxylic acid is first reacted with phosphorus pentachloride, until the mixture has completely melted and then to the melt with stirring at a temperature which is kept at 60 to 70 ° C, adds anhydrous bromine. The bromine derivative formed in this way can then be in the usual way Way to be isolated.

In a preferred embodiment for producing the Monomercapto derivatives of dicarboxylic acids are placed in 1 mole Dicarboxylic acid with 50 g of phosphorus pentachloride. Subsequently the reaction product is reacted with 60 ml of anhydrous bromine, the anhydrous bromine over approximately 6 hours is added in small proportions. Here, the monobromo derivative of dicarboxylic acid formed. Then you put 1 mole of Monobromo derivative with 50 ml ethyl alcohol and 1.1 mol thiourea um to get the corresponding ethylthiouronium salt form, which is then saponified to the corresponding Monomercaptoderivat to obtain.

In a preferred embodiment for producing the Dimercapto-substituted dicarboxylic acid derivatives are used 1 mol of acid with 50 g of phosphorus pentachloride and 120 ml anhydrous bromine to the melt obtained in the course of 18 hours in small increments while keeping the temperature down holds at 90 to 100 ° C. Then you put 1 mole of the obtained Dibromids with 2.2 moles of thiourea in 100 ml of ethyl alcohol um to form the corresponding alkylthioronium salt which is then saponified to give the corresponding dimercapto derivatives to obtain.

The dicarboxylic acids described above or their derivatives or pharmaceutically acceptable salts can be in various pharmaceutically acceptable carriers are administered, the Choice depends on the type of treatment. So you can for example in the form of an injectable suspension of active material in a saline solution. But if they are intended for topical administration, can they are applied as creams. You can also in one orally administrable form. The amount of active ingredient present in these medicines can vary slightly. It is only essential that the Dicarboxylic acids or their derivatives in therapeutically effective Amount available.

The amount of dicarboxylic acid or the derivatives or pharmaceutical compatible salts of these compounds, which in agents according to the invention are present, varies depending on dose form and / or condition being treated. With oral Administration can be the amount of active ingredient Total or essentially the total amount of the dosage form turn off. However, if the active substance is in a Dose form is included which is suitable for subcutaneous injection it may be about 20 to 30% by weight, and preferably about 25% by weight based on the total weight of the By means of make out. If the remedy as a cream or lotion for topical administration, the Dicarboxylic acid or its derivative between about 10 and 20 wt .-%, preferably about 15 wt .-%, based on the Make up the total weight of the product.

It has also been found that it is advantageous to use a keratolytic agent in the medicaments according to the invention bring in. This is particularly the case if the Agents should be applied to the skin. As examples for keratolytic agents in the medicament according to the invention can be used, one can use salicylic acid, vitamin A acid; Resorcinol, phenol, cresol and the like. The amount of keratolytic agent that is used advantageously can also vary. Usually it does roughly 2 to about 4% by weight based on the total weight of the agent.

The following examples serve to explain the production of the derivatives according to the invention without the subject to limit the invention.

Manufacturing example (a) Preparation of the alpha monobromo derivative

1 mol of dicarboxylic acid (for example azelaic acid) into a 3 liter flask which is attached to a magnetic stirrer Heating plate is placed, and gives 500 g of phosphorus pentachloride to. After implementation (complete Melt) 60 ml of anhydrous bromine are added in small Shares for about 6 hours under continuous Stir too. The reaction temperature is kept at 60 to 70 ° C.

After the reaction is complete, cool and then give Carefully add about 500 ml of distilled water then on the magnetic stirrer for about 30 minutes and cools down.

The lower organic phase, which consists of a dark yellow If there is oily liquid, the raw Monobromo derivative, which is distilled in vacuo.

(b) Preparation of the mercapto derivative

Place 1 mole of the alpha-monobromo derivative under one Trigger in a 2 liter flask equipped with a condenser and then gives 50 ml of ethyl alcohol at 95 ° C and 1.1 moles of thiourea. The mixture is heated 6 hours at the boiling point, whereupon the alkyl thiouronium salt is separated by cooling.

To saponify this salt, 500 ml of 5N NaOH are added to the mixture and hold under reflux for a further 2 hours at the boiling point. After cooling, the reaction mixture is acidified with 5N HCl and then after about 10 minutes has stirred an oily layer, which Will get removed. The aqueous layer is extracted three times with ethyl ether and gives this ether extract to the previously removed oily layer, which is then over anhydrous Na₂SO₄ is dried. After seeing the ether removed by distillation, the crude mercapto derivative cleaned on a silica gel column.

Repeated to make the dimercapto derivatives following the procedure of the above example Differences:

• 1. The dibromo derivative of dicarboxylic acid is like that Monobromic derivative manufactured, but doubled the amount of bromine added and tripled the response times; the reaction temperature will kept at 90 to 100 ° C.
• 2. In the manufacture of the mercapto derivative double the amounts of alcohol, thiourea and Sodium carbonate used per mole of dibromide.

To the effectiveness of the agents according to the invention and their corresponding To evaluate active substances were both pharmacological Investigations and experiments carried out in vivo.

From the combined lipid extracts (from cells and from the filtrate) of Pityrosporum orbicular cultures (strain 4709) which is 20 to 30 days from a conventional synthetic Medium to which oleic acid was added was grown, you got a saponifiable portion with considerable Tyrosinase inhibitory activity. During an investigation this portion by means of thin layer chromatography (TLC), a fraction with Rf = 1.3 was isolated, which the Can inhibit dopa tyrosinase response.

Gas chromatography analysis and subsequent mass spectrometric Analysis showed that there was a Series of C₅-C₉ dicarboxylic acids were included, the Pimelic acid and azelaic acid predominated in terms of quantity.

In comparative experiments using samples more pure Acids could cause any tyrosinase for glutaric acid (C () inhibitory effects are excluded while this Effect with compounds from 7 C atoms is evident and is maximum for compounds with 9 and 11 carbon atoms.

In particular, enzymatic kinetic experiments showed that azelaic acid is a useful tyrosinase inhibitor with Ki = 4.10 ^-4 M.

Example 1

The in vivo application of the agents according to the invention is described in illustrated the following attempts:

A cream based on azelaic acid (see below Examples 3 to 5) are applied to the dark for 30 days Patches of the following patients applied:

• (a) 20 patients suffering from chloasma,
• (b) 3 patients suffering from Civatte poikiloderma,
• (c) 1 patient suffering from pre-cancerous melanosis to Dubreuilh (malicious freckles) suffers.

All patients showed up after the end of treatment a clear brightening of the hyperpigmented zones and in most cases it became an obviously complete one Healing achieved without side effects. After 5 months of observation did not show up in any of the treated patients any traces of leukoderma.

It should be noted that precancerous circumscribed melanosis falls into the category of precancerous dermatoses, and it is of fundamental importance that this Patients not only have a clinical cure but also histological healing resulted.

Examples 3 to 5 are exemplary of creams such as these were used in Example 2 above.

Example 2

% By weight

Azelaic acid 15.0

Chlorocresol 0.1

Titanium dioxide 1.0

Salicylic acid 2.0

Glycerol monostearate 2.0

Cetyl alcohol 3.0

Tween 80 5.0

Sodium lauryl ether sulfate 10.0

Ethanolamine lauryl ether sulfate 1.0

Olive oil 2.0

Vitamin C 1.0

make up to 100% by weight with distilled water

Example 3

The average corresponds to that according to Example 3, with the exception that that 3% salicylic acid is used.

Example 4

The average corresponds to that according to Example 3, with the exception that that 4% salicylic acid was used.

Example 5

Regarding the treatment of melanoma, laboratory animals have been used carried out the following experiments:

Infected rats were sampled from Hardey-Passey melanoma removed and in small pieces into the subcutaneous tissue planted the left side of Balb's C. rats. The Animals were divided into two groups of 30 rats each, one of which is through daily intraperitoneal Injections of saline suspension with 2 mg alpha-mercaptoazelaic acid was treated.

The control animals became 0.1 ml of 0.9% saline injected. Treatment was continued until the control animals died Histological examinations were continued both on the melanoma of the treated animals and also the control animals.

The following preliminary conclusions can be drawn from these Try to be pulled:

• (a) The mean survival of the animals with the Substance containing azelaic acid was treated, is extended;
• (b) There is a significant delay in the treated animals at the beginning of the development of melanoma observed;
• (c) Some of the animals treated are melanoma significantly reduced in size and extent;
• (d) in other treated animals, instead of Tumor observed the formation of a black crust, or there is no melamon at all; and
• (c) Finally, the histological examination extensive necrotic in the treated animals Areas found.

Example 6

Human volunteers suffering from malignant melanoma were treated orally with pure azelaic acid. This was taken orally in a daily dose of 10 grams for a month with good tolerance administered.

Example 7

The following agent is for subcutaneous injections of Alphamercapto-azelaic acid suitable:

Alpha-monomercapto-azelaic acid 2 mg Tween 805 mg Vitamin C1 mg

Example 8

For further investigation of the inhibitory effect of azelaic or dodecanedicarboxylic acid and their corresponding Sodium salts on Harding-Passey melanoma in intraperitoneal, Subcutaneous or oral administration were as follows Experiments carried out:

Balb's C albino rats, what Harding-Passey melanoma had been transplanted, were intraperitoneal, subcutaneous or treated orally with agents containing azelaic acid (C-9) or dodecanedicarboxylic acid (C-12) or their corresponding Contained sodium salts. The treatment was 24 hours started with melanoma after inoculation. The Control animals were intraperitoneally or subcutaneously daily 120µl saline, which 1 mg vitamin C and 2.5 mg Tween 80 contained, injected.

Each laboratory animal was treated in one of the following ways:

(a) C₉ intraperitoneally (1)

Daily intraperitoneal injection of 120 µl saline, which 1 mg azelaic acid dissolved in 5 mg their Dimethyl ester, 1 mg vitamin C and 2.5 mg Tween 80 contains.

(b) C₉ subcutaneous (1)

Daily subcutaneous injection of the one described in (a) above Means

(c) C₁₂ subcutaneous (1)

Daily subcutaneous injection of 120 µl saline, which 1 mg of dodecanedicarboxylic acid, dissolved in 5 mg of their Dimethyl ester, 1 mg vitamin C and 2.5 mg Tween 80 contains.

C₉ oral

Oral administration ad libitum of an aqueous solution, which is 20 mg of the sodium salt of azelaic acid and Contains 1 mg vitamin C per cm³ water.

C₁₂ orally

Oral administration ad libitum of an aqueous solution, which 20 mg of the sodium salt of dodecanedicarboxylic acid and Contains 1 mg vitamin C per cm³ water.

The results of these experiments are summarized in Table I below. It has been shown that intraperitoneal, subcutaneous or oral administration of azelaic acid, dodecanedicarboxylic acid or their sodium salts to albino mice with transplanted Harding-Passey melanomas caused a significant delay in tumor growth.

Treatment was started 24 hours after inoculation began.

Control: Daily intraperitoneal or subcutaneous injection of: 120 µl saline, 1 mg Vit. C, 2.5 mg Tween 80.

• (1): Daily injection of 120 µl saline, 1 mg of C₉ or C₁₂ dicarboxylic acid (azelaic or dodecanedicarboxylic acid), dissolved in 5 mg of the corresponding dimethyl ester; 1 mg vitamin C, 2.5 mg Tween 80.
• (2): Oral ad libitum: sodium salt of azelaic acid or Sodium salt of dodecanedicarboxylic acid: 20 mg / cm³ H₂O; 1 mg vitamin C.

Claims (3)

1. Agent for the treatment of hyperpigmentary dermatoses or skin hyperpigmentations with at least one active ingredient in a pharmaceutically acceptable carrier, characterized in that it is at least one dicarboxylic acid having 7 to 13 carbon atoms, an α- mono- or an α, α ′ as active ingredient -Dimercapto derivative thereof or a pharmaceutically acceptable salt thereof. 2. Composition according to claim 1, characterized in that it is a keratolytic agent, especially salicylic acid, contains. 3. Composition according to claim 1 or 2, characterized in that it is azelaic acid or Contains 1,12-dodecanedicarboxylic acid.