DE2803592A1 - Psoriasis topical treatment compsns. - contg. non-allergenic pyrazinamide and nicotinamide derivs. - Google Patents

Abstract

Compsn. for topical treatment of psoriasis contains as active component 0.01-5 wt% of 2-amino-pyrazinamide (I), 2-carbamoyl-pyrazinamide (II) or a nicotinamide deriv. of formula (III): In the formula n is 0 or 1, X is halogen, OH, CONH2 or NR1R2, R1 and R2 are each H or 1-4C alkyl, and R2 can also be NH2 or CHO, Y is O or S. R is OH, NH2 or 1-4C alkyl or Y and R together are N, provided -C(Y)-R is not CONH2 when X is NH2. (I)-(II) are relatively non-toxic and non-irritant. They are not antimycotic agents or allergens. It is unnecessary to induce immunological tolerance, before treatment with (I)-(III). Symptoms are completely alleviated in 1-3 weeks. Cpds. are storage stable.

Description

Therapeutic agent

The invention relates to pharmaceutical agents, which one or more Contain compounds that, when applied topically, help improve and heal Skin lesions are effective in people with psoriasis.

Psoriasis is a chronic disease that affects millions of people a disfiguring and incapacitating skin damage remains. Your etiology is still completely unknown and therefore contraception is not possible. The therapy is necessarily empirical, including systemic administration more antimitotic Medicines, such as methotrexate, are heard to bring about remission of the damage.

Have acute and chronic toxicity to tissues other than skin however make the use of methotrexate inappropriate. That's why it is necessary to find other therapies for external use of drugs, where the toxicity is mainly limited to the skin, or new To create agents with non-toxic properties.

There has also been topical application of a mechlorethamine hydrochloride ointment considered, the compound forming a stable agent in an oil base. At first Mechlorethamine hydrochloride, H3C-N (CH2-CH2-Cl) z'HCl, was commonly considered to be used for treatment of psoriasis considered unsuitable as the patient at effective dosage ranges became allergic. In addition, the compound was found to be in aqueous solution highly unstable and rapidly decomposed into one that is considered ineffective by those skilled in the art By-product. When using this remedy it was also necessary to first do an immunological one To induce tolerance in order to avoid allergic reactions later. In addition one injected weekly G, 2 mg Mechlorethaydrochlorid in aqueous solution at least three weeks long before topical treatment was started.

It was then also found that one of the decomposition products was also of mechlorethamine hydrochloride, namely N-methyldiethanolamine, successfully used for treatment from psoriasis can be used. This connection is primarily neither antimitotic nor does it cause allergies; it is useful in both animals and humans non-toxic when used topically in a therapeutic agent, which Contains 0.5 to 5% by weight of this compound. There were also no visible skin irritations observed.

Then there was also the use of 6-aminonicotinamide and thionicotinamide suggested for psoriasis treatment.

Albeit 6-aminonicotinamide when applied topically to humans and animals showed no signs of toxicity, causing it in systemic cases Administration at a dose of 40 mg / kg in animals various symptoms of toxicity.

Another disadvantage of this compound is that it works topically Treatment of psoriasis which can irritate psoriatic skin. In patients who more than 20% of the skin was affected by psoriatic damage, '6-aminonicotinamide appeared when administered topically to irritate the damaged skin and thus the disease to get worse.

Thionicotinamide is a relatively non-toxic substance, however the skin suffering from psoriasis is even more irritated than by it 6-aminonicotinamide.

A remedy has now been found which can be used to treat psoriatic States is useful, and certain 6-substituted nicotinamides, 2-substituted Contains pyrazinamides or closely related compounds which are relatively non-toxic and do not irritate the skin.

The compounds of the invention, which can be used in topical compositions to relieve psoriasis symptoms, correspond to the formula in which: Z is CH or N, N is zero or 1, X is hydroxyl, halogen, CONH2 or a compound of the formula -N-R1R2, in which R1 and R2, which can be identical or different, are hydrogen or alkyl with 1 can mean up to 6 carbon atoms and R2 can also stand for NH2 or CHO, Y stands for 0 or S, R stands for OHN, NH2 or lower alkoxy with up to 5 carbon atoms, or Y and R together mean N, with the prerequisite that when X stands for NH2, the substituent in 3-Stelluno cannot be carbamoyl, and it is also a prerequisite that when Z stands for CH, X is in the 6-position and when Z stands for N, X is in the 2-position.

Preferred compounds of the formula I are the compounds of the formula wherein X, Y, R and n have the meanings given above. Even more preferred are the compounds of the formula: wherein X, Y and R have the meanings given above.

The compounds of the above formulas are primarily neither antimitotic nor do they cause allergies. It is therefore not necessary before topical Use of the compounds according to the invention to induce immune tolerance Agents according to the invention can also contain one or more of the compounds of the above Formulas included. They can either be in the free base form or as acid salts of HCl, H2S04, HNO3 or any other commonly used acid are present, made for example by dissolving the free bases in an acid solution will.

Preferred compounds of formula I, which are found to be particularly effective are: (1) 6-aminonicotinic acid, (2) 6-aminonicotinic acid methyl ester, (3) ethyl 6-aminonicotinate, (4) tert-butyl 6-aminonicotinate, (5) Nicotinic 6-aminonicotinate, (6) 6-aminonicotinaldehyde, (7) 6-hydroxynicotinic acid, (8) 6-methylaminonicotinamide, (9) 6-dimethylaminonicotinamide, (10) 6-formylaminonicotinamide, (11) 6-hydrazinonicotinamide, (12) 6-ethylaminonicotinamide, (13) 6-hydrazinonicotinic acid ethyl ester, (14) 6-chloronicotinamide, (15) 6-carbamoylnicotinamide, (16) 6-aminothionicotinamide, (17) 6-aminonicotinonitrile, (18) 6-aminonicotinamide- 1-oxide, (19) 2-aminopyrazinamide, (20) 2-carbamoylpyrazinamide, (21) 6-nicotinalaminonicotinamide and (22) 6-aminonicotine hydrazide. id.

It has also been found that while the compounds listed above Most effective are nicotinamide, nicotinic acid, isoniazid and 2-rminonicotinic acid were completely ineffective when used for curing psoriatic conditions will.

Extensive experiments on psoriasis patients have also found that the topical application of an alcoholic or aqueous solution or a Ointment or lotion containing 0.01 to 5% of the compounds of the above general formula included is effective for remission of psoriatic conditions. Although the connections in a concentration of 0.01 to 5 wt .-%, based on the total weight of the By means of being effective, the preferred concentration range is between 0.02 and 2% by weight. The therapeutic agents of the invention have been found to be effective proven when applied daily, then within 1 to Restore normal skin condition for 3 weeks.

Accordingly, it is an object of the present invention to provide relatively non-toxic, to create non-allergenic pharmaceutical preparations which are used in topical application reliably relieves psoriasis symptoms. That also includes the creation of a pharmaceutical. By means of which at least a 6-substituted nicotinamide, a 6-substituted nicotinic acid or ester thereof, Contains 2-substituted pyrazinamides and closely related compounds, which at topical administration relieve symptoms of psoriasis.

The agents of the invention can be in the form of relatively non-toxic Ointments or aqueous or alcoholic solutions containing 6-substituted Contain nicotinamides, 2-substituted pyrazinamides or closely related compounds. With regular topical application, the agents according to the invention cause healing within 1 to 3 weeks. They usually contain from about 0.01 to 5% at least a compound selected from 6-substituted nicotinamides, 6-substituted Nicotinic acid and esters thereof, 2-substituted pyrazinamides, 6-aminothionicotinamide and 6-aminonicotinamide-1 oxide.

Manufacture of the therapeutic agents For the manufacture of the above Agent you first dissolve at least one of the above compounds in one Solvents such as water, ethanol, acetone or in HCl.

The solution produced in this way can then be used in a conventional manner with general available ointment bases, such as hydrophilic ointments, USP, are mixed. the The concentration of the compounds ranges from 0.01 to 5.0% by weight, based on the total mean. However, the preferred concentration range is from 0.01 to about 2% and still more preferably, between 0.02 and about 2%.

If desired, two or more of the above compounds can be used are mixed to form an agent according to the invention. In this case, focus should be of the compounds are preferably not more than 2% by weight of the total composition.

That used to initially dissolve the compound of the invention Solvents such as water, ethanol, acetone or HCl can be used in an amount from 1 to 20% by volume of the total agent are present. The preferred concentration range is but about 10% by volume of the total agent.

The therapeutic ointments prepared as described above can be stored in jars of ointment at room temperature for long periods of time. It there was no impairment of clinical efficacy due to prolonged storage established.

The compounds according to the invention can also be in the form of solutions or lotions are used. A typical solution according to the invention contains at least one of the above compounds, directly dissolved in a mixture of water, Ethanol and propylene glycol in a volume ratio of preferably 40:40:20 each. The proportions of the respective compounds can vary, but are preferred Concentration ranges of ethanol and propylene glycol should not be 70% and 30%, respectively exceed. If solutions are produced according to the invention, the concentration of the active substance can 0.01 to 5 wt%, but a concentration of 0.1 to 2 wt% is preferred. One or more compounds according to the invention can be mixed in a solution, however, the total active ingredient concentration of the mixture should preferably be about 2% by weight not exceed.

In an alternative method of making the therapeutic One of the abovementioned compounds according to the invention can be used directly without use a solvent into which agents are incorporated.

The following examples are intended to illustrate the invention in more detail. Although the examples use a specific compound, they are not limited to this particular compound; rather, any of the above can be described groups of compounds or combinations thereof within the scope of the present Invention to be replaced.

(A) Synthesis of 6-aminonicotinamide-1-oxide: 50 g of 6-aminonicotinamide are dissolved in 500 ml of warm glacial acetic acid and slowly adds to this clear solution while stirring 80 ml of 30% hydrogen peroxide. The mixture is heated to 100 ° C. for 5 hours, the slightly brownish solution that has formed evaporates to a syrupy one A residue which crystallizes after cooling in an ice water bath. The crystals are washed with acetone and dried. The yield of practically pure 6-aminonicotinamide-1-oxide is 51.6 g. The product has a mobility (Rf) of 0.48 on thin layer chromatography when using a solvent system of benzene: methanol = 1: 1.

(B) Synthesis of 6-formylaminonicotinamide: 5.6 g of 6-aminonicotinamide are added to 15 ml of 90% formic acid. When all the crystals are dissolved, heat the clear solution for 10 minutes at 100 ° C. The mixture is cooled and added then 4N NaOH to adjust the pH to 2.8. The white crystals that form are collected by filtration, once with cold water and then with acetone washed. The yield of 6-formylaminonicotinamide is 5.6 g. The product has an Rf value of 0.53 on thin layer chromatography using a solvent system of benzene-methanol = 1: 1.

(C) Synthesis of 6-aminonicotinic acid: Dissolve 200 g of 6-aminonicotinamide in 700 ml of warm 85% phosphoric acid and the clear solution is heated for 8 hours to 100 OC. The solution is then diluted with 1.5 kg of ice water. The so obtained white crystals are collected by filtration and with ice water and then with Acetone washed. The yield of 6-aminonicotinic acid-phosphoric acid salt is 310 g. This product, in the form of its phosphoric acid salt, can be used directly in the invention therapeutic agents are included.

(D) Synthesis of 6-aminonicotinic acid ethyl ester: 40 g of 6-aminonicotinic acid are mixed (or 62 g of the 6-aminonicotinic acid phosphoric acid salt) with 500 ml of anhydrous ethanol, cools the mixture from the outside in an ice water bath and slowly adds 50 ml of thionyl id chloride to the mixture. (You can add 50 ml of N, + dimethylforma nide to possibly still undissolved phosphoric acid salt). The reaction mixture 5 is heated Hours to 80 OC and then evaporated to a syrupy residue, which upon addition crystallized from acetone.

These crystals are collected by filtration and poured into 400 g of ice water solved again. 4N KOH is added to the solution to adjust the pH to 8. the white crystals so formed are again collected by filtration and washed with Water washed. The yield of practically pure 5-aminonicotinic acid ethyl ester is 41.8 g. This product has an Rf value of 0.79 on thin layer chromatography using a solvent system of benzene: methanol, 1: 1.

Example 1 An ointment containing 1% 6-aminonicotinic acid is prepared as follows: 1 g of 6-aminonicotinic acid is dissolved in 7 ml of 1N HCl and 2 ml of water, the solution mixed with 90 g of hydrophilic ointment (USP grade) until it becomes a results in a uniform consistency.

The ointment so prepared is in opaque jars at room temperature kept.

Example 2 An ointment with a content of 0.5% 6-aminonicotinic acid methyl ester can be prepared as follows: 0.5 g of 6-aminonicotinic acid methyl ester is dissolved in 12 ml of ethanol and mixes the solution with 90 g of a hydrophilic ointment base (USP grade) until the consistency is uniform. The ointment made in this way is also stored in opaque jars at room temperature.

Example 3 An ointment containing 1% ethyl 6-aminonicotinate can be prepared as follows: 1 g of ethyl 6-aminonicotinate is dissolved in 8 ml of ethanol and 4 ml of acetone and mixed the solution with a hydrophilic ointment base USP (90 g) until a uniform consistency is obtained. The ointment made in this way can also be stored in opaque jars K riJ at room temperature.

Example 4 An ointment containing 0.1% 6-formylaminonicotinamide can be prepared as follows: 0.1 g of 6-formylaminonicotinamide is dissolved in t water and 4.9 ml of ethanol and then mixed this solution with 90 g of hydrophilic ointment (USP grade) until you get an even consistency.

This ointment can be stored in opaque jars at room temperature will.

Example 5 An ointment containing 0.5% 6-aminonicotinamide-1-oxide can be prepared as follows: Dissolve 0.5 g of 6-aminonicotinamide-1-oxide in 12 ml of ethanol and mixed this solution with 90 g of hydrophilic ointment (USP grade) up to uniform consistency results.

The ointment so prepared is in opaque jars at room temperature kept.

Example 6 An ointment containing 0.5% 6-aminothionicotinamide can be prepared as follows: Dissolve 0.5 g of 6-aminothionicotinamide, which is in In the form of yellowish crystals, add 12 ml of ethanol and mix the solution with 90 g of hydrophilic ointment (USP grade) until the consistency is uniform. This ointment can be stored in opaque jars at room temperature.

Example 7 An ointment containing 1% 6-aminonicotinonitrile can be prepared as follows: 1 g of 6-aminonicotinonitrile is dissolved in 15 ml of acetone and mixes the solution with 87 g of hydrophilic ointment (USP grade) until you get a uniform Maintains consistency. The ointment produced in this way is supplied in opaque jars Stored at room temperature.

Example 8 An ointment containing 1% 2-carbamoylpyrazinamide is made as follows: 1 g of 2-carbamoylpyrazinamide, also known as 2,3-pyrazine dicarboxamide known, it is dissolved in 5 ml of acetone and the solution is mixed with 90 g of hydrophilic ointment (USP grade) until there is a uniform consistency. The ointment can be opaque Jugs can be stored at room temperature.

Example 9 A lotion containing 0.2% ethyl 6-aminonicotinate is prepared as follows: 0.2 g of ethyl 6-aminonicotinate is dissolved in 6 ml Ethanol and mixed the solution with 95 g of a water-in-oil lotion, which made Mineral oil, cottonseed oil, isopropyl palmitate and water with a surfactant Means of how sorbitol sesquioleate is made. The components of this water in-bl Lotion are for example in a weight ratio from 10: 10: 5: 70: 5 contain. The lotion so produced is stored in a plastic bottle that has a valve, and from which the lotion can be squeezed out. The lotion is suitable for use on the scalp, for example.

EXAMPLE 1 10 A formulation without any solvent can be prepared as follows: 1 g of 6-aminonicotinamide-1-oxide powder is mixed directly with 99 g of a water-in-oil ointment made from mineral oil, petrolatum, Spermacet wax and water with a surfactant such as sorbitol sesquioleate. The components of this water-in-oil ointment are each in the following parts by weight before 10: 10: 6: 68: 6. The ointment produced in this way is supplied in opaque jars Stored at room temperature.

Example 11 An ointment containing 1% methyl 6-aminonicotinate can be prepared as follows: 1 g of 6-aminonicotinic acid methyl ester is dissolved in 9 ml of anhydrous ethanol and mix the solution with 54 g of white petrolatum (USP grade) and 36 g of liquid petrolatum (USP grade) until it has a uniform consistency results.

This ointment can be stored in opaque jars at room temperature will.

B e i s p i e 1 12 An ointment containing 1% 6-aminonicotinaldehyde is prepared as follows: 1 g of 6-aminonicotinaldehyde is dissolved in 10 ml of ethanol and mixes the solution with 90 g of hydrophilic ointment (USP grade) until it is even Gives consistency. The ointment produced in this way is supplied in opaque jars Stored at room temperature.

Test Results In order to evaluate the compounds according to the invention, More than 30 patients suffering from psoriasis were treated as follows: Psoriasis sufferers were asked to apply a thin film of an ointment or lotion according to the above Examples to apply to a delimited area with skin damage.

Topical application twice a day was carried out for several weeks. In general, the affected skin became less flaky and less inflamed afterwards had been treated topically for a week. The lesions were scaly and inflamed generally healed enough after 2 weeks of treatment that the skin looked normal. The places where the damage had existed and those now without dandruff and inflammation generally reached within two to three weeks after the beginning of the banding a condition that was comparable to normal skin.

Once the skin was restored, it remained for several weeks up to several months in the improved condition without further ointment treatment was necessary. However, this varied from patient to patient. However, it is necessary To continue the ointment treatment to make the skin more noticeable from recurring Keep disease free.

In all experiments means were used according to the above Examples were prepared and the compounds according to the invention in a total concentration from 0.2 to 1% by weight.

Connection number d. Therapeutic patient efficacy 1. 6-Aminonicotinic acid 4 4+ 2. 6-aminonicotinic acid methyl ester 20 4+ 3. 6-aminonicotinic acid ethyl ester 20 4+ 4. 6-aminonicotinic acid tert-butyl ester 2 4+ 5. 6-aminonicotinic acidicotinic acid ester 2 4+ 6. 6-aminonicotinaldehyde 2 4+ 7. 6-hydroxynicotinic acid 3 4+ 8. 6-methylaminonicotinamide 2 3+ 9. 6-Dimethylaminonicotinamide 3 3+ 10. 6-Formylaminonicotinamide 3 4+ 11. 6-Hydrazinonicotinamide 2 3+ 12. 6-Ethylaminonicotinamide 2 3+ 13. 6-Hydrazinonicotinic acid ethyl ester 2 3+ 14. 6-chloronicotinamide 2 3+ 15. 6-carbamoyl nicotinamide 2 4+ 16. 6-aminothionicotinamide 3 3+ 17. 6-aminonicotinonitrile 3 3+ 18. 6-aminonicotinamide-1-oxide 10 4+ 19th 2-aminopyrazinamide 2 4+ 20. 2-carbamoylpyrazinamide 4 4+ 21. 6-nicotinalaminonicotinamide 2 4+ 22. 6-Aminonicotinhydrazid 3 3+ 3+: The scales disappear from the damaged ones Place.

4+: A normal looking skin is restored.

As can be seen from the table above, obtained ten compounds a 4+ result, which means that the skin looked normal again in all patients. The rest of the compounds showed at least a 3+ result in terms of recovery a skin with normal tissue structure, the lesions only inflamed was. The compounds were generally applied topically twice a day and the scaly lesions essentially disappeared after two weeks of treatment.

As already said above, however, leads to the application of the invention Means not a permanent cure.

It has been observed that when the regular use of the invention Means stopped having normal looking skin for different depending on the patient Periods of a few weeks to several months are preserved.

But if you then continue with the regular application, so the damage disappears again and the skin regains its normal appearance.

The invention thus provides relatively non-toxic agents which are neither antimitotic nor cause allergies and relieve psoriasis symptoms to serve. This means can either in the form of an ointment, a Cream, lotion or in the form of an aqueous or alcoholic solution and one or more of the 6-substituted nicotinamides and described above 1-oxides thereof, 6-substituted nicotinic acids and esters thereof, and 2-substituted ones Contain pyrazinamides. The most effective compounds of the invention are in particular 6-aminonicotinic acid, 6-aminonicotinic acid methyl ester, 6-aminonicotinamide-1-oxide, 6-hydroxynicotinic acid, 6-carbamoylnicotinamide, 2-aminopyrazinamide and 2-carbamoylpyrazinamide. One or more of these compounds is in the carrier, either in the form an ointment, cream, lotion, aqueous or alcoholic solution in one total concentration from 0.01 to 5% by weight.

Claims (11)

Claims 1. Therapeutic agent for alleviating psoriasis symptoms by topical application to the affected parts of the body, characterized in that the agent has at least one compound selected from 2-aminopyrazinamide, 2-carbamoylpyrazinamide and a compound of the formula wherein n is zero or 1; X represents hydroxy, halogen, CONH2 or a compound of the formula -NR1R2, in which R1 and R2, which can be identical or different, represent hydrogen or alkyl having 1 to 6 carbon atoms and R2 can also represent NH2 or CHO; Y is 0 or S; R signifies hydrogen, OH, NH2 or lower alkoxy with up to 5 or 6 carbon atoms, or Y and R together represent N; with the prerequisite that when X stands for NH2, there is no carbamoyl in the 3-position; at a concentration of about 0.01 to 5% by weight of the total composition in a pharmaceutically acceptable carrier. 2. Composition according to claim 1, characterized in that it is a pyrazinamido compound contains. 3. Means according to claim 1, characterized in that it is at least contains one of the following compounds: 6-aminonicotinic acid, 6-aminonicotinic acid methyl ester, 6-aminonicotinic acid ethyl ester, 6 -hydroxynicotinic acid, 6-methylaminonictonamide, 6-dimethylaminonicotinamide, 6-formylaminonicotinamide, 6-hydrazinonicotinamide, 6-ethylaminonicotinamide, 6-hydrazinonicotinic acid ethyl ester, 6-chloronicotinamide, 6-carbamoylnicotinamide, 6-aminothionicotinamide, 6-aminonicotinonitrile, 6-aminonicotinamide-1 oxide, 2-aminopyrazinamide, 2-carbamoylpyrazinamide, 6-nicotinalaminonicotinamide and 6-aminonicotinhydrazide. 4. Means according to claim 1, characterized in that the active Compounds in a concentration of from about 0.01 to about 2% by weight, preferably about 0.02 to 2 wt .-%, based on the total weight of the agent, are included 5. Agent according to claim 1, characterized in that it also contains a solvent, selected from water, hydrochloric acid, preferably in HCl, ethanol or Acetone, in a concentration of 1 to 20%, based on the total volume of the Means, contains. 6. Agent according to claim 5, characterized in that the solvent is contained in a concentration of about 10 vol .-%. 7. Means according to claim 1, characterized in that the carrier is selected from petrolatum and a hydrophilic ointment base. 8. Means according to claim 1, characterized in that the carrier consists of a mixture of a liquid solvent with an ointment base, where the liquid represents 5 parts by volume of water and 4.9 parts by volume of ethanol, which are mixed with the ointment base, and liquid and ointment base can be used in a volume to weight ratio of 9.9 ml to 90 g. 9. Means according to claim 1, characterized in that the carrier consists of a mixture of anhydrous ethanol and petrolatum, with ethanol and petrolatum are present in a volume to weight ratio of 9 ml to 90 g. 10. Means according to claim 1, characterized in that the carrier consists of a mixture of a liquid solvent and an ointment base, The liquid is divided into 5 volumes of water and 4 volumes of acetone that are mixed with this ointment base, the liquid and the ointment base in the agent in a volume-to-weight ratio of 9 ml 90 g are present. 11. Means according to claim 1, characterized in that the carrier consists of a mixture of a liquid solvent and an ointment base, where the liquid is 8 parts by volume of ethanol and 4 parts by volume of acetone, which are mixed with the ointment base, with liquid and ointment base in the agent in a volume-to-weight ratio of 12 ml to 90 g.