JPS6327326B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to psoriasis treatments, and more particularly to compositions containing one or more compounds that have been found to be effective when applied topically to treat human skin disorders caused by psoriasis. Psoriasis is a chronic disease that leaves unsightly scars on the skin of millions of people. The causes of its occurrence are not completely known and therefore prevention is not possible. Treatment was necessarily empirical and involved systematic use of antimitotic agents such as metholtrexylate to reduce inflammation. However, metholtrexylate could not be safely used due to its severe chronic toxicity to tissues other than the skin. It was therefore essential to find alternative means of treatment, either by external application of drugs whose toxicity is primarily confined to the skin, or by the discovery of new non-toxic drugs. . It has now been discovered that psoriasis symptoms can be successfully treated using certain relatively non-toxic and non-inflammatory 6-substituted nicotinamides, 2-substituted pyrazinamides or similar compounds thereof. Ta. According to the present invention, a compound of the following formula () which is effective when incorporated into a topically applied composition to alleviate psoriasis symptoms (However, Z in the formula is CH or N, n is 0:1, and X is hydroxyl, halogen,
CONH ₂ or -NR ¹ R 2 , R ¹ and ^{R 2 are} each independently hydrogen or alkyl of 1 to 6 carbon atoms, R ² may be NH ₂ or CHO, and Y is oxygen or sulfur. and R is H, OH, NH ₂ or lower alkoxy of 1 to 6 carbon atoms, and Y and R may be taken together to form N, provided that X is NH ₂ In this case, the 3-position of the formula is a group other than carbamoyl, and when Z is CH, X is at the 6-position, and when Z is N, X is at the 2-position. ) is provided. Among the compounds belonging to the above formula (), the preferred one is the following formula () These are compounds that have the following. X, Y, R and n in the formula () are the same as defined in the formula (). Psoriasis symptoms can be effectively treated by utilizing compounds of the above formula that do not have side effects or allergic effects like anti-mitotic agents. There is therefore no need to develop immune tolerance before topical treatment when using the compounds according to the invention. The above compounds may be used as free bases or alternatively
Can be incorporated into therapeutic compositions as addition salts of HCl, H ₂ SO ₄ , HNO ₃ or other common acids, e.g., as acid addition salts produced by dissolving the free base in an acid solution. . The following compounds within the range of formula () above have been found to be particularly preferred. (1) 6-aminonicotinic acid (2) 6-aminonicotinic acid methyl ester (3) 6-aminonicotinic acid ethyl ester (4) 6-aminonicotinic acid tertiary butyl ester (5) Nicotine 6-aminonicotinic acid Ester (6) 6-aminonicotinic aldehyde (7) 6-hydroxynicotinic acid (8) 6-methylaminonicotinamide (9) 6-dimethylaminonicotinamide (10) 6-formylaminonicotinamide (11) 6-hydrazine Nicotinamide (12) 6-ethylaminonicotinamide (13) 6-hydrazine nicotinic 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-nicotinal aminonicotinamide (22) 6-aminonicotine Hydrazide Although the above compounds are highly effective, nicotinamide, nicotinic acid, isoniazid and
-It is particularly noteworthy that aminonicotinic acid has no effect on alleviating psoriasis symptoms. Through extensive testing on humans with psoriasis, it has been established that alcoholic, aqueous solutions, ointments or lotions containing 0.01 to 5% of a compound of the above general formula are useful in producing relief from psoriasis symptoms. These compounds may be present in therapeutic compositions ranging from 0.01 to 5.
Although it has been found to be effective when present in a range of % by weight, a preferred concentration range is
It is 0.02 to 2% by weight. It has been found that the therapeutic compositions of the present invention can restore areas of psoriatic skin to normal skin condition in about 1 to 3 weeks when applied daily. It is therefore an object of the present invention to provide a relatively non-toxic, non-allergenic pharmaceutical composition which, when applied topically, reliably alleviates the symptoms of psoriasis. Another object of the present invention is to provide at least one 6-substituted nicotinamide, 6-substituted nicotinic acid and its ester, 2-substituted pyrazinamide and similar compounds thereof, which, when applied topically, alleviate psoriasis symptoms. An object of the present invention is to provide a pharmaceutical composition containing the following. Yet another object of the present invention is to provide a method of treating psoriasis using relatively non-toxic ointments or aqueous or alcoholic solutions containing 6-substituted nicotinamides, 2-substituted pyrazinamides, or similar compounds. There is a particular thing. Yet another object of the present invention is to provide a safe and effective treatment for psoriasis in which periodic topical application of a pharmaceutical composition promotes healing in about 1 to 3 weeks. . Yet another object of the invention is 6-substituted nicotinamide, 6-substituted nicotinic acid and its esters, 2-substituted pyrazinamide, 6-aminothionicotinamide and 6-aminonicotinamide-
Provided is a method for safely and effectively treating psoriasis by periodically topically applying a pharmaceutical composition containing about 0.01 to 5% by weight of at least one compound selected from the group consisting of 1-oxides. There is a particular thing. Preparation of Therapeutic Compositions To make the compositions of the invention, at least one of the compounds described above is dissolved in water, ethanol, acetone, or 1NHCl, unwashed. The solution thus created can then be mixed in a conventional manner with a commonly available ointment base, such as a hydrophilic ointment USP.
The concentration of this compound is 0.01-5.0% by weight of the total composition
span. However, the preferred concentration range is 0.01 to about 2
%, more preferably 0.02 to about 2%. If desired, two or more of the above compounds can be mixed as described above to form compositions of the invention. In this case, it is preferred that the concentration of the compounds does not exceed about 2% by weight of the total composition. The water, ethanol, acetone or HCl solvent used to initially dissolve the compounds of the invention can have a concentration of 1 to 20% by volume of the total composition. However, its preferred concentration is about 10% by volume of the total composition. The therapeutic ointments of the present invention prepared as described above can be stored in ointment bottles at room temperature for extended periods of time. No change in clinical efficacy was observed with long-term storage. The compounds of the invention can also be used in the form of solutions or lotions. A typical solution utilizing the compounds of the invention consists of at least one of the above compounds directly dissolved in a mixture of water, ethanol and propylene glycol, preferably in a solubilities ratio of 40:40:20, respectively. . However, although the proportions of each component can be varied, the preferred concentrations of ethanol and propylene glycol should not exceed 70% and 30%, respectively. When formulating solutions according to the invention, the active compound concentration can also be between 0.01 and 5% by weight, although concentrations between 0.1 and 2% are preferred.
One or more compounds can be mixed into the solutions of the invention, the total concentration of the mixture being about 2
It is preferable not to exceed % by weight. As an alternative method of making the therapeutic composition, one of the compounds of the invention can be added directly into the composition without the use of a dissolution solution. The following examples are formulation examples of compositions of the present invention. Although the examples use the compounds listed therein, there is no intention to limit these examples to the specific compounds listed therein, and the present invention does not include any member of the above compound group or any combination thereof. Substitutions may be made within the scope of the invention. (A) Synthesis of 6-aminonicotinamide-1-oxide 50 g of 6-aminonicotinamide was dissolved in 500 ml of warm glacial acetic acid, and 80 ml of 30% hydrogen peroxide was slowly added to this clear solution with stirring.
This mixture was then heated to 100°C for 5 hours.
The resulting light brown solution was evaporated to a syrupy residue, which was cooled in an ice-water bath to crystallize. The crystals were washed with acetone and dried. The yield of practically pure 6-aminonicotinamide-1-oxide was 51.6 g. The mobility (RF) of this product was 0.48 in thin layer chromatography using a 1:1 benzene to methanol solvent system. (B) Synthesis of 6-formylaminonicotinamide 5.6g of 6-aminonicotinamide was mixed with 90% formic acid.
After all the crystals had dissolved, the clear solution was heated to 100° C. for 10 minutes. The mixture was cooled and then 4N NaOH was added to adjust the PH to 11-2.8. The white crystals formed were separated by filtration and washed once with cold water and then with acetone. The yield of 6-formylaminonicotinamide was 5.6 g. The RF value of this product was 0.53 in thin layer chromatography using a 1:1 benzene to methanol solvent system. (C) Synthesis of 6-aminonicotinic acid Dissolve 200 g of 6-aminonicotinic acid in 700 ml of warm 85% phosphoric acid, and add this clear solution.
Heated to 100°C for 8 hours. The solution was then diluted with 1.5 kg of ice water and the white crystals thus obtained were separated and washed with ice water and then with acetone. The yield of 6-aminonicotinic acid phosphate was 310 g. The phosphate form of this product can be added directly into the therapeutic compositions of the invention. (D) Synthesis of 6-aminonicotinic acid ethyl ester 40 g of 6-aminonicotinic acid (or 62 g of 6-aminonicotinic acid phosphate) was added to anhydrous ethanol.
The mixture was externally cooled in an ice-water bath and 50 ml of thionyl chloride was slowly added into the mixture. (50 ml of N,N-dimethylformamide may be added to dissolve undissolved ST-11 phosphoric acid.) The reaction mixture is heated to 80°C for 5 hours and then evaporated to a syrupy residue.
Acetone was added to crystallize. The crystals were overseparated and redissolved in 400 g of ice water.
4NKOH was added to this solution to adjust the pH to 8. The white crystals thus formed were separated by filtration again and washed with water. In fact, the yield of pure 6-aminonicotinic acid ethyl ester was 41.8 g. The RF value of this product was 0.79 in thin layer chromatography using a 1:1 benzene to methanol solvent system. Example 1 A 1% 6-aminonicotinic acid ointment is prepared as follows. 1 g of 6-aminonicotinic acid, 1 NRC 17 ml and 2 water
Dissolve in ml. Add this solution to USP grade hydrophilic ointment.
Mix with 90g to a homogeneous consistency.
The ointment thus prepared is stored in an opaque bottle at room temperature. Example 2 A 6-aminonicotinic acid methyl ester 0.5% ointment can be made as follows. Dissolve 0.5 g of 6-aminonicotinic acid methyl ester in 12 ml of ethanol and mix this solution with 90 g of USP grade hydrophilic ointment to a homogeneous consistency. The ointment thus prepared is also stored in opaque bottles at room temperature. Example 3 A 6-aminonicotinic acid ethyl ester 1% ointment can be made as follows. 1 g of 6-aminonicotinic acid ethyl ester is dissolved in 8 ml of ethanol and 4 ml of acetone, and this solution is mixed with 90 g of USP grade hydrophilic ointment to a uniform consistency. The ointment thus produced is also stored in an opaque bottle at room temperature. Example 4 A 6-formylaminonicotinamide 0.1% ointment can be made as follows. 0.1 g of 6-formylaminonicotinamide is dissolved in 5 ml of water and 4.9 ml of ethanol and this solution is mixed with 90 g of hydrophilic ointment USP grade to a homogeneous consistency. This ointment can also be stored in an opaque bottle at room temperature. Example 5 6-aminonicotinamide-1-oxide 0.5
% Ointment can be made as follows. 6-aminonicotinamide-1-oxide 0.5
Dissolve g in 12 ml of ethanol and add this solution to USP
Mix with 90 g of grade hydrophilic ointment to a homogeneous consistency. The ointment thus produced is also stored in an opaque bottle at room temperature. Example 6 A 6-aminothionicotinamide 0.5% ointment can be made as follows. Yellowish crystals of 6-aminonicotinamide
Dissolve 0.5g in 12ml of ethanol and add this solution to
Mix with 90 g of USP grade hydrophilic ointment to a uniform consistency. This ointment can also be stored in opaque bottles at room temperature. Example 7 A 6-aminonicotine nitrile 1% ointment can be made as follows. 1g of 6-aminonicotine nitrile to 15% of acetone
ml and pour the solution into USP grade hydrophilic ointment 87
g to a homogeneous consistency. The ointment thus produced is also stored in opaque bottles at room temperature. Example 8 A 2-carbamoylpyrazinamide 1% ointment is prepared as follows. Dissolve 1 g of 2-carbamoylpyrazinamide (also known as 2,3-pyrazinedicarboxamide) in 5 ml of acetone and mix the solution with 90 g of USP grade hydrophilic ointment to a uniform consistency. . This ointment can also be stored in opaque bottles at room temperature. Example 9 A 6-aminonicotinic acid ethyl ester 0.2% lotion is made as follows. 95 g of a water-in-oil lotion is prepared by dissolving 0.2 g of 6-aminonicotinic acid ethyl ester in 6 ml of ethanol and using this solution with mineral oil, cottonseed oil, isopropyl palmitate, water and a surfactant such as sorbitan sesquioleate. Mix with.
The ingredients in the above water-in-oil lotion are present, for example, in amounts of 10:10:5:70:5 parts by weight, respectively. The lotion thus produced is stored in a compression bottle with a plastic nozzle. This lotion is suitable for use on areas such as the scalp. Example 10 A formulation that does not use a dissolving solvent can be made as follows. One gram of 6-aminonicotinamide-1-oxide powder was mixed directly with 99 grams of a water-in-oil ointment made from mineral oil, petrolatum, spermaceti, and water and a surfactant such as sorbitan sesquioleate. The ingredients of each of the above water-in-oil ointments are 10:
Present in 10:6:68:6 parts by weight. The ointment thus produced is stored in opaque bottles at room temperature. Example 11 A 1% 6-aminonicotinic acid methyl ester ointment can be made as follows. Dissolve 1 g of 6-aminonicotinic acid methyl ester in 9 ml of absolute ethanol and mix the solution with 54 g of white petrolatum USP grade and liquid petrolatum USP.
Mix with 36 g of grade to obtain a homogeneous consistency. This ointment can also be stored in opaque bottles at room temperature. Example 12 A 1% 6-aminonicotinaldehyde ointment is prepared as follows. Dissolve 1 g of 6-aminonicotinaldehyde in 10 ml of ethanol and mix this solution with 90 g of USP grade hydrophilic ointment to a homogeneous consistency. The ointment thus produced is also stored in opaque bottles at room temperature. Test Results To evaluate the compounds of the present invention, a total of more than 30 psoriasis patients were treated with the compositions as follows. The psoriatic patient is instructed to apply a thin film of ointment or lotion formulated according to the above examples to the restricted area of the lesion. Topical application twice daily was continued for several weeks. Generally, after one week of topical treatment, the affected skin became less scaly and erythematous. After two weeks of treatment, the scaly and erythematous lesions usually substantially resolved to substantially normal appearing skin. Within 2-3 weeks after the first treatment, the lesion area reached an improved condition, free of any scaling and erythema, and usually comparable to normal skin. Once normal appearance of the skin is restored, it remains improved for weeks to months without further ointment, depending on the patient.
However, continued application of ointment is necessary to maintain the skin without any obvious recurrence of the disease. The compositions used in each test were formulated according to the representative examples described above and contained compounds of the invention at a total concentration of 0.2-1% by weight.

【table】

Table: As shown in the table above, ⁴⁺ results were achieved with the 10 compounds, and all tested patients regained normal appearance of their skin. The remaining compounds achieved at least a ³⁺ result, with lesions still erythematous but restoring normal textured skin. The application method used here generally requires twice-daily topical application, and the scale lesions were usually substantially clear after two weeks of treatment. However, as mentioned above, the use of the compositions of the present invention does not result in permanent healing. It has been observed that when regular application of the compositions of the invention is discontinued, the skin remains normal in appearance for a period of time ranging from a few weeks to several months, depending on the patient. However, upon resuming regular application, the lesions disappear again and normal appearance of the skin is restored. In summary, the present invention involves the discovery of relatively non-toxic compositions that are neither antimitotic nor allergenic and are effective in alleviating the symptoms of psoriasis. These compositions include ointments, creams, lotions or aqueous or alcoholic solutions of one or more of the above 6-substituted nicotinamides and their 1-oxides, 6-substituted nicotinic acids and their esters, and 2-substituted pyrazinamides. can do. In particular, the most effective compounds of the invention are 6-aminonicotinic acid, 6
-aminonicotinic acid methyl ester, 6-aminonicotinamide-1-oxide, 6-hydroxynicotinic acid, 6-carbamoylnicotinamide,
Representative examples include 2-aminopyrazinamide and 2-carbamoyl-pyrazinamide. One or more of these compounds are present in vehicles, ointments, creams, lotions, aqueous or alcoholic solutions at a total concentration of 0.01 to 5% by weight. The invention may be embodied in other specific forms without departing from its spirit or essential characteristics. Accordingly, the embodiments of the present invention should be considered in all respects as illustrative and not as restrictive. The scope of the invention is indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning of the claims and their range of equivalents are intended to be embraced by the invention.

Claims (1)

[Claims] 1 2-aminopyrazinamide, 2-carbamoylpyrazinamide, and a compound of the formula (wherein n is 0 or 1, and X is hydroxy, halogen, -CONH ₂ or NR ¹ R ² Yes, R ¹ and R ²
are each independently hydrogen or alkyl of 1 to 6 carbon atoms; R ² may also be NH ₂ or CHO; Y is oxygen or sulfur; R is hydrogen;
OH, NH ₂ or lower alkoxy of up to 6 carbon atoms, and Y and R may together form N, provided that when X is NH ₂ , the 3rd position of the formula is carbamoyl. from about 0.01 to 10% of the total composition in a pharmaceutically acceptable carrier.
1. A therapeutic composition for alleviating psoriasis by topically applying it to an affected area of the human body, comprising a concentration of 5% by weight. 2. The composition of claim 1, wherein said compound is present in a concentration of about 0.01% to 2% by weight of the total composition. 3. A composition according to claim 1, further comprising a solvent selected from the group consisting of water, hydrochloric acid, ethanol or acetone, present in a concentration of 1 to 20% by volume of the total composition. 4. The composition of claim 1, wherein said solvent is present at a concentration of about 10% by volume. 5. The composition of claim 1, wherein said carrier is selected from the group consisting of petrolatum and hydrophilic ointment. 6. The carrier comprises a mixture of a liquid solvent and an ointment base, the liquid solvent comprises 5 parts by volume of water and 4.9 parts by volume of ethanol, and the liquid solvent and the ointment base constitute 9.9 ml of the composition. A composition according to claim 1, present in a volume-to-weight ratio of 90g. 7. The composition of claim 1, wherein the carrier comprises a mixture of absolute ethanol and petrolatum, and the ethanol and petrolatum are present in the composition in a volume-to-weight ratio of 9 ml to 90 g. 8. The carrier comprises a mixture of a liquid solvent and an ointment base, the liquid solvent comprises 5 parts by volume of water and 4 parts by volume of acetone, and the liquid solvent and the ointment base are present in the composition at a ratio of 9 ml to 90 g. A composition according to claim 1, wherein the composition is present in a volume-to-weight ratio of . 9. The carrier comprises a mixture of a liquid solvent and an ointment base, the liquid solvent comprises 8 parts by volume of ethanol and 4 parts by volume of acetone, and the liquid solvent and the ointment base are present in the composition at a ratio of 12 ml to 90 g. A composition according to claim 1, wherein the composition is present in a volume-to-weight ratio of .