WO2008067774A1

WO2008067774A1 - An antimycotic pharmaceutical composition

Info

Publication number: WO2008067774A1
Application number: PCT/CN2007/071195
Authority: WO
Inventors: Tao Zhang; Hui Wang; Jia Li; Caihua Mu; Bin Fan; Weihai Chen
Original assignee: Chongqing Pharmaceutical Research Institute Co., Ltd.
Priority date: 2006-12-07
Filing date: 2007-12-06
Publication date: 2008-06-12
Also published as: CN1969874B; CN1969874A

Abstract

An antimycotic pharmaceutical composition comprising the 2-aminothiazoles of the general formula (I) and corticoid drugs and the use of which for the treatment or prevention skin infection caused by fungus, wherein the definition of substituent group of general formula (I) as described in the description. Particularly, the antimycotic pharmaceutical composition can be used to treat or prevent skin infection caused by fungus, superficial fungal diseases, itching, the mixed infection caused by fungus and bacterium or various dermatitis

Description

Antifungal pharmaceutical composition technical field

The invention belongs to the field of antifungal drugs. More specifically, the present invention relates to an antifungal pharmaceutical composition comprising a 2-thiazole compound and an adrenocortical hormone, and the use thereof for treating or preventing a fungal infection of a human or an animal. Background technique

Fungal infections, especially superficial mycosis, are a common and frequently-occurring disease. The superficial fungal infection is caused by dermatophytes such as the genus Epidermidis, Trichophyton, and Microsporum, and all of them can invade the skin, causing hand, foot, phlegm, femoral hernia, valence, etc. Both can invade the fingers (toes) and cause convulsions; the latter two can invade the hair, causing head lice, jaundice, and the like. Superficial mycosis is highly contagious, with a high incidence, stubbornness and recurrence. For example, athlete's foot, that is, athlete's foot, the national average incidence rate is one-third, and in some high-incidence areas, the incidence rate is as high as 60%.

Skin fungal infections are often accompanied by the presence of inflammation and bacteria, but the effects of antifungal drugs alone are often poor; skin inflammation, whether infectious or non-infectious, is susceptible to fungal or bacterial infections when hormones are used alone.

At present, there are many varieties of antifungal drugs, but most of these drugs only exert antifungal effects when the fungus grows, and have a poor effect on the fungi in the stationary phase.

2-aminothiazoles with antifungal activity, especially Abafungin (N-[4-[2-(2,4-didecyloxy)phenyl]-1,3- Thiazol-2-yl]-1,4,5,6-tetrahydropyrimidin-2-amine) is a broad-spectrum antibacterial agent developed in recent years, which kills both fungal cells in growth and in quiescence, and It has the dual functions of inhibiting fungi and killing fungi, and can target stationary fungal cells, effectively preventing recurrence of infection, and thus can treat mixed infection of some fungi and bacteria, and has better effect on Candida. The preparation and properties of such compounds are described in U.S. Patent Nos. 4,956,370 and 5,104,879.

Adrenal cortex hormone is a general term for various hormones secreted by the adrenal cortex. According to animal experiments and clinical observation of patients with adrenal dysfunction, it is known that the adrenal cortex secretes two major hormones, mineralocorticoid and glucocorticoid, which are important for the life activities of the body, and also secrete a small amount of sex hormones. Mineralocorticoid plays an important role in maintaining sodium, water and potassium in the human body, and plays an important role in maintaining normal water and salt metabolism, body fluid volume and osmotic balance. Glucocorticoids include cortisone (cortisol) and hydrocortisone (cortisol). These hormones have an effect on the metabolism of sugar, protein and fat. The main function is to promote eggs. White matter breakdown and hepatic gluconeogenesis. As a drug, large doses of glucocorticoids have anti-inflammatory, anti-allergic, anti-toxin effects, anti-shock and immunosuppressive effects, so they are widely used in medicine, but there are also side effects that cannot be ignored. In general, adrenocortical hormone used as a drug has an anti-inflammatory effect and has no fungicidal action.

There is still a need in the art for new antifungal drugs to better inhibit or treat fungal infections. Summary of the invention

The present inventors have unexpectedly discovered that when a thiazole compound having antifungal activity, particularly abifipin bafungin, is formulated with a combination of adrenocorticotropic hormone (ie, a pharmaceutical composition containing both), It has a synergistic therapeutic effect on fungal infections.

Accordingly, the present invention provides an antifungal pharmaceutical composition comprising an optionally substituted thiazole compound of the formula (I) or a physiologically acceptable addition salt thereof and an adrenocortical hormone,

among them

Wherein R ³ , R ⁴ , R ⁵ and R ⁶ each independently represent hydrogen, fluorine, chlorine, bromine, iodine, nitro, d. ₄ alkyl, d. ₄ alkane L &, C ₄ alkoxy, di(d . ₄ alkyl) l &, d ₄ alkylthio, d ₄ alkylsulfinyl, d ₄ alkylsulfonyl, or having 1-9 a halogenated d ₄ alkyl group selected from a halogen atom of fluorine, chlorine, bromine or iodine, a halogenated d ₄ alkane L & a halogenated d ₄ alkylthio group, a halogenated d ₄ alkylsulfinyl group or a halogenated d_ ₄ -alkylsulfonyl; X represents oxygen, sulfur, sulfinyl or sulfonyl; Αΐ» represents phenyl, a-naphthyl, anthracene-naphthyl which is unsubstituted or substituted by one, two or more substituents , tetrahydronaphthyl or anthracenyl, which is selected from the group consisting of fluorine, chlorine, bromine, iodine, <^- ₈ alkyl, C _1-8 alkoxy, d. ₈ alkoxycarbonyl, bis (d. ₈ alkane) And a C _1-8 alkylthio group, a d ₈ alkylsulfinyl group, a d ₈ alkylsulfonyl group, an alkyl halide having 1 to 9 identical or different halogen atoms selected from the group consisting of fluorine, chlorine, bromine and iodine Base, halogenated alkane! L &, halogenated d ₄ alkylthio, halogenated d ₄ alkylsulfinyl or halogenated d ₄ alkylsulfonyl, cycloalkyl having 3-7 carbon atoms, or phenyl C "alkyl, Phenoxy C "alkyl or phenoxy,

Wherein the compound of formula (I) is in equilibrium with the tautomeric compounds of formula (la) and (lb),

Wherein R ¹ and R ² are as defined above.

The antifungal pharmaceutical composition according to the invention may also optionally comprise one or more antibacterial shields.

The present invention also provides the use of the antifungal pharmaceutical composition of the present invention as described above for the preparation of a medicament for treating or preventing fungal infection, pruritus, mixed infection of fungi and bacteria, and various dermatitis drugs, wherein the individual is an individual animal. Preferably, it is a mammalian individual, more preferably a human individual. The antifungal pharmaceutical composition of the present invention is also useful for treating or preventing diseases such as vaginal candidiasis and external vaginitis.

The present invention also provides a method of treating or preventing a fungal infection, itching, a mixed infection of fungi and bacteria, various dermatitis and the like, wherein an individual having a risk of or suffering from these conditions is preferably a mammalian individual. More preferably, the human individual, the antifungal pharmaceutical composition according to the invention is administered. The antifungal pharmaceutical composition of the present invention can be used for the treatment of mixed infections of fungi and bacteria in the skin and gynecology (the vulva and vagina of women).

The antifungal pharmaceutical composition can be used in the form of a dosage form for treating or preventing a fungal infection of the skin, a superficial mycosis, itching, a mixed infection of fungi and bacteria, or various dermatitis. Stimulating effect.

In the antifungal pharmaceutical composition of the present invention, one or more compounds represented by the above formula (I) may be contained. Preferably, the one or more compounds of the formula (I) are each independently, R ¹ represents hydrogen, decyl or ethyl, preferably hydrogen; R ³ , R ⁴ , R ⁵ and R ⁶ Each independently represents hydrogen, fluorine, chlorine, bromine, iodine, nitro, decyl, ethyl, 曱L &, ethoxy, oxime! Li t &, ethoxylated, dimercapto, 1⁄2, diethyl^, sulfonylthio, ethylthio, decylsulfinyl, ethanesulfinyl, decylsulfonyl, ethyl a sulfonyl group, or a halogenated fluorenyl group having 1 to 5 identical or different halogen atoms selected from fluorine, chlorine, bromine or iodine, a halogenated ethyl group, a halogenated hydrazine L &, a halogenated ethyl group L & a halogenated Anthracenylthio, haloethylthio, halosulfinylsulfinyl, haloethylsulfinyl, halosulfonylsulfonyl or haloethylsulfonyl, preferably hydrogen, decyl, ethyl , 曱L &, ethoxy;

X represents oxygen, sulfur, sulfinyl or sulfonyl, preferably oxygen; Ar represents unsubstituted or substituted by one, two or more substituents phenyl, a-naphthyl, P-naphthyl, tetra a hydronaphthyl or an anthracenyl group, wherein the substituent is selected from the group consisting of fluorine, chlorine, bromine, iodine, <^- ₆ alkyl, d- ₆ alkoxy, d. ₆ alkoxy^&, di((^alkyl) & , d. ₃ alkylthio, d. ₃ alkylsulfinyl, d_ ₃ alkylsulfonyl group having 1-7 identical or different halogen atoms selected from fluorine, chlorine, bromine, iodine halogenated alkyl d_ ₃ a halogenated d ₃ alkylthio group, a halogenated d ₃ alkylsulfinyl group or a halogenated d ₃ alkylsulfonyl group, a cycloalkyl group having 3 to 7 atoms, or a phenyl d ₃ alkyl group, Phenoxy d_ ₃ alkyl or phenoxy, preferably phenyl, 2-mercaptophenyl, 4-nonylphenyl, 2,6-dianonylphenyl, 2,4-didecylbenzene Base, 2,4,6-tridecylphenyl, _α -naphthyl, anthracenyl-naphthyl, tetrahydronaphthyl or anthracenyl.

More preferably, the compound of the formula (I) of the present invention is abifene.

The compound of the formula (I) can be obtained in a variety of ways, including, for example, commercially available, or can be prepared by reference to U.S. Patent Nos. 4,956,370 and 5,104,879. The contents of these two U.S. patents are hereby incorporated by reference in their entirety.

In the present invention, any pharmaceutically acceptable adrenocortical hormone known in the art can be applied. Such adrenocortical hormones are well known to those of ordinary skill in the art. Preferably, the adrenal glucocorticoid is capable of enhancing the antifungal efficacy of the antifungal pharmaceutical composition. More preferably, the adrenocortical hormone is selected from one or more of the following compounds: fluocinolone and its acetate, triamcinolone and its acetate, isobutyrate and succinate, Hasenide, hydrogenation Cortisone and its esters, butyrate, butyrate propionate, cyclopentanoate, tert-butyl acetate, valerate and ester acid propionate, dexamethasone and its acetate, Diisopropyl fluorophosphate, phenyl phthalate, t-butyl acetate and 2-chloro-62-fluoroester, trioxo-undecate, isonicotinic acid ester and valerate, fluorine Hydrocortisone and its acetate and succinate, triamcinolone acetonide and its acetate, betamethasone and its acetate, dipropionate, ethyl butyl ester, decanoate, Succinate, benzoate, phosphate and pentyl acetate, beclomethasone and its dipropionate, clobetasol propionate, fluorohydrogen, prednisone and its acetate and palmitate , prednisolone and its acetate, phenyl phthalate, hexadecane ester, decanoate and pentanic acid ester, diflunisone and its acetate, ansinide, mometasone and its oxime Acid ester, sputum nylon and its acetate, cyclopentyl propionate, phosphate and succinate, clobetasol butyrate, flumetasone, effluzol and its dipropionate, difluorocoron, ground Spironone and its propionate, fluorohydrogen, deoxymetazone. It is particularly preferred that the adrenocortical hormone is selected from one or more of the following: Hasenide, triamcinolone acetonide, benzalkonium acetate, betamethasone acetate, dexamethasone, triamcinolone, flurazepam , Triamcinolone, hydrocortisone, fluconazole, dexamethasone, fludrocortisone. Adrenal cortex hormones suitable for use in the present invention can be obtained in a variety of ways, including, for example, commercially available from manufacturers such as Shanghai Hualian Pharmaceutical Co., Ltd. and Henan Lihua Pharmaceutical Co., Ltd.

In the antifungal pharmaceutical composition of the present invention, the thiazole compound and the adrenocortical hormone represented by the formula (I) may be present in various suitable amounts. Preferably, the antifungal pharmaceutical composition contains a synergistically effective amount of a 2-aminothiazole compound of the formula (I) and an adrenocortical hormone. In the present invention, "a synergistically effective amount" means an amount capable of enhancing the antifungal or antipruritic effect of the antibacterial pharmaceutical composition. In general, in the antifungal pharmaceutical composition of the present invention, the compound represented by the formula (I) is from 0.01 to 30% by weight, preferably from 0.01 to 20%, more preferably from 0.2 to 10%, particularly preferably 0.5% by weight of the composition. 5%, for example 1-2%; the adrenocortical hormone comprises from 0.005 to 1% by weight of the composition, preferably from 0.01 to 1%, more preferably from 0.01 to 0.5%. Alternatively, in the antifungal pharmaceutical composition of the present invention, the weight ratio of the compound represented by the formula (I) to the adrenocorticoid drug is 2000:1 to 0.1:1, preferably 1000:1 to 1:1, more Preferably 500:1-5:1, for example 200:1-10:1.

Also included in the antifungal pharmaceutical composition of the present invention is any suitable pharmaceutical excipient or carrier. The pharmaceutical excipient or carrier is any conventional pharmaceutical excipient or carrier suitable for the preparation of the preparation. Preferably, the pharmaceutical adjuvant or carrier is selected from one or more of an oily base, a water soluble base, a gel base, a preservative, an antioxidant, and distilled water. In addition, the adjuvant or carrier may further comprise other commonly used types of emulsifiers, odorants, pigments, dyes, propellants and the like which are suitable for various preparation types, and may also include a humectant such as glycerin or thioglycoside if necessary. , propylene glycol and the like, preferably glycerin and propylene glycol.

As used herein, when referring to an oily base, it refers to any pharmaceutically acceptable oily base, especially preferably from petrolatum, lanolin, liquid paraffin, stearic acid, glyceryl monostearate, Tween-80, beeswax, whales. One or more of wax alcohol, stearyl alcohol, cetyl alcohol, stearyl alcohol, acetylated monoglyceride. When the antifungal pharmaceutical composition of the present invention contains an oily base, the content thereof may be, for example, 4 to 55% or 8 to 50% by weight of the composition. As used herein, reference to an aqueous base refers to any pharmaceutically acceptable aqueous base, particularly preferably one or more selected from the group consisting of polyethylene glycol, magnesium aluminum silicate, triethanolamine, carboxyethyl cellulose, glycerin. When the antifungal pharmaceutical composition of the present invention contains an aqueous base, the content thereof may be, for example, 0 to 30%, such as 3 to 25%, or 5 to 20% by weight of the composition.

As used herein, reference to a preservative refers to any pharmaceutically acceptable preservative, particularly preferably from paraben, ethylparaben, propylparaben, butylparaben, sorbic acid, sorbus One or more of an acid clock and sorbic acid. When the antifungal pharmaceutical composition of the present invention contains a preservative, the content thereof may be, for example, 0 to 1% by weight of the composition, such as 0.001 to 0.8%. 0.01 to 0.8%. or 0.05 to 0.6%.

As used herein, when referring to an antioxidant, it refers to any pharmaceutically acceptable antioxidant, particularly preferably from sodium sulfite, sodium metabisulfite, ethylenediaminetetraacetic acid, di-tert-butylhydroxybenzene, sodium hydrogen sulfite, thiosulfuric acid. One or more of sodium. When the antifungal pharmaceutical composition of the present invention contains an antioxidant, the content thereof may be, for example, 0 to 1% by weight of the composition, such as 0.001 to 0.8%. 0.01 to 0.8%. or 0.05-0. 6ο/ _ο .

As used herein, reference to a gel matrix refers to any medicinal condensate, particularly preferably from carbomer, hydroxypropylcellulose, magnesium aluminum silicate, sodium alginate, hyaluronic acid, cross-linked polyacrylic resin One or more of propylene glycol, ethanol, and gelatin. When the anti-bacterial pharmaceutical composition of the present invention contains a gel matrix, the content thereof may be, for example, 4 to 45%, such as 8 to 40% or 12 to 35% by weight of the composition.

In the antifungal pharmaceutical composition of the present invention, the content of the adjuvant or carrier can be determined by routine experimentation according to the requirements of the desired dosage form. For example, based on the weight of the composition, the amount of the oily substrate is 4 to 55%, the amount of the aqueous substrate is 0 to 30%, the amount of the gel matrix is 4 to 45%, and the amount of the preservative is 0 to 1%. The amount of antioxidant used is 0 ~ 1%, and water can be the balance. For example, based on the weight of the composition, the preparation may be in the form of a cream, and the oily base may be selected from 4 to 45%. The aqueous base is 0.1 to 30%. The preservative is 0.01 to 1%, the antioxidant is 0.01 to 1%, and the balance is distilled water. For the gel, choose 4~45% of gel matrix, 0~1% of preservative, 0~1% of antioxidant and the balance of distilled water.

In the antifungal pharmaceutical composition of the invention, one or more antibacterial substances may also optionally be included. The antibacterial substance may be any substance having antibacterial activity which can be combined with the compound of the formula (I) and the adrenocorticotropic hormone, including but not limited to, chlorhexidine sulfate, clinson, ofloxacin, mo One or more of pilocarpine, chlorhexidine acetate, chlorhexidine and nitrofurazone. A person skilled in the art can determine the effective amount of the antibacterial substance in the antifungal pharmaceutical composition of the present invention by a conventional method, for example, in an amount of 0.01 to 10%, preferably 0.1 to 2% by weight based on the total amount of the composition. These antibacterial substances are available in a variety of commercial ways. The compositions of the present invention may be in a variety of suitable dosage forms. Preferably, the dosage form is a topical dosage form conventionally used in the art, such as an ointment, cream, gel, cream, lotion, suppository, oil or spray.

The antifungal compositions of the invention can be prepared by a variety of methods. Such methods of preparation are well known to those of ordinary skill in the art and are taught in a variety of technical documents, such as Remington's Pharmaceutical Handbook, and the like. These methods include conventional formulation preparation techniques such as mixing, dissolving, emulsifying, suspending, and the like.

The antifungal pharmaceutical compositions of the invention can be administered to a variety of animals, including mammals, particularly humans. For an animal or human subject in need of administration of the antifungal pharmaceutical composition of the present invention, the dosage can be determined by the medical practitioner depending on the condition of the subject, including, for example, the severity of the patient's condition, general health, weight, age, and the like. The antifungal pharmaceutical composition of the present invention can be administered by a variety of suitable routes including, for example, transdermal, transdermal, and topical administration and the like. For example, the antifungal pharmaceutical composition of the present invention can be formulated into an ointment, a gel, a cream, or the like, applied to the affected part of the skin surface by application, and used for treating a fungal or fungal-bacterial mixed infection and dermatitis and eczema thereof. Wait. Alternatively, the antifungal pharmaceutical composition of the present invention may be formulated as a suppository or gel for the treatment of vaginal fungi or mixed infection of fungi with bacteria and inflammation thereof. The frequency of administration of the antifungal pharmaceutical composition of the present invention can also be determined by a variety of factors including, for example, the particular disease to be treated, the general health of the subject, and the like. Usually, 1 to 2 times a day for human subjects.

Further, in the present invention, the active ingredient thiazole compound and adrenocortical hormone may be separately packaged and applied to the subject sequentially or simultaneously at the time of application. Accordingly, the present invention relates to a pharmaceutical combination of a 2-thiazolyl compound and an adrenocortical hormone, wherein the thiazole compound and the adrenocortical hormone are present separately or in a mixture. The present invention also provides a kit comprising a separately packaged 2-thiazole compound and adrenocortical hormone, and instructions for use. In this aspect of the invention, the 2-aminothiazole compound and the adrenocortical hormone are as defined above. Preferably, the thiazole compound is abifene. Further preferably, the adrenocortical hormone is selected from one or more of the following: Hasenide, triamcinolone acetonide, fluridine acetate, betamethasone acetate, dexamethasone, triamcinolone, fluorohydrogen Shrink, Triamcinol, Hydrocortisone, Hydronson, Dexamethasone, Fluorocortisone. In this case, the thiazole compound and the adrenocortical hormone may be administered alone or in combination in various suitable dosage forms including, for example, ointments, gels, creams and the like as described above. The dosage and dosage regimen can also be readily determined by the physician based on the patient's severity of illness, general health, weight, age, and the like.

The antifungal pharmaceutical composition or pharmaceutical combination of the invention is administered to an animal subject such as Mammals, especially humans, have one or more of the following beneficial effects: (1) synergistically enhanced therapeutic effects against fungal infections; (2) alleviation of fungal and bacterial damage to the skin, inhibition of various inflammatory responses It also has good curative effect on vaginal candidiasis and vulvovaginitis; (3) It has an enhanced antipruritic effect and has almost no irritating effect on human or animal when applied locally. detailed description

The following examples are not intended to limit the invention, and are provided to facilitate the understanding of the invention.

Example 1 Cream

Formulation: (1) abifene net 10g, (2) dexamethasone l _g , (3) petrolatum 10g, (4) stearic acid 110g, (5) liquid paraffin 60g, (6) glyceryl monostearate 35g, (7) propylparaben 0.2g, (8) octadecyl alcohol 50g, (9) triethanolamine 4.5g, (10) nipa ruthenate 1.8g, (11) di-tert-butyl hydroxy benzene 2g (1 glycerol 40g, (13) sodium pyrosulfite 10g, (14) ethylenediaminetetraacetic acid 1 _g , (1 plus distilled water to 1000g.

Preparation method: After glycerin and sodium metabisulfite are placed in a mortar and ground uniformly, abifene and dexamethasone are added, and the mixture is prepared for use, and the main drug mixture 1 is obtained; petrolatum, stearic acid, glyceryl monostearate , octadecyl alcohol, liquid paraffin, propylparaben, mixed in a water bath 70 ~ 8 (^ stir and dissolve, get oil phase 2; will be paraben, di-tert-butyl hydroxy benzene, ethylene diamine Mix tetraacetic acid and distilled water, put in water bath 70 ~ 80, stir and dissolve, get water phase 3; slowly add 2 to 3, stir vigorously to make the emulsion complete, after cooling, add the same amount to 1 Evenly spread, sub-package, you can. Implement 2 cream

Formulation: (1) Abufenfen 15g, (2) Triamcinolone acetonide 0.15g, (3) Fluorohydrogen acetate

0.05 g, ( ⁴ ) lanolin 45 g, (5) acetylated monoglyceride 70 g, (6) liquid paraffin 60 g, (7) cetyl alcohol 80 g, (8) nipa gold ethyl ester 1.8 g, (9) sodium sulfite 2 g, (10) 35 g of magnesium aluminum silicate, (11) plus distilled water to 1000 g.

Preparation method: mixing lanolin ester, acetylated monoglyceride, liquid paraffin, cetyl alcohol, placed in a water bath 65 ~ 75, stirring and dissolving to obtain oil phase 1; ethylparaben, sodium sulfite, magnesium aluminum silicate The distilled water is placed in a water bath 70 ~ 80, stirred and dissolved to obtain the aqueous phase 2; while stirring 2, 1 is added, cooling; abifene, triamcinolone acetonide, and chlorinated acetate are mixed to obtain the main drug mixture 3, The above 12 mixtures were added in equal amounts to 3, mixed uniformly, and loaded. Example 3 cream

Formulation: (1) abifene net 40g, (2) betamethasone acetate 0.3g, (3) glycerol 100g, (4) stearyl alcohol 40g, (5) glyceryl monostearate 35g, (6) petrolatum 100 g, (7) Tween-80 20 g, (8) 1.5 g of n-butyl butyl acrylate, 1.8 g of (9) di-tert-butyl hydroxy fluorene, and (10) distilled water to 1000 g.

Preparation method: octadecyl alcohol, glyceryl monostearate, petrolatum, Tween-80, placed in a water bath 70 ~ 80 stirred and dissolved, to obtain oil phase 1; will be paraben, di-tert-butyl hydroxyl曱、, mixed with distilled water, placed in a water bath 70 ~ 80 stirred and dissolved, to obtain aqueous phase 2; while stirring 2 to add 1; Abanfine, betamethasone acetate, glycerol mixed evenly, to obtain the main drug mixture 3; Then add the above 12 mixture to the same amount, mix well, and load. Example 4. Gel

Formulation: (1) Abafenjing 20g, (2) Dexamethasone 0.5g, (3) Propylene glycol 800g, (4) 2% paraben, (5) Gelatin 20g, (6) Steamed water to 1000g.

Preparation method: Take gelatin, add distilled water, water bath, soak until fully swollen into gel, spare; take dexamethasone and ethylparaben, add proper amount of propylene glycol, heat to dissolve, let cool, add abaffin Net and residual propylene glycol, stir evenly, get the liquid; stir the gel into the liquid, and continue to homogenize, stir well, add water to 1000g, stir evenly, the amount is obtained. Example 5. Gel

Formula: (1) Abafenjing 30g, U) Triamcinolone 0.2g, (3) Carbomer 5g, ( ⁴ ) Glycerol 11.2g, (5) Sodium metabisulfite lg, (6) Sorbic acid clock 2g, ( 7) Distilled water was added to 1000 g.

Preparation method: taking distilled water, adding carbomer, adding appropriate amount of glycerin in a water bath 50 ~ 70, stirring and dissolving into a gel matrix; adding abifene and triamcinolone to the remaining glycerin, mixing evenly; The amount is added to the glycerin containing the main drug, mixed evenly, and then added with sodium metabisulfite and sorbic acid clock, and the mixture is mixed, that is, it is obtained. Example 6. Gel

Formulation: (1) Abufenfen 15g, U) Fluorohydroxene 0.15g, (3) Crosslinked polyacrylic resin 20g, (4) Sodium alginate 40g, (5) Propylene glycol 50g, (6) Glycerol 200g, (7) 100 g of ethanol, (8) 0.2 g of propylparaben, and (9) distilled water to 1000 g.

Preparation method: mixing cross-linked polyacrylic resin, sodium alginate, glycerin, ethanol and partially distilled water, placed in a water bath 30 ~ 40, stirred and dissolved, into a gel matrix; Abafen, fluorohydrogen, propylene glycol After the propylparaben is uniformly mixed, the same amount of gel is added. The matrix, mix it, and load it. Example 7. Oil agent

Formulation: (1) Abafenjing 100g, (2) Triamcinolone acetonide 0.1g, (3) Glycerol 500g, (4) Ethyl alcohol 300g, (5) 2% paraben.

Preparation method: Abaffinol, triamcinolone, glycerin, and butylparaben are uniformly mixed, and then added with ethanol to mix and prepare, and the amount is obtained. Example 8. Spray

Formulation: (1) Ababafin 200 g, (2) hydrocortisone 9.5 g, (3) glycerol 200 g, (4) sorbic acid 3 g, (5) ethanol 200 g, (6) steamed water to 1000 g.

Preparation method: Abaffinol, hydrocortisone, sorbic acid, glycerin are uniformly mixed, and then added with ethanol and distilled water to be evenly mixed, and the amount is obtained. Example 9. Suppositories

Formulation: (1) Abamfinin 2 g, (2) Fluorohydrogen 0.5 g, (3) Glycerol 700 g, (4) Gelatin 140 g, (5) Nipaquinone 2 g, (6) Distilled water to 1000 g.

Preparation method: mixing gelatin, glycerin and distilled water, heating and melting in water bath; when it is in the form of paste, add abifene and fluorohydrogen, stir evenly, and when it is close to solidification, pour into suitable pessary mold, slightly overflow After cooling and solidifying, it is smoothed, and the package is taken out. Example 10. Lotion

Formulation: (1) Abafenjing 40g, (2) Dexamethasone 0.95g, (3) Glycerol 40g, (4) 1.5g of ethylparaben, (6) Distilled water to 1000g.

Preparation method: the distilled water is placed in a water bath for 40 ~ 50 heating; another glycerin and abifene, dexamethasone, and parabens are mixed and added to the distilled water of the above water bath and glycerin, mixed evenly, loaded The quantity is available. Example 11. Ointment

Formula: (1) Abafenjing 10g, (2) Fluorocortisone 0.05g, (3) Red trial 0.8g,

( ⁴ ) Vaseline 200g, (5) acetylated monoglyceride 80g, (6) liquid paraffin 200g, (7) glycerin 500g, (8) propylparaben 0.2g.

Preparation method: mixing petrolatum and acetylated monoglyceride, placed in a water bath 40 ~ heating, to obtain oil phase 1; mixing liquid paraffin and glycerin, placed in a water bath 40 - 50 heating, to obtain aqueous phase 2; In the case of adding 1 and then adding Nipogin C Ester, abifene, fludrocortisone, red trial, stir evenly, the amount is available. Pharmacological test

Inhibition of fungal infection in guinea pig skin

Drug: Formulation 1 and preparation prepared separately according to the formulation of Example 1 and the formulation of Example 2

2; containing 2% abifene detergent; physiological saline.

Experimental animals: Guinea pig, 250-300 g, male, provided by the Experimental Animal Center of Chongqing Institute of Chinese Materia Medica, Certificate No.: SCXK (渝) 20020004.

40 guinea pigs were shaved with about 3cm X 3cm on the left and right sides of the back. The guinea pigs were repeatedly rubbed with sandpaper to remove the skin. The skin had exudate but no bleeding, and the prepared hairy mites were treated with a glass rod. 10 ⁵ / mL of the bacterial suspension was applied to the damaged skin, and incubated at lmLo per 1 cm ^{2 for} 30 days at room temperature. After the animal was inoculated with fungus, erythema, redness, rash, scales or molting appeared. Guinea pigs infected with Trichophyton rubrum were randomly divided into 4 groups, 10 in each group, respectively, Formulation Group 1, Formulation 2, 2% Abufenfen Group, and saline-negative control group. Apply the test substance to the affected area so that the contact time is 30 min, once a day for 7 days. The symptoms of skin infection before and after treatment were scored, 0 points showed no skin damage, 1 was point-like erythema, 2 was divided into full-range erythema, 3 was divided into redness and scaly, and 4 was divided into erythema and scar.

Result:

Before and after treatment, the guinea pigs were infected with Trichophyton rubrum and skin and skin infections. The statistical analysis showed that there was no difference before the treatment of each group. There was significant difference between the groups and the drug before treatment, and the control group was significantly aggravated ( Ρ<0·05 ), all treatment groups were relieved (Ρ<0·05), and there was significant difference between the drug preparation group 1 and the preparation group 2 and the abifene group and the control group (Ρ<0.05). Post-drug preparation 1, preparation 2 was significantly different from the abifene group (Ρ<0.05) „ The results suggest that Formulation 1, Formulation 2 and Abafenfen treatment of guinea pigs with Trichophyton rubrum infection癣 has a good therapeutic effect, and the efficacy of Formulation 1 and Formulation 2 is significantly better than that of abamfene alone (see Table 1).

Table 1 Therapeutic effects of each group on the surface infection of guinea pigs

Group η ankle score physique score

After the drug prodrugs, the control group 10 2.5 soil 0.5 3.3 soil 0.6 2.7 soil 0.6 3.1 soil 0.7 abaffin net group 10 2.6 soil 0.7 1.9 + 0.7 * 2.7 soil 0.7 1.9 + 0.5 * preparation group 1 10 2.5 soil 0.7 1.0 + 0·6* ^Δ 2.4 soil 0.7 1.1 soil 0·7* ^Δ preparation 2 groups 10 2.6 soil 0.7 1.0 + 0·6* ^Δ 2.5 soil 0.7 1.2 ± 0·6* ^Δ Note: compared with the control group: ^Α Ρ <0.05, compared with the abifene group: ^Δ Ρ<0.05 The antipruritic effect of this product

Forty guinea pigs were randomly divided into 4 groups, 10 in each group, namely, saline negative control group, abifene net group, preparation group 1 and preparation group 2. The guinea pigs in each experimental group were shaved on the right hind paw, and the test subjects were applied to the affected area so that the contact time was 30 min, once a day for 3 days. After the last administration, lh, the shaved area of the right hind paw was rubbed with a coarse sandpaper, the area was lcm x lcm, and 0.01% phosphoric acid histamine 0. 05 ml/only was started at the wound surface. Thereafter, the concentration of histamine phosphate was increased by 0.1, 0.2, 0.4, 0.8, 1.6, 3.2, 6.4, 12.8, 25.6, and 51.2 mg/ml every 3 minutes, each time being 0.05 ml/mouse. Until the guinea pig appeared to return to the hind paw, the concentration of histamine phosphate administered at the end of the guinea pig hind paw was the itch threshold, and the itch threshold was recorded and compared.

RESULTS: The itch threshold of Abafenjing group and Formulation 1 and Formulation 2 group was significantly increased (P<0.05), and the itch threshold of Formulation 1 and Formulation 2 was significantly higher than that of Abafenjing alone (P<0.05). . The results suggest that the combination preparation of the present invention has an obvious antipruritic effect (see Table 2).

Table 2 Effect of itch threshold in each group

Group n mean itch threshold (mg/ml) control group 10 0.28 + 0.19

Abafon net group 10 3.76 soil 1.81*

Formulation 1 group 10 15.72 soil 6.75* ^Δ

Formulation 2 group 10 15.36 soil 6 · 60 * ^Δ

Note: Compared with the control group: ^Α Ρ<0.05, compared with the abifene group: ^Δ Ρ<0.05 skin local irritation test

In order to study the local stimulating effect of the compound preparation of the present invention, the experiment was performed on the left and right sides of the same body. Take 6 guinea pigs and shave about 3cm X 3cm on the left and right sides of the back. The guinea pigs after shaving were randomly divided into 2 groups, 3 in each group, namely, the preparation group 1 and the preparation group 2. The left hair removal area was coated with the test substance lml, and the right side was coated with physiological saline as a control, and fixed with gauze. Each animal was subcultured in cages, and after 24 hours of administration, the test article was removed by washing with warm water and observed. Visual observation and histopathological examination were performed at 1 hour, 24 hours, 48 hours, and 72 hours after removal of the test substance, and the presence or absence of erythema and edema at the site of application, and the recovery and time of the above were recorded.

The results showed that there was no local irritation such as erythema and edema in the test area of each group of animals; histological sections showed that no irritative pathological changes were found in the test areas of each group. It is indicated that the combination preparation of the present invention is not locally irritating. The above results show that the combination of abifene and adrenocortical hormone can not only improve the curative effect, but also reduce the damage of the infection to the skin, and has a rapid antipruritic and anti-inflammatory effect, and has no irritating effect on the local.

The invention has been described above by way of illustration. However, it should be understood that the present invention is by no means limited to these specific embodiments. A person skilled in the art can make various modifications and changes to the invention without departing from the spirit and scope of the invention.

Claims

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An antifungal pharmaceutical composition comprising an optionally substituted 2-aminothiazole compound represented by the formula (I) or a physiologically acceptable addition salt thereof and an adrenocortical hormone drug,

Wherein R ¹ represents hydrogen or d ₄ alkyl, and R ² represents a substituent represented by the following formula

Wherein R ³ , R ⁴ , R ⁵ and R ⁶ each independently represent hydrogen, fluorine, chlorine, bromine, iodine, nitro, d. ₄ alkyl, d. ₄ alkoxy, d. ₄ alkoxycarbonyl, (d. ₄ alkyl) &, d ₄ alkylthio, d ₄ alkylsulfinyl, d ₄ alkylsulfonyl, or an alkyl halide having 1-9 halogen atoms selected from fluorine, chlorine, bromine and iodine a halogenated d ₄ alkoxy group, a halogenated d ₄ alkylthio group, a halogenated d ₄ alkylsulfinyl group or a halogenated d ₄ alkylsulfonyl group; X represents an oxygen, sulfur, sulfinyl group or sulfonyl group; Ar represents a phenyl group, a-naphthyl group, P-naphthyl group, tetrahydronaphthyl group or anthracenyl group which is unsubstituted or substituted by one, two or more substituents, wherein the substituent is selected from the group consisting of fluorine, chlorine and bromine , iodine, d_ ₈ alkyl, d_ ₈ alkoxy I & C ₈ alkoxycarbonyl, bis((alkyl)J^, (^alkylthio, (^alkylsulfinyl, d- ₈ alkylsulfonyl, having 1-9 selected from fluorine, chlorine , bromo, halo d_ same or different halogen atoms iodine _C4 alkyl, halo d_ ₄ alkyl! L &, halo d_ ₄ alkylthio, halo d_ ₄ alkylsulfinyl, or halo d_ ₄ An alkylsulfonyl group, a cycloalkyl group having 3 to 7 carbon atoms, or a phenyl d- ₄ alkyl group, a phenoxy d- ₄ alkyl group or a phenoxy group,

Wherein the compound of the formula (I) is in equilibrium with the tautomeric compounds represented by the formulae (la) and (lb),

Wherein R ¹ and R ² are as defined above.

The antifungal pharmaceutical composition according to claim 1, wherein in the formula (I), R ¹ represents hydrogen, decyl or ethyl, preferably hydrogen; R ³ , R ⁴ , R ⁵ and R ⁶ Each independently represents hydrogen, fluorine, chlorine, bromine, iodine, nitro, decyl, ethyl, decyloxy, ethoxy, decyloxycarbonyl, ethylcarbonyl, diindolyl, diethyl^, hydrazine Thio, ethylthio, decylsulfinyl, ethanesulfinyl, decylsulfonyl, ethylsulfonyl, or having 1-5 of the same or not selected from the group consisting of fluorine, chlorine, bromine, and iodine Halogenated fluorenyl group of the same halogen atom, haloethyl group, halomethoxy group, haloethoxy group, halosulfonylthio group, haloethylthio group, halodecylsulfinyl group, haloethyl group Sulfonyl, halosulfonylsulfonyl or haloethylsulfonyl, preferably hydrogen, decyl, ethyl, decyloxy, ethoxy; X represents oxygen, sulfur, sulfinyl or sulfonyl, Preferably Oxygen; Ar represents a phenyl group, a-naphthyl group, P-naphthyl group, tetrahydronaphthyl group or anthracenyl group which is unsubstituted or substituted by one, two or more substituents, wherein the substituent is selected from fluorine, chlorine , bromine, iodine, <^- ₆ alkyl, d- ₆ alkane L &, d- ₆ alkoxycarbonyl, bis(<^- ₆ alkyl)amino, C alkylthio, C alkylsulfinyl, C alkylsulfonyl group, a halogen atom having the same or different halo d_ 1-7 substituents selected from fluoro, chloro, bromo, iodo _alkyl, haloalkyl D_ ₃ alkylthio, halo ₃ alkylsulfinyl D_ d_ ₃ haloalkyl or alkylsulfonyl group, a cycloalkyl group having 3 to 7 carbon atoms, or a phenyl d_ ₃ alkyl group, a phenoxy group d_ ₃ alkyl or phenyl L &, preferably phenyl, 2- Nonylphenyl, 4-nonylphenyl, 2,6-didecylphenyl, 2,4-didecylphenyl, 2,4,6-tridecylphenyl, a-naphthyl, P - Naphthyl, tetrahydronaphthyl or anthracenyl.

The antifungal pharmaceutical composition according to claim 1, wherein the adrenocortical hormone drug is one or more selected from the group consisting of fluocinolone and its acetate, triamcinolone and its acetate, Isobutyrate and succinate, Hasinide, hydrocortisone and its ester esters, butyrate, butyrate propionate, cyclopentanoate, t-butyl acetate, valerate Propionic acid propionate, dexamethasone and its acetate, diisopropyl fluorophosphate, phenyl phthalate, t-butyl acetate and 2-chloro-62-fluoroester, trioxane-ten Monoester, isonicotinic acid ester and valerate, fludrocortisone and its acetate and succinate, triamcinolone acetonide and its acetate, betamethasone and its acetate, dipropionate, ethyl acetate Esters, phthalates, succinates, benzoate, phosphates and pentanates, beclomethasone and its dipropionates, clobetasol propionate, fluorohydrogen, prednisone and its acetic acid Ester and hexadecane ester, prednisolone and its acetate, phenyl phthalate, hexadecanate, decanoate and pentyl acetate, Flurazine and its acetate, ansinide, mometasone and its phthalate, sputum and its acetate, cyclopentanoate, phosphate and succinate, clobetasol butyrate, flumethasone , amilamicin and its dipropionate, Diflupredone, despirone and its propionate, fluorohydrogen, dessamesolone, and preferably one or more selected from the group consisting of: Hashimide, triamcinolone acetonide, fluorohydrogen acetate Pine, betamethasone acetate, dexamethasone, triamcinolone, flurazepam, triamcinolone, hydrocortisone, fluconazole, dexamethasone, fludrocortisone.

The antifungal pharmaceutical composition according to claim 1, wherein the compound represented by the formula (I) is from 0.01 to 30% by weight, preferably from 0.01 to 20%, more preferably from 0.2 to 10% by weight of the composition, particularly preferably It is 0.5 to 5 %, for example, 1-2%; the adrenocortical hormone drug is 0.005 to 1% by weight of the composition, preferably 0.01 to 1%, more preferably 0.01 to 0.5%.

The antifungal pharmaceutical composition according to claim 1, wherein the weight ratio of the compound represented by the formula (I) to the adrenocorticoid drug is 2000:1 to 0.1:1, preferably 1000:1: 1, more preferably 500:1-5:1, for example 200:1-10:1.

6. An antifungal pharmaceutical composition according to claim 1 further optionally containing a pharmaceutically acceptable adjuvant or carrier.

The antifungal pharmaceutical composition according to claim 6, wherein the pharmaceutically acceptable adjuvant or carrier is selected from one or more of an oily base, an aqueous base, a gel base, a preservative, an antioxidant, and water.

The antifungal pharmaceutical composition according to any one of claims 1 to 6, wherein the composition is a pharmaceutical dosage form, preferably an external dosage form, more preferably an ointment, a cream, a gel, or a cream. , lotions, suppositories, oils or sprays.

9. The antifungal pharmaceutical composition of claim 1 further comprising one or more antibacterial materials.

10. The antifungal pharmaceutical composition according to claim 9, wherein the antibacterial substance is selected from the group consisting of chlorhexidine sulfate, clinson, ofloxacin, mupirocin, chlorhexidine acetate, One or more of chlorhexidine and nitrofurazone.

The antifungal pharmaceutical composition according to claim 9 or 10, wherein the antibacterial substance is contained in an amount of from 0.01 to 10%, preferably from 0.1 to 2%.

The antifungal pharmaceutical composition according to any one of claims 1 to 11, wherein the compound represented by the formula (I) is abifene.

Use of an antifungal pharmaceutical composition according to any one of claims 1 to 12 for the manufacture of a medicament for the treatment or prevention of fungal infections, pruritus, mixed infections of fungi and bacteria, and various dermatitis.

Use according to claim 13, wherein the individual is an animal, preferably a mammal, more preferably a human.

, a method of treating or preventing a fungal infection, pruritus, a mixed infection of fungi and bacteria, various dermatitis and the like in an individual, including an individual, preferably a mammal, more preferably a human suffering from or at risk of developing such conditions The antifungal pharmaceutical composition according to any one of claims 1 to 12 is administered.