JPS58140018A - Remedy for superficial mycosis - Google Patents

Abstract

PURPOSE:The titled remedy, containing a substituted indoline as an active constituent, capable of exhibiting a high antimicrobial activity against fungi without irritation with low toxicity, and effective for treating superficial mycosis, e.g. trichophytosis, etc. CONSTITUTION:A remedy for superficial mycosis containing a substituted indoline of formulaI(R is H, halogen or nitro) as an active constituent. In formulating the remedy, one or more compounds of the active constituent in the form of fine powder may be applied to the affected part, and usually dissolved or dispersed in a liquid carrier, e.g. an alcohol such as methyl alcohol or ethyl alcohol, to give an alcoholic agent or lotion or incorporated with a solid carrier, e.g. vaseline or white ointment or a hydrophobic oily base, e.g. the silicone type, to give an ointment for application. The active constituent of the above-mentioned formula is synthesized by reacting a substituted indoline compound of formula II with 2-chloroacetyl chloride in the presence of an organic solvent and a base.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a therapeutic agent for hypertrophic syndrome containing substituted indoline a' as an active ingredient.

Mycosis refers to the transmission of fungal infections that affect the human body.
Depending on the location of the infection, it can be divided into 9 superficial fungal infections and deep fulminant fungal infections. It is rare for this to occur and have deep repercussions.

Self-destruction, yellowing, spiral 1. Noodle fever, candida disease, etc. belong to this category, and it is not uncommon for them to be transmitted from one person to another through infected skin, chest drop, diseased hair, etc. Among these diseases, yellow 11 is yellow @ @ (TriOhOph7tOn#OhO
＠nlθ1nii) is a true fulminant disease.

Trtohophyton, which is rare in Japan,
Conoent-riorm) is a fungal disease found in the tropics and subtropics, but it is also caused by white attack caused by dermatophytes (Demato-riorm), I-type infection caused by Malasse++ia furfur, and candida.・Albi sword (0arol 1daalb)
In Japan, candidiasis caused by candidiasis (Ioans) is a highly serious disease.

However, in Japan, candidiasis has been on the rise in recent years, but since the weather is hot and humid, especially in the summer, candidiasis has been known for a long time, and treatments such as 9-night concoction medicine, etc. It was the seed of a great many people's enthusiasm that even superstitious ideas were proposed about it. In other words, the self-destruction includes the white l1m1 genus (TI”) as a shallow self-destruction.
10hOph7tOn or less is abbreviated as Tr. ) than by ferrugineum (!r, ferrugineum), violet-(!r, ma1olaa@um), hair healing soda (Tr,
mentagrophytes), Trichophytes (Tr,
tonsurans), Miorospo
rum MiOr, and 1ljs)'s gypsum-like vesicles 1M1or.

gypseun) + Mior, oani
s) The number of cases due to l1ii1iI is increasing! Tr, rubrum
Massive small water marks often caused by white spots (commonly known as Zenitamushi)
, Iepider-mophy
ton) hairy epidermal bacteria (Ipi (141r!ooph)
Tr, inte
rdigitale), awn-like Cao (Tr, aate)
foot mouth habit and hand self-destruction (commonly known as misumushi) caused by ``rotdes'', nail whitening caused by crimson 1. In addition, there are deep-seated whites, such as Narzus baldness, which is often caused by baldness, white baldness caused by red skin, and generalized baldness and Mayotsky baldness granuloma. 0 And each of these symptoms is called JIIl, for example, scale.

Hair loss, desquamation, water eruptions, erosions, turtle cysts, papules, and thickening.

Keratinization and other symptoms occur, and persistent itching, pain, and analgesia are observed.

Treatments include topical antifungal agents, oral antifungal antibiotics such as griseofulvin, trichomycin, and
Ultraviolet therapy for external use or as phototherapy is a must!
Although there are surgical treatments depending on the condition, the current situation is that a complete and appropriate treatment has not yet been found. In other words, oral antibiotics require large doses and long-term administration, which may cause gastrointestinal disorders, or the therapeutic effect may not necessarily be accurate. However, even ultraviolet light therapy requires a long period of time, and care must be taken to prevent skin damage due to irradiation, so the appropriate M
◎Additionally, the method of using topical antifungal agents is unlikely to have a significant therapeutic effect.

Various ointments containing various antifungal compounds depending on the symptoms,
This method is simple and the most commonly used method, as it involves applying a hard product such as a tincture directly to the affected area.Many compounds have been proposed for this purpose.
Some products may not be completely effective, some may be effective but cause pain when applied to the affected area, the active ingredient may stain clothing due to its coloring properties, or there may be an unpleasant odor. The advantages and disadvantages of the project were not necessarily satisfactory.

The present inventors completed the present invention as a result of conducting antifungal screening of a huge number of new and existing compounds in order to solve these problems. Specifically, the present invention provides a therapeutic agent for superficial mycosis, characterized in that the active ingredient is a substituted indoline represented by the general formula (wherein R represents a hydrogen atom, a halogen atom, or a nitro group). It is.

The substituted indolines represented by the general formula CI) in the present invention include those in which the substituent R is a hydrogen atom, a chlorine atom; a herogen atom such as a bromine atom, or a nitro group, for example, as shown below. A chemical compound can be discovered. Compound name and physical properties first! ! Among the compounds of the present invention shown in Table 1, Compound No. 1 is a new compound that has not been described in any literature.

Thus, it can be produced by reacting a substituted indoline compound, which is an active ingredient of the present invention, with 2-chloroacetyl chloride in the presence of a base. In addition, these bases include trimethylamine and triethylamine.

Preferably, a base such as pyridine is used.

Next, the antibacterial test results of the active ingredient compound of the present invention against pathogenic microorganisms, particularly bacteria and fungi, will be described.

Example 1 (Antibacterial test 1) Staphylococcus aureus was used as a bacterium.
aus&ur@Bm) Tt t As fungi, ゛'゛ ヰbachi w4, jQ njida, albicans li (0a
ndid & albioans), gypsum microsporum (
Miar gypssum) *Tr, ma
Using Sabouraud agar medium, the minimum inhibitory concentration (1μI/ml) of each compound, 8, and undecylene as a control product was determined by decreasing dilution method after culturing at 26°C for 7 days. In the case of Staphylococcus aureus (Tr, rubsum), trapping was carried out in the same manner as above using a broth medium. The results are shown in Table 2.

As described above, one of the component compounds of the present invention was found to have high antibacterial properties f:N against fungi, and it was found that it can be used as an effective therapeutic agent against fungi.

Examples Each (stimulation test) +11-limit mucosal stimulation (frequent eye drops) Healthy white domestic rabbits with no abnormalities in their eyes and with a blackout of 2.5 to 3.0 were subjected to experiments in groups of 5, and each of the above-mentioned inventions Ingredient combination IwI
Dissolved in 14 parts each in cottonseed oil.

α05sJ was instilled into the eyes 9 times at 15 minute intervals, and the Q judgment was observed over time using the tube 6 hours after the last instillation.

The test was carried out according to the evaluation table of Draii+.

The results are shown in Table 3.

(2) Using a domestic rabbit similar to the skin-ocular mucosal stimulation test, the abdominal hair was kept as short as possible 24 hours before the test.

Apply approximately α5t of 1qh ointment at a time to 4 to 5 locations on each specimen with a diameter of approximately 2 mm, bordering on the midline.
<3rd I!
Shown below.

Example 3 (Acute Toxicity) Using 6- to 7-week-old ddY mice (male), a 5% suspension of gum arabic containing each of the above-mentioned unexploded 1I11 component compounds was orally administered according to a conventional method, and the mice were observed for 7 days. .

Half 1 IrIk dead amount (LD5.) was determined. MA3 result
In the table, - means *jl'i e lk shi.

Table 3 From the results of these initial tests, it was confirmed that the component compounds of the present invention are non-irritating and have low acute toxicity.
Sakura*sen 1. These powders may be applied to the affected area as a fine powder, but 2 usually in a liquid carrier.

For example, methyl alcohol, ethyl alcohol.

It can be dissolved or dispersed in an alcohol such as ethylene glycol or glycerin to form an alcoholic agent or a soap agent (including a propellant), or it can be prepared using a solid carrier, e.g.
Vaseline, white ointment, purified lanolin, simple ointment, etc. (all listed in the Japanese Pharmacopoeia), or hydrophobic fat-based bases such as silicone thread, 'or hydrophilic ointment, @water ointment, hydrophilic petrolatum, etc. (all listed in the Japanese Pharmacopoeia) It can be applied by mixing or adsorbing it with a hydrophilic base such as crystals, cold cream, macrogol ointment, etc. and applying it to the affected area as an ointment. There is no problem in adding and co-using preservatives such as esters.Furthermore, excipients, WI mixtures, and disintegrants that are commonly used according to the Japanese Pharmacopoeia according to each JillIjM.

-Thickening agent, emulsifying agent, lubricant2. It can be used in dosage forms such as suspensions, emulsions, S+ granules, and two-mention preparations by adding the additives (a) and (a). anti-agents such as i&solubilizing agents, such as undecylenic acid bombardment and others;
For example, antibiotics such as penicillins, streptomycin, etc. may be added without any problem.

The amount of the component compound of the present invention added to the therapeutic agent is 2.
It is mixed at a rate of 15 to 3 times 7% (15 to 3 times) for the vM disease treatment agent.

However, the therapeutic agent of the present invention may be used as usual.

By repeatedly applying it to the affected area once or several times a day, it can reduce and eliminate the itching and inflammation in the affected area, and can finally be used to completely treat superficial myopathies. ◎ Example 4 (Lotion) 1-(2-chloroacetyl)-5-bromoindoline 2
1. Glycerin 1st and ethyl alcohol 82F were mixed and dissolved to make a lotion Example 5 (Ointment) 1-(2-chloroacetyl)-6-Takasumi loindoline 1
F, diethyl sebaceous acid) 5F was thoroughly and uniformly mixed with *IJ ethylene ointment from the Japanese Pharmacopoeia to prepare an ointment.

Example 6 (Ointment) 1-(2-100% cetyl-6-10 loindoline 1)
An ointment was prepared by thoroughly and uniformly mixing a water-absorbing ointment prepared by adding 5 parts of zinc monoxide to several Japanese Pharmacopoeia ointments containing 5, 9 ethyl sebacate 5F as a base.

Next, we will discuss a treatment experiment for one guinea pig's palatability.

Example 7 (Experimental animal self-destruction therapy experiment) Guinea pig (
Alpino III) 10 animals per group.

After removing the hair from the 4 spots on the back of the MS to a width of about 3mm, and forming the hair by rubbing it with sandpaper, #
I-liquid was applied. After 48 hours of application, using the compound of the present invention, a lotion preparation with the same concentration as in Example 4 and a predetermined concentration, and an ointment with the same concentration as in Example 5, Apply once a day for 8 days, changing the application site to each animal.

The next day, the epidermis was cut off, cut into 25 equal parts, immersed in α1 ice water for 30 minutes, then washed with sterile distilled water, and each piece was transplanted onto a slope of 4 slices of Glucose Sabouraud medium. , after 14 days of incubation at 26±51°C. The presence or absence of II growth was examined. The effectiveness was determined by the 1 growth negative rate for each section (section - rate wrinkle section number ↑ section number x 100),
This was done by determining the severe growth negative rate (complete negative rate - number of complete annular lesions/number of experimental lesions x 100) for all five sections of one lesion.The results are shown in #4.

4th Il Example 8 (Sudden barbarian rousing test)
rlum), TM9 & TAloQ, 'l'Al5
35. TA1557. TA155g, each nut
Tested using rientbroth liquid medium. As a result, the number of revartant colonies produced was counted and compared with the negatlve oontro technique (solvent dimethyl sulfoxide alone). The result is the fifth
Shown in 11 @ Table 5 Patent applicant Ihara Chemical Industry Co., Ltd.

Claims (1)

[Claims] A treatment M for superficial mycosis, characterized in that it contains a substituted indoline rut represented by the formula (in the formula, a hydrogen atom, a halogen atom, or a nitro group) as an active ingredient.