JPS62126182A - 2-furanmethyl n-(2,3-xylyl)anthranilate - Google Patents

Abstract

NEW MATERIAL:2-Furanmethyl N-(2,3-xylyl)anthranilate expressed by the formula. USE:A medicine and agent for exoderm. White tetragonal crystals capable of exhibiting ready solubility in organic solvents, e.g. hydrocarbons, alcohols, ketones, etc.,having improved anti-inflammatory action and analgesic action and further safety, e.g. oral toxicity, etc., and useful for acute and chronic eczema, atopic dermatitis, contact dermatitis, herpes zoster and eczema dermatitis from various causes, various wounds, burns, arthritis, lumbago, muscular pain, etc. PREPARATION:N-(2,3-Xylyl)anthranilic acid or a halide thereof is reacted with furfuryl alcohol in a solventm, e.g. toluene, etc., or an alkali salt of the N-(2,3- xylyl)anthranilic acid is reacted with a 2-methyl halide of furan in a solvent, e.g. dimethylformamide, etc., to afford the aimed compound expressed by the formula.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to 2-furanmethyl-N-(2,3-xylyl)
The present invention relates to anthranilate and a skin preparation containing the compound as an active ingredient.

2-Furanmethyl-N-(2,3-xylyl) anthranilate according to the present invention is a new compound that has not been described in any literature,
It has remarkable anti-inflammatory and analgesic effects and is an industrially useful compound as a new pharmaceutical.

[Prior Art] The novel compound of the present invention, 2-furanmethyl-N-(2,3-
N-(2
, 3-xylyl) anthranilic acid, commonly called mefenamic acid, is a substance widely used as an anti-inflammatory, anti-rheumatic, antipyretic and anticancer agent.

[Problems to be Solved by the Present Invention] However, the N-(2,3-xylyl)anthranilic acid is extremely insoluble in water, alcohol, oil, etc.
It has been used exclusively as an oral preparation in the form of powders, tablets, and capsules, and its use as a dermal preparation has not been indicated.

In addition, oral toxicity was high, and there were also problems in terms of safety.

In view of the above circumstances, the present inventors have conducted extensive research to obtain an anti-inflammatory and analgesic agent that has high transdermal absorption, has remarkable anti-inflammatory and analgesic effects even when applied to the skin, and is also excellent in terms of safety such as oral toxicity. As a result of repeated research, it was discovered that the above object could be achieved by introducing a 2-methylfuryl group into the carboxyl group of N-(2,3-xylyl)anthranilic acid.Based on this knowledge, the present invention was completed. reached.

Means and actions for solving problem E] That is,
The present invention is a novel 2-furanmethyl-N-(2,3-xylyl) anthranilate represented by formula (A), and a skin preparation containing the new compound as an active ingredient.

A novel compound according to the present invention, 2-furanmethyl-N-(2
, 3-xylyl) anthranilate is a white rectangular crystal that is easily soluble in organic solvents such as hydrocarbons such as hexane and benzene, alcohols such as ethyl alcohol and propyl alcohol, and ketones such as acetone and methyl ethyl ketone. As for its production method, a conventional method of acid esterification reaction can be used. For example, N-(2,3-xylyl)anthranilic acid or its halide is treated with furfuryl alcohol;
2 of furan to the alkali salt of anthranilic acid (xylyl)
- It can be produced by a method in which a methyl halide is applied.

EXAMPLES The present invention will be specifically explained below with reference to examples for producing the novel compounds of the present invention. Note that the present invention is not limited to this.

Production example 1゜Sodium N-(2,3-xylyl)anthranilate 2
After dissolving 5.3 g in 200 ml of dimethylformamide, 11.7 g of 2-chloromethylfuran was added, and the mixture was heated at 90°C.
The mixture was reacted for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with diethyl ether. The residue obtained by distilling off the ether after dehydration was recrystallized from ethanol to obtain a white square 2-7ranemethyl-N-(2,
28.3 g of 3-xylyl) anthranilate was obtained.

Melting point = 50~51℃ Elemental analysis' C20H19NO3 Calculated value (parcel) C74,75H5,96N 4.36
Actual value (X) C75, 12H5, 92N 4.29
Mass spectrum parent ion (m/e) = 321 Production example 2 24.1 g of N-(2,3-xylyl) anthranilic acid and 36.0 g of thionyl chloride were mixed in 20 Od of benzene and reacted under reflux for 3 hours. Ta. Next, the solvent and excess thionyl chloride were distilled off under reduced pressure, and 500 ml of tetrahydrofuran and 9.8 g of furfuryl alcohol were added to the resulting residue, and then 15.0 g of triethylamine was gradually added at room temperature and stirred for 30 minutes. The mixture was reacted under reflux for 1 hour. After the reaction was completed, water was added to the residue and extracted with diethyl ether. The oily residue obtained by distilling off the ether after dehydration was recrystallized from ethanol to obtain white square 2
29.6 g of -furanmethyl-N-(2,3-xylyl)anthranilate was obtained.

Melting point: 50-51℃ Mass spectrum parent ion (m/e) = 321 Production example 3゜N-(2,3-xylyl)anthranilic acid 38.6g, toluene 750 WIt and furfuryl alcohol 7
．． After refluxing for 15 hours with stirring, the toluene layer was washed successively with dilute hydrochloric acid, carbonic acid, and distilled water. The residue obtained by distilling off toluene after dehydration was recrystallized from ethanol to obtain white square 2-furanmethyl-N-(2,3-xylyl) anthranilate 24.
8g was obtained.

Melting point = 50-51°C Mass spectrum parent ion (m/e) = 321 Next, the new compound 2-furanmethyl-N-(2,3
The toxicity tests and pharmacological effects of -xylyl) anthranilate are shown below.

JLt Co., Ltd. 11 1CR female mice (body weight 18-22 g, 10 mice per group) were suspended in 2.0% carboxymethylcellulose/physiological saline and adjusted to a predetermined amount using an oral needle. I gave it to you. Post-administration observation of toxic symptoms was continued, and acute oral toxicity values (LDso) were calculated from the dead cases during the 7-day observation period by the van der Weerden method. Display the results -
Shown in 1.

As is clear from Table 1, the novel compound 2-furanmethyl-N-(2,3-xylyl) anthranilate according to the present invention is more effective than the known N-(2,3-xylyl) anthranilic acid. 4 times more LDs.

It was found that the toxicity was extremely low.

A: The rat/carrageenan paw edema method is commonly used to measure the anti-inflammatory effects of drugs, and as it has been shown to have a high correlation with the anti-inflammatory effects in humans, it has been designated as a standard test method. ing.

Procedures of Winter et al.
the 5oci-ety for experience
tal Biology & Mediains,
111, p. 554, 1962), 0 was administered to male Wistar rats (body weight 110-130 g, 8 rats per group).
．． A test compound suspended in a 5% aqueous carboxymethyl cellulose solution was orally administered (100 mg/kg).

After 1 hour, 1% λ-Lageniragenin/
Physiological fluid was subcutaneously administered to the heel of one hind limb of the rat for 0.1 d to induce edema. The heel volume of each foot was measured before and at a certain time after administration of the inflammatory substance, and the foot l! The capacity increase rate of 7J (■1) was determined. As a control group, the rate of increase in constant volume (VO) was measured when λ-carrageenan was similarly injected into rats administered with a 0.5% carboxymethylcellulose aqueous solution that did not contain the test compound.
t) The carrageenan edema suppression rate (%) was calculated using the formula 100/Vo, and was taken as the anti-inflammatory activity of the test compound. The larger this value is, the higher the anti-inflammatory activity is.

Table 2 shows the measured values 5 hours after injection of λ-carrageenan.

As is clear from Table 2, novel compound 2 according to the present invention
-Furanmethyl-N-(2,3-xylyl) anthranilate, like the known N-(2,3-xylyl) anthranilate, exhibits a strong edema suppression rate and is said to have excellent anti-inflammatory effects. Understand.

4: The ultraviolet erythema method is suitable as a test to measure the anti-inflammatory effect of a drug applied to the skin. That is, Hartley type Alpino guinea pig (weight 450-500g, 1
After trimming and pricking the dorsal skin of the group of 10 animals, a rubber plate was used to inject 1.41 × 1.4
Set up a 1 cm section and use medium wavelength ultraviolet light (280 to 320
nra, λtaax = 305 nta) to 2. Erythema was induced by irradiation at OJ/cm. After UV irradiation, add 10 uL of olive oil solution of test compound to one compartment.
It was applied and the formation of erythema was determined over time. The average value of erythema (E, ) at the site where the test compound was applied and the average value (Eo) of the erythema at the site where no test compound was applied were determined, and (Eo - Et) x 10
The inhibition rate (%) of ultraviolet erythema was calculated from the formula 0/Eo and was taken as the anti-inflammatory activity of the test compound. The larger this value is, the higher the anti-inflammatory activity is. Table 4 shows the judgment values 3 hours after UV irradiation.

Table 4 As is clear from Table 4, the new compound according to the present invention exhibits a stronger erythema suppression rate than the known N-(2,3-xylyl)anthranilic acid, and also has excellent effects as a topical anti-inflammatory agent. It has been found.

As a test method for measuring the analgesic effect of drugs applied to the skin, the Randall-Selicito method is used as a standard test method when evaluating non-narcotic analgesics.
L, 0. and 5elitto, J, J, +
Archives of International
Pharmacodynamics, Volume 111, 4
09, 1957) was applied mutatis mutandis. That is, Wistar male rats (body weight 100-120 g, 1 group 1
50 μL of an ethanol solution of the test compound was applied to both hind paws of each mouse (0 mice). One hour later, the test compound solution was applied again in an amount of 50 μL, and immediately 0.1 μL of 5% brewer's yeast/physiological saline was subcutaneously administered to one paw of the rat as an inflammatory substance. At a certain time after administration of the inflammatory substance, the carcinogenic weight was measured using a horizontal balance pressurizer, and the rate of decrease in pain threshold (
Pl) was determined. As a control group, the rate of decrease in pain threshold (Pa) was determined when brewer's yeast was similarly injected into rats to which only a solvent containing no test compound was applied, and (P o
-P+)100/Po The beer yeast pain suppression rate (%) was calculated as the analgesic activity of the test compound. The larger this value is, the higher the analgesic effect is.

Table 5 shows the values measured at the mouth 5 hours after the brewer's yeast was injected.

Table 5 As is clear from Table 5, the new compound according to the present invention is a known compound N-(2,3-xylyl)anthranilic acid and a known compound described in JP-A-52-78848. Compound 2-(p-isobutylphenyl)
It was found that it exhibited a higher analgesic effect than propionic acid-2-pyridylmethyl ester, and also had an excellent effect as an external analgesic.

The above test results revealed that the novel compound of the present invention is highly safe and has excellent anti-inflammatory and analgesic effects.

The novel compound of the present invention can be administered either orally or parenterally.

For example, oral administration in tablets, capsules, powders, granules, syrups, etc., enteral administration in suppositories, ointments, creams, pastes, poultices, liquids, aerosols, etc.
Examples include external skin preparations such as gel preparations and bath preparations. In particular, the novel compound of the present invention is easily soluble in organic solvents such as alcohols such as ethyl alcohol and propyl alcohol, and ketones such as acetone and methyl ethyl ketone, as well as in cream-based solvents such as polyalcohol, liquid paraffin, and ester oil. It is highly compatible with ointment bases such as vaseline and lanolin, making it easy to formulate as a topical drug. When applied to the topical area, it has a beneficial anti-inflammatory effect and is effective against accompanying pain. Since it has an excellent analgesic effect, it can be said to be a drug suitable for use as a skin preparation.

The indications for the topical anti-inflammatory analgesic include acute eczema, chronic eczema, atopic TH inflammation, contact dermatitis, herpes zoster, eczema dermatitis caused by various causes, various wounds, vulgaris burns, and acute chronic These include arthritis, periarthritis, lower back pain, and muscle pain.

The dosage of the anti-inflammatory analgesic of the present invention varies depending on age, individual differences, medical conditions, etc., but in general, when administered to humans, it is
g, 1 to 400 mg orally per day, and can be administered once or in divided doses. 0.01-100mg, preferably 0.1-10m for dermal administration
The purpose can be achieved by applying g to the affected area once to several times a day.

Formulation examples of the novel compound of the present invention will be described in more detail below with reference to Examples. Note that the present invention is not limited to this.

Formulation example 1. Ointment (1) 2-Furanmethyl-N-(2,3-xylyl)anthranilate 2.5g total
(1) was kneaded with (2) consisting of 50° Og liquid paraffin (95%) and polyethylene (5%) and degassed under reduced pressure to obtain an ointment.

Formulation example 2. Cream (1) 2-furanmethyl-N-(2,3-xylyl) anthranilate 0.5g (2
) Cetostearyl alcohol 2.0g (3)
Liquid paraffin 20.0 g (4
) Lanolin 3.5g (5
) Stearic acid monoglyceride 1.1g (6)
Polyoxyethylene (20) sorbitan monostearate 1.4g (7) 1.3-butylene gelicol 3
．． 4g (8) Ethylparaben 0.
1g (1) (2) (3) (4) (5) and (6)
Dissolve by heating and maintain at 70°C, and add to (7), (8) and (9) heated to 70°C with stirring. A homomixer treatment was performed to make the emulsified particles fine, and then the emulsified particles were rapidly cooled while stirring to obtain cream.

Formulation example 3. Lotion (1) 2-Furanmethyl-N-(2,3-xylyl)anthranilate 0.1 g (
2) Glycerin 4.0g (3)
1.3-Butylene glycol 4. Og(
4) Ethanol 7.0g (5
) Polyoxyethylene oleyl alcohol 0.5g (6) Methylparaben 0.05
g(7) Citric acid 0.01
g(8) Sodium citrate 0.1
Dissolve (2), (3), (7), and (8) in g(9). Separately, (1), (5), and (6) were dissolved in (4), added to the above-mentioned aqueous solution, solubilized, and filtered to obtain a lotion.

Formulation example 4. Pasta agent (1) 2-furanmethyl-N-(2,3-xylyl) anthranilate 10.0 g
(2) Zinc oxide 12.0
g(3) Starch 12.
0 g (4) White petrolatum 16
．． Dissolve part of 0 g (4) on a water bath, add (1), knead the sieved (2) and (3), add the remaining (4) and knead thoroughly to make the whole mixture even. Manufactured.

Formulation Example 5 Emulsion (1) Stearic acid 2.5 (
2) Cetyl alcohol 1.5 (3
) Vaseline 5.0 (4)
Liquid paraffin 10.0(5)2
-furanmethyl-N- (2,3-xylyl) anthranilate 1.0 (6
) POE (10) Monooleic acid ester 2.0
(7) Polyethylene glycol 1500 3.
0(8) Potassium hydroxide 0.3
(9) Purified water remainder (10
) Flavoring agent appropriate amount (11) Preservative appropriate amount (9) (7)
Add (8) and heat and keep at 70°C (aqueous phase). Mix other ingredients, heat and dissolve and keep at 70°C (oil phase). The oil phase was added to the aqueous phase and the mixture was emulsified uniformly using a homomixer. After emulsification, the mixture was cooled to 30° C. with stirring to obtain a milky lotion.

The anti-inflammatory analgesics of Production Examples 1 to 5 have active ingredients that remain stable over time, and can be applied directly to the affected area as a skin preparation, or applied to an appropriate cloth such as gauze and then applied to the affected area. An anti-inflammatory effect was observed.

Claims (2)

[Claims] (1) 2-Furanmethyl-N represented by the following formula (A)
-(2,3-xylyl)anthranilate. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(A) (2) A skin preparation containing 2-furanmethyl-N-(2,3-xylyl)anthranilate as an active ingredient.