JPS61236765A - Novel pyridylalkyl n-(2,3-xylyl)anthraniliate derivative - Google Patents

Abstract

NEW MATERIAL:A pyridylalkyl N-(2,3-xylyl)anthranilate derivative expressed by the formula (R is 1-3C alkyl substituted by pyridyl group). EXAMPLE:2-Pyridylmethyl N-(2,3-xylyl)anthranilate. USE:An anti-inflammatory and analgesic agent for external use, having high safety, excellent percutaneous absorbability, and capable of exhibiting remarkable anti-inflammatory and analgesic action by application to the affected part. PREPARATION:N-(2,3-Xylyl)anthranilic acid or a halide thereof is reacted with a pyridylalkyl alchol or an alkali N-(2,3-xylyl)anthranilate is reacted with a halide of the pyridylalkyl alcohol to afford the aimed compound expressed by the formula.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention is based on the general formula CI) [wherein R is a pyridyl group! A novel N-(2,3-xylyl)anthranilic acid pyridyl alkyl ester derivative represented by the following formula, and a skin preparation containing the compound as an active ingredient. Regarding.

The novel compound of the present invention, N-(2,3-xylyl)anthranilic acid pyridyl alkyl ester, is a group of novel compounds that have not been described in any literature, and has remarkable anti-inflammatory and analgesic effects, and can be used as a new drug. It is an industrially useful compound.

[Prior Art] Conventionally, N-(2,3-xylyl)anthranilic acid is called by the common name of mefenamic acid and has been widely used as an anti-inflammatory, anti-rheumatic, antipyretic analgesic. However, known N-(2,3-xylyl)anthranilic acid is extremely difficult to dissolve in water, alcohol, oil, etc., and is used exclusively in powders, tablets, etc.
It is used as an oral drug in the dosage form of capsules.
No use as a dermal agent was indicated. In addition, when the well-known N-(2,3-xylyl)anthranilic acid is orally applied, it may cause side effects such as gastrointestinal disorders, kidney disorders, and dizziness.
22, 1984) is also known, but this point is also unresolved.

[Problems to be Solved by the Present Invention] In view of the above circumstances, the present inventors have attempted to increase the percutaneous absorption and skin affinity of N-(2,3-xylyl)anthranilic acid, and to As a result of extensive research with the aim of reducing oral toxicity, we have found that by introducing an alkylpyridyl group into the carboxyl group of a low-intensity compound, it is highly safe and has excellent transdermal absorption. The present invention was completed by discovering that wX exhibits remarkable anti-inflammatory and analgesic effects when applied locally.

[Means and actions for solving the problem] That is,
The present invention provides novel N-(2,
3-xylyl) anthranilic acid pyridyl alkyl ester conductor, and an external anti-inflammatory analgesic agent containing the same as an active ingredient.

New compound according to the present invention, N-(2,3-xylyl)
Anthranilic acid pyridyl alkyl ester is a pale yellow crystal that is not easily soluble in alcohols such as ethyl alcohol and propyl alcohol, and organic solvents such as ketones such as acetone and methyl ethyl ketone. The conventional method can be used. For example, N-(2,3-xylyl)anthranilic acid or its halide is treated with pyridylalkyl alcohol, or an alkali salt of N-(2,3-xylyl)anthranilic acid is treated with a pyridylalkyl alcohol halide. It can be manufactured by a method of causing the reaction to occur.

The alkyl chain of the pyridyl alkyl group is a methyl chain, ethyl chain, n-propyl chain, or isopropyl chain, and methyl chains and ethyl chains are preferred because the anti-inflammatory effect decreases as the number of carbon atoms increases.

Examples of the novel compounds of the present invention include the following.

2-pyridylmethyl-N-(2,3-xylyl)anthranilate 3-pyridylmethyl-N-(2,3-xylyl)anthranilate 4-pyridylmethyl-N-(2,3-xylyl)anthranilate Rate 2-(2-pyridyl)ethyl-N-(2,3-xylyl)anthranilate 2-(3-pyridyl)ethyl-N-(2,3-xylyl)anthranilate 2-(4-pyridyl) Ethyl-N-(2,3-xylyl)anthranilate 2-(2-pyridyl)propyl-N-(2,3-xylyl)anthranilate 2-(3-pyridyl)pro and RuN-(2, 3-xylyl) anthranilate 2-(4-pyridyl)propyl-N-(2,3-xylyl) anthranilate 3-(2-pyridyl)propyl-N-(2,3-xylyl) anthranilate 3 -(3-pyridyl)propyl-N-(2,3-xylyl)anthranilate 3-(4-pyridyl)propyl-N-(2,3-xylyl)anthranilate Preparation of the novel compound of the present invention as follows EXAMPLES The present invention will be specifically explained by way of examples. Note that the present invention is not limited to this.

Production Example 1 After dissolving 2.36 g of sodium N-(2,3-xylyl) anthranilate in 20 mm of dimethylformamide, 1.25 g of 2-chloromethylpyridine was added,
The reaction was carried out at 90°C 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 ether.

The residue obtained by distilling off the ether after dehydration was recrystallized from methanol to give pale yellow 2-pyridylmethyl-N-(2,
3°OOg of 3-xylyl) anthranilate was obtained.

Melting point: 63-64℃ Elemental analysis: C21H2o02N2 Calculated value ($) C75,88H6,07N 8.43
Actual value (X) C76,02H5,92N 8.39
Mass spectrum parent ion (a+/e) = 332 Production example 2゜N-(2,3-xylyl)anthranilic acid 2゜41g
and 3.6 g of thionyl chloride in benzene:
The mixture was mixed in a vacuum and reacted under reflux for 3 hours. The solvent and excess thionyl chloride were then distilled off under reduced pressure, and 50 ml of tetrahydrofuran and 1.37 g of 3-(4-pyridyl)propanol were added to the resulting residue, followed by 1.5 g of triethylamine gradually at room temperature. was added, stirred for 30 minutes, and allowed to react under reflux for 1 hour.

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 ether. The obtained oily residue was recrystallized from methanol to give pale yellow 3-(4-pyridyl)propyl-
N-(2,3-xylyl)anthranilic acid 3.2g
I got it.

Melting point: 56-57°C Elemental analysis: C23H24o2N2 calculation (a) C76,64H6,71N?.7
7 Actual value (%) C76,51H6,43N 7.5
8 mask vector parent ion (m/e) = 360 Production Examples 3 to 6 The compounds shown in Table 1 were synthesized according to the methods of Production Examples 1 and 2.

Table 1 The low toxicity and excellent anti-inflammatory effect of the novel compound according to the present invention are evident from the experimental results shown below.

(Experiment 1) Poisoning and observation of ddY male mice (body weight 18-22 g, 10 per group)
Each specimen was suspended in 0.5% carboxymethylcellulose/physiological saline and administered to a predetermined amount using an oral needle. Continue to observe symptoms of toxicity after administration.
The Litchfield-Wilcox method was used for mortality cases during the 7-day observation period.
Acute oral toxicity value (LD5 on a+ethod)
o) was calculated. The results are shown in Table-2. In addition, the compound (-R) in Table 2 is a group (R) shown in general formula (I).
It was expressed as. In addition, R=H is the well-known N − (2,
3-xylyl)anthranilic acid.

Table 2 As is clear from Table 2, the compound according to the present invention has an LDso value about three times that of known N-(2,3-xylyl)anthranilic acid, and has extremely low toxicity. There was found.

(Experiment 2) Anti-inflammatory effect, Procedures of Winter et al.
the 5oci-ety for experience
tal Biology & Mediains,
111, p. 554, 1962), Wistar male rats (body size: 110-130 g, 8 animals in 11 groups) were given 0.
The test compound suspended in 5x carboxymethyl cellulose aqueous solution was administered orally (100 mg/kg). 1
After a period of time, 0.1 ml of 1% λ-carrageenan/physiological saline as an inflammatory substance was subcutaneously administered to the hind limbs of one side of the rat to induce edema. Before and after administration of the inflammatory substance, the volume of each foot was measured, and the rate of increase in foot volume (Vl) was determined. As a control group, 0.5! does not contain the test compound. The rate of increase in paw volume (V) was measured when λ-carrageenan was similarly injected into rats administered with an aqueous solution of carboxymethyl cellulose, and (Vo-V)
The carrageenan edema suppression rate (%) was calculated using the formula: /VoX100 and was taken as the anti-inflammatory activity of the test compound.
The larger this value is, the higher the anti-inflammatory activity is.

This test method is called the carrageenan foot edema method, and it has been shown to have a high correlation with anti-inflammatory effects in humans.
It is a standard test method used to measure anti-inflammatory effects.

Table 3 shows the measured values 5 hours after injection of λ-carrageenan. In addition, the compound (R) in Table 3 was represented by the group (R) shown in general formula (I).

Moreover, R=H represents the well-known N-(2,3-xylyl)anthranilic acid.

Table 3 As is clear from Table 3, the novel compound of the present invention exhibits a strong anti-inflammatory effect and exhibits excellent anti-inflammatory effects, similar to the known N-(2,3-xylyl)anthranilic acid. have-
It has been found.

In addition, 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. It is highly compatible with ointment bases such as vaseline, lanolin, and glycols, making it easy to formulate as a topical preparation. It was found to have a suppressive effect on pain.

The ultraviolet erythema method is suitable as a test for measuring the anti-inflammatory effect of drugs applied to the skin. That is, Hartley type Alpino guinea pig (weight 450-500g, 1
After pricking the dorsal skin of a group of 10 animals, the dorsal skin was 1.41 x 1.41 using a rubber plate with the midline as a control.
am section, mid-wavelength ultraviolet rays (280-320
n@, λwax = 305 nm) 2. O.J.
/am2 irradiation to penetrate the erythema. After irradiation with ultraviolet rays, 10 ul of an olive oil mixture of the test compound was applied to one compartment, and the formation of erythema was determined over time. The average value of erythema (El) 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-E)/EoX10
The ultraviolet erythema suppression rate (%) was calculated from the formula of 0 and used 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.

In addition, the compound (R) in Table 4 was represented by the group (R) shown in general formula (I). Furthermore, R=H is the well-known N
-(2,3-xylyl)anthranilic acid.

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

(Experiment 3) As a test method for measuring the analgesic effect of externally applied drugs, the Randall-Selicito method, which is used as a standard test method when evaluating non-narcotic analgesics, is used. ,
L, 0. and 5elftto, J, J,,
Archives of International
Pharmacodynamics, Volume 111, 4
09, 1957) was applied mutatis mutandis. That is, 50% of an ethanol solution of the test compound was applied to both hind limbs of male Wistar rats (body weight 100-120 g, 10 rats per group).
It was applied every ul. After 1 hour, add 50% of the test compound solution again.
Apply every μl and immediately use 5x vinyl hydroxide as an inflammatory substance.
0.1 ml of physiological saline was subcutaneously administered to one side of the rat's foot. 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 sought. As a control group, the rate of decrease in pain threshold (P) was determined when brewer's yeast was similarly injected into rats to which only a solvent containing no test compound was applied.
, )1Po×100 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 measured values at the 5th hour after brewer's yeast injection.

Table 5 As is clear from Table 4, the new compound according to the present invention is based on the known parent compound N-(2,3-xylyl)anthranilic acid and the known parent compound N-(2,3-xylyl)anthranilic acid described in JP-A-52-78848 Compound 2-(p-isobutylphenyl)
It was found that it exhibited a higher analgesic effect than 2-pyridylmethylnistylpropionate and also had an excellent effect as an external analgesic.

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

Although the novel compound of the present invention can be administered either orally or parenterally, it is preferably used as a dermal preparation since it exhibits excellent percutaneous absorption. Therefore, the novel compound of the present invention can be used as a topical anti-inflammatory analgesic to treat acute eczema, chronic eczema, atopic dermatitis, contact dermatitis, herpes zoster, and eczema dermatitis caused by various causes, various wounds, burns, and acute chronic arthritis. It is judged to be effective for periarthritis, lower back pain, muscle pain, etc. For such purposes, the compounds of the present invention can be administered in the form of common external preparations such as ointments, creams, pastes, poultices, liquids, aerosols, and gels, and any form is effective. be.

The dosage of the anti-inflammatory analgesic of the present invention is influenced by age, individual differences, medical conditions, etc., but in general, when administered to humans, it is
g, 0.01 to 100 mg per day, preferably 0.1 to 10 mg, can be applied to the affected area once to several times a day to achieve the purpose.

EXAMPLES The present invention will be specifically explained below by presenting examples of formulations of the novel compounds of the present invention. Note that the present invention is not limited to this.

Formulation example 1. Ointment (1) 2-pyridylmethyl-N-(2,3-xylyl)
Anthranilate 2.5g (2) Plastibase 50W 47.
5 g total (so, o g) (1) was combined with (2) consisting of liquid paraffin (95X) and polyethylene (5 pieces) and degassed under reduced pressure to obtain an ointment.

Formulation example 2. Cream (1) 3-pyridylmethyl-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 1.4° (7) 1.3-Butylene glycol 3
．． 4g (8) Ethylparaben 0
．． 1 g total 50.0 g (1) (2) (3) (4) (5) and (6) were heated and dissolved and kept at 70°C.
7) Add to (8) and (9) while 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) 3-(4-pyridyl)propyl-H-<2.3
-xylyl) anthranile-'p 0.1 g (2
) Glycerin 4.0g (3)
1.3-Butylene glycol 4.0g (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
g(9) Purified water 84.24
Total g: 100.00 g Dissolve (2), (3), (7), and (8) in (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-(3-pyridyl)ethyl-〇-(2,3-
xylyl) anthranilate 10.0 g(2) r
Zinc a chloride 12゜Og (3)
Starch 12.0 g (
4) White petrolatum 16.0
g meter so, o g Dissolve part of (4) on a water bath, add (1), then sieve (2) and (3) together. Add the remaining (4) and mix thoroughly. , manufactured with uniform quality throughout.

In the formulations according to Formulation Examples 1 to 4, the active ingredients 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. Excellent anti-inflammatory effect was observed.

Claims (2)

[Claims] (1) General formula▲ Numerical formulas, chemical formulas, tables, etc.▼ [In the formula, R means an alkyl group having 1 to 3 carbon atoms substituted with a pyridyl group] A new N-(2,3- xylyl) anthranilic acid pyridyl alkyl ester derivative. (2) An anti-inflammatory analgesic for external use containing an N-(2,3-xylyl)anthranilic acid pyridyl alkyl ester derivative as an active ingredient.