JPH07112960A - N-substituted-o-toluidine derivative, its salt and drug-dissolution agent containing the compound as active component - Google Patents

Abstract

PURPOSE:To obtain an N-substituted-o-toluidine derivative having excellent dissolving power to various agents, free from side actions such as skin irritation, odor and disagreeable feeling, inert to principal agent, having excellent compatibility with the agent and capable of keeping the principal agent to a state extremely stable to physical and chemical influence. CONSTITUTION:A compound of formula I (R1 is a lower alkyl; R2 is an alkyl) and its salt such as N-pentanoyl-N-ethyl-o-toluidine. This compound can be produced by reacting an N-substituted-aniline derivative of formula II with a carboxylic acid of formula III or its reactive derivative. The compound is useful as a dissolution agent for pharmaceuticals, quasi-drugs, cosmetics, agrochemicals, etc. Chemicals can be dissolved in an extremely small amount of the compound I compared with conventional dissolution agent.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention comprises an N-substituted-o-toluidine derivative and its salt, which are useful as a solubilizer for compounds such as medical products, quasi drugs, cosmetics and agricultural chemicals, and an active ingredient thereof. It relates to a drug dissolving agent.

[0002]

2. Description of the Related Art Conventionally, various solubilizers have been studied as a means for administering a poorly soluble drug. This is because the drug, which is the active substance, is effective only after it is dissolved in the dissolution agent and absorbed by the human body. Therefore, generally, the solubility stability of a drug in a base is important at the stage of designing a drug product containing an active substance, and the physicochemical stability depends only on the existing state of the drug in the base. In addition, the release of the drug from the base material, the absorption into the human body, and the medicinal effect are also significantly affected. Currently, as solubilizers, fatty acids such as oleic acid and myristic acid, fatty acid esters such as isopropyl myristate and isopropyl palmitate, essential oils such as limonene, peppermint oil, eucalyptus oil, and polyhydric alcohols such as polyethylene glycol and propylene glycol. , Surfactant, glycol salicylate, crotamiton, etc. are used. In particular, crotamiton is commonly used as a dissolving agent for poorly soluble drugs. For example, Japanese Patent Fairness 3-3
In 3688, crotamiton is used as a dissolving agent for indomethacin. In JP-A-51-73115, a steroid solubilizer is disclosed in JP-B-2-365.
In Japanese Patent Laid-Open No. 72, an example is seen as a precipitation inhibitor of dexamethasone valerate. Also, JP-A-59-116212
The publication discloses an indomethacin-containing cream preparation containing crotamiton as a dissolving agent.

[0003]

However, in the above-mentioned conventional structure, crotamiton has a problem that it is poor in stability due to heat, has an odor due to decomposition products, is difficult to perform quality control, and lacks long-term storage stability. Was there. The present invention is to solve the above conventional problems, various drugs and cosmetics, has excellent dissolving power for compounds such as agricultural chemicals, has no side effects such as skin irritation, is odorless and does not cause discomfort, and the main agent is PROBLEM TO BE SOLVED: To provide an N-substituted-o-toluidine derivative and a salt thereof which are inactive and excellent in compatibility and can be maintained in a physically and chemically extremely stable state, and to effectively utilize an N-substituted-o-toluidine derivative and a salt The purpose is to provide a drug dissolving agent contained as an ingredient.

[0004]

In order to achieve this object, an N-substituted-o-toluidine derivative and a salt thereof according to claim 1 of the present invention have the general formula (I) (wherein R ₁ is A lower alkyl group and R ₂ represents an alkyl group).

[Chemical 2] The N-substituted-o-toluidine derivative and the salt thereof according to claim 2 are the same as those in claim 1, wherein R ₁ is a lower alkyl group having ₁ to ₄ carbon atoms and R ₂ is ₁ to ₈ carbon atoms. And an alkyl group of. N-Substitution- according to claim 3.
o- toluidine derivatives and salts thereof according to claim 1, the R ₁ is a methyl group or an ethyl group, R ₂ carbon atoms C ₄ ~
It has a constitution of being a C ₈ alkyl group (provided that R ₂ is an ethyl group, R ₂ excludes a tert-butyl group and an n-pentyl group). N-substituted-o- according to claim 4.
The toluidine derivative and the salt thereof are the same as those in claim 1
-Substituted-o-toluidine derivative is N-pentanoyl-N
-Ethyl-o-toluidine or N-isopentanoyl-
It has a constitution which is any one of N-ethyl-o-toluidine. The drug solubilizer according to claim 5 has a composition containing one or more kinds of the N-substituted-o-toluidine derivative and the salt thereof according to any one of claims 1 to 4 as an active ingredient. is doing.

Next, a method for producing the N-substituted-o-toluidine derivative and its salt of the present invention will be described. N-substituted-o-toluidine derivative of the present invention and salt thereof (I)
Is an N-substituted aniline derivative represented by the general formula (II) according to the following reaction formula (in the formula, R ₁ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc. And a reactive derivative thereof represented by the general formula (III) (in the formula, R ₂ is a direct alkyl group such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl). It represents a chain or branched alkyl group) and can be produced.

[Chemical 3] The N-substituted aniline derivative (II) and the carboxylic acid (III) or a derivative thereof are condensed by an N-substituted-o-
The toluidine derivative and its salt can be easily produced. N-
As the substituted aniline derivative, _{one in} which R ₁ is a C _{1 to} C ₄ lower alkyl group is preferably used. Carboxylic acid (III
), R ₂ is preferably an alkyl group having a carbon number of C _{1 to} C ₈ . Examples of the reactive derivative of carboxylic acid (III) include acid halides and acid anhydrides such as acid chloride and acid bromide, mixed acid anhydrides with alkyl carbonic acid, mixed acid anhydrides such as p-toluenesulfonic acid mixed anhydride and the like. Is mentioned. In the reaction step, the N-substituted aniline derivative (II) and the carboxylic acid (III) or its reactive derivative are used in approximately equimolar amounts or in excess amounts, and an organic solvent inert to the reaction, such as pyridine, tetrahydrofuran or dioxane is used. , Ether, benzene, toluene, xylene, methylene chloride, dichloroethane, chloroform, ethyl acetate, acetonitrile and the like or without solvent. Depending on the kind of reaction derivative, the reaction proceeds smoothly by adding a base such as triethylamine, pyridine, N, N-dimethylaniline, potassium carbonate or sodium hydroxide during the reaction. The reaction temperature depends on the type of reactive derivative and is not particularly limited.

[0006]

EXAMPLES The N-substituted-o-toluidine derivatives and salts thereof of the present invention will be described below with reference to Examples and Test Examples. Example 1 Synthesis of N-pentanoyl-N-ethyl-o-toluidine 1 in 135 g (1 mol) of N-ethyl-o-toluidine
Slowly add 86 g (1 mol) of valeric anhydride to 90
Stir at 7 ° C for 7 hours. The reaction solution is neutralized and washed and then distilled (131
˜132 ° C./3 mmHg) to obtain 155 g of N-pentanoyl-N-ethyl-o-toluidine. Yield 71
%Met. Boiling point of this substance, infrared absorption spectrum, M
The S spectrum and elemental analysis values were as follows. Boiling point: 131-132 ° C / 3 mmHg MS spectrum: 219 (M ⁺ ) Infrared absorption spectrum (neat cm ^-1 ): 1655 Elemental analysis value: Calculated value as C ₁₄ H ₂₁ NO C 76.67%, H 9. 65%, N
6.39% analytical value C 76.52%, H 9.47%, N
6.27%

(Example 2) N-isopentanoyl-N
Synthesis of -ethyl-o-toluidine 1 in 135 g (1 mol) of N-ethyl-o-toluidine
Slowly add 86 g (1 mol) of isovaleric anhydride,
The mixture was stirred at 90 ° C for 7 hours. The reaction solution is neutralized and washed, and then distilled (1
24-125 ° C./3 mmHg) to obtain 145 g of N-isopentanoyl-N-ethyl-o-toluidine. The yield was 66%. The boiling point, infrared absorption spectrum, MS spectrum and elemental analysis value of this substance were as follows. Boiling point: 124 to 125 ° C./3 mmHg MS spectrum: 219 (M ⁺ ) Infrared absorption spectrum (neat cm ⁻¹ ): 1655 Elemental analysis value: Calculated value as C ₁₄ H ₂₁ NO C 76.67%, H 9. 65%, N
6.39% Analytical value C 76.42%, H 9.48%, N
6.20%

Test Example 1 Drug Dissolution Test <Confirmation of Solubility> N-substituted-o-toluidine derivatives of Examples 1 and 2 were used as a solubilizer, and ethanol was used as a comparative example.
Polyethylene glycol (molecular weight 400), propylene glycol and isopropyl myristate were prepared. Ketoprofen, indomethacin, and isosorbide dinitrate were used as drugs. Regarding the dissolution conditions, a sample was prepared in which the weight ratio of the dissolution agent to the drug was varied as shown in (Table 1).
It was heated at 20 ° C. and gradually dissolved. Taking into consideration the stability of the drug, the durability in practical use, etc., heating was performed for up to 2 hours. Those that were insoluble after heating for 2 hours were considered to have no dissolving power. <Confirmation of Dissolution Stability> Dissolution stability is determined by allowing the drug solution obtained in the solubility confirmation test to stand at room temperature for 2 weeks or more.
The state of precipitation of crystals was observed. In addition, when the crystal precipitation was not clear, the sample was left standing at -5 ° C. The results of the dissolution test for ketoprofen, indomethacin and isosorbide dinitrate are shown in (Table 1), (Table 2) and (Table 3), respectively.

[Table 1]

[Table 2]

[Table 3] As is clear from (Table 1) to (Table 3), the N-substituted-o-toluidine derivative of the present example shows a higher solubility than the typical solubilizers currently used, and It can be seen that even a wide range of drugs has an excellent dissolving action. Further, it is found that the drug has an extremely excellent compatibility and can dissolve the drug in an extremely small amount as compared with the conventional dissolving agent.

Test Example 2 Thermal Stability Test Using the N-substituted-o-toluidine derivatives of Examples 1 and 2 as a solubilizer, crotamiton was prepared as a comparative example.
The test method is to prepare a stoppered sample tube containing 100 mg of each of the solubilizers, and place it on a hot plate at 180 ° C.
After heating for 5 hours, after 5 hours, the state of the sample is visually observed, and a gas chromatography (GC) analysis of each of the above-mentioned dissolving agents before and after heating is performed to obtain the residual ratio of the dissolving agent after heating. It was The GC charts are shown in FIGS. 1 and 2, and the residual ratio of the dissolving agent is shown in (Table 4). Figure 1
2 is a GC chart of N-pentanoyl-N-ethyl-o-toluidine of Example 1 before and after heating, and FIG. 2 is a GC chart of crotamiton of Comparative Example before and after heating. As is clear from FIG. 1 and FIG.
The C chart shows almost no change before and after heating, but in the case of the comparative example, the peaks of the cis body and the trans body are shifted and the number of by-product peaks is large in the case of after heating compared to before heating. Admitted. As is clear from this (Table 4) and FIG. 1 and FIG.
The o-toluidine derivative was found to have better thermal stability than crotamiton. It was also found from this that the degree of freedom in drug formulation can be significantly expanded.

[0010]

As described above, according to the present invention, a novel N
A -substituted-o-toluidine derivative and a salt thereof are obtained, and the N-substituted-o-toluidine derivative and a salt thereof show remarkable drug solubility in a wide variety of compounds such as drugs and cosmetics, and the formulation design The freedom of can be significantly expanded. Further, it has excellent stability in the base material, and since it is odorless, it does not cause discomfort, and is therefore excellent in usability. Furthermore, since the formulation of the present invention using the N-substituted-o-toluidine derivative and its salt as a solubilizer can significantly improve the effectiveness of the main ingredient, the therapeutic effect of the drug can be remarkably enhanced.

[Brief description of drawings]

FIG. 1 is a GC chart in a thermal stability test of Example 1.

FIG. 2 is a GC chart in the thermal stability test of crotamiton.

[Table 4]

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shinpei Maruyama 1-2 Ohiradai, Shoo-cho, Katsuta-gun, Okayama Ogawa Kaori Co., Ltd. Okayama Research Institute (72) Inventor Ya Kameda 1-2 Ohiradai, Katsuta-cho, Katsuta-gun, Okayama Prefecture Ogawa Kaori Co., Ltd. Okayama Laboratory (72) Inventor Mitsuru Kuribayashi 408 Tadai Daikanmachi, Tosu City, Saga Prefecture Hisamitsu Pharmaceutical Co., Ltd. (72) Inventor Eiji Oda 408 Tadai Daikancho, Tosu City, Saga Prefecture Hisamitsu Yaku Co., Ltd. (72) Inventor Munehiko Hirano 408 Tashiro Daikancho, Tosu City, Saga Hisamitsu Pharmaceutical Co., Ltd. (72) Inventor Akira Nakagawa 408, Tashiro Daikancho, Tosu City, Saga Hisamitsu Pharmaceutical Co., Ltd.

Claims (5)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ₁ represents a lower alkyl group and R ₂ represents an alkyl group.) An N-substituted-o-toluidine derivative and a salt thereof. 2. The N-substituted according to claim 1, wherein R ₁ is a C ₁ -C ₄ lower alkyl group and R ₂ is a C ₁ -C ₈ alkyl group. -O-toluidine derivatives and salts thereof. 3. R ₁ is a methyl group or an ethyl group, R ₂ is a C ₄ -C ₈ alkyl group (provided that when R ₁ is an ethyl group, R ₂ is a tert-butyl group and n-pentyl group). Group is excluded.) The N-substituted-o-toluidine derivative and the salt thereof according to claim 1. 4. The N-substituted-o-toluidine derivative is N-
N-substituted- according to claim 1, characterized in that it is either pentanoyl-N-ethyl-o-toluidine or N-isopentanoyl-N-ethyl-o-toluidine.
o-Toluidine derivatives and salts thereof. 5. A drug dissolving agent comprising one or more N-substituted-o-toluidine derivatives and salts thereof according to any one of claims 1 to 4 as active ingredients.