JPS6033099B2 - Novel naphthylpropionate derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel naphthylpropionate ester derivatives represented by the general formula [wherein R means a phenyl group substituted with a halogen atom or a lower alkyl group, or [a low pyridyl group]] It is related to.

The compound of the present invention represented by the general formula (1) is a novel compound that has not yet been published in the literature, and is an industrially useful compound as a pharmaceutical having significant pharmacological effects such as key synergistic effect, anti-inflammatory effect, and antipyretic effect. be. To explain more specifically the substituent R in the general formula (1), R is substituted with a halogen atom such as chlorine, bromine, iodine, or marmine, or a lower alkyl group such as methyl, ethyl, propyl, butyl. It means a phenyl group, and the pyridyl group represents a 2-pyridyl group, a 3-pyridyl group, or a 4-pyridyl group.

Conventionally, most topical anti-inflammatory agents have been adrenocortical hormone preparations.

However, steroid preparations, when used externally for a long period of time, exhibit severe side effects, so there is currently a desire for the development of non-steroidal external anti-inflammatory agents with fewer side effects. Therefore, as a result of extensive research in search of a new non-steroidal compound, the present inventors found that the naphthylpropionate derivative represented by the general formula (1) has a remarkable analgesic effect and anti-inflammatory effect when administered orally and locally. has an effect,
Furthermore, they discovered that oral administration causes fewer side effects in the gastrointestinal tract, and that it is also useful as an internal medicine, thereby completing the present invention. Next, a method for producing the compound according to the present invention will be described. The compounds of the present invention can be obtained in good yields by the methods described below, but these manufacturing methods are merely examples, and of course they can be manufactured by other chemically similar methods.
Production method A A compound represented by the general formula (oa) and its reactive derivative is added to the compound represented by the general formula (m
) RCH 20th (m) [In the formula, R
has the same meaning as above], production method B A method of reacting an alcohol represented by the general formula (b) [wherein M means an alkali metal] with a compound represented by the general formula (W) RCH2×
(W) A method of reacting a compound represented by [wherein, ' means a lower alkyl group] is reacted with an alcohol represented by the general formula (m) to carry out transesterification.

Next, the method of implementing the present invention will be explained in more detail.

Production method A is carried out by reacting 2-(6-methoxy-2-naphthyl)propionic acid (Ua) and its reactive derivatives (eg, acid halide, acid anhydride, etc.) with an alcohol.

The reaction between compound (roa) and alcohol (m) can be carried out under reflux in the presence of a dehydrating agent such as sulfuric acid, polyphosphoric acid, or p-toluenesulfonic acid, in an organic solvent such as benzene, toluene, or xylene. Alternatively, if the alcohol used is inexpensive, it may be used as a solvent for the reaction. When using an acid anhydride as a reactive derivative of (oa), compound (m) is
It may be used in an excess of ~10 moles and heated in the presence of a small amount of acid. In addition, when using an acid halide, in the presence of a deoxidizing agent (for example, pyridine, trimethylamine, triethylamine, etc.), in an organic solvent that does not participate in the reaction, such as tetrahydrofuran, diglyme, acetone, chloroform, benzene, toluene, etc., under cooling or at room temperature. All you have to do is react. Production method B involves adding general formula (W) to a metal salt represented by general formula (ob).
Compounds represented by tetrahydrofuran, diglyme,
It may be heated in an organic solvent such as dioxane, acetone, chloroform, benzene, toluene, xylene, or dimethylformamide.

Production method C uses an excess molar amount of the alcohol represented by the general formula (m) in the compound represented by the general formula (oc), and when heated directly or in the presence of a small amount of alkali metal, the transesterification reaction proceeds quickly. .

Next, the results of pharmacological experiments regarding the compounds of the present invention will be shown.

Experimental example 1 Carrageenin paw edema suppression effect test in rats (experimental method)
: Groups of 5 male Wistar rats weighing 140-150 mm were fed for 1 hour, and 1 hour after oral administration of the test compound, a 1% aqueous carrageenan solution was applied to the rats' paw pads.
．． 1 I was injected subcutaneously.

Three hours after the injection of the antiinflammatory agent, the paw volume was measured, and the paw edema rate and edema suppression rate were calculated from the following formula. The test compound was suspended in a 0.5% aqueous solution of gum tragacanth, and only the solvent was administered to the control group. Edema rate (%) = carrageenin injection hind paw volume - carrageenin injection paw volume XI.

〇Carrageenin injection paw volume edema suppression rate (%) = Edema rate of control group - Edema rate of drug treated group Edema rate in control group The experimental results are shown in Table 1.

(Compounds used in the experiment) {1) [2-(6-methoxy-2-naphthyl)propionic acid-P-methylbenzine ester]...Hereinafter, referred to as the compound of Example A.

'2' [2-(6-methoxy-2-naphthyl)propionic acid-4-pyridylmethyl ester]...Hereinafter, referred to as the compound of Example B.

[3'[2-(6-methoxy-2naphthyl)propionic acid-m-fluorobenzine ester]...Hereinafter,
It is referred to as the compound of Example C.

'41 (6-methoxy-2-naphthyl-2-methyl acetate)...hereinafter referred to as a comparative compound.

Table 1. Carrageenin paw edema suppression effect test in rats**:
It shows that there is a significant difference in edema rate compared to the control group at a risk rate of 1%. Example 2 Test of inducing effect on different pressure injuries in rats Male Wistar rats weighing 170-180 kg were
After fasting for 2 hours, the test compound was administered orally to 7 animals in a group.3. After several hours, the rats were sacrificed by plating and their stomachs were removed.

After injecting 1% formalin solution LOW' into the stomach and fixing it, the stomach was incised and the presence or absence of erodion was observed. The test compound was suspended in a 0.5% gum tragacanth aqueous solution, and only the solvent was administered to the control group. The experimental results are shown in Table 2. The compounds of Examples A, B, and C and the comparative compounds are Experimental Example 1.
The same compound as used in is shown.

Table 2 Test for inducing effect on stomach irritation in Rasotho From the experimental results of Experimental Examples 1 and 2 above, it is clear that the compound of the present invention has a remarkable anti-inflammatory effect, and gastric ulcer is more common in non-steroidal anti-inflammatory drugs. This drug was found to be a highly safe drug with very few side effects.

EXAMPLES The present invention will be specifically explained below with reference to Examples, but it goes without saying that the present invention is not limited only to the compounds in these Examples.

Example 1 2-(6-methoxy-2-naphthyl)propionic acid2.
A mixture of 3.6 parts of thionyl chloride and 30 parts of anhydrous benzene was heated under reflux for 3 hours.

After the reaction, excess thionyl chloride and benzene were removed under reduced pressure, and the resulting oil was dissolved in anhydrous tetrahydrofuran (40 mL).
1.5 liters of dissolved o-fluorobenzyl alcohol was added to the gunwale. After adding 2 parts of triethylamine while cooling on ice, the mixture was incubated at room temperature for 30 minutes. After the reaction was completed, tetrahydrofuran was distilled off under reduced pressure, water was added to the residue, the resulting oily substance was extracted with methylene chloride, dried over anhydrous magnesium sulfate, the solvent was removed, and the resulting substance was diluted with ether. Recrystallization from a mixed solvent of petroleum ether gave colorless needle-like crystals of monofluorobenzyl 2-(6-methoxy-2-naphthyl)propionic acid ester. The melting point and elemental analysis values of this substance were as follows.

Melting point 72-74°C Elemental analysis value C2, day, 8F03 Theoretical value C:74. Separation date: 5.66 Actual value C: 74.15 H: 5.52 Example 2 2-(6-methoxy-2-naphthyl)probionic acid 2.
The solution was dissolved in 30% dimethylformamide, 0.6% 50% sodium hydride was added, and the mixture was lit for 30 minutes at room temperature.

Next, add 3.2 hours of o-chlorobenzyl chloride and
Heated for 10,000 hours. After the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, the resulting oily substance was extracted with methylene chloride, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the resulting substance was diluted with ether. Recrystallization from a mixed solvent of petroleum ether gave colorless needle-like crystals of 2-(6-methoxy-
2.8 hours of 2-naphthyl)propionic acid-o-chlorobenzyl ester were obtained. The melting point and elemental analysis values of this substance were as follows.

Melting point 79-80°C Elemental analysis value C2, day, 9CI03 Theoretical value C:71. Female H: 5.40 Actual value C: 70.89 H: 5.32 The following compounds were synthesized according to the methods of Examples 1 and 2.

2-(6-methoxy-2-naphthyl)propionic acid-2
-Pyridylmethyl ester melting point 88-892-(6-methoxy-2-naphthyl)propionic acid-3-pyridylmethyl ester melting point 6-60 2-(6-methoxy-2-naphthyl)propionic acid-4
-Pyridyl methyl ester melting point 76-7 orbit○ 2-(6-methoxy-2-naphthyl)propionic acid-m
-Chlorobenzyl ester tree point 43-45℃ 2-(6-methoxy-2naphthyl)propionic acid-p
-k.

Lobenzyl ester melting point 78-8 pi○ 2-(6-methoxy-2-naphthyl)propionic acid-m
-Fluorobenzyster cocoon point 35-370 2-(6-methoxy-2-naphthyl)propionic acid-p
-Fluorobenzyl ester melting point 61-6 poly○ 2-(6-methoxy-2-naphthyl)propionic acid-o
-Methyl benzyl ester eagle & point 79-81℃ 2-(6-methoxy-2-naphthyl)bropionic acid-m
-Methylbenzylester Melting point 45-46℃ 2-(6-methoxy-2-naphthyl)propionic acid-p
- Methylbenzyl ester figure insect point 89-90℃

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R means (a) a phenyl group substituted with a halogen atom or a lower alkyl group, or (b) a pyridyl group) ) A naphthylpropionate derivative represented by