JPS6125014B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () (In the formula, X is a hydrogen atom or a halogen atom, n
is an integer of 1 or 2, and R ¹ is (a) a hydroxyl group, (b) a trihalomethyl group, (c) a phenyl group, (d) a phenyl group substituted with a halogen atom, a lower alkyl group, or a trifluoromethyl group. The present invention relates to a novel indanecarboxylic acid ester derivative represented by , (e)pyridyl group. The compound of the present invention is a novel compound that has not been described in any literature, and has significant analgesic and anti-inflammatory effects and is industrially useful as a pharmaceutical. To explain more specifically about X and R ¹ in the above general formula (), X is a halogen atom such as a hydrogen atom or a chlorine atom, and R ¹ is a hydroxyl group or a trihalomethyl group such as a trichloromethyl group and a trifluoromethyl group. or a phenyl group, or a halogen atom such as chlorine, bromine, or fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl,
It represents a phenyl group substituted at any position with a lower alkyl group such as isobutyl, a trifluoromethyl group, or a pyridyl group such as 2-pyridyl, 3-pyridyl, or 4-pyridyl. Conventionally, general formula (a) is used as a compound having a similar structure to the compound represented by general formula (). (However, X represents a hydrogen atom or a chlorine atom)
5-cyclohexyl-1-indanecarboxylic acid and 5-cyclohexyl-6-chloro-1-indanecarboxylic acid represented by are known. However, although these compounds have strong pharmacological activities such as analgesic and anti-inflammatory effects, they have the disadvantage that they have side effects such as gastrointestinal disorders and must be administered with caution. Therefore, the present inventors conducted intensive research in search of a new compound that reduces such side effects and has strong analgesic and anti-inflammatory effects, and as a result, converted the compound represented by general formula (a) into an ester derivative (). However, it was discovered that gastrointestinal disorders were significantly alleviated, and the analgesic and anti-inflammatory effects were comparable to or greater than those of the compound (a). When applied topically, they found that it has a remarkable anti-inflammatory effect and has excellent transdermal absorption, leading to the completion of the present invention. The method for producing the compound according to the present invention will be described below. The compound of the present invention can be obtained in good yield by the method described below, but this is only an example, and of course it can also be produced by other chemically similar methods. However, X, n and R ¹ have the same meanings as above. However, X, n and R ¹ have the same meanings as above. However, A represents a halogen atom or an organic sulfonyl group, M represents an alkali metal, and X, n and R ¹ have the same meanings as above. Next, a method for implementing the present invention will be specifically explained. The manufacturing method A has general formula (a) and general formula ()
Alcohols represented by sulfuric acid, polyphosphoric acid,
In the presence of a dehydrating agent such as p-toluenesulfonic acid, alcohols represented by the general formula () may be used in excess as a solvent, or the reaction may be carried out under reflux in an organic solvent such as benzene, toluene, or xylene. good. Production method B involves treating compound (a) with a halogenating agent to form acid halide (b), and then adding an alcohol represented by the general formula () to an organic solvent that does not participate in the reaction (e.g., tetrahydrofuran, diglyme, dioxane, chloroform). , benzene, toluene, etc.) in the presence of a deoxidizing agent such as pyridine, trimethylamine, or triethylamine. In production method C, compound (a) is treated with potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, etc. to form compound (c), and then the compound represented by the general formula () is treated with benzene, toluene, etc. The reaction proceeds rapidly if the reaction is carried out in an organic solvent such as , xylene, tetrahydrofuran, dioxane, diglyme, dimethylformamide, or dimethyl sulfoxide at room temperature or with heating if necessary. Next, pharmacological tests of the compounds of the present invention will be described. 1 Experimental method (1) Carrageenin paw edema suppression test in rats Groups of 5 Wistar male rats weighing 140-150g
The animals were used after fasting for 18 hours. The test compound was orally administered, and 1 hour later, 1 hour was administered to the rat's hind paw pad.
0.1 ml of % carrageenan aqueous solution was injected subcutaneously. The paw volume was measured 3 hours after the injection of the inflammatory agent, and the paw edema rate and edema suppression rate were calculated using the following formula. The test compound was suspended in 0.5% gum tragacanth saline, and only the solvent was administered to the control group. Edema rate (%) = Paw volume after carrageenin injection - Paw volume before carrageenin injection / Paw volume before carrageenin injection x 100 Edema suppression rate (%) = Edema rate of control group - Edema rate of test compound treated group / Control Group edema rate x 100 The experimental results are shown in Table 1.

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[Table] (2) Gastric ulcer-inducing effect in rats One group of 7 male Wistar rats weighing 170-180 g
The animals were used after fasting for 24 hours. After oral administration of the test compound, rats were killed by exsanguination at 3.5 hours.
The stomach was removed. After injecting 10 ml of 1% formalin solution 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 0.5% gum tragacanth saline, and only the solvent was administered to the control group. The experimental results are shown in Table 2.

[Table] As is clear from the results of the above pharmacological tests, the compound of the present invention exhibited an inhibitory effect on carrageenan foot edema equivalent to or better than that of the comparative drug, and it was also found that the occurrence of ulcers in the stomach was significantly reduced. This is considered to be due to the specificity of the ester residue in the compounds of the present invention. It also suggests a possibility as an anti-inflammatory agent with remarkable pharmacological action and less gastrointestinal disturbance. EXAMPLES The present invention will be explained in more detail with reference to Examples below. Example 1 5-cyclohexyl-1-indanecarboxylic acid
A mixture of 2.4 g of thionyl chloride, 3.6 g of thionyl chloride, and 20 ml of benzene was reacted under reflux for 3 hours. Next, the solvent and excess thionyl chloride were distilled off under reduced pressure, and 30 ml of tetrahydrofuran and 3.8 g of o-fluorobenzyl alcohol were added to the resulting residue, and then 1.5 g of triethylamine was added under ice cooling, and the mixture was stirred at room temperature for 2 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 ether layer was washed with water several times, dehydrated, and then evaporated under reduced pressure to obtain an oily substance. This was distilled under reduced pressure to obtain 2.9 g of 5-cyclohexyl-1-indanecarboxylic acid-o-fluorobenzyl ester as a pale yellow oil. The boiling point and elemental analysis values of this substance were as follows. Boiling point 180-185℃/0.2mmHg Elemental analysis value C ₂₃ H ₂₅ FO ₂ Theoretical value C: 78.38 H: 7.15 Actual value C: 78.43 H: 7.08 Also, the parent ion (m/e ) showed 352. Example 2 A mixture of 2.78 g of 6-chloro-5-cyclohexyl-1-indanecarboxylic acid, 3.6 g of thionyl chloride, and 20 ml of benzene was reacted under reflux for 3 hours.
Next, the solvent and excess thionyl chloride were distilled off under reduced pressure, and 30 ml of tetrahydrofuran and o
-Trifluoromethylbenzyl alcohol 5.28g
After that, 1.50 g of triethylamine was added under ice-cooling, and the mixture was stirred at room temperature for 2 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 ether layer was washed with water several times, dehydrated, and then evaporated under reduced pressure. The resulting residue was adsorbed onto a column packed with silica gel and developed with chloroform. The eluate was evaporated under reduced pressure to obtain pale yellow prismatic crystals of 6-chloro-5. 2.6 g of -cyclohexyl-1-indanecarboxylic acid-o-trifluoromethylbenzyl ester was obtained. The melting point and elemental analysis values of this substance were as follows. Melting point 70-71℃ Elemental analysis value C ₂₄ H ₂₄ ClF ₃ O ₂ Theoretical value C: 65.98 H: 5.54 Actual value C: 65.92 H: 5.46 Also, the parent ion (m/e) of the mass spectrum of this substance showed 436. Example 3 2.8 g of 6-chloro-5-cyclohexyl-1-indanecarboxylic acid, 3.0 g of 2,2,2-trifluoroethanol, and 2 ml of concentrated sulfuric acid were reacted under reflux for 10 hours. After the reaction was completed, excess 2,2,2-trifluoroethanol was distilled off, ice water was added to the residue, and the mixture was extracted with ether. After washing the ether layer with water and dehydrating it,
The ether was distilled off. The obtained oil was distilled under reduced pressure to obtain 6-chloro-5-cyclohexyl-1-indanecarboxylic acid 2,2,2 as a pale yellow oil.
-1.9 g of trifluoroethyl ester was obtained. The boiling point and elemental analysis values of this substance were as follows. Boiling point 125-130℃/1mmHg Elemental analysis value C ₁₈ H ₂₀ ClF ₃ O ₂ Theoretical value C: 59.92 H: 5.59 Actual value C: 59.76 H: 5.52 Also, the parent ion (m/ e) showed 360. Examples 4-36 The following compounds were synthesized according to the methods of Examples 1-3.

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Claims (1)

[Claims] 1. General formula (In the formula, X is a hydrogen atom or a halogen atom, n
is an integer of 1 or 2, and R ¹ is (a) a hydroxyl group, (b) a trihalomethyl group, (c) a phenyl group, (d) a phenyl group substituted with a halogen atom, a lower alkyl group, or a trifluoromethyl group. , (e) pyridyl group, meaning an indancarboxylic acid ester derivative.