JPS581119B2 - xanthenyl - Google Patents

Description

[Detailed description of the invention] The present invention provides pharmaceutically useful formulas (In the formula, Y represents oxygen or sulfur.

) and its salts, such as alkali metal, alkaline earth metal, aluminum, ammonium, and organic amine salts.

The novel xanthenyl acetic acid derivatives that are the object of the present invention have useful pharmaceutical properties, and are particularly useful as anti-inflammatory agents, anti-rheumatic agents, analgesics, and antipyretics.

(1) The xanthenyl acetic acid derivative of formula (I) has the formula (wherein,
Y has the same meaning as above.

) is produced by reducing the 9-oxo compound represented by the following by a method known per se.

As a reduction method, a carbonyl compound semicarbazone or hydrazone is reduced by heating in the presence of an alkali catalyst, as described by Wolf-Kishner and Hua.
Improved method of ng-Minlon, method using metal and acid, e.g. reduction of Cle using zinc amalgam and hydrochloric acid.
mmensen method, Bauveault-Blanc method using metallic sodium and alcohol, high pressure catalytic reduction method,
Examples include reduction with a complex metal hydride such as sodium borohydride.

(2) The xanthenyl acetic acid derivative of formula (I) has the formula (wherein,
Z represents lower alkoxycarbonyl, cyan, or carbamoyl, and Y has the same meaning as above.

) can be obtained by hydrolyzing the compound represented by

Hydrolysis can be carried out using acids such as hydrochloric acid, sulfuric acid, or caustic potassium, as appropriate.
It can be carried out under conventional conditions in an alkaline medium such as caustic soda.

(3) The xanthenyl acetic acid derivative of formula (I) has the formula (X1 represents a residue of a Grignard reagent, and Y has the same meaning as above).

) can be obtained by reacting the compound represented by the formula with carbon dioxide using conventional means.

An example of a method for synthesizing the raw material compounds used in the present invention is the compound of the general formula (■), for example, patent application No. 46-807.
No. 26 (Japanese Patent Publication No. 47-48389), the compounds of formulas (■) and (■) can also be synthesized by the following course.

The compound of formula (■) is a xanthone compound described in J. chem
．． Soc. 1949 1569, J. chem. So
c. 1956 812, J. Org. chem. 25
It can be easily obtained by reduction using a method such as 1519.

Acetylation is then performed as described in J, chem, Soc. 196
A compound of formula (■) can be obtained by reacting anhydrous aluminum chloride in the presence of an acetylating agent such as acetyl chloride or acetic anhydride instead of succinic anhydride according to the method of 02556.

Furthermore, according to conventional methods (for example, lithium aluminum hydride, sodium borohydride, Meerwein-Po
nndorf et al.) and halogenation (e.g., thionyl chloride, thionyl bromide,
(e.g., phosphorus tribromide), a compound of formula (■) can be obtained.

For example, a halogen compound of formula (■) can be reacted with metallic magnesium or n-butyllithium in tetrahydrofuran to form general formula (■), and can also be reacted with potassium cyanide, cuprous cyanide, etc. in dimethyl sulfoxide. By doing so, a compound of the general formula (■) (formula ■) can be obtained.

Next, the excellent pharmacological effects of the compounds of the present invention will be shown.

Test Example 1 Carrageenin edema inhibitory effect Winter et al.'s method [Proc. Soc, Expt.
l. Biol. Med. , 111, 544 (1962)
] According to

A test compound was orally administered to a group of 5 male Dongliu rats weighing around 150 g.

One hour later, 0.05 ml of a 1% carrageenan solution was subcutaneously injected into the right hind foot pad to induce edema.

Paw volume was measured 3 hours after inflammatory substance injection.

The results were determined by calculating the rate of increase in foot volume before administration of the inflammatory substance.
It is shown as the inhibition rate relative to the control group.

Test Example 2 Ultraviolet erythema suppression effect Winder et al.'s method [Arch. Int. Pharm
acodyn. , 116, 261 (1958)].

Using a guinea pig weighing 250 to 450 g, a rubber plate with three holes of 7 mm in diameter was placed on the flank, which had been previously depilated, and irradiated with a mercury lamp (manufactured by Toshiba, 600 W) from a distance of 15 cm for 80 seconds.

After 2 hours, the degree of erythema was scored according to the scoring method of Winder et al., and the effectiveness rate was determined.

The test solution was orally administered in half doses one hour before and immediately after irradiation.

Results: Test compound A: 2-(xanthen-2-yl)propionic acid B: 2
-(thiaxanthene-2-yl)propionic acid C: xanthene-2-ylacetic acid D: 2-(9-oxoxanthene-2-yl)propionic acid A and B are compounds of the present invention, and C and D are French Patent No. 20
It is a compound of No. 35989.

Example 1 A mixture of 10 g of 2-(9-oxoxanthen-2-yl)propionic acid, 7 g of potassium hydroxide, 7 ml of 85% hydrazine hydrate, and 50 ml of diethylene glycol was
Reflux at 50°C for 3 hours.

Next, the reflux condenser was removed and the volatile substances were distilled off while gradually raising the temperature. It took 25 hours to reach 190°C. After cooling, water was added and the crystals that precipitated were removed as hydrochloric acid. After washing with water and purifying with ethyl acetate, 5.3 g of 2-(xanthene-2-yl)propionic acid having a melting point of 188 to 190°C is obtained.

Example 2 6 g of 2-(9-oxoxanthen-2-yl)probionic acid was dissolved in 140 ml of hot ethanol, and 14 g of metallic sodium was added in 4 to 5 portions under reflux. Ethanol is distilled off under reduced pressure, and the residue is dissolved in water and acidified with hydrochloric acid to precipitate crystals.

If filtered, washed with water and purified with ethyl acetate, the melting point will be 190~
3.5 g of 2-(xanthen-2-yl)propionic acid at 191 DEG C. are obtained.

Example 3 2.5 g of 2-(xanthen-2-yl)propionic acid is dissolved in 70 ml of isopropyl alcohol, and a solution of 2.1 g of aluminum isopropoxide and 25 ml of isopropyl alcohol is added dropwise while stirring.

White crystals precipitate immediately. After refluxing for 1 hour, water 3
ml and refluxed again for 1 hour. After cooling, the crystals were collected by filtration, washed with isopropyl alcohol, and dried to obtain 2.4 g of aluminum salt of 2-(xanthen-2-yl)propionic acid as white crystals.

Example 4 3 g of ethyl 2-(thiaxanthene-2-yl)propionate was added to 30 ml of ethanol and 0.5 g of sodium hydroxide.
, Hydrolysis is carried out using 5 ml of water at 60-70° C. for 1 hour.

After concentration, the residue is dissolved in water, treated with activated carbon, and then acidified with hydrochloric acid to precipitate crystals.

When the crystals are collected by filtration and purified using aqueous ethanol, 2-(thiaxanthene-2-
2.1 g of propionic acid are obtained.

Example 5 5 g of 2-(1-cyanoethyl)xanthene, 50 g of glacial acetic acid
ml, 25 ml of concentrated hydrochloric acid is refluxed for 4 hours in a nitrogen stream to perform hydrolysis, and then concentrated to dryness. The obtained crystals are dissolved in an aqueous sodium bicarbonate solution, treated with activated carbon, and then acidified with hydrochloric acid to precipitate white crystals. do.

The crystals are collected by filtration, washed with water, and then purified with ethyl acetate to obtain 3.5 g of 2-(xanthene-2-yl)propionic acid with a melting point of 190°C.

Example 6 Magnesium metal 0O. 31 g and 2.9 g of 2-(1-bromoethyl)xanthene in 1 part of anhydrous tetrahydrofuran.
Make a Grignard reagent in 0 ml, add a large excess of dry ice to it, leave it overnight, pour it into dilute hydrochloric acid, collect the precipitated crystals by filtration, take the soluble part in an aqueous sodium bicarbonate solution, and acidify with hydrochloric acid. White crystals will precipitate.

If purified from ethyl acetate, 2-
0.8 g of (xanthen-2-yl)propionic acid is obtained.

Claims (1)

[Scope of Claims] A method for producing a compound represented by the formula 1 and a salt thereof, which comprises reducing the compound represented by the formula 1. (In the formula, Y represents oxygen or sulfur.) A method for producing a compound represented by the formula 2 and salts thereof, which comprises hydrolyzing the compound represented by the formula 2. (In the formula, 2 represents lower alkoxycarbonyl, cyano, or carbamoyl, and Y represents oxygen or sulfur.) A method for producing a compound represented by the formula 3, which comprises reacting the compound represented by the formula with carbon dioxide gas. (In the formula, X1 represents a residue of a Grignard reagent, and Y represents oxygen or sulfur.)