JPS5817449B2 - Kanjiyouka Gobutsuno Seizouhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula [wherein R represents a phenyl group which may have a lower alkyl group or a halogen atom as a substituent.

A general formula characterized by subjecting a compound represented by ] or a reactive derivative thereof at a carboxyl group to an intramolecular ring-closing reaction.

[In the formula, R has the same meaning as above.

This invention relates to a method for producing a novel cyclic compound represented by the following.

In the general formula (IL(n)), when the phenyl group represented by R has a substituent, the substituent has a carbon number of 1-
4 straight or branched lower alkyl groups (e.g. methyl, ethyl, propyl).

isobutivir butyl isobutyl 5ec-butyl,
(t-butyl group), halogen atoms (eg, fluorine, chlorine, bromine, iodine).

One or more of these substituents, which may be the same or different, may be substituted at any position of the phenyl group.

Further, as the reactive derivative of the carboxylic acid represented by the general formula (I), any derivative may be used as long as the object of the present invention is achieved, and examples thereof include acid halides and acid anhydrides.

Examples of acid halides include acid chlorides, acid bromides, acid iodides, and acid fluorides.

Examples of acid anhydrides include anhydrides of carboxylic acids of the general formula CI), carboxylic acids of the general formula CI), and other acids (
Examples include acid anhydrides with organic acids such as formic acid and acetic acid, and inorganic acids such as silicic acid and boric acid.

The intramolecular ring-closing reaction in the present invention is generally advantageously carried out in the presence of a catalyst, and any catalyst that can be used as a catalyst in a Friedel-Craf reaction, ie, a Friedel-Craf catalyst, can be used. , such as metal halides (e.g., aluminum chloride, aluminum bromide, aluminum chloride, iron chloride, iron bromide, antimony chloride, antimony bromide, titanium chloride, tin chloride,
Lewis acids such as tin bromide, zinc chloride, bismuth chloride) or boron triride, mineral acids such as sulfuric acid, phosphoric acid, and polyphosphoric acid, and hydrogen fluoride.

When using Lewis acids among the above catalysts, alkali metal halides (e.g. potassium chloride, sodium chloride,
Sodium bromide, potassium bromide, sodium iodide, potassium iodide, etc. may also be present.

The amount of these catalysts used is not particularly limited, but if the general formula C
It is preferably about 1 to 10 moles per mole of the carboxylic acid or reactive derivative thereof (I).

However, when the above-mentioned mineral acid or hydrogen fluoride is used as a catalyst, a large excess amount may also be used as the solvent.

Furthermore, the reaction of the present invention is carried out without a solvent or in the presence of a solvent, and any solvent may be used as long as it is inert to the reaction, such as nitrobenzene, halogenated hydrocarbons (e.g., methylene chloride, Examples include ethylene chloride, 1,1,2,2-tetrachloroethane (1.chlorobenzene, dichlorobenzene), etc.

There are no particular limitations on reaction conditions such as reaction temperature and time, but the reaction temperature is preferably about 200°C to about 200°C.

The compound of general formula (II) thus obtained can be easily separated and purified by known separation and purification means such as extraction, distillation, recrystallization, and chromatography.

The compound of general formula (II) obtained in the present invention is a new compound that has not been described in any literature, and has excellent anti-inflammatory, analgesic, and antipyretic effects, for example, by the method shown below. This can lead to the compound IV).

[In the formula, R has the same meaning as above.

] The compounds of the above general formulas [tan] and [■] are useful as medicines such as anti-inflammatory agents, analgesics, and antipyretics.

When these compounds are used as medicines, the dosage is appropriately selected depending on the route of administration, purpose of administration, etc., but for example, they are used to treat rheumatoid arthritis, osteoarthritis, osteoarthritis, spondylosis, arthralgia, low back pain, etc. When administered for the purpose of
The usual daily dose for adults is approximately 10 to 1,000 mg per day, administered orally in an appropriate dosage form such as tablets, capsules, or powders, or a single dose for adults of approximately 5 to 500 mg as an injection, suppository, etc. It is best administered parenterally.

The compound of general formula CI) used in the present invention is, for example, anasine.

Dell, Hemi (Annalender Ch emle)
), 553, 250 (1942) as follows.

EXAMPLES The present invention will be explained in more detail below using Examples and Experimental Examples, but it goes without saying that the present invention is not limited thereto.

Example 1 a) 50 g of anhydrous aluminum chloride is stirred in 100 rrLl of methylene chloride, and 28 g of benzoyl chloride is added dropwise.

16.4.9 While stirring this solution at 30-40°C.
of β-phenylpropionic acid methyl ester was added dropwise over about 1 hour.

After completion of the dropwise addition, the mixture was stirred at 30 to 40°C for 2 hours.

After cooling, decompose with water and hydrochloric acid, and extract with methylene chloride.

The extracted layer is washed with dilute hydrochloric acid, water, dilute aqueous sodium hydroxide solution, and water, and then dried.

The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography (silica gel = I kg, eluted with benzene) to obtain P-pensoyl-β-phenylpropionate methyl ester and O-benzoyl-β-phenylpropion. Acid methyl ester is obtained.

20 g of P-benzoyl-β-phenylpropionic acid methyl ester obtained above and 15 g of potassium hydroxide,
Add to a mixed solvent of 20 ml of ethanol and 100 r/L of water and reflux for 2 hours.

After cooling, the solvent was distilled off, water was added, and the mixture was washed with ether.

The aqueous layer is acidified with hydrochloric acid and the precipitate is extracted with ether.

The extracted layer is washed with water, dried, and then the solvent is distilled off under reduced pressure.

Crystallization of the residue from benzene-hexane gives p-benzoyl-β-phenylpropionic acid.

Melting point 98-100°C Elemental analysis value C16H1403 Calculated value C,75,57;H,5,55 Experimental value C,75,57;H,5°44 The above p-benzoyl-β-phenylpropionic acid methyl ester Instead, use 0-benzoyl-β-phenylpropionic acid methyl ester and proceed as above with 0
-benzoyl-β-phenylpropionic acid is obtained.

b) p-benzoyl-β-phenylpropionic acid 5.0
Mix 13 g of anhydrous aluminum chloride and 1.3 g of common salt, and heat separately at 160°C for 1 hour.

After cooling, add water to decompose and extract with chloroform.

The extracted layer is washed with a 5-part aqueous sodium bicarbonate solution and water, and then dried.

The residue obtained by distilling off the solvent under reduced pressure is dissolved in ethanol, decolorized with activated carbon, and then crystallized from ethanol.

6-penzoyl-1-indanone is obtained as a crystal with a melting point of 121.5-123.5°C.0 Elemental analysis value C16 (120° Calculated value c, 81.34;) (,5,12 Experimental value c, 81 .22 ; H, 4,99 Example 2 From 5.0 g of 0-benzoyl-β-fetylpropionic acid obtained in Example 1-a), 13 g of anhydrous aluminum chloride, and 1.3 g of common salt, 4-benzoyl-1-indanone is obtained analogously to Example 1-b).

Melting point 86-88℃ Elemental analysis value C16H1□02 Calculated value c, 81.34; H, 5,12 Experimental value c, 81.16; H, 5,01 Example 3 Same as Example 1-a) , p-toluoyl chloride and β-phenylpropionic acid methyl ester, o-
(p-Toluoyl)-β-phenylpropionic acid is obtained.

5.69 o-(p-toluoyl)-β-phenylpropionic acid, 1.3 I anhydrous aluminum chloride, and 1
．． From the salt of 3.9, in the same manner as in Example 1-b), 4
-(P-toluoyl)-1-indanone is obtained.

Melting point 106-108℃ (recrystallization solvent cyclohexane) Elemental analysis value C17H1402 Calculated value c, 81.58; H, 5,64 Experimental value
c, 81.47; H, 5,57 Example 4 In the same manner as in Example 1-a), o-(p-chlorobenzoyl)-β was prepared from p-chlorobenzoyl chloride and β-phenylpropionic acid methyl ester. -Phenylpropionic acid is obtained.

Add 50 ml of thionyl chloride to 5.69 o-(p-40 rubenzoyl)-β-phenylpropionic acid and let stand overnight at room temperature.

The crude o-(p) obtained by distilling off excess thionyl chloride under reduced pressure
-Chlorpenz 4/L/) -β-phenylpropionic acid chloride, 13 g of anhydrous aluminum chloride, 1
．． Add the salt from step 3.9 and heat at 160°C for 1 hour.

After cooling, add water to decompose and extract with chloroform.

The extracted layer is washed with a 5-part aqueous sodium bicarbonate solution and water, and then dried.

The residue obtained by distilling off the solvent under reduced pressure was crystallized from a mixed solvent of benzene-cyclohexane (1:1) to give 4-(p-chlorobenzoyl)-1 as crystals with a melting point of 145.5-146°C. -Indanone is obtained.

Elemental analysis value C16H110□C1 Calculated value C, 70, 98; H, 4, 10; C1゜310 Experimental value C, 70,98; H, 4,25; CI.

13.43 Reference Example 1 a) Sodium ethoxide prepared from 1.1 g of sodium metal was dissolved in a mixture of 24 ml of absolute ethanol and 48 ml of anhydrous dimethoxyethane, and 9.5 g of 4
-Benzoyl-1-indanont 9.4 g of N-(paratoluenesulfonylmethyl)isonitrile was dissolved in 120 rrll of anhydrous dimethoxyethane, and the solution was added dropwise over 20 minutes with stirring while cooling with ice water.

After the addition was completed, the mixture was stirred for another 30 minutes at the same concentration, and then stirred at Murobuchi for 3.5 hours.

Add water, wash the extracted layer with ether, and then dry.

The residue obtained by distilling off the solvent under reduced pressure is purified by silica gel column chromatography (silica gel I kg).
, eluting with benzene-ethyl acetate (50:1)).

1-Cyano-4-benzoylindane is obtained as an oil.

Elemental analysis value C1□H13ON Calculated value C, 8257; H, 530; N.

5.66 Experimental values C, 82, 34; H, 5, 21; N.

5.43 b) Add 3 g of 1-cyano-4-benzoylindane to dilute sulfuric acid made from 54 ml of water and 45 mA' of concentrated hydrochloric acid, and reflux for 3 hours and 30 minutes in a nitrogen stream.

After cooling, add water and extract with ether.

The ether layer is further extracted with a 5% aqueous potassium carbonate solution, washed with ether, and then acidified with hydrochloric acid.

The precipitate is extracted with chloroform, and the extracted layer is washed with water and then dried.

When the solvent was distilled off under reduced pressure, 4-benzoylindane-1
- A carboxylic acid is obtained.

Crystallization from benzene-cyclohexane (7;20) gives a melting point of 100-102°C.

Elemental analysis value CI? R14,03 Calculated value C, 76,67; H, 5,30 Experimental value C, 76,54; H, 5,19 Experimental example Derived from the target compound of the present invention by Reference Example 1 or a method similar to this The following test compounds were examined for their analgesic and anti-inflammatory effects.

a) Test compound A; 4-benzoylindane-1-carboxylic acid B: 4-
(P-methylbenzoyl) indan-1-carboxylic acid C: 4-(p-chlorobenzoyl) indan-1-carboxylic acid b) Experimental method a) Carrageenin edema method (anti-inflammatory effect) 6 months old, weight 180-200 g Using 6 male rats per group, the method of Winter et al.
C, A, , R151ey, E, A, and
Nuss, G.W., Proc, Soc.
Exp, Biol.

The anti-edema effect was investigated according to Med 6, 111.544 (1962)).

First, the volume of the right hind limb of the animal was accurately measured to 0.01 ml, and then the sample was orally administered, and water was additionally administered to make the total volume 5 ml.

One hour later, 0.05 ml of 1-strength lagenin physiological saline was subcutaneously injected into the foot to induce edema.

Three hours after carrageenin injection, the volume of the right hind paw was measured again.
The edema suppression rate (%) due to sample administration was calculated using the following formula.

Control group single sample administration edema of group edema of group Edema suppression rate (a) = xio.

Control group edematous mouth) Phenylquinone rice writing method (Phenylquinone writing method)
) (Analgesic effect) Male mice, 35 weeks old, weight 16-20 g, 1 group 10
The fish were used.

First, the specimen was orally administered, and 30 minutes later, 0.1 ml of a 0.021% aqueous phenylquinone solution (dissolved in 5% ethanol) was injected intraperitoneally.

From this, phenylquinone-stimulated writthing and stretching responses were counted for each individual animal over a 20 minute period.

Claims (1)

[Scope of Claims] 1 General formula [wherein R represents a phenyl group which may have a lower alkyl group or a halogen atom as a substituent. A method for producing a compound represented by the general formula [wherein R has the same meaning as defined above], which comprises subjecting the compound represented by the above formula or a reactive derivative thereof at the carboxyl group to an intramolecular ring-closing reaction.