JPS6018659B2 - Novel benzofuran derivative - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula [1] [wherein R is a C2-C6 alkyl group, a C,-C6 alkoxy group, a C3-C6 cycloalkyl group, a C3-C6
6 cycloalkoxy group, C3-C4 alkenyl group,
C3-C4 alkenyloxy group, cyclohexenyl group, cyclohexenyloxy group, phenyl group, general formula [0
] A layered phenyl group (in the formula, R2 means a lower alkyl group such as methyl, ethyl, isopropyl, etc., a halogen atom, or a methoxy group), a phenoxy group, a bromine atom, a fluorine atom, a trifluoromethyl group , a benzyl group, a substituted penzyl group represented by the general formula [m] (wherein R2 means any of the same meanings as in the above formula (2))], which is a 5-substituted novel benzofuran derivative. -3-methyl-2
-Relating to benzofuryl acetic acid and its pharmacologically non-toxic salts.

The object compound of the present application represented by the above general formula [1] has analgesic and anti-inflammatory effects and is used as a medicine.

Anti-inflammatory analgesics are broadly classified into steroids and non-steroids.

Although it depends on the formulation, all of them have side effects. In particular, long-term use of steroids increases the side effects.
Therefore, an excellent non-steroidal anti-inflammatory analgesic agent with fewer side effects is desired.

The present inventors synthesized various non-steroidal compounds,
As a result of searching for its pharmacological effects, it was found that the compound represented by the general formula [1] has weak side effects and excellent anti-inflammatory and analgesic effects, which led to the completion of the present invention.

The target compound of the present invention is synthesized, for example, by the following methods A to E.

A method using 5-substituted-3-methyl-2-cyanomethylbenzofuran as a starting material.

5- represented by the general formula [N] (wherein R has the same meaning as above)
Substituted-3-methyl-2-cyanomethylbenzofurans (obtained by the method described in German patent 1203277) are hydrolyzed in an aqueous solvent in the presence of an acid or alkali, if necessary with heating.

Examples of acids used here include inorganic and organic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, and paratoluenesulfonic acid. Strongly acidic ion exchange resins can also be used for the same purpose. Examples of the alkali used here include hydroxides of alkali metals and alkali metals, such as sodium hydroxide, potassium hydroxide, and calcium hydroxide.

As the solvent, an organic solvent that does not participate in the reaction and water are used in combination. Examples of organic solvents that do not participate in the reaction include lower alcohols such as methanol, ethanol, n-pro/gnol, isopropanol, and rt-butanol, dioxane, tetrahydrofuran, acetone, 2-methoxyethanol, and 2-ethoxycetanol. can give. Normally, water and organic solvent are 1/4 part of organic solvent for 1 part of water.
It is used at a ratio of 4 to 4 customers. The reaction temperature is preferably the boiling point of the solvent system, and is usually carried out at 50 to 100 qo. Isolation of the target compound is carried out as follows.

That is, after the hydrolyzed reaction solution is treated with activated carbon if necessary, it is concentrated if necessary, the reaction solution is acidified with an acid (for example, hydrochloric acid, sulfuric acid, etc. are used), and then cooled.
Let it crystallize. Furthermore, if necessary, the crude crystals are recrystallized from a suitable solvent system, such as hydrous alcohol. B
5 A method using monosubstituted-3-methyl-2-acetylbenzofuran as a starting material.

5-monosubstituted-3-methyl-2-acetylbenzofuran represented by the general formula [V] (wherein R has the same meaning as above)
Mountain B 1. Soc. Chim. Fr. )1970(10)
, page 3601] is reacted with hydrogen sulfide or one of sulfur and one of ammonia, primary and secondary amines in an aqueous solution or in a water-containing organic solvent solution. A thioamide of a compound represented by V] is synthesized.

Typical amines used at this time include methylamine, dimethylamine, piperidine, and morpholine. Further, as the organic solvent used in the reaction, dioxane, piverizine, etc. are preferable, and in some cases, the amine used in the reaction can also serve as a solvent.

The reaction temperature is 130-20000, and the reaction time is 5-25
time is preferable.

After the reaction, thioamide crystals precipitate when the reaction solution is cooled, but in order to obtain thioamide with a higher yield, concentrate the reaction solution, distill off the solvent, and add water to obtain thioamide with a higher yield. When the obtained thioamide is hydrolyzed with acid or alkali, 5-mono-3-methyl-penzofuryl acetic acid represented by the general formula [1] is obtained.

The acids used here include inorganic and organic acids such as hydrochloric acid, sulfuric acid, para-toluene sulfonic acid, etc. The alkalis used include hydroxides of alkali metals and alkali metals such as sodium hydroxide, potassium hydroxide, etc. can give. Isolation of the target compound is carried out as follows. That is, a reaction solution containing the target product obtained by hydrolysis is mixed with a dilute alkali,
For example, after neutralizing with soda carbonate, etc., washing with a suitable organic solvent (such as benzene), the aqueous layer is made acidic with a dilute acid such as dilute hydrochloric acid or dilute sulfuric acid to liberate the desired acid, and this is converted into an organic solvent. , for example, with ethyl acetate, and the organic solvent layer is dehydrated, concentrated, and recrystallized from a suitable solvent system, such as aqueous methanol, ethanol, etc.
A method using C2-halomethyl-3-methyl-5-substituted penzofuran as a starting material.

Magnesium metal in the form of shavings, fine particles, powder or ribbons with a fresh metal surface is dissolved in a suitable solvent such as ethers (such as lower alkyl ethers or tetrahydrofuran) or tertiary amines (such as dimethylaniline). or by suspending it in an aromatic hydrocarbon (eg benzene, toluene, xylene, etc.) and adding iodine crystals if necessary to form a magnesium suspension.

General formula [W] 2-halomethyl-3 represented by (R, in the formula has the same meaning as above, and x means a chlorine atom or a bromine atom)
-Methyl-5-substituted penzofurans (German Patent No. 120)
3277) in the same solvent used to suspend magnesium is added dropwise to the magnesium suspension obtained above and heated to reflux to produce a Grignard reagent.

At this time, the appropriate amount of magnesium is approximately equimolar to 0.1 molar excess relative to the raw material compound. The amount of solvent in the magnesium suspension should be at least enough to cover the magnesium, or 2 to 3 times as much. The concentration of the solution of the raw material compound is not particularly limited, but is preferably 30 to 5% by weight. Although the mechanism of action of added iodine is not clear, it is effective as a magnesium activator. Next, a carbonic acid adduct is produced by blowing carbon dioxide gas into the resulting Grignard reagent solution after cooling it, or by pouring the Grignard reagent solution onto solid carbon dioxide gas.

This reaction is carried out at a relatively low temperature, for example between 0 and 10°C, preferably between -5°C and 0°C. The amount of carbon dioxide gas used in the reaction is preferably 5 to 10 times the amount of the Grignard reagent. When the produced carbonic acid adduct is hydrolyzed by a conventional method, for example, with a dilute mineral acid, the target product, 5-substituted-3-methyl-2-penzofuryl acetic acid, is produced.

The target product is isolated from the reaction product as follows. That is, the reaction product is extracted with an organic solvent such as ether, dichloroform, or ethyl acetate, and the organic layer is extracted with an aqueous solution of a dilute alkali such as sodium carbonate, and then acidified with a dilute acid such as dilute hydrochloric acid or dilute sulfuric acid to liberate it. The desired acid is extracted with an organic solvent such as ethyl acetate, and the resulting solution is dehydrated, concentrated, and recrystallized from a suitable solvent system such as aqueous methanol, ethanol, etc. D 5-substitution-
A method using 3-methyl-2-penzofuroylazomethane as a starting material.

5- represented by the general formula [W] (wherein R has the same meaning as above)
Substituted-3-methyl-2-penzophyldiazomethane [
Khimiya Geterotsiklicheski
khSMdinenii. 1973(5), page 579,
(obtained by the method described in USSR)] is subjected to Wolff rearrangement in the presence of water to obtain the object compound of the present invention represented by the general formula [1].

Catalysts used for Wolff rearrangement include silver oxide, oxidized steel,
Platinum oxide, sodium thiosulfate, a triethylamine solution of silver benzoate, a water-ethanol mixed solution of sodium hydroxide, potassium hydroxide, etc. can be used. The solvent used here is not particularly limited as long as it does not participate in the reaction; examples thereof include dioxane, tetrahydrofuran, and the like. The reaction temperature may be room temperature, but may be heated if necessary. Isolation of the target compound is carried out as follows.

That is, after the completion of the reaction, if necessary, activated carbon is added to the reaction solution and it is passed through a decolorizing oven, and then a suitable mineral acid or organic acid such as hydrochloric acid, sulfuric acid, acetic acid, etc. is added to the oven solution to acidify it and liberate the desired acid. Let it come out. The crude crystals are recrystallized from a suitable solvent system such as aqueous methanol or ethanol. E 4
- A method using [(5-layer fusuma-3-methyl-2-penzofuryl)methyl]-2H-1,3,5-oxadiazin-2-one as a starting material.

4-[(5-substituted-3-methyl-2-benzofuryl)methyl]- represented by the general formula [skin] (in the formula, R has the same meaning as above) is -1,3,5-oxadiazine-2
-one [obtained, for example, according to the method described in Indian Journal of Chemistry 2 (11), pp. 459-60, 1964] in an organic solvent such as acetic acid, ethanol, dioxane, benzene, etc., hydrochloric acid, sulfuric acid, etc. Boiled in the presence of an organic acid such as hinaic acid or p-toluenesulfonic acid, and after the reaction, concentrated and cooled to give 5-substituted-3-methyl-2-
Crude crystals of benzofuryl acetic acid are obtained.

The target compound is isolated and purified by recrystallizing the crude crystals collected from the reaction solution using a suitable solvent such as methanol. As mentioned above, the 5-substituted-3-methyl-2-benzofuryl acetic acid represented by the general formula [1] synthesized by the methods A to E may contain sodium, potassium, calcium, aluminum, ammonia, etc. as necessary. It can be a salt of an amine such as diethylamine or triethanolamine.

These salts can be produced by a generally known method of reacting the compound represented by the general formula [1] with an organic base such as ammonia or amine, and an inorganic base such as a metal oxide or metal hydroxide. can. The object compound of the present invention and pharmacologically non-toxic salts synthesized as described above have anti-inflammatory and analgesic effects and are used as anti-inflammatory and analgesic agents.

Examples thereof are shown in Table 1 below along with the test methods. The non-steroidal anti-inflammatory drug ibuprofen (up
rofen) was used. Test method A Anti-edema effect against carrageenan edema in rat hindlimbs: method of Yamazaki et al. [Japanese Pharmacological Journal Vol. 63, p. 302 (1)
The anti-edema effect was observed according to [967].

A group of 5 male Wistar rat rats weighing 11M±10cm were used as the test animals, and a 1% carrageenan solution was used as the inflammatory agent. The specimen is orally administered to the animal, and 1 hour later, 0.1% of an inflammatory agent is subcutaneously administered to one hind leg.
The edema rate is calculated 1, 3, and 5 hours after administration of the antiinflammatory agent in comparison with a control foot to which no antiinflammatory agent was administered. The effectiveness was evaluated at 3 hours and expressed as the edema suppression rate compared to the control group. The results are shown in Table 1. B Analgesic effect Randall-Selit method (method of Ra Mall-Selit et al.
,L. 0. &Selitb, J. J. Alceive internationale do pharmacodinami e doe therapy (ch.lnt.p rmacodW.)
, Vol. 111, p. 409 (1957)].

Using a group of 5 male Wistar rats weighing 110±10 mm, 1% inflammatory agent was administered subcutaneously to one of the rats' hind legs.
A carrageenan solution of 0.1% was injected, and 3 hours later, pressure was applied using a pressure device (manufactured by Ugobasile, Italy), and the pain point value was measured using crying and struggling as indicators. At this time, select a highly responsive rat whose dark value is 70 ta or less, immediately administer the sample orally, and then
After 3 hours, the rash pain level of the inflamed paw and the normal paw was measured. The group to which no specimen is administered will be the control group. The analgesic coefficient was calculated using the following formula. The results are shown in Table 1. Analgesic coefficient muscle Q dark value (9) of sample administration group - dark value side XI of control group.

〇200 - Dark value of control group) Results As shown in Table 1 above, the compound shown in the present invention has strong anti-inflammatory and analgesic effects.

Next, examples of the present invention will be shown, but the present invention is not limited thereto.

Example 1 6.03 g of 5-methoxy-3-methyl-2-cyanomethylbenzofuran was dissolved in 100 g of 10% caustic soda.
After heating under reflux for a long time, decolorize with activated carbon for 0.5 hours and filter through a furnace.

The furnace liquid was made acidic with 41.5 g of concentrated hydrochloric acid and crystallized on cooling. When the crystals are separated in a furnace and recrystallized with 50% methanol, 5
-Methoxy-3-methyl-2-benzofuryl acetic acid 3.7
6 days (yield 57%) is obtained. Melting point 113-114
00 elemental analysis C (%) day (%) C,2
Theoretical value as day, 204 65.44 5.49 Actual value 65.83 5.72 Example 25-fluoro-3-methyl-2-acetylbenzofuran 8.3 hours, sulfur 1.92 hours and anhydrous morpholine 5
．． Heat to reflux temperature for 6 hours for 15 hours.

After the reaction, the reaction solution was concentrated under reduced pressure and 20 ml of water was added to the residue to precipitate crystals. This is taken in a furnace and boiled for 6 hours with 20 parts of acetic acid, 3.6 parts of concentrated sulfuric acid, and 5.3 parts of water to hydrolyze it. After cooling, the solution is neutralized with sodium carbonate and washed with benzene. The aqueous layer was acidified with hydrochloric acid to liberate the desired acid, extracted with ethyl acetate, the ethyl acetate layer was dehydrated with reed sulfur, concentrated, and the residue was recrystallized from 85% methanol. 5.1 portions of -3-methyl-2-benzofuryl acetic acid are obtained. Yield 56.2% Melting point 129-13pp0 Elemental analysis C (%) day (%) F (%) C,. Theoretical value as day 903F 63.464.
369.13 Actual value 63. Iso 4.229.20 Example 3 A 5-necked flask with a capacity of 500 cm was equipped with an airtight flywheel device, a reflux condenser, a dropping funnel, a nitrogen gas introduction tube, and a thermometer, and the inside of the flask was connected to outside air through a calcium chloride tube. Insulate from humidity.

Into this flask were placed 2.55 kg of powdered magnesium, 20 kg of anhydrous ether, and several iodine crystals, and nitrogen gas was introduced. Next, stir this and drop 0.5 parts of a solution prepared by dissolving 25.7 parts of 5-phenyl-3-methyl-2-chloromethylbenzofuran in 80 parts of anhydrous ether. Once the reaction has started, the remaining ether solution of 6-phenyl-3-methyl-2-chloromethylbenzofuran is added dropwise at such a rate that the ether is refluxed.
After the addition is complete, stir and reflux for an additional 15 minutes. Thereafter, the dropping funnel and nitrogen gas introduction tube were removed, a carbon dioxide gas introduction tube was attached, and the reaction solution was cooled to -5°C. Temperature -6
Carbon dioxide gas dried with calcium chloride is introduced for about 5 hours while stirring and maintaining the temperature at ℃. After introducing carbon dioxide gas, add dilute sulfuric acid (2. 100% sulfuric acid to 100% sulfuric acid) and 20% ether.
Add 0 I, transfer to a separating funnel and separate the liquids. The ether layer was washed with water, extracted with 200% 10% caustic soda aqueous solution, washed with ether, and further extracted with 2. The ether layer was acidified with hydrochloric acid and extracted twice with 200% of ether. The ether layer was dried with sulfuric acid, the ether was distilled off, and the residual light was recrystallized with 85% methanol to give 5-phenyl-3-methyl-2-benzofuryl acetic acid. One day (yield 72%) was obtained. Melting point 173-17400 Elemental analysis C (%) days (%) C, 7 days, theoretical value as 403 76. Spots 5.
30 Actual value 76.84 5.34 Example 4 5-penzyl-3-methyl-2-penzofuroyl chloride (9.96 g) was dissolved in 350 g of tetrahydrofuran, and this was dissolved in an ether solution of diazomethane (30 g. It took about 0 hours to drip into the inside of the bottle.

The reaction solution was further stirred at room temperature for 3 hours, and then concentrated under reduced pressure. This concentrated residue was dissolved in dioxane 80 mm,
The mixture was added dropwise to a suspension of 8.2 parts silver oxide, 22 parts sodium thiosulfate pentahydrate, and 430 parts water and stirred over 1 hour while maintaining the temperature at 60 to 7 parts. This reaction solution was heated for another 1 hour at 60~
After stirring at 70°C, activated carbon was added and the mixture was passed through a decolorizing oven. The solution was acidified with 40% acetic acid and the precipitated crystals were collected using the oven.
This was recrystallized from 85% methanol to obtain 5.4% of 5-benzyl-3-methyl-2-benzofuryl acetic acid. Yield 55% Melting point
149-15000 elemental analysis OC (%) day (%) C, 8 days,
Theoretical value as 603 77.12 5.75 Actual value 77.38 5.70 Example 5 4-[(5-t-butyl-3-methyl-2-betanzofuryl)methyl]-6-phenyl-2H-1,3,6- Add 3.7 hours of oxadiazin-2-one to a mixture of 40 degrees of acetic acid and 4 hours of hydrochloric acid, and reflux for about 5 hours until it becomes colorless.

After the reaction, the mixture is concentrated and cooled to precipitate crystals. The crystals are separated by furnace and recrystallized with 0% benzene to obtain 1.5% 5-tert-butyl-3-methyl-benzofuryl acetic acid. yield
67.6% Melting point 169-170q○ Elemental analysis C (%) Day (%) Theoretical value as C, Rainbow, 803 73.14 7.3
7 Actual value 73.01 7.44 Example 6 After reacting in the same manner as in Example 1 using 51 sec-butyl-3-methyl-2-cyanomethylbenzofuran for 10 min, it was made acidic with 43 ml of concentrated hydrochloric acid. 51s
When the crude crystals of ec-butyl-3-methyl-2-benzofuryl acetic acid are recrystallized from cyclohexanone, purified 5-s
ec-butyl-3-methyl-2-penzofuryl acetic acid7.
6 days (yield 70.4%) is obtained.

Washimushi point 127-129q○ Elemental analysis C (%) Day (%) Theoretical value as C, illusion, 803 73.14 7.3
7 Actual value 73.21 7.62 Example 7 51 n-hexy-3-methyl-2-benzofuryl acetic acid was prepared in the same manner as in Example 2 using 11.0 ml of 51 n-hexy-3-methyl-2-acetylbenzofuran. Crude crystals are obtained.

Purified by recrystallization from methanol 51n-hexyl3-
Methyl-2-penzofuryl acetic acid 5.7 hours (yield 48.7
%) is obtained. Melting point 175-700 Elemental analysis C (%) days (%) C, 7 days 2.

Claims (1)

[Claims] 1 General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [However, in the formula, R_1 is an alkyl group of C_2 to C_6,
5-substituted-3-methyl-2-benzofuryl acetic acid represented by C_1 to C_6 alkoxy group, phenyl group, fluorine atom or benzyl group] and pharmacologically non-toxic salts thereof.