JPS6054318B2 - Method for producing aroyl-substituted phenyl acetic acid derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the field of alloyed phenylacetic acid esters which exhibit anti-inflammatory activity.

The compounds of the invention differ from conventional compounds primarily by their aroyl functionality. The prior art is shown in the following documents: French Medical Patent Specification 8440M; French Patent No. 1589691; French Medical Patent Specification 7956 Mi; Chemical Abstracts, Dl9lO97S; Chemical Abstracts, 'I3s66268g; French Patent, 15
16775; French Medical Patent Specification No. 5903M; Chemical Abstracts, including No. 77035e; and French Medical Patent Specification No. 6444M. The present invention relates to novel aroyl-substituted phenylacetic acid esters.

The novel compound can be represented by the following formula: where R2 represents lower alkyl and R4 represents alkyl having 1 to 8 carbon atoms or di(lower alkyl)amino lower alkyl.

As used herein, lower alkyl is a straight or branched chain having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc. I can do it.

65 to Logeno13 include fluoro, chloro, bromo and iodo.

The paraalloy-substituted phenylacetic acid ester of formula (1) is prepared by combining a suitable aryl-ketone of formula (2), where z is a suitable residue, preferably a fluorophenyl-aryl ketone, with a suitable reactive inert organic ester. In a solvent, formula (3)
It is conveniently prepared by reacting with di-lower alkyl 2-R2-malonate. Prior to the reaction with (2), the active hydrogen at the 21-O position of (3) is treated with an alkali metal hydride such as sodium hydride. It is advantageous to substitute preferably with sodium. As used herein, the term ``reactive inert organic solvent'' refers to a solvent that dissolves or disperses reaction components (2) and (3) without interfering with the interaction between them, such as hexamethylphosphoramide. , nitromethane, dimethylsulfoxide, dimethylformamide, and the like. The di-ester (4) thus obtained is then heated using preferably alkaline hydrolysis conditions, e.g. by heating a mixture of (4) with an alkali metal hydroxide solution to give the equivalent of the corresponding acid. After generating an alkali metal salt, the generated salt is acidified to obtain the desired phenylacetic acid (1-a).
It is hydrolyzed by giving By then applying standard esterification treatments to the latter, e.g.
(b) first converting the acid into the corresponding alkali metal salt form by treatment with a suitable alkali metal base, e.g. sodium hydride, and then converting the salt into a suitable polar by reaction with a suitable R,-halide in a solvent; or (c
) The acid is converted into an acid halide, and then the acid halide is reacted with a suitable alcohol to obtain a compound in which R4 is alkyl or di(lower alkyl)amino lower alkyl having 1 to 8 carbon atoms. Desired ester (1
-b) can be given. The above reactions can be schematically illustrated by the following reaction formulas. Furthermore, the formula (1
) can also be conveniently prepared, for example, by transesterification of lower alkyl esters with higher alkanols or suitable dialkylaminoalkanols in the presence of alkaline reaction promoters.

Although it is recognized that the above reaction between (2) and (3) can give a mixture of di-ester (4) and mono-ester (4-a), the mono-ester , resulting from the decomposition of di-esters: by adding standard ester-to-acid hydrolysis to mono-esters which can be isolated by conventional methods, e.g. by distillation. , the desired expression (1
The phenylacetic acid derivative of -a) can be obtained.

Di-lower alkyl malonates of formula (4) are believed to be novel compounds, and in view of their usefulness as precursors for the synthesis of compounds of formula (1), they are included as additional compounds of the present invention. This can be seen as a serious situation.

Arylketones of formula (2) are Lewis acids, preferably eg aluminum chloride, between thiophene and a suitable carbonyl halide having the formula, preferably chloride, where Z is as defined above. Suitable solvents such as those typically used in Friedel-Crafts type reactions, such as methylene chloride, 1,2-dichloroethane, carbon disulfide, nitrobenzene, anhydrous, in the presence of metal halides such as stannous chloride, etc. It can be easily obtained by Friedel-Crafts reaction in benzene (with SnCl4) or the like.

Conversely, ketones of formula (2) can be prepared by a Friedel-Crafts reaction between a substituted benzene having the formula (where Z is as defined above, preferably fluoro) and 2-theonoyl chloride. You can get it.

Some of the fluorophenyl aryl ketones of formula (2) are also considered to be novel compounds, and in view of their usefulness as precursors to the compounds of the present invention; these ketones are also included in the present invention. This constitutes one aspect. These new ketones can be represented by the general formula.

Esters of aroyl phenylacetic acid (1-g), where R4 is as defined above, can also be alkylated at the alpha-1 position.

In one method, the ester is prepared in a suitable inert organic solvent such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, etc.
After treatment with a suitable amount of a metallating agent such as sodium hydride, the α-alkyl substituted compound is formed by reaction with a suitable amount of a suitable alkyl halide.

Another method is to convert the ester of formula (1-g) into a metal enolate, preferably lithium enolate, by treatment with a suitable lithium amide, preferably lithium diisopropylamide, in tetrahydrofuran, and then convert it into a metal enolate, preferably lithium enolate. , preferably in the presence of hexamethylphosphoramide. The present invention consists of reacting with a convenient alkylating agent, such as an alkyl halide.

It is clear that the available asymmetric α-1 carbon atom present in the target compound (1) allows the existence of the target compound in the form of stereochemical aberrations (stereomorphism).

The corresponding (-) or (+) form of the desired compound can be obtained by standard methods of resolution. Such pharmacologically active laterality is, of course, intended to be included within the scope of the present invention. The target compound (1) is H
It has useful anti-inflammatory properties, as demonstrated by activity in the OAC-induced Rice Thing (Wr'Thing) test and/or the Wr'Thing test.

In these studies, the target compound was found to be an effective antagonist of acetic acid-induced Rice syndrome (WT'Ithe) in rats and/or of B. bovine-induced arthritis in rats. According to the acetic acid-induced rice swing test, female Wistar rats (body weight 100±5y
) were fasted overnight, and then 0.5 mt of 1% acetic acid solution was injected intraperitoneally.

Rats exhibiting at least 10 Rice symptoms within the first dose of acetic acid injection are selected and treated 5 minutes later by oral administration of the compound under study or vehicle (control). Rice symptoms, i.e., the number of backward extensions of the hind limbs, were determined 45 to 60 minutes after oral treatment and during the experimental period.
count. A minimum of 3 rats are used for each dose level tested. If the number is less than 15 during the test period of one test, this is significantly different from the control test (P less than 0.
05), it can be said that the remarkable medicinal effect occurred.

According to the bovine butyric acid-induced arthritis test, male Wistar rats (body weight 235 ± 15 f) had:
0.05 ml of an oily suspension of Mycobacterium bovis is injected subcutaneously.

Hind paw and joint diameters are measured on the day of injection and 2 weeks later. Rats with acupuncture arthritis, ie a significant increase in paw and joint diameter, are used for efficacy testing.

Groups of animals in three separate cages are fed the drug under test mixed with powdered feed at different concentrations for 14 consecutive days. After this treatment period, hindlimb diameters are again measured and the effect of drug treatment is evaluated by comparing the final degree of swelling in treated animals to that occurring in untreated control animals. The lowest effective dose is the dose at which a significant reduction in swelling is observed compared to untreated control animals. In the table below, results for compounds included in formula (1) are shown, but these compounds are not shown to limit the present invention to these, and are referred to as "compounds within the scope of formula (1)." It should be understood that these are provided solely to illustrate the full range of useful anti-inflammatory properties of.

As already demonstrated in other anti-inflammatory agents, formula (1)
Compounds have been shown to inhibit platelet aggregation.

The following examples illustrate the scope of the invention, but include:
It is not limited to this.

All parts are by weight unless otherwise specified. Reference Example 1 9.6 parts of a 55% dispersion of sodium hydride are suspended three times in anhydrous benzene and the latter is decanted each time.

Then 20 CE) of hexamethylphosphoramide and 34.8 parts of diethyl 2-methylmalonate (dropwise) are added. If the mixture is heated gently, a violent reaction will occur. When the reaction has subsided, the mixture is cooled and
Add 41.2 parts of p-fluorophenyl 2-thienyl ketone. The whole liquid is heated to 100° C. and stirred at this temperature for 1 hour. The reaction mixture is diluted with 400 m of benzene, washed twice with water, dried and evaporated. Distillation of the oily residue gives diethyl 2-methyl-2-[p-(2-thenoyl)phenyl]malonate; boiling point 205-210° C. at 0.4 m pressure. p-fluorophenyl 2-thienyl ketone is replaced by a suitable amount of a suitable p-fluorophenyl aryl ketone, and diethyl 2-methylmalonate is replaced by a corresponding amount of a suitable diethyl malonate. By repeating the method of Reference Example 1, the following compound is obtained: 2-ethyl-2-[p-(2
-Thenoyl)phenyl]diethyl malonate; melting point 0.1
At the pressure of
A mixture of diethyl phenylmalonate and 20 ml of 5% sodium hydroxide solution is stirred under reflux for 6 hours.

The reaction mixture is allowed to cool while stirring. The whole is filtered and the aqueous phase is separated. The latter is washed with benzene, acidified with concentrated hydrochloric acid solution and stirred for 15 minutes. Extract the product with chloroform. The extract is washed with water, dried and evaporated. The oily residue is triturated twice in petroleum ether. Solid product? Separately, from acetonitrile, initially -20
C. and then at 0.degree. C., p-(2-thenoyl)hydratropinic acid is obtained; melting point 124(s); it is p-(2-thenoyl)-α-methyl-phenyl ．． It can also be called acetic acid. 2-
By repeating the method of Reference Example 2 using a corresponding amount of the appropriate diethyl aroyl phenylmalonate in place of diethyl methyl-2-[p-(2-thenoyl)phenyl]malonate, the following compound was prepared. ．． Obtain the compound: 2-[p-(
2-Thenoyl)phenyl]butyric acid: melting point 122.8°C.

Example 1 A mixture of 52 parts of p-(2-thenoyl)hydratropinic acid, anhydrous denatured ethanol of Kube and 0.5 part of a hydrochloric acid solution is stirred and refluxed for two hours.

The reaction mixture is concentrated and the residue is taken up in ether. The ether solution is shaken with alkaline water, separated and shaken twice with water. The ether phase is dried, filtered, and concentrated to obtain ethyl p-(2-thenoyl)hydratropate, also known as ethyl p-(2-thenoyl)-α-methyl-phenylacetate, as a residue. IR absorption: Ester carbonyl extension, up to 1720C77! -1, ketone carbonyl extension, maximum 1640c1-1, UV absorption (2-
Compound dissolved in 0.01N hydrochloric acid in propanol)
: Maximum, absorption coefficient = 1440 at 265nm 293n
Tr1. By repeating the esterification procedure of Example 1, except using an amount of the appropriate aroy-substituted phenylacetic acid corresponding to the absorption coefficient = 14100 μ, the products were obtained by the following formula (1), respectively: Obtain the ester: p-(
2-Thenoyl)-α-ethyl-ethyl phenylacetate; Example 2 52 parts of p in dry hexamethylphosphoramide
0.86 part of a 55.3% dispersion of sodium hydride is added to the stirred mixture of -(2-thenoyl)-hydratropin'' acid and the whole is stirred for 1 hour.

Then 3.86 parts of octyl bromide and 0.01 part of potassium iodide are added. After completion, stirring at room temperature is continued for 18 hours. The reaction mixture is poured onto benzene and the whole is shaken successively twice with water, twice with sodium hydroxide solution and twice again with water. The organic phase is dried, filtered and concentrated. The residue is taken up in ether and stirred with activated charcoal. The latter is separated and the liquid is concentrated again. The residue is purified by column chromatography on silica gel using chloroform. Collect the pure fraction and evaporate the solvent to obtain octyl p-(2-thenoyl)-hydratropate as a residue. IR absorption: Ester carbonyl extension, up to 1725c7n-1, ketone carbonyl extension, up to 1630 cr! l-1, UV absorption (compound dissolved in 0.01N hydrochloric acid in 2-propanol) maximum,
265nm 1 trowel absorption coefficient = 13800, 293r1T
r! By repeating the esterification procedure of Example 2 except using amounts of the appropriate aroyl-substituted phenylacetic acids and the appropriate alkyl halides, respectively, the products have the following formulas: Obtain the ester of (1): p-(2-thenoyl)-α
Mono-ethyl-butyl phenyl acetate.

Example 3 A mixture of 1 part sodium hydroxide in 96 parts 2-propanol is heated to reflux and stirred until a homogeneous mixture is obtained.

Then 6.25 parts of p-(2-thenoyl)hydratropinic acid are added and the whole is stirred under reflux for 1 hour. The mixture is treated with 0.5 part of activated carbon and filtered over diatomaceous earth. After stirring, the Oki liquid was stirred at room temperature for two hours, and the product was separated and vacuum dried over calcium chloride at 70'C to obtain p-(2-thenoyl)hydratropinic acid, sodium salt; Melting point: 187.4°C. Into a stirred mixture of 282 parts of the sodium salt of p-(2-thenoyl)-hydratropic acid and 250 m of hexamethylphosphoramide are added 56.8 parts of methyl iodide at room temperature (slightly exothermic reaction). .

The whole is stirred for 1 hour at room temperature. reaction mixture to 10
00 parts of water and the product is extracted three times with 140 parts of diisopropyl ether. Wash the strained extract with 2 (1) parts of water, dry, filter, and concentrate. The residue was crystallized from 35 parts of diisopropyl ether at 0°C, washed with cold ether, dried and p
-Methyl (2-thenoyl)hydratropate is obtained; melting point 62°C. By repeating the method of Example 3 using the corresponding amount of 1-bromopropane instead of methyl iodide, the compound propyl p-(2-thenoyl)hydratropate is obtained as a yellow oil. do.

Example 4 1.3 parts of a 78% sodium hydride dispersion are suspended three times in anhydrous benzene, and the latter is decanted each time.

then 75 parts of hexamethylphosphoramide, then 1
Add 0.4 parts of p-(2-thenoyl)-hydratropic acid. The whole is heated to 50° C. and when the reaction has subsided (sodium salt formation) the mixture is cooled to room temperature. After adding 7 parts of N-(2-chloroethyl)-N-N-dimethylamine, the whole was heated to 1811 at 50°C.
Stir for 8 minutes.

The reaction mixture is cooled and extracted with 24 hours of benzene. The organic layer is washed successively with 100 parts of water, dilute sodium hydroxide solution and again with 10 parts of water, dried, filtered and concentrated. The residue is purified twice by column chromatography on silica gel, first using chloroform as eluent and then using a mixture of chloroform and 5% methanol. After distilling off the solvent,
The residue is converted to oxalate in 2-propanol. The crude salt is separated and crystallized from 2-propanol (activated carbon) at -20°C to give p-(2-thenoyl)hydratropinic acid 2-(dimethylamine)ethyl oxalate; melting point 117.4°C. . N-(2-chloroethyl)-
Instead of N-N-dimethylamine, a corresponding amount of N-(
By repeating the esterification procedure of Example 4 using 3-chloropropyl)-N-N-dimethylamine or a corresponding amount of N-(2-chloroethyl)-N●N-dimethylamine, to obtain the compound p-(2-thenoyl)hydratropinic acid 3-(dimethylamino)propyl oxalate; melting point 135-145°C: and p-(2-
2-(dimethylamino)ethyl tenoylhydratropinate hydrochloride: melting point 126.4°C.

Example 5 A mixture of 4.27 parts of lithium diisopropylamide and 1 part of tetrahydrofuran was heated to -78
Cool it down.

Claims (1)

[Claims] 1 A compound of the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Represents 8 alkyl or di(lower alkyl)amino lower alkyl]
Formulas characterized by esterification with alcohol or its reactive derivative ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [However, in the formula, R_2 and R_4 have the above meanings]
A method for producing aroyl-substituted α-R_2 phenylacetic ester. 2 Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [However, in the formula, R_4 represents alkyl or di(lower alkyl)amino lower alkyl having 1 to 8 carbon atoms]
Formula ▲ There are mathematical formulas, chemical formulas, tables, etc., which are characterized by alkylating a compound with a compound of the formula ▲ [In the formula, R_2 represents lower alkyl and X represents a halogen]. etc. ▼ [However, in the formula R
_2 and R_4 have the above meanings] A method for producing an aroyl-substituted α-R_2 phenylacetic ester.