FI66369C - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA P-2-TENOYL) FENYLALKANSYROR OCH DERIVAT AV DESSA - Google Patents

Description

ra1 „„ ANNOUNCEMENT,, Ύ, n ^ ^ UTLÄCCNINGSSICAIFT 6 6 369 (51) K * Ji? /ht.a.3 C 07 D 333/22 FINLAND — FINLAND pi) p * ~ * m * ~ m - ** ***. «, ** 3278/73 (22) H« kwri ^ mv - AmOlmlnpdit 23.10.73 p3) AMnflMl — GHtiglMtadaf 23.10.73 (41) T »it Mtbria» —MMf nB — rt% 25.04.74

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Patent · och registerityreleen AmBlawuthfdodieUtoanpnHlwd 29.06.84 (32) (33) (31) ΡΧΤ «·« Τ «« oJIt —- a ^ lrt rrtortM 24.10.72 10.09.73 USA (US) 300079, 395877 True-Styrkt (71) Janssen Pharmaceutica Naamloze Vennootschap, Turnhoutsebaan 30,

Beerse, Belgium-Belgium (BE) (72) Paul Adriaan Jan Janssen, Vosselaar, Georges Henri Paul Van Daele, Turnhout, Jozef Martin Boey, Wilrijk (Antwerp), Belgium-Belgium (BE) (74) Oy Kolster Ab (54) Process for the preparation of therapeutically useful p- (2-thenoyl) phenylalkanoic acids and their derivatives - For the preparation of therapeutically useful p- (2-thenoyl) phenylalkanesyror and derivatives thereof

The invention relates to a process for the preparation of therapeutically useful p- (2-thenoyl) phenylalkanoic acids and their derivatives of formula W 1, wherein X is hydrogen, chlorine or methyl, R is hydrogen or chlorine, R 2 is hydrogen or methyl, and R 3 is methyl or ethyl and Y is hydroxy, alkoxy of 1 to 8 carbon atoms, di-lower alkylamino-lower alkyloxy or hydroxylamino.

2 66369

The compounds of the invention have anti-inflammatory activity and differ greatly from previously known compounds in the nature of the aroyl function. The prior art can be represented by the following references: French. pat. No. 8 440M, French. pat. No. 1,589,691, French. pat. No. 7,956M, South Afr. pat. No. 68/4682 (Chem. Abstr. 71, 91097s), Saks. hak. Publication No. 1,963,824 (Chem. Abstr. 73, 66268g), French. pat. No. 1,516,775, French. pat. 5,903M, Chem. Abstr. 73, 77035e, and French. pat. 6 444M. The compounds disclosed in these publications have a phenyl group, instead of the thienyl or substituted thienyl group of the new compounds. The new compounds are significantly more active than the known compounds, as shown below.

The process according to the invention is characterized in that a) a compound of formula R 1 is hydrolyzed

X—— co - C-COOalkyl IV

COOalkyl wherein X, R and are as defined above, preferably under basic conditions to prepare a compound of formula XL -CO - {/ -CH-COOH Ia s W / 3 66369 wherein X, R and R2 are as defined above, and if desired a barrier -processing said compound Ia by known esterification methods to prepare a compound of formula _, E \ _ R2

1 L

x - ^ Λ-co-r y-ch -cor4 i-b wherein X, R and R 2 are as defined above and R 1 is alkyl or di-lower alkylamino-lower alkyl, or b) hydrolysing a compound of formula> 2

pN VI

R3 wherein X, R, R and R- are as defined above, in a manner known per se, to give the corresponding acid of formula R \ r2 _p il _j ~ \\ XL J-CO- ('') -C- COOH 1-0 \ = / 1 R3 wherein X, R, R2 and have the same meaning as above, or c) monoalkylating a compound of formula -Rv x -JjLco-J7 ^ \) -CH2 ~ COOH Id 4 66369 wherein X and R is as defined above, preferably by metallating one of the Λ hydrogen atoms and then treating with an alkyl halide to give a compound of formula

R

R 1 Va X CO 2 - (H-COOH 1-6 alkyl wherein X and R are as defined above, or d) a mono- or dialkylated ester of formula

R

X 1, CO 2 -CH 2 -COOR 4 Ig wherein X, R and R 4 are as defined above, preferably by first metallating the CX hydrogen atom or atoms and then reacting with an alkyl halide to give a compound of formula R 1. alkyl m> X - CO C t CH-COOR4 Ih or R alkyl J il> ~ \ j \ = / | 4 alkyl 5 66369 in which X, R and have the same meaning as above, or by converting a compound of formula Ig to a metal enolate and then reacting with an alkylating agent to give a compound of formula R 1-4 alkyl li il} / \ i i_h x -ky —Co — r) —ch-coor.

s \ = / wherein X, R and R 2 have the same meaning as above, and if desired said compound of formula Ia is converted into an acid halide of formula i-i R \ _ ΐ2 ϊ i 1 1 1 XC y-CO Γ \) -CH-C-halide s \ = / wherein X, R and R E have the same meaning as above, and the halogen in compound V or OR 1 - in group Ib is further replaced by a hydroxylamino group by known methods, and if desired, said esters are converted to the formula I by known methods to the corresponding acids and their corresponding derivatives, after which, if desired, the compounds of the formula I are divided into the (+) - or (-) - stereochemical isomers in a manner known per se.

Because the compounds of formula I have an asymmetric carbon atom, they may exist in the form of stereochemical isomers (in the form of enantiomorphs). Conventional component division methods provide the corresponding (-) or {+) forms of the desired compounds.

The compounds of formula I have useful anti-inflammatory properties, as demonstrated by their activity in the acetic acid-induced seizure test and / or in the Mycobacterium buty-ricum test. In these experiments, the compounds have been found to be potent antagonists of acetic acid-induced seizures in rats and / or Mycobacterium butyricum'11a-induced arthritis in rats.

The seizure test was performed as follows. Female Wistar rats (100-5 g body weight) were fasted overnight and injected intraperitoneally with 0.5 ml of acetic acid solution. Rats with at least 10 seizures during the first 10 minutes after acetic acid injection were selected and 5 minutes later orally administered the test compound. The number of seizures, i.e., posterior limb tension, was counted over a 15-minute test period, 45 to 60 minutes after administration of test compound vehicle. At least three rats were used for each dose. A significant drug effect was considered to occur if there were less than 15 seizures calculated during the 15-minute trial period (P <0.05).

The results presented below show the lowest effective dose (ED 2, mg / kg) of the test compound, p- (2-thenoyl) -phenylpropionic acids, compared to the corresponding benzoyl compound. Under these experimental conditions, the former compound proves to be 16 times more active than the latter compound.

Lowest effective dose

Compound (EE> 50 · mg / kg) Strength ratio oral p- (2-thenoyl) phenylpropionic acid 0.08 (1) p-benzoyl-phenylpropionic acid 1.25 1/16 7 66369

The arthritis test was performed as follows. Male Wistar rats (body weight 235 and 15 g) were injected subcutaneously at the base of the tail with 0.05 ml of an oil suspension of Mycobacterium butyricum. The paw and joint diameters of the hind limbs were measured on the day of injection and 2 weeks later, and those rats that showed arthritis, i.e., a significant increase in paw and joint diameters, were selected and the rats were divided into groups of 3 animals.

The experimental animals were administered the test compound mixed with a juicy food for 14 consecutive days. After this treatment period, hindlimb diameters were remeasured and the efficacy of the compounds was evaluated by comparing the final swelling rates of the treated animals to the corresponding untreated control animals. The lowest effective dose is the dose at which a significant reduction in swelling is observed compared to untreated control animals. The results are shown in the following table.

Lowest effective dose

Compound (ED 2 q, mg / kg) Strength ratio p- (2-thenoyl) phenylpropionic acid 0.63 (T) p-benzoyl-phenylpropionic acid 10.0 1/16

The following table shows the results of experiments with other compounds of formula I.

8 66369

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9 66369

The following examples illustrate the invention. Unless otherwise indicated, all amounts are by weight.

Example 1 2- [p- (2-thenoyl) phenyl: L] propionic acid

A mixture of 30.3 parts of diethyl 2-methyl-2- [p- (2-thenoyl) phenyl] nalonate and 200 parts of 5% sodium hydroxide solution is stirred and refluxed for 6 hours. The reaction mixture is allowed to cool with stirring. The mixture is filtered and the aqueous phase is separated. This is washed with benzene, acidified with concentrated hydrochloric acid and stirred for 15 minutes. The product is extracted with chloroform. The extract is washed with water, dried, filtered and evaporated, the oily residue is washed twice with petroleum ether. The solid product is filtered and crystallized twice from acetonitrile; first at -20 ° C and then at 0 ° C to give 2- [p- (2-thenoyl) -phenyl] -propionic acid, m.p. 124.3 ° C.

By repeating the procedure of Example 1 and substituting an equivalent amount of diethyl aroylphenyl malonate for diethyl 2-methyl-2- (p-2-thenoyl) phenyl malonate, the following compounds are obtained: 2- [3-chloro-4- (2-thenoyl) phenyl, 7-propionic acid, m.p. 82.5 ° C, 2- [2- (5-methyl-2-thenoyl) phenyl] propionic acid, m.p. 93.7 ° C, 2- [p- (2-thenoyl) phenyl] butyric acid, m.p. 122.8 ° C, and 2- [3-methyl-4- (2-thenoyl) phenyl] propionic acid, m.p. 100.2 ° C.

Preparation of starting materials 9.6 parts of a sodium hydride dispersion, 55%, are suspended 3 times in anhydrous benzene and this is decanted each time. 200 parts of hexamethylphosphoramide are then added successively and 34.8 parts of diethyl 2-methylmalonate are added dropwise. The mixture is gently heated to give a vigorous reaction. When the reaction is complete, cool the mixture and add 41.2 parts of p-fluorophenyl-2-

* O

tienyyliketonia. The mixture is heated to 100 ° C and stirred at this temperature for 10 hours. The reaction mixture is diluted with 400 parts of benzene, washed twice with water, dried and evaporated. The oily residue is distilled to give diethyl 2-methyl-2- [p- (2-thenoyl) phenyl / malonate, b.p. 205-210 ° C / 0.4 Torr.

10 66369

By repeating this procedure and replacing p-fluorophenyl-2-thienyl ketone with an appropriate amount of the appropriate p-fluorophenylaryl ketone and replacing diethyl 2-methylmalonate with an equivalent amount of the appropriate diethyl malonate, the following compounds are obtained: diethyl 2-methyl-2- / 4- (2- tenoyl) -m-tolyl-malonate, b.p.

186-193 ° C / 0.2 Torr, diethyl 2- [3-chloro-4- (2-thenoyl) phenyl] -2-methylmalonate, b.p. 225-235 ° C / 0.6-0.8 Torr, diethyl 2-methyl-2- [p- (2-thenoyl) phenyl] malonate, b.p. 235 -240 ° C / 1 Torr, diethyl 2-ethyl-2- [p- (2-thenoyl) phenyl] malonate, b.p. 175 -199 ° C / 0.1 Torr.

Example 2 2- [p- (2-Tenoyl) phenyl] propionic acid

A mixture of 7.3 parts of 2- [p- (2-thenoyl) phenyl] -propionitrile, 18 parts of sulfuric acid, 10 parts of water and 10 parts of acetic acid is stirred and refluxed for 2 hours. The reaction mixture is poured onto crushed ice and the product is extracted with ether. The organic layer is washed with dilute sodium hydroxide solution. The aqueous phase is acidified with hydrochloric acid and the product is extracted with ether. The organic layer is dried, mixed with activated carbon, filtered and evaporated in vacuo. The residue solidifies on trituration with petroleum ether. The solid product is filtered and crystallized from acetonitrile to give 2- [p- (2-thenoyl) phenyl] propionic acid # m.p. 121.1 ° C.

By repeating the procedure of Example 2 and replacing 2- [p- (2-thenoyl) phenyl] propionitrile with an equivalent amount of the corresponding aroylphenylacetonitrile, the following compounds are obtained: 2- [p- (5-chloro-2-thenoyl) phenyl] propionic acid, m.p. 137.4 ° C, and 2-methyl-2- [p- (2-thenoyl) phenyl] propionic acid, m.p. 138.8 ° C.

11 66369 Preparation of starting materials 2- [p- (2-thenoyl) phenyl] propionitrile

A suspension of 4.9 parts of sodium cyanide in 55 parts of dimethyl sulfoxide is stirred while heating to 60 ° C. 8.5 parts of p- (1-chloroethyl) -phenyl-2-thienyl ketone are then added in one portion and stirring at 60 [deg.] C. is continued for 4.5 hours. The reaction mixture is poured into water and the product is extracted with ether. The organic layer is washed with water, dried, filtered and evaporated to give 2- [p- (2-thenoyl) phenyl] propionitrile as a residue.

p- (1-chloroethyl) phenyl-2-tienyyliketoni

To a stirred and cooled solution of 43.7 parts of p- (1-hydroxyethyl) phenyl-2-thienyl ketone in 180 parts of dry benzene is added dropwise 16 parts of thionyl chloride. After the addition, stirring is continued at room temperature overnight. The reaction mixture is evaporated to dryness. Toluene is added to the residue and evaporated once more. The residue obtained is distilled and the distillate is crystallized from ethanol at room temperature to give p- (1-chloroethyl) phenyl-2-thienyl ketone, m.p. 60 ° C.

Example 3 Sodium salt of 2- [p- (2-thenoyl) phenyl] propionic acid

The mixture containing 1 part of sodium hydroxide in 96 parts of 2-propanol is heated to reflux and stirred until a homogeneous mixture is obtained. Then 6.25 parts of 2- [p- (2-thenoyl) phenyl, 7-propionic acid are added and the mixture is stirred for 1 hour at reflux. The mixture is treated with 0.5 parts of activated carbon and filtered through diatomaceous earth. After stirring the filtrate for 24 hours at room temperature, the product is filtered and dried in vacuo over calcium chloride at 70 ° C to give the sodium salt of 2- [p- (2-thenoyl) phenyl] propionic acid, m.p. 187.4 ° C.

methyl-2- / p- (2-thenoyl) fenyyli7propionaatti

To a stirred mixture of 28.2 parts of sodium 2-Zβ- (2-thenoyl) phenyl] propionate and 250 parts of hexamethylphosphoramide is added 56.8 parts of methyl iodide at room temperature (slightly exothermic reaction). The mixture is stirred at room temperature for one hour. The reaction mixture is poured into 1,000 parts of water and the product is extracted 3 times with 140 parts of diisopropyl ether. The combined extracts are washed with 200 parts of water, dried, filtered and evaporated. The residue is crystallized from 35 parts of diisopropyl ether at 0 [deg.] C., washed with chilled ether and dried to give methyl 2- [N- (p-2-thenoyl) phenyl] propionate, m.p. 62 ° C.

Example 4 2- (Dimethylamino) ethyl 2- [p- (2-thenoyl) phenyl] propionate oxalate 1.3 parts of a 78% sodium hydride dispersion are suspended 3 times in anhydrous benzene, which is decanted each time. 75 parts of hexamethylphosphoramide are then added, followed by the addition of 10.4 parts of 2- [p- (2-thenoyl) phenyl] propionic acid. The mixture is heated to 50 ° C, and when the reaction (sodium salt formation) ceases, the mixture is cooled to room temperature. 7 parts of N- (2-chloroethyl) -N, N-dimethylamine are added and the mixture is stirred for 18 hours at 50 ° C. The reaction mixture is cooled and extracted with 240 parts of benzene. The organic layer is washed successively with 100 parts of water, dilute sodium hydroxide solution and again with 100 parts of water, dried, filtered and evaporated. The residue is purified twice by chromatography on a silica gel column, eluting first with chloroform and then with a mixture of chloroform and 5% methanol. After evaporation of the eluent, the residue is converted into the oxalate salt in 2-propanol. The crude salt is filtered and crystallized from 2-propanol (activated carbon) at -20 ° C to give 2- (dimethylamino) ethyl 2- [p- (2-thenoyl) phenyl] propionate oxalate, m.p. 117.4 ° C.

By repeating the esterification procedure of Example 4 and replacing N- (2-chloroethyl) -yyli, Ν-dimethylamine with an equivalent amount of N- (3-chloropropyl) -Ν, Ν-dimethylamine or with an equivalent amount of N- (2-chloroethyl) -N, N- diethylamine, the following compounds are obtained: 3- (dimethylamino) propyl-2- (2-thenoyl) phenyl] propionate oxalate, m.p. 135-145 ° C, 2- (diethylamino) ethyl 2- [p- (2-thenoyl) phenyl] propionate hydrochloride, m.p. 126.4 ° C.

66369

Example 5 2- [p- (2-Tenoyl) phenyl] propionhydroxamic acid

To a stirred solution of 12.6 parts of ethyl 2- [p- (2-thenoyl) phenyl] propionate in 35 parts of methanol is added successively, first cooling, a solution of 6.05 parts of hydroxylamine hydrochloride in 35 parts of methanol and then 7.3 parts of potassium hydroxide. slide solution in 35 parts of methanol. The mixture is then stirred for 30 minutes. The mixture is filtered and the filtrate is stirred for 3 days at room temperature. The reaction mixture is evaporated and the residue is taken up in water. The aqueous solution is acidified with hydrochloric acid solution and the product is extracted with ether. The extract is washed with water, dried, filtered and evaporated. The residue is dissolved in water, basified with sodium hydroxide solution, washed with ether and the aqueous phase is acidified with concentrated hydrochloric acid. The product is extracted with ether, washed with water, dried, filtered and evaporated. The residue is purified by chromatography on a column of silica gel using a mixture of chloroform and 10% methanol as eluent. The pure fractions are collected and the rinse aid is evaporated. The residue is triturated with a mixture of petroleum ether and diisopropyl ether. The solid product is filtered and crystallized from 2-propanol to give 2- [p- (2-thenoyl) phenyl] propionhydroxamic acid, m.p. 143.5 ° C.

Example 6 (+) -2- [p- (2-thenoyl) phenyl] propionic acid

To a stirred mixture of 20 parts of 2- [p- (2-thenoyl) phenyl] propionic acid and 9.3 parts of (-) - O-methylbenzylamine in 200 parts of ethanol is added 50 parts of water. The precipitated salt is filtered and crystallized from a mixture of ethanol and water (10: 2 by volume) to give the crude salt form. This fraction is recrystallized several times from a mixture of ethanol and water (10: 2 by volume) until a constant rotation angle is obtained, to give (-) - 2- [p- (2-thenoyl) phenyl] propionic acid O1-methylbenzylamine derivative, m.p. 170.5 ° C, phot (1.98% in methanol) = -13.74 °.

1.5 parts of (-) - 2- [p- (2-thenoyl) phenyl] propionic acid-Ct-methylbenzylamine are suspended in water and acidified with hydrochloric acid. The product is extracted with ether. The organic filtrate is washed with water, dried and evaporated, the oily residue crystallizes from triturated petroleum ether. The crystalline product is filtered and dried in vacuo at 50 ° C to give (+) - 2- [p- (2-thenoyl) -phenyl] propionic acid r DU (1% in methanol) = + 44.5 °.

Example 7 (-) - 2- [p- (2-thenoyl) phenyl] propionic acid

To a stirred mixture of 30 parts of 2- [p- (2-thenoyl) phenyl] propionic acid and 14 parts of (+) - Cf-methylbenzylamine in 200 parts of ethanol is added 50 parts of water. The precipitated salt is filtered and crystallized from a mixture of ethanol and water (10: 2 by volume) to give the crude salt form. This fraction is recrystallized several times from a mixture of ethanol and water (10: 2 by volume) until a constant rotation angle is obtained to give the (+) - 2- [p- (2-thenoyl) phenyl] propionic acid QS-methylbenzylamine derivative, m.p. 171 # 1 ° C, C <* J (2.02% in methanol) = + 13.55 °.

1 part of (+) - 2- [p- (2-thenoyl) phenyl] propionic acid-O-methyl-benzylamine is suspended in water and acidified with hydrochloric acid. The product is extracted with ether. The organic layer is washed with water, dried, filtered and evaporated in vacuo. The oily residue crystallizes on trituration in petroleum ether. The crystalline product is filtered and dried in vacuo at 50 ° C to give (-) - 2- [p- (2-thenoyl) phenyl] propionic acid, M (1% in methanol) = -45.6 °.

Example 8 2-Methyl-3- (2-thenoyl) -2-phenylpropionic acid

A mixture of 6 parts of 2-methyl-3- (2-thenoyl-2-phenylpropionitrile, 2.7 parts of potassium hydroxide, 28 parts of ethanol and 3.5 parts of water is stirred and refluxed for 44 hours. The residue is taken up in water and washed twice with 80 parts of ether, the aqueous phase is acidified with concentrated sulfuric acid solution, the separated oily product is extracted with ether, dried and evaporated. methyl-3- (2-thenoyl) -2-phenylpropionic acid> mp 118.7 DEG C. The mother liquor is evaporated and the residue solidifies on trituration with petroleum ether to give 2-methyl-3- (2-thenoyl) - as a second fraction. 2-phenylpropionic acid, mp 100 ° C.

Example 9 2- [p- (2-Tenoyl) phenyl] propionic acid To 400 parts of liquid ammonia is added a small amount of ferric chloride and 3 parts of sodium. The mixture is stirred for 30 minutes, after which 14.8 parts of 2- [p- (2-thenoyl) -phenyl] acetic acid are slowly added over 30 minutes and the mixture is further stirred for 45 minutes. 13.6 parts of methyl iodide are added dropwise and the reaction mixture is stirred for 2.5 hours. 400 parts of diethyl ether are then added and the mixture is then stirred overnight. The ammonia is evaporated off and the remaining solution is acidified with dilute hydrochloric acid. The ether layer is separated and extracted with 10% sodium hydroxide solution. The extract is washed with ether, acidified and extracted with ether. The ether solution is dried over sodium sulfate and the ether is evaporated in vacuo. The residue is triturated in petroleum ether, filtered and crystallized twice from acetonitrile, first at -20 ° C and then at 0 ° C to give 2- [p- (2-thenoyl) phenyl] propionic acid, m.p. 121.1 ° C.

Example 10

Methyl-2- / p- (2-thenoyl) fenyylj / propionate

A mixture of 4.27 parts of lithium diisopropylamide and 50 parts of tetrahydrofuran is cooled to -78 ° C. 10.4 parts of methyl 2- [p- (2-thenoyl) phenyl] acetate are then added and the mixture is stirred for 40 minutes. 6.25 parts of methyl iodide dissolved in 2.15 parts of hexamethylphosphoramide are added at -78 ° C and the mixture is further stirred for one hour after being allowed to warm to room temperature. The mixture is poured into water. The resulting mixture is extracted with diisopropyl ether. The organic phase is washed with water, dried and evaporated. The residue is crystallized from diisopropyl ether at 0 ° C to give methyl 2- [p- (2-thenoyl) phenyl] propionate, m.p. 62 ° C.

16 66369

Example 11

To a stirred mixture of 5.2 parts of 2- [p- (2-thenoyl) phenyl] propionic acid in 50 parts of dry hexamethylphosphoramide is added 0.86 parts of a 55.3% sodium hydride dispersion and this is stirred for 1.5 hours. 3.86 parts of octyl bromide and 0.01 part of potassium iodide are then added. Stirring is then continued for 18 hours at room temperature. The reaction mixture is poured into benzene and shaken twice successively with water, twice with sodium hydroxide solution and again twice with water. The organic phase is dried, filtered and evaporated. The residue is taken up in ether and mixed with activated carbon. Filter and re-evaporate the filtrate. The residue is purified by chromatography on a column of chloroform using silica gel. The pure fractions are combined and the solvent is evaporated to give octyl 2- [E- (2-thenoyl) -phenyl] -propionate.

-1 IR absorption: ester carbonyl, max. 1725 cm ketone carbonyl, max. 1630 cm LIV absorption: (0.01-m HCl, 2-propanol): max. 265 nm, t = 13,800 and max. 291 nm, L · = 13,500.

The corresponding ethoxy compound was prepared in an analogous manner; the product was oily.

IR absorption: ester carbonyl, max. 1720 cm-2 ketone carbonyl, max. 1640 cm UV absorption (0.01-m HCl, 2-propanol): max. 265 nm, ε = 14,400, and max. 293 nm , E = 14,100.

Example 12

A mixture of 5.2 parts of 2- [p- (2-thenoyl) -phenyl] -propionic acid, 4.8 parts of thionyl chloride and 32 parts of anhydrous benzene is stirred and refluxed for 3.5 hours. The reaction mixture is evaporated and the residue is evaporated once more from benzene to give 2- (β- (2-thenoyl) -phenyl] propionyl chloride as a residue.

To a solution of 1.5 parts of hydroxylamine in 20 parts of dioxane is added a solution of 4.2 parts of 2- [p- (2-thenoyl) -phenyl] propionyl chloride in 25 parts of dioxane. An additional 30 parts of dioxane are then added and the mixture is stirred and refluxed for one hour. The reaction mixture is allowed to cool to room temperature. After filtration, the filtrate is treated with activated carbon, filtered and evaporated in vacuo. The residue solidifies on trituration with a mixture of petroleum ether and diisopropyl ether. The solid product is filtered off and the product is crystallized from 2-propanol to give 2- [p- (2-thenoyl) phenyl / propionic hydroxamic acid; mp. 143 ° C.

Claims (1)

A process for the preparation of therapeutically useful p- (2-thenoyl) phenylalkanoic acids and their derivatives having the formula 2 ~! _> V2 ° X y-co-vx> -C-C-YIS \ - / R K3 wherein X is hydrogen, chlorine or methyl, R is hydrogen or chlorine, R 2 is hydrogen or methyl, and is methyl or ethyl, and Y is hydroxy, alkoxy of 1 to 8 carbon atoms, di-lower alkylamino-lower alkyloxy or hydroxylamino, characterized in that a) a compound of the formula R 1 -R 2 -CO - ((C 1 -C) -COOalkyl IV or COOalkyl in which X, R and R 2 are as defined above is hydrolysed, preferably under basic conditions to prepare a compound of formula, wherein R, R 1 and R 2 are as defined above, and if desired, the barrier -processing said compound Ia by known esterification methods to prepare a compound of formula _, R \ K2 XT X 1 X -LJ-CO-Γ x) -CH -COOR - Ib wherein X, R and R 2 are as defined above, and R 1 is alkyl or di-lower alkylamino-lower alkyl, or b) hydrolyzing a compound of formula R. R x -X ccX VJ 2 Y pN VI R 3 wherein X, R, R and R 1 are as defined above, in a manner known per se, to give the corresponding acid of the formula -R 1 R 2 1 x -L 1 - CO-K x) -C-COOH IC s 1 -R 3 wherein X, R, R 2 and R 3 are as defined above, or c) monoalkylating a compound of formula. Wherein X and R are as defined above, preferably by metallizing one of the hydrogen atoms and then treating with an alkyl halide to give a compound of formula R X 1 - CO 2 --CH-COOH If alkyl wherein X and R are as defined above, or d) mono- or dialkylating an ester of the formula -O- - X - CO- (y-CH -COOR Ig w wherein X, R and R 1 are as defined above, preferably by first metallizing the CX hydrogen atom or atoms and then reacting with an alkyl halide to give a compound of formula Rv alkyl JTH> Λ 1 X- CO-S , Γ-CH-COOR 4 Ih or R alkyl i n 1 alkyl 21 66369 wherein X, R and are as defined above, or by converting a compound of formula Ig to a metal enolate and then reacting with an alkylating agent to give a compound of formula Rv alkyl i L _J '\ 1 X kj— CO- () CH-COOR. s \ = / where X, R and R ^ and, if desired, converting said compound of formula Ia into an acid halide of formula i ii_y ~ \ 1 * X * -CO / \\ - CH-C-halide s \ = / wherein X, R and the same as above, and further replacing the halogen in compound V or the R4R group in compound Ib with a hydroxylamino group by known methods, and further, if desired, converting said esters into the corresponding acids of formula I and their corresponding derivatives by known methods, followed by partitioning of compounds of formula I (+) - or (-) stereochemical isomers in a manner known per se. 22 66369 For the preparation of a therapeutically active compound containing p- (2-thenoyl) phenylalkyl and derivative of this form, which form a compound of the formula j ~ l va * 2? XA s — CO —V 7— C - C - YI \ = / i, color X is a statement, chlorine or methyl, R is a statement or chlorine, Rj Mr statement or methyl, and R 2 is a methyl or ethyl, och Y hydroxyl, alkoxy of 1-8 cholaters, di-lapgyl-alkylamino-lapg-alkyloxy or hydroxylamino, to which a mixture of R _ \ _ R2 X-li J-CO - (/ 7-C-COOalkyl) IV s \ = JI COOalkyl of the group X, R and R2 are selected from the group consisting of hydrolysers, which are obtained under basic conditions, for the purposes of the formulation, _, R2 fi I / ~ \ 1 X - ^ - CO-C y CH-COOH Ia 23 66369 for X, R and R2 are defined as such, and for example, for the first time and for the first time the method is used for the preparation of formulas 1-1 Κχ I2 I 1 1 x - ^ - {fy -Ch -cor4 ib is X, R and R2 are selected from the group consisting of alkyl and R1 is alkyl or di-alkyl alkylamino-alkyl, or b) is used in the form of «jjLc ^ Y-Ic i- ™ or R3 is X , R, and R ^ betecknar decamma som tidigare, hy drolyseras pä i och för sig känt sätt, fr framställning av motsvarande syra med formuleln R \ R2 Ji il Kl x—— co — y — c-cooH ic R3 där X, R, R2 och R ^ betecknar Decamma som tidigare, eller 24 66369 (c) in the case of formulas _ R \ _ X Ls.-C0 - CH2-COOH Id där X and R betecknar decamma som tidigare, monoalkyleras, företrä-desvis genom metallbindning av en av five-väteatomerna, följt av be-handling with alkyl halides, for the purpose of the reaction with the formula RPL x —y — CO—) CH-COOH If alkyl of X and R is a specific solution, or d) an ester with the formula R X- □ -C0 - ^ - CH2 -COOR4 Ig där x, R and R4 betecnar decamma som tidigare, mono-eller dialky-leras, företrädesvis genomta först metallaisera Ct-väteatomen eller -atom, atomic reaction with alkyl halides, framställ-Ning av en förening med formeln 25 6 6369 R>. alkyl ΓΧ X \ J x—— co— (r — ch-coor4 ih eller R XI Xv1 ^ \ = y I 4 alkyl i vilka formler X, R och R ^ betecknar decamma som tidigare # eller ombildande av en förening med formuleln Ig to a metal atom, which may be substituted by an alkylation mixture for the form of a mixture of _ R \ _ alkyl x —Il sJ-co —ch-coor4 is a mixture of X, R and R ^ a member of the invention which, on its own, is these are formed with the formula I and the halohydride with the formula R R2 0 [j ii i il CQ -y-CH -C-halide V