IE43448B1 - Substitued pheylacetic acids - Google Patents

Description

The present invention relates to certain novel substituted phenylacetic acids, their preparation and compositions containing them.

The invention is an improvement in, or a modifi·. cation of, the invention (herein termed the main invention) which is the subject of our Irish patent Specification No. 39683 (herein termed the main specification).

The compounds according to the main invention °· are 2-amino-3(and 5-) benzoylphenylacetic acids having the formula:- . ). wherein: R represents hydrogen or lower (C^Cg)-alkyl; and R1 represents hydrogen, lower-alkyl, halogen, nitro or trifluoromethyl.

Compounds of Formula I are effective in preventing inflammatory response to pleural irritation.

It has now been discovered that other compounds analogous to the compounds of Formula I also have pharmacological properties and are useful as pharmaceutical agents.

The compounds according to the present invention are 2-amino-3-(and 5- and 6-) benzoylphenylacetic acids and derivatives thereof having the formula :- Formula 11 - 2 43448 wherein: R is as set forth above; ' Rg represents hydrogen, halogen or lower-alkoxy; R^ represents hydrogen, lower-alkyl, alkali metal or . alkaline earth metal, X represents hydrogen, lower-alkyl, lower alkoxy,. halogen, nitro or trifluoromethyl; Y represents hydrogen, lower-alkyl, lower-alkoxy, halogen, nitro or trifluoromethyl; or . X and Y together represent a lower-alkylene dioxy group; Am represents primary amino (NHg), methylamino (NHCHj), or dimethylamino (NiCH^Jg), subject to the proviso that when R , R and Y are all hydrogen and the benzyl group is at the 3 or 5 position on the benzene ring of the phenylacetic acid . group, Am is methylamino or dimethylamino; and x x n represents 1 when Ris monovalent or 2 when R is divalent.

As in the case of the main invention, the term loweralkyl as used herein means straight and branched chain . radicals of up to 6 carbon atoms inclusive, preferably no more than 4 carbon atoms, and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, n-butyl, sec. butyl, tertiary butyl, n-amyl, isoamyl and n-hexyl.

The term lower-alkoxy means -O-lower-alkyl.

. The term lower-alkylene means an alkylene group of to 6, preferably 1 to 4, carbon atoms.

When halogen is referred to herein, preferably but not necessarily a halogen of atomic weight not greater than 80 is employed.

. Compounds of the Formula II exhibit anti-inflammatory activity, lower cholesterol levels in hyperlipemic rats and inhibit blood platelet aggregation. - 3 »r<' The anti-inflammatory activity was demonstrated using a modification of the Evans Blue-Carrageenan Pleural Effusion Assay of Sancilio, L.F., J. Phamacol, Exp.

Ther. 168, 199-204 (1969).

· When Rj is an alkali metal and n is 1 in Formula II, the preferred alkali metal salts are sodium and potassium salts. These salts themselves posses antiinflammatory activity, and are also useful intermediate in the preparation of the esters of Formula II. When LO. Rj is an alkaline earth metal and n is 2 in Formula II, the preferred alkaline earth metal salts are calcium and magnesium.

As already indicated, the substituent which can be attached to the mono-substituted benzoyl radical oan be a -5. lower alkyl, lower-alkoxy, halogen, nitro or trifluoromethyl radical. The substituents which can be attached to the disubstituted benzoyl radical can be any two of these In any combination. The monosubstituted and disubstituted benzoyl radicals therefore include, for 0. example, lower-alkyl benzoyl, halobenzoyl such as chlorobenzoyl, bromobenzoyl and fluorobenzoyl, nitrobenzoyl , trifluoromethylbenzoyl,3,5-dichlorobenzoyl, 2.4- dichlorobenzoyl, 3-trifluoromethyl-4-chlorobenzoyl, 2.4- dimethylbenzoyl, 3,5-dimethylbenzoyl, 3-nitro-45, chlorobenzoyl, 2-methyl-4-chlorobenzoyl, 3-methoxy4-chlorobenzoyl or 3,4-methylenedioxybenzoyl.

When used hereinafter the term benzoyl refers to the unsubstituted benzoyl radical, the monosubstituted benzoyl radical or the disubstituted benzoyl 3. radical, unless the context implies that the unsubstituted - 4 4 314 8 benzoyl radical is meant.

Methods of Preparation The preparation of the novel 2-amino-3- (and 5and 6-)benzoylphenylacetic acids (II) of the present · invention may be accomplished by hydrolysis of 4(and 5- and 7-)benzoylindolin~2-ones (III) in aqueous basic solution followed by neutralization of the basic reaction mixture. The reaction sequence is illustrated by the following: (III) (II) . ' wherein R, R , X, Y and Am are as defined above.

The hydrolysis of an indolin-2-one (III) may be carried out in dilute aqueous base, for example 3N sodium hydroxide solution, for a period of from about 0.5 hour to about 1.0 hour. The hydrolysis may be ruh . in an inert atmosphere using nitrogen. The hydrolysis mixture may be filtered to remove base-insoluble materials. The pH of the basic solution is adjusted to pH 6-pH 7 by the addition of a weak organic acid such as glacial acetic acid or a dilute mineral acid such as hydrochloric acid. When (II) is a 2-amino5-benzoylacetic acid or a 2~amino-6-benzoylacetic acid the product can be readily recrystallized from a suitable solvent. When (II) is a 2-amino-3-benzoyl~ acetic acid, recrystallization may result in partial . cyclization to the precursor 7-benzoylindolin-2-one (III). Therefore, in the preparation of a 2-amino-3- 5 - ¢3-148 benzoylacetic acid (II) the product is preferably not recrystallized and is isolated by careful acidification of the filtered basic hydrolysis mixture.

The lower-alkyl esters of Formula II are prefer5. ably prepared from the acids which are converted to an alkali metal salt, preferably the sodium or potassium salt, which is isolated, dried and then reacted in a suitable solvent, for example dimethylformamide, with an alkyl halide, preferably an alkyl . iodide, to furnish the desired ester.

The compounds of Formula II wherein Am is dimethylamine may be prepared by reacting a 2-aminophenylacetic acid of Formula II wherein Am is primary amino (-NH^) with formaldehyde and sodium cyanoborohydride in a L5. solvent such as acetonitrile under mildly acidic conditions as provided by the use of glacial acetic acid.

The starting materials for the process of the present invention are the appropriately substituted ’-0· 4-(5- and 7-)benzoylindolin-2-ones. The 5-benzoylindolin-2-ones can be prepared by reacting an indolin2-one of Formula IV with a benzoyl chloride in the presence of aluminium chloride to give an indolin-2one of Formula III.

(IV) (III) The indolin-2-ones (IV) are either commercially - 6 4 3 4 4 8 available or they can be prepared by known methods such as are disclosed by Wenkert et al., J. Am. Chem. Soc. 81, 3763-3768 (1959).

The 7-benzoylindolin-2-ones of Formula III may 5. be prepared by the following reaction sequence. - 7 4 3 4 4 8 - 8 ~ The l-aminoindolin-2-one starting materials (V) can be prepared by suitable known methods such as are disclosed by Baumgarten et al., J. Am. Chem. Soc. 82. 3977-62 (I960). The l-aminoindolin-2-one (V) is . reacted with an appropriately substituted phenylacetone to give a l-(a-methylphenethyl-indenimino) indolin-2-one (VX) which is cyclized in ethanolic hydrogen chloride to an ethyl a-(2-methyl-3-phenylindol-7-yl)acetate (VII). The indolylester is . treated with ozone in acetic acid solution to give an ethyl 2-acetamido-3-benzoylphenylacetate (VIII) which is hydrolyzed and cyclized in dilute mineral acid to a 7-benzoylindolin-2-one (III).

Alternatively, an ethyl a-(2-methyl-3-phenylin15, dol-7-yl) acetate (VII) is hydrolyzed in aqueous basic solution to an a-(2-methyl-3-phenylindol-7-yl) acetic acid (IX) which is treated with ozone in acetic acid solution to give a 2-acetamido-3benzoylphenylacetic acid (X). The acid is hydrolyzed . and cyclized in dilute acid to the 7-benzoylindolin2-one (III).

Compounds of Formula III wherein R is methoxy may he prepared by catalytic reduction of 7-carboxy5-methoxyisatin, a known compound prepared by a modi25. fication of the procedure of Cragoe, E. J. et al., J. Org. Chem. 18, 561 (1953), to 7-carboxy-5-methoxyindolin-2-one and reaction of the latter compound with phenyllithium.

Compounds of Formula III wherein R is chlorine . may be prepared by reacting the known compound - 9 5-chloroindolin-2-one with a benzoyl chloride in the presence of aluminium chloride.

The 4-(5- und 7-)benzoylindolin-2-onea (III) can also be prepared from appropriately substituted * aminobenzophenones (XI) by the following reaction p sequence, wherein ft, R , X and Y have the meanings defined above and R^ represents lower-alkyl.

(Ill) The following Preparations describe in more detail the methods of preparation of. intermediates outlined above, by way of illustration. - 10 4 3 14 8 Preparation 1 ~Benzoyllndolin-2-one.

A stirred slurry of 66 g (0.5 mole) of aluminium chloride' and 42.5 g (0.3 mole) of benzoyl chloride was heated to 150% and then 133 9 (O.l mole) of indolin-2-one was slowly added at a rate so that the temperature of the stirred reaction mixture was maintained at l8i)-l85°C. After .addition the reaction mixture was stirred for five minutes at l85°C , cooled and poured into ice water. The 5-l>enzoylindolin-2-one which precipitated was collected and recrystallized from methanol; it melted at 2o4-2O5°C. The yield was 17·5 9 (73^)Analysis: Calculated for CigHnNiOs: C,75-94; H,4.67; Ν,5·9Ο Found ;· c,75-76; h,4.69; n,5-82 Preparation 2 -Benzoyl-3-methylindolin-2-one. ' When, in the procedure of Preparation 1, an equal molar amount of 3-methylindolin-2-one is used in place of indolin-2- . one, there is obtained 5henzoyl“3-methylindolin-2-one.

Preparation 5 l-(o;-Methylphcinethylideniniiiio) indolin-2-one.

A mixture of 10 g (0.07 mole) of l-aminoindolin-2-one and 9.Ο5 g (0.07 mole) of phenylacetone in 65 ml of absolute ethanol was heated until all the l-aminoindolin-2-one dissolved. The solution was treated with 0.5 ml of acetic acid and heated on a steam bath an additional 15 minutes. After cpoling, the product was filtered off and the filtrate was treated with water. The additional product which precipitated from the 4s * filtrate was combined with the original material and recrystallized from absolute alcohol; yield 16 g (90%); m.p. 1O2-1O4°C. Analysis: Calculated for Cj^H^gNjO: C,77.25; H,6.10; N,10.60 Found : C,77.26; H,6.16; N,10.58 Preparation' 4 Ethyl ct - (2-methyl-3-phenylindol-7-yl) acetate.

A solution of ethanolic hydrogen chloride was prepared by bubbling dry hydrogen chloride into 100 ml of absolute ethanol until the solution began to boil. At that point 10 g (0.04 mole) of 1-(a.-methylphenethylidenimino) indolin-2-one (see Preparation 3) was added and the mixture was stirred for 30 minutes. Additional hydrogen chloride was bubbled into the hot mixture until thin layer chromatography showed no starting material remained. The reaction was allowed to cool and the solid which separated from the cooled reaction mixture was filtered off and was shown to be l-aminoindolin-2-one. The filtrate was concentrated and the residual brown oil was shown by nuclear magnetic resonance to be a mixture of phenylacetone and product. The mixture was distilled at 165-175°C (0.5 mm); the oily distillate solidified θ upon cooling. The solid was recrystallized from ligroin to give ethyl a -(2-methyl-3-phenylindol-7-yl)acetate which melted at 1O8-1O9°C and weighed 2.2 g (21%).

Analysis: Calculated for CjgHjgNOj: C,77.79; H,6.53; N,4.77 • Found : C,77.6O; H,6.54; N,4.77 Preparation 5 α-{ 2-Methyl-3-phenylindol-7-yl)acetic acid.

To a solution of 8 g of potassium hydroxide in 100ml of water was added 6 g (0.02 mole) of ethyl a-(2-methyl-3phenylindol-7-yl acetate (see Preparation 4). The mixture was refluxed for two hours. The cooled reaction mixture was filtered and the filtrate diluted with an equal volume of water. Acidification of the basic solution with 3N hydrochloric acid gave a- (2-methyl-3-phenylindol-7-yl)acetic acid which was recrystallized from benzene; yield 3.7 g (67%); m.p. 165°C (dec.).

Analysis; Calculated for Cj^H^NOg: C,76.96; H,5.7O; N,5.28 Found : C,77.09; H,5.70; N,5.22 Preparation 6 Ethyl 2-acetaraido-3-benzoylphenylacetate.

A solution of 5 g (0.017 mole) of ethyl a-(2-methyl-3phenylindol-7-yl)acetate (see Preparation 4) and 75 ml of acetic acid was treated with ozone for 25 minutes.

After ozonation, the acetic acid solution was diluted with water and extracted with ether. The ether extracts were washed with water, 5% sodium carbonate, dried (magnesium sulphate) and concentrated, Recrystallization from isopropanol gave 2.6 g (14%) of product which melted at 133-134°C.

Analysis: Calculated for C^gH^NO^: C,70.14; H,5.89; N,4.30 Found : C,69.95; H,5.99; N,4.12 Preparation 7 2-Acetamido-3-benzoylphenylacetic Acid.

A solution of 2 g of a -(2-methyl-3-phenylindo-7-yl)acetic acid (see Preparation 5) in 60 ml of acetic acid was treated with ozone for 15 minutes. The reaction mixture was treated with 10 ml of water and allowed to evaporate overnight. The residue (1.7 g) was recrystallized from isopropanol; yield 1.6 g (71%); m.p. 188-19O°C.

Analysis: Calculated for ci7Hi5NO4: 0,68.68; H,5.O8; N,4.71 Found : 0,68.33; H,5.11; N,4.58 Preparation 8 7-Benzoylindolin-2-one.

Method A A mixture of 2.5 g (0.0077 mole) of ethyl 2-acetamido-3benzoylphenylacetate (see Preparation 6) in 50 ml of 3N hydrochloric acid was refluxed for one hour. The reaction mixture was filtered and the filtrate was poured into a mixture of ice and water. The precipitate was collected and recrystallized from acetone; yield 1 g (55%); m.p. 154°C. Analysis: Calculated for C]_5H;qNO2: C,75.94; H,4.67; N,5.90 Found : C,75.84; H,4.76; N,5.78 Method B A solution of 1.3 g (0.0044 mole) of 2-acetamido-3benzoylphenylacetic acid (see Preparation 7) in 15 ml of 3N hydrochloric acid and 15 ml of acetic acid was refluxed for three hours. The cooled solution was poured into ice water and the 7-benzoylindolin-2-one which precipitated was collected and dried.

, Preparation 9 Other 5-t>enzoylindolin-2-onesj 5-(p~cllloroLenzoyl)indolin-2-one, 5“(2.~fIuor°Benzoyl) indolin-2-one, 5-(p-meth'oxybenzoyl)indolin-2-one and 5-(2-trifluoromethylbenzoyl)indolin2- one were prepared in the manner of Preparation 1 from indolin5 2-one and the corresponding substituted benzoyl chloride.

Preparation 10 Other l-(a-methylphenethylidenimino)indolin-2-ones; l-(a-methyl-p-chlorophenethylidenimino)indolin-2-one, l-(amethyl-o-fluorophenethylidenimino)indolin-2-one and 1-(«-methy110 m-trifluoromethylphenethylidenimino)indolin-2-one were prepared in the same manner of Preparation 3 from l-aminoindolin-2-one and the corresponding substituted phenvlacetone.

Preparation 11 Other ethyl a-(2-methyl-3-phenylindol-7-yl)acetates; ethyl a-[2-methyl~3-(p-chlorophenyl)indol-7-yl]acetate, ethyl e-[2-methyl-3-(o-fluorophenyl)indol-7-yl]acetate and ethyl .«“t^-methy1-3-( m-trifluoromethylphenyl)indol-7-yl]acetate were prepared in the same manner of Preparation 4 from the corresponding l-(a-methylphenethylidenimino)indolin-2-one.

' — Preparation 12 Other n-(2-methyl~3-phenylindol-7-yl)acetic acidsj a-[2-methyl-3-(p-chlorophenyl)indol-7-yl]acetie acid, a-[2-methyl 3- (o.-fluorophenyl) indol-7-yl]acetic acid and re-[2-methyl-3-(nt trifluoromethylphenyl)indol-7-yl]acetic acid were prepared in the same manner of Preparation 5 from the corresponding ethyl tt-(2-methyl-3-phenyl-indol-7-yl)acetate. -1543448 Preparation 13 Other ethyl 2-acetamido-3-benzoylacetatesj ethyl 2acetamido-3-(p-chlorobenzoyl)phenylacetate, ethyl 2-acetamido5-(o-fluorobenzoyl)phenylacetate and ethyl 2-acetamido-j5(m-trifluoromethylbenzoyl)phenylacetate were prepared 'in the same manner of Preparation 6 by ozonation of the corresponding ethyl a-(2-methyl-3-phenylindol-7~yl)acetates.

Preparation 14 Other 2-acetamido-3-benzoylphenylacetic acidsj · 2- acetamido-3-(p-chlorobenzoyl)phenylacetic acid, 2-acetamido3- (o-fluorobenzoyl)phenyIaeetie acid and 2-acetamido-3-(m7 * trifluoromethylbenzoyl)phenylacetic acid-were prepared.in the same manner of Preparation 7 by ozonation of the corresponding ' a-(2-methyl~j5-phenylindol-7-yl)acetic acids.

Preparation 1¾ Other 7-benzolindolin-2-ones5 · 7-(p-chlorobcnzoyl)indolin-2-one, 7-(2.-fluorobenzoyl) indolin-2-one and7-(’2rtri.fluoromethylbenzoyl)indolin-2-one ware prepared in the same manner of Preparations by cyclization of the‘corresponding ethyl 2-acetamido-3-benzoylph6hylacetate or 2-acetamido-3benzoylphenylacetic acid. .

Preparation 16 7-Benzoyl-5-chloroindolin-2-one.

A mixture of 162,5 g (1.08 mole) of benzoyl chloride and 260 g. of aluminium chloride (1.80 mole) heated to 200°C with stirring was treated with 65 g (0.360 mole) of recrystallized 5~chloroindolin-2-one. This mixture was stirred for 15 min. and poured over ice. The resulting precipitate was triturated with boiling water and then chloroform. The chloroform solution was washed with 5% sodium bicarbonate, water, dried over sodium sulphate, and stripped to yield approximately 55 g of a glossy solid. This material was then triturated with hot methanol and the methanol evaporated under vacuum to yield approximately 20 g. of a solid yellow material. Extraction of a benzene solution of this material removed any starting 5-chloroindoline2-one present and after washing with water and drying the benzene yielded on evaporation 3 g of a blue-gray material. Trituration of this material with room temperature methanol gave a residue which on recrystallization from methanol yielded 2·5 g of a tan solid identified as product, m.p. 186-187°C. Analysis: Calc'd for CiSHioClNO2: C,66.31; Η,3·71; Ν,5·16 Found : c,66.27; Η,3·δ3; N,5.07 Preparation 17 -Methoxy-7-benzoylindolin-2-one.

A suspension of 1.0 g (4.9 mmole) of 5-methoxy-7-carboxy- . indolin-2-one in 20 ml of tetrahydrofuran was treated dropwise with 12 ml of commercially prepared phenyllithium solution (2.3 molar ether: benzene; 0.28 moles). After stirring for two hours the reaction mixture was poured into water and extracted several times with ethyl ether and benzene. The combined extracts were washed with water, dried over sodium sulphate and concentrated using a rotary evaporator to a solid residue which on recrystallization from acetone-water gave 259 mg (21%) of a yellow powder which melted at 154°C. ό. 3 4 4 3 Analysis: Calc'd for CleH13NO3: C,71-90; 11,4.90; N,5-24 Found : c,71-72; H,5-15: N,5-15 Preparation 18 4-Benzoyl-3-methylthioindolin-2-one A solution of 30.0 g (0.152 mole) of 3-aminobenzophenone in 600 ml of methylene chloride was cooled to -78°c in a dry ice/acetone bath and treated dropwise under a nitrogen atmosphere with a solution of 16.5 0 (0.152 mole) of t-butylhypochlorite in 60 ml of methylene chloride. After stirring for 1 hour after addition was complete, thin layer chromatography showed no starting material. A solution of 20.2 g (0.152 mole) of ethyl α-methylthioacetate in 60 ml of methylene chloride was added dropwise and stirring continued at -78°C for 2.5 hr. A solution of 15-4 g (0.152 mole) of triethylamine in 60 ml of methylene chloride was added dropwise at -78°C and the reaction mixture allowed to warm to room temperature while stirring for 16 hr (overnight). The dark brown solution was treated with 100 ml of 3N hydrochloric acid and stirred for 3 hrs at room temperature. Precipitation of a tan solid began after 15-30 minutes. Filtration gave 18-5 g. of solid, m.p. 224-228°C (dec.) The layers of the filtrate were separated, the organic phase dried over magnesium sulphate, evaporated under reduced pressure, and the residue triturated in isopropyl ether (25 g )· The gummy solid was triturated in cold methanol to give 8.3 g of product, m.p. 222-225 c (dec.). The total yield was 26.8 g (62%). A 7.0 g sample recrystallized from methanol weighed 5-6 g and melted at 235-237°c (dec.). - 18 63448 Analysis: Calc'd for ClaHi3N0aS: C,67-823; H,4.625; Ν,4·943 Found : C,6?.86 ; H,4.71 ; N,4.85 Preparation 19 7-(4-chlorobenzoyl)-3-methyl thio i.ndol in-2-one.

A solution of 23.1 g. (0.1 mole) of 2-amino-41-chlorobenzophenone in 400 ml of methylene chloride was cooled to -65°C and treated dropwise with 12.4 g (0.1 mole) of t-butyl hypochlorite. After 15 min., 13.4 g of ethyl a-methylthioacetate (0.1 mole) was added dropwise maintaining -65°C temperature. After 1.5 hr.,10.1 g. of triethylamine (0.1 mole) was added and the reaction mixture allowed to come to room temperature. The solution was then washed with water and stripped. The residue was taken into methanol and brought to reflux at which time IN hydrochloric acid was added and the resulting mixture refluxed overnight. The mixture was cooled, resulting precipitate filtered off and recrystallized from toluene, giving 10 g of a cream-coloured solid. The product (33$ yield) melted at l86-l88°C.

Analysis: calc'd for CxSHiaClNOES: C,60.47; H,3.8l; N,4.4l Found : c,60.29; h,3-76; n,4.43 Preparation 20 7-Benzoyl-3-methyl-3-methylthioindolin-2-one.

A stirred solution of 3-9^ 9 (0.02 mole) of 2-aminobenzophenone in methylene chloride at -65°c was treated with 2.l6 g (0.02 mole) of Jt-butylhypoohlorite. After 15 min. 2.96 g- ethyl a-methylthiopropionate was added dropwise and stirring continued for 1 hour.At the end of this time 2.02 g. ί 3 -1 48 of triethylamine (0.02 mole) was added dropwise and the reaction solution was allowed to warm to room temperature. This Was followed by treatment with IN hydrochloric acid and stirred for 15 min. The methylene chloride solution was then separated and stripped under vacuum. The yellow oil. residue was triturated with isopropyl ether and 3 g· of a yellow solid was filtered off (51$)· Recrystallization from absolute ethanol gave a creamcoloured solids, m.p. 135-137°C.

Analysis: Calc'd for C1THiSNO2S: C,68.66; Η,5·θ8; N,4.71 Found : C,68.54; Η,5·θ8; N,4.63 Preparation 21 7-Benzoy1-5-methylth io indo 1 in-2 -o ne.

A solution of 300 9- (1-52 mole) of 2-aminobenzophenone in 4 litres of methylene chloride was chilled to -4o°C and then treated with 204 g (1.52 mole) of the ethyl a-methylthioacetate dissolved in 5 litres of methylene chloride. The reaction mixture was then cooled to -65°C and treated dropwise with 500 ml. o£ a methylene chloride solution containing 164 g (I.52 mole) of t-butylhypochlorite. After addition was complete, stirring was continued for 2 hr at -70°C. The solution was then treated with 182 g (1.8 mole) of triethylamine and allowed to come to room temperature overnight. The methylene chloride solution was washed twice with 3 litres of ice water followed by drying over sodium sulphate and concentrating the dried solution to a yellow oil under reduced pressure. The oil was taken into 1.5 litres of methanol treated with 1 litre of IN hydrochloric acid and refluxed for 2 hrs. After cooling in an ice bath 3 14 8 343 g (79.9%) of crude product was recovered after filtering and drying. Two recrystallizations from toluene gave creamy white flakes; m.p. 130°C.

Analysis: Calc’d for C, 1,67.82; A,4.62* \',4.97 Found : C,68.06; H,4.68; N,4.87 Preparation 22 4-Benzoylindolln-2-one.

A stirred suspension of 7.0 g (0.0248 mole) of 4-benzoyl3-methylthioindolin-2-one (see Preparation 18) in 400 ml of tetrahydrofuran was treated portionwise under a nitrogen atmosphere with 35.0 g of Raney nickel over a 2.5 hr. period.

The reaction mixture was stirred for 1.5 hr. after addition was complete and the catalyst removed by filtration. The filter cake was washed well with tetrahydrofuran and methylene chloride and the filtrate evaporated under reduced pressure.

The residue (5.6 g) was recrystallized from methanol and gave 4.45 g. (76%) of product m.p. 210.5-212°C.

Analysis: Calc'd for C^H^NO^ c,75.937; H,4.673; N,5.9O4 Found ; C,75.85 ; H,4.59 ; N,5.92 Preparation 23 7-(4-Chlorobenzoyl) indolin-2-one A stirred solution of 9 g (0.028 mole) of 7-(4-chloro-benzoyl)3-meth.lthioindolin-2-one (see Preparation 19) in 180 ml of tetrahydrofuran was treated over a two hour period with 45 g of a commercial Raney nickel water suspension. After the addition was complete the mixture was filtered. A drop of concentrated hydrochloric acid was added to the filtrate which removed some colour and (ί 3 ί ·18 the resulting solution was then stripped under water pump vacuum to yield a cream-coloured material. Recrystallization from toluene gave pink needles, (93% yield); the material sintered at 177°C and melted at l86°C.

Analysis: Calc'd for Ci5HioClNOa: C,66.31; Η,3·71ΐ Ν,5·1δ Found : 0,65.97; η,3·56; n,5.11 Preparation 24 7-BenzOyl-3-roethylindolin-2-one.

A stirred solution of 8 g (0.027 mole) of 7-benzoyl-3-methyl-3methylthioindilin-2-one /see Preparation 20) in 80 ml of tetrahydrofuran was treated under N2 with 40 g. of a commercial Raney nickelwater mixture over a 2 hr. period. At the end of this period the mixture was filtered and the residue washed thoroughly with tetrahydrofuran. One drop of concentrated hydrochloric acid was added to the filtrate and the dark orange’solution turned pale yellow. The solution was stripped under vacuum to a yellow oil which crystallized on seeding. The material was recrystallized from toluene petroleum ether to give a white crystalline material. The solid (6.0 g , 89% yield) melted at 125-127°C.

Analysis: Calc'd for CisHieNOa: C,76.43; Η,5·22; Ν,5·57 Found : C,76.38; Η,5·22; Ν,5·52 Preparation 25 7-Benzoyl'-T,3','3'-trimethylind'Olin'-2'-On'e.

A solution of 3 g (0.0126 mole) of crude 7-benzoyl3,3-dimethylindolin-2-one in 50 ml of dry dimethylformamide S was first treated with crushed sodium hydroxide pellets and then 6 g (0.043 mole) of methyl iodide. The mixture was stirred for 2 hr., then poured into water and extracted several times with ethyl ether. The combined ether solutions were washed with water, dried over sodium sulphate, filtered, and stripped (0 under vacuo. The residual oil was triturated with petroleum ether and solidified slowly. Recrystallized from isopropanolpetroleum ether, yield 2 g, m.p. 79-81°C.

Analysis: Calc'd for ClgH17N02; C,77.4O; H,6.13; N,5.01 Found : 0,77.47; H,6.14; N,4.96 ,,- Preparation' 2 6 3-Isopropylidene-7-benzoylindolin-:2-one.

A solution of 2 g (0.0085 mole) of 7-benzoylindolin-2-one (see Preparation 8) in approximately 100 ml of acetone containing 2 ml of concentrated hydrochloric acid was refluxed for 15 hours.

Jjj At the end of this period the solution was cooled. The precipitate which formed was collected and dried. The product (2.3 g, 98% yield) melted at 174-176°C.

Analysis: Calculated for CjgHjgN02: C,77.96; H,5.45; N,5.O5 Found : C,77.58; H,5.43; N,4.99 — Preparation 27 7-(4-Fluorobenzoyl)indolin-2-one.

A stirred suspension of 12,3 g (0.41 mole) of 7-(4fluorobenzoyl)-3-methylthioindilin~2-one (analogous to the 4-chloro-compound of Preparation 19) in 250 ml of tetrahydrofuran was treated over a two hour period with 60 g of a commercial Raney-nickel water suspension. The mixture was filtered under nitrogen and the residue washed with titrahydrofuran and methylene chloride. The filtrate was treated with a few drops of cone, hydrochloric acid and concentrated under reduced pressure to give 9.5 g (91%) of 7-(4-fluorobenzoyl) indolin-2-one.

The following Examples illustrate the invention.

Example 1 2-Amino-5-benzovl-5-chlorophenylacetic Acid Hemihydrate A mixture of 1,5 g (0.055 mole) of 7-benzoyl-55. chloroindolin-2-one (see Preparation 16) in 25 ml of 3N sodium hydroxide was refluxed for 45 min. and the resulting solution filtered and diluted with an equal volume of water. The solution was then neutralized slowly with glacial acetic acid. The resulting yellow10. green precipitate was filtered, off and dried in a drying pistol (no heat). The compound weighed 1.0 g (63%) and melted at 85-87°C.

Analysis: Calc’d for C^H^ClNOy (0.5H20);C,60.31; H.4.39; N.4.69 Found j 0,60.59; H,4.09; N.4.65 . Example 2 Sodium 2-amino-5-benzovl-5-methoxyphenylacetate Sesquihydrate.

A suspension of 75 mg (0.27 mole) of 5-methoxy7-benzoyl-indolin-2-one (see Preparation 17) in 5 ml . of 3N sodium hydroxide was refluxed for 2.5 hr. The resulting yellow-orange solution was cooled, diluted with several volumes of water, filtered and saturated with sodium chloride. The solution was then passed slowly through a polyethylene column (1/4” d. x 8 long) . containing Amberlite XAD-2 polymeric sorbent. The column was then washed with a saturated sodium chloride solution to remove all residual base. While attempting to wash off the sodium chloride, however, the desired product began to elute as well (as noted by following its 50. distinctive yellow colour). A number of fractions were collected to ensure removal of all the sodium chloride and as the colour began to fade from the eluate the column was finally flushed with methanol and acetone. Evaporation of this organic solution yielded (80%) a . yellow solid which decomposed above 265°C, and analyzed for 1.5 moles of water as confirmed by the nuclear magnetic resonance spectrum.

Analysis: Calc'd for C./TL/NO. .1-1/2 H90: C,57.49; H,5.126; N.4.19 Found : 0,57.63; H.4.90; N,4.25 . Example 5 Sodium 2-amino-ZS-benzoylphenylacetate Dihydrate.

A mixture of 2.6 g of 2-amino-3-benzoylphenyl acetic acid (see Example 3 of the main specification) and sodium hydroxide (0.1 mole) in 25 ml of water was . stirred for approximately 10 min. and then heated to reflux under nitrogen. The reaction mixture was then cooled and filtered. The filtrate was evaporated down to approximately 2 ml , refiltered and a large volume of acetone added to the filtrate to precipitate the . product as bright yellow flakes. Yield 70%.

Analysis: Calc'd for C1sH16N0cNa(0.2H?0): C, 57-51; H,5.15; N,4.47 Found : 0,58.22; H,4.62; N,4.47 Example 4 Ethyl 2-amino-3-benzoylphenylacetate.

. A solution of 2.5 g (0.009 mole) of the sodium salt of 2-amino-3-benzoylphenylacetic acid (see Example 3 of this specification) in 25 ml of dry dimethylformamide was treated with 5.0 g (0.035 mole) of ethyl iodide.

The mixture was stirred two hours at room temperature . using a magnetic stirrer. The mixture was diluted with 3 14 8 water and the aqueous solution extracted several times l with ethyl ether. The combined extracts were washed with water, dried over sodium sulphate and concentrated under vacuum to a yellow solid. The solid was recrystal5. lized from absolute ethanol to give 1.7 g (61.0%) of yellow needles which melted at 77-78°C.

Analysis: Calc’d for C17H17N03: C,72.07; H.6.05; MT,4.94 Found : C,72.33; H.5.83; N,5.07 Example 5 . Methyl 2-amino-5-benzoylphenylacetate.

A solution of 4.0 g (0.014 mole) of the sodium salt of 2-amino-3-benzoylphenylacetic acid (see Example 3) in 100 ml of dry dimethylformamide was treated with 8.0 g (0.057 mole) of methyl iodide. After stirring . for two hours the solution was poured into water and the aqueous solution extracted several times with ethyl ether. The combined extracts were washed with water, dried over sodium sulphate and concentrated under vacuum to a yellow oil. The oil was crystallized from . a chilled methanol-water solution to give 3.5 g (90%) of a yellow solid which melted at 52-54°C.

Analysis: Calc’d for C^H^NO^: 0,71.36; H,5.61; N,5.20 Found : C.71.51; H,5.63; N.5.27 Example 6 . Methyl 2-dimethylamino-5-benzoylphenylacetate A stirred solution of 4.6 g. (0.0165 mole) of methyl 2-amino-3-benzoylphenylacetate (see Example 5) and 13.2 ml (0.165 mole) of 37% formaldehyde in 66 ml. of acetonitrile was treated with 3-14 g (0.0495 mole) . of sodium cyanoborohydride. Glacial acetic acid (1.65 ml) was added over a ten minute period and stirring continued for 2.0 hrs. at room temperature. An additional 1.65 ml of glacial acetic acid was added and the mixture stirred over a weekend (ca. 65 hours). The . mixture was diluted with ether and the ether solution was successively washed with 3N potassium hydroxide solution, water, dried over sodium sulphate and concentrated under vacuum to give approximately 1.0 g (18%) of a yellow oil. A portion of the oil was mole10. cularly distilled for an analytical sample.

Analysis: Calc'd for C^H^NO^: 0,72.71; H.6.44; N.4.71 Found : C,72.33; H.6.26; N,4.99 Example 7 2-Dimethylamino-3-benzoylphenylacetic Acid.

. A mixture of 500 mg. (1.85 mole) of methyl 2dimethylamino-3-henzoylphenylacetate (see Example 6) and 15 ml of 3N sodium hydroxide was refluxed for 1.5 hr. under nitrogen. The cooled, filtered reaction mixture was diluted with an equal volume of water and neutralized . with glacial acetic acid. The precipitate which formed could not be recrystallized and was therefore dissolved in benzene and placed on a magnesium silicate column. The. column was eluted with benzene-acetone to give 300 mg of product which melted at 144-146°C . after recrystallization from benzene-isooctane.

Analysis: Calc'd for C^H^NO^: C,72.07; H,6.06; N,4.94 Found : C,72.32; H,6.09; N,4.85 Example 8 Sodium 2-amino-6-benzoylphenylacetate Hydrate.

. A suspension of 4.5 g (0.0190 mole) of 4-benzoylin27 dolin-2-one (see Preparation 22) in 200 ml of 3N sodium hydroxide was refluxed under a nitrogen atmosphere for 4 hr. The volume of water was reduced hy approximately half, and the solution saturated with . sodium chloride. The solution was chromatographed on a 230 ml (wet volume) column of Amberlite SAD-2 ion exchange resin packed in distilled water. The product precipitated on the top of the column packing, but dissolved as the column was eluted with distilled . water. The fractions containing the product were collected, combined, and the solvent removed under reduced pressure to give 4.6 g of solid. Recrystallization from methanol-ether gave 0.91 g of a yellow solid, m.p. 256.5-258.5°C (dec). The filtrate was evaporated (5. under reduced pressure and the residue was dissolved in hot isopropanol by adding a small amount of water.

The hot solution was filtered to remove a suspended solid. The filtrate was seeded and placed in a freezer for 12 hr. The pale yellow solid which separated was 0. collected by filtration and yielded 2.84 g (50.3%) of product, m.p. 254.5-256°C (dec.). A portion of the bulk product was dried under high vacuum at room temperature.

Analysis: Calc'd for C^H^WaNO’^^: C,61.017; H,4.779; N.4.74 . Found : C.60.63; H.4.50 ; N.4.71 Example 9 Sodium 2-amino-3-(4—chlorobenzoyl) phenylacetate Hydrate.

A mixture of 3.5 g (0.0125 mole) of 2-amino-33. (jj-chlorobenzoyl) phenylacetic acid (see Example 5 of the main specification) in a water solution containing 0.5 g of sodium hydroxide (0.125 mole) was refluxed 45 minutes, cooled and filtered. The filtrate was concentrated to an oily consistency and poured into a · large volume of acetone. A yellow precipitate separated which was collected and identified by nuclear magnetic resonance spectrum as the desired product.

The product (2.6 g ) (67%) melted at 265°C (dec.), after crystallization from ethanol-ethyl ether.

. Analysis: Calc'd for C^H^ClNO^Na: 0,54.64; H.3.97; N.4.24 Found 0,55.61; H,3.68; N,4.31 Example 10 Sodium 2-amino-3-benzoyl-a-methylphenylacetate Hydrate.

. A suspension of 9 g (0.036 mole) of 7-benzoyl-3methylindolin-2-one (see Preparation 24) in 100 ml of 3N sodium hydroxide was refluxed for 18 hrs. under nitrogen. The mixture was filtered and stripped under water pump vacuum to yield a gummy mixture of . sodium hydroxide, water and product. The mixture was triturated with boiling isopropanol and filtered.

The isopropanol solution was cooled and filtered to separate the bright yellow product. The product weighed 4,0 g and melted at 218°C (dec.).

. Analysis: Calc'd for C^H^NO^.Na: 0,57.31; H.5.41; N,4.18 Found : C;57.69; Η,5·12; N.4.27 Example 11 Potassium 2-amino-5-benzoylphenylacetate Hydrate.

A solution of 4.0 g (0.015% mole) of 2-amino-330. benzoylphenylacetic acid (see Example 3 of the main specification) in 40 ml of tetrahydrofuran was treated with 5.06 g (0.045 mole) of 50% potassium hydroxide solution; a precipitate separated immediately. The cold solution (ice bath) was stirred one hour under . nitrogen and filtered. The dried product was recrystallized from ethanol-isopropyl ether to give 3.5 g (72%) of product as long yellow needles.

Analysis: Calc'd for C15H12W03K.H20: 0,57.86; H,4.53; N.4.50 Found : 0,57.78; H.4.47; N,4.62 . Example 12 2-Amino-5-(3.4-methylenedioxybenzoyl)phenylacetic Acid.

A mixture of 0,004 mole of 5-(3i4~methylenedioxybenzoyl)indolin-2-one and 30 ml of 3N sodium hydroxide was refluxed for 0.5 hour. The reaction . mixture was cooled, acidified to pH 6 with 3N hydrochloric acid and the slightly acidic solution was extracted with chloroform. The chloroform extracts were dried (magnesium sulphate) and concentrated to a solid. On recrystallization from methanol there was obtained ’0. 2-amino-5-(3,4-methylenedioxybenzoyl) phenyiacetic acid.

Example 13 2-Amino-5-(5.4-dimethoxybenzoyl) phenyiacetic Acid.

When, in the procedure of Example 12, an equal molar amount of 5-(3,4-dimethoxybenzoyl)indolin-2-one !5. is used in place of 5-(3,4-methylenedioxybenzoyl)indolin-2-one, there is obtained 2-amino-5-(3,4dimethoxybenzoyl) phenyiacetic acid.

Example 14. 2-Amino-5-(3.4-dichlorobenzoyl)phenylacetic Acid. 0. When, in the procedure of Example 12, an equal - 30 «3448 molar amount of 5-(3,4-dichlorobenzoyl)indolin-2-one is used in place of 5-(3,4-methylenedioxybenzoyl) indolin-2-one, there is obtained 2-amino-5-(3.4dicfclorobenzeyl' phenylacetic acid.

. Example 15 2-Amino-5-(3-methoxy-4-chlorobenzoyl)phenylacetic Acid.

When, in the procedure of Example 12, an equal molar amount of 5-(3-methoxy-4-chlorobenzoyl)indolin2-one is used in place of 5-(3,4-methylendioxylbenzoyl) . indolin-2-one there is obtained 2-amino-5-(3-methoxy4-chlorobenzoyl)phenyl acetic acid.

The alkali metal salts prepared as described in the above Examples are isolated in hydrated forms. They can be dehydrated under vacuum and maintained in an . anhydrous form in the absence of moisture.

Example 16 Ethyl 2-amino-3-(4-chlorobenzoyl) phenylacetate.

Fourteen grams of sodium 2-amino-3-(4-chlorobenzoyl) phenylacetate (see Example 9) was dissolved in approx20. imately 150 ml of dimethylformamide and the solution treated with 30 g of ethyl iodide. The solution was stirred at room temperature for 2.5 hrs,, the solution added to water and the mixture extracted several times with benzene. The combined benzene . extracts were washed with dilute base and water, dried over sodium sulphate and concentrated to an oil which crystallized on trituration with petroleum ether (30-60). Reciystallization from absolute ethanol gave 11.6 g of yellow flakes; m.p. 101-102°C.

. Analysis: Calc'd for C17H16C1NO3: C.64.26; H.5.08; N,4.41 3-3 48 Found : C,65.14; H,5.06; N,4.51 Example 17 Sodium 2-Amino-3-(4-fluorobenzoyl)phenylacetate Hydrate.

Part 1. i A mixture of 1.5 σ (0.006 mole) of 7-(4-fiuorobenzoyl)indolin-2-one (see Preparation 27) in 50 ml of 3N sodium hydroxide was refluxed under nitrogen for 45 min. The solution was cooled, diluted with an equal volume of water, filtered, and the filtrate was extracted twice with 50 ml of ether. The aqueous basic solution was treated dropwise with glacial acetic acid until a heavy yellow precipitate formed. The precipitate was filtered off, washed thoroughly with water and air-dried. The yield was 1.1 g (68%); m.p. 136-137°C. The product was 2-amino-3-(4-fluorobenzoyl)phenylacetic acid.

Analysis: Calc'd for c15a12PNO3: C,65.93; H,4.43; N,4.17 Found : C,65.79; H,4.49; N,4.94 Part 2.

A solution of 1 g (0.0036 mole) of 2-amino~3) (4-fluorobenzoyl)phenylacetic acid prepared as Part 1 in 10 ml of tetrahydrofuran was treated with 0.7 g of a 50% sodium hydroxide solution (0.009 mole) and stirred under nitrogen for 15 min. before a yellow precipitate developed. The stirred mixture was cooled > in an ice bath for 2 hrs. The precipitate was then filtered off and air-dried. Recrystallization from tetrahydrofuran-water yielded 150 mg (20%) of product which melted at 24O-25O°C (dec.).

Analysis: Calc'd for Ο-^Η^ΡΝΟ^Na.HjO: C,57.51; H,4.18;N,4.47 Found λ Λ 4 ·18 : C,58.23; Η,3.81; Ν,4.55 Example 18 2-Amino~3~(4-methoxybenzoyl)phenylacetic Acid A solution of sodium methoxide maintained under 5. nitrogen (2.27 g of sodium in 25 ml of methanol) was treated successively with 50 ml of benzene and 3.4 g (0.013 mole) of 7-(4-fluorobenzoyl)indolin-2-one (see Preparation 27). The mixture was refluxed for 4 hrs. The mixture was concentrated and the residue was . treated with 100 ml of 3N sodium hydroxide and refluxed under nitrogen for 2 hr. The resulting solution was cooled, diluted with 100 ml of water and filtered.

The filtrate was washed three times with 60 ml of ether, treated with charcoal and filtered. The . filtrate was then treated dropwise with glacial acetic acid giving a yellow precipitate which was filtered off, washed thoroughly with water and air-dried. The yield 2.5 g (66%); m.p. 117-118°C.

Analysis: Calc'd for C^H^NO^: C,67-36; Η,5·30; N.4.91 . Found : C,67.25; Η,5·18; N.4-99 Example 19 Magnesium 2-amino-3-benzoylphenylacetate Trihydrate .

An aqueous solution of 6.36 g (0.02 mole) of . 2-amino-3-benzoylphenylacetic acid (see Example 3 of the main specification) was treated with an aqueous solution of magnesium chloride (0.01 mole), A precipitate formed immediately. After 15 min. of stirring, the bright yellow precipitate was filtered . and dried. The yield was 4.06 g and the salt ,134*18 melted over the broad range of 150-190°C.

Analysis: Calc'd for θ30Η30Ν2°9Μ®: C,61.40; Η,5.15ϊ N.4.77 Found : C,61.18; Η,5.19ί N.4.72 Example 20 . Calcium 2-amino-3-benzoylphenylacetate Dihydrate.

A stirred solution of 5 g (0.02 mole) of sodium 2-amino-3-benzoylphenylacetate (see Example 3 of this specification) in 50 ml of water was treated with 1.2 g of calcium chloride (0.01 mole) in 10 ml of . water. An immediate precipitate developed. After an additional 15 min. stirring the precipitate was collected. Recrystallization from ethanol-water gave bright yellow needles which melted over the broad range of 16O-24O°C (dec.).

. Analysis: Calc'd for C3oH28N2°8Cas H.4.85; N.4.60 Found : C,60.70; H.4.92; N.4.72 Formulation and Administration The present invention also embraces compositions containing, the compounds of the invention as active . ingredients. Effective quantities of any of the foregoing pharmacologically active compounds may be administered to a living animal body in any of various ways; for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or >5. suspensions, and in some cases intravenously in the form of sterile solutions. In forming the compositions of this invention, the active ingredient is incorporated in a suitable carrier, illustratively a pharmaceutical carrier. Suitable pharmaceutical carriers which are . useful in formulating the compositions of this . . . invention include starch, gelatin, glucose, magnesium carbonate, lactose and malt. For compositions in liquid form suitable liquid pharmaceutical carriers include ethyl alcohol, propylene glycol, glycerine and glucose syrup.

The pharmacologically active compounds may be advantageously employed in a unit dosage of from 0.1 to 150 milligrams. The unit dosage may be given a suitable number of times daily so that the daily dosage may vary from 0.3 to 450 milligrams. Five to 25 milligrams appears optimum per unit dose.

The pharmacologically active compounds of the invention may be combined with other pharmacologically active agents, or with buffers or antacids or other substances appropriate for administration, and the proportion of the active compounds in the compositions may be varied widely.

The following are examples of compositions formed in accordance with this invention. 1. Capsules Capsules of 5 nig , 25 mg , and 50 mg , of active ingredient per capsule are prepared, e.g. as under.

Typical blend for Mg per capsule encapsulation .

Active ingredient Lactose Starch Magnesium stearate Total .0 296.7 129.0 _ 4.3 435.0 mg.

. Additional capsule formulations preferably contain a higher dosage of active ingredient and are 434 48 as follows.

Ingredients Mg per capsule Active ingredient 25.0 Lactose 306.5 . Starch 99.2 Magnesium stearate 4.3 Total 435.0 mg.

With higher amounts of active ingredient, the amount of lactose or starch may he correspondingly . adjusted.

In each case, uniformly blend the selected active ingredient with lactose, starch and magnesium stearate and encapsulate the blend. 2. Tablets . A typical formulation for a tablet containing .0 mg of active ingredient per tablet follows. The formulation may be used for .other strengths of active ingredient by adjustment of the weight of dicalcium phosphate.

. Per tablet, mg . 11) Active ingredient 2) Com starch 3) Com starch (paste) 4) Lactose ) Dicalcium phosphate 6) Calcium stearate .0 13.6 3.4 79.2 68.0 0.9 170.1 mg.

Uniformly blend 1, 2, 4 and 5. Prepare 3 as a 10 per cent paste in water. Granulate the blend with starch paste and pass the wet mass through an 8 mesh 30. screen and dry the granules. Pass the dry granules - 36 43448 through a 12 mesh screen, blend them with the calcium stearate and press into tablets. 3. Injectable - 2% sterile solutions.

Per ml . Active ingredient......... 20 mg Preservative, e.g. chlorobutanol ...... 0.5% weight/volume Water for injection.___ q.s.

Prepare solution, clarify by filtration, fill . into vials, seal and autoclave. 1. 2-Amino-3-(and 5- and 6-) benzoylphenylacetic acids and derivatives thereof having the formula:-

Claims (30)

1. wherein: Ib R represents hydrogen or lower-alkyl; R represents hydrogen, halogen or lower-alkoxy; x R represents hydrogen, lower-alkyl, alkali metal or alkaline earth metal; X represents hydrogen, lower-alkyl, lower-alkoxy, halogen, nitro or trifluoromethyl; Ί represents hydrogen, lower-alkyl, lower-alkoxy, halogen, nitro or trifluoromethyl; or X and X together represent a lower-alkylene dioxy group; Am represents primary amino, methylamino or dimethylamino, subject to the proviso that when R 2 , E? and Y are all hydrogen and the benzoyl group is at the 3- or 5' position on the benzene ring of the phenylacetic acid group, Am is methylamino or dimethylamino; and x n represehts 1 when R is monovalent or 2 when ' x R is divalent.

2. 2-Amino-3-benzoyl-5-chlorophenylacetic acid.

3. Ethyl 2-amino-3-benzoylphenylacetate.

4. Methyl 2-amino-3-benzoylphenylacetate.

5. Methyl 2-dimethylamino-3-benzoylphenylacetate.

6. 2-Dimethylaraino-3-benzoylphenylacetic acid.

7. Calcium 2-amino-3-ben2oylphenylacetate dihydrate.

8. Magnesium 2-amino-3-benzoylphenylacetate trihydrate.

9. Sodium 2-amino-3-benzoyl-5-methoxyphenylacetate.

10. Sodium 2-amino-3-benzoyl-5-methoxyphenylacetate sesquihydrate.

11. Sodium 2-amino-3-benzoylphenylacetate.

12. Sodium 2-amino-3-benzoylphenylacetate dihydrate.

13. Potassium 2-amino-3-benzoylphenylacetate.

14. Potassium 2-amino-3-benzoylphenylacetate hydrate.

15. Sodium 2-amino-3-(4-chlorobenzoyl)phenylacetate hydrate.

16. Ethyl 2-amino-3-(4-chlorobenzoyl)phenylacetate.

17. Sodium 2-amino-3-benzoyl-a-methylphenylacetate hydrate.

18. Sodium 2-amino~3~(4-fluorobenzoyl) phenylacetate hydrate. 63448

19. Sodium 2-amino-6-benzoyIphenylacetate.

20. Sodium 2-amino-3-benzoyl-a-methylphenylacetate.

21. 2-Amino-5-(3,4-methylenedioxybenzoyl) phenylacetic acid.

22. 2-Amino-5-(3,4-dimethoxybenzoyl) phenylacetic acid.

23. 2-Amino-5-(3,4-dichlorobenzoyl) phenylacetic acid.

24. 2-Amino-5-(3-methoxy-4-chlorobenzoyl) phenylacetic acid.

25. Sodium 2-amino-3-(4-fluorobenzoyl) phenylacetate.

26. 2-Amino-3- (4-methoxybenzoyl) phenylacetic acid.

27. A therapeutic composition comprising a compound as claimed in any of the preceding Claims and a pharmaceutically acceptable carrier therefor.

28. A therapeutic composition as claimed in Claim 27 in unit dosage form containing from 0.1 to 150 milligrams of the said compound.

29. Any compound according to claim 1, the preparation of which is described herein.

30. A therapeutic composition containing a compound according to claim 29.