GB2105708A

GB2105708A - 2-amino-3-(alkylthiobenzoyl)- phenylacetic acid

Info

Publication number: GB2105708A
Application number: GB08214848A
Authority: GB
Inventors: David Allan Walsh; Dwight Allen Shamblee
Original assignee: AH Robins Co Inc
Current assignee: AH Robins Co Inc
Priority date: 1979-08-01
Filing date: 1982-05-21
Publication date: 1983-03-30
Also published as: ES8106702A1; LU82672A1; EG14771A; KE3368A; FI74457C; NO150080C; AT369648B; HK49084A; ZA804703B; PT71632B; JPH0314820B2; NO150080B; GB2105708B; KE3390A; GB2055820B; NZ194515A; AR226855A1; CH648295A5; IE50293B1; CA1147746A

Abstract

Novel 2-amino-3- (alkylthiobenzoyl)phenylacetic acids, esters and metal salts have the formula: <IMAGE> wherein R represents a hydrogen atom or a lower alkyl group, R<1> represents hydrogen atom or a lower alkyl group or pharmaceutically acceptable metal cation, R<2> represents a hydrogen or a halogen atom or a lower alkyl or lower alkoxy group, and Am represents a primary amino (-NH2), methylamino or dimethylamino group. The compounds have anti- inflammatory activity; have effective analgesic activity, and inhibit blood platelet aggregation.

Description

1 GB 2 105 708 A 1

SPECIFICATION 2-Amino-3-(alkylthiobenzoyi)-phenylacctic acids

The present invention relates to certain novel 2-amino-3benzoylphenylacetic acids having aiky[thio substitution on the benzoyl moiety, their alkylesters and metal salts, pharmaceutical compositions incorporating such compounds, uses of such compounds and certain intermediates for the preparation of such compounds.

Certain 2-amino-3-(5 and 6) be nzoyl phenyl acetic acids having the benzoyl moiety substituted by lower alkyl, halogen, nitro and trifluoromethyl groups and methods of preparing and using the same are disclosed in U.S. Patent 4,045,576. The compounds of the present invention cannot be prepared by the procedure disclosed therein. 10 The invention is more specifically concerned with 2-amino-3- (aikyithiobenzoyi)pheny]acetic acids, alkylesters and metal salts having the formula:

,CHRCOOR' R 2---QAM 6-S-loweralkyt wherein:

Formula 1 R represents a hydrogen atom or a lower alkyl group, R' represents a hydrogen atom or a lower alkyl group or a pharmaceutically acceptable metal cation, R' represents a hydrogen or a halogen atom or a lower alkyl or lower alkoxy group, and Am represents a primary amino (-NH2), methyl-amino or dimethylamino group.

The novel compounds of Formula 1 possess valuable pharmacological properties and are useful as 20 pharmaceutical agents. The compounds exhibit anti-inflammatory and analgesic activity and inhibit blood platelet aggregation in warm-blooded animals.

Certain novel intermediates, the 7-(S-loweralkyithiobenzoyi)indolin-2ones may be represented by Formula ll:

H R R CO H 6_ Formula 11 25 wherein R, R' and R 2 are as hereinabove defined. The anti-inflammatory activity has been demonstrated in laboratory animals using a modification of the Evans Blue Carrageenan Pieural Effusion Assay of Sancilio, L. R, J. Pharmacol. Exp. Ther. 168, 199-204 (1969). 30 The compounds of Formula 1 have been demonstrated to be inhibitors of blood platelet aggregation by use of the test of reduction of platelet aggregation as described by Born, J. of Phys. 162, 67-68 p. (1962) and Evans et al, J. of Expt. Med. 128, 877-894 (1968). Rats were orally administered test drugs and after 2 hrs the rats were bled and platelet rich plasma obtained. Collagen was added to the platelet rich plasma to induce platelet aggregation and comparisons were made between control and treated samples.

The compounds of Formula 1 also act as analgetics as determined by the Bradykinin Analgetic Test Method of Dickerson et ai, Life Sci. 4, 20632069 (1965) as modified by Sancilio and Cheung, Fed. Proc. 35, 774 (1976).

It is an object of the present invention to provide novel compounds and compositions. Another object is to provide methods for the preparation of the novel compounds. A still further object is to provide a novel method for the treatment of a living animal body and especially mammalian bodies for purposes of alleviating inflammation and pain and inhibiting blood platelet aggregation with a minimum, of undesirable side effects.

2 GB 2 105 708 A 2 The present invention encompasses the compounds of Formula 1 set forth above with accompanying definitions as composition of matter and the utilization of these novel compounds in living animals for their pharmacological effects as set forth herein.

In the definition of the symbols of the formulae hereof and where they appear elsewhere 5 throughout this specification, the terms have the following significance.

The term -lower alkyl- as used herein includes straight and branched chain groups of up to six carbons inclusive, and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, secondary buty], tertiary butyl, amy], isoamyl and hexyL Preferably lower alkyl groups having no more than four carbon atoms are used. The term -lower alkoxy- has the formula -0-lower alkyl.

The term---halogen-when referred to herein means Cl, F, Br and 1.

Illustrative of pharmaceutically acceptable metal cations are sodium, potassium, calcium, magnesium, zinc, copper and the hydrates thereof.

The starting fluorobenzoylindolin-2-ones used to prepare the compounds of this invention may be prepared by one or more of the methods disclosed in U.S. Patent 4,045,576. One method disclosed therein begins by reacting 2amino-4'-halobenzoyibenzophenone with ethyl methylthioacetate, tBuOCI (tertiary butyl oxychloride) and Et,N (triethylamine) to give 7(halobenzoyl)-3-methylthioindolin-2-ones which are then reduced using a Raney nickel catalyst to produce the 7-(halobenzoyl)-3indolin-2-one. A modification of this procedure was used wherein the Raney nickel was replaced by tin powder in alcohol and concentrated hydrochloric acid. The following equation is representative of the preparation of 7-(fluorobenzoyi)-indolin-2-ones used to prepare the compounds of the invention: 20 R2 Am+CHSCH3)COOR 1 C=0 0 R2 R SCH3 0 1 C=0 H & F (1) t-Buoct (2) H+ ly Ifi H-R 0 11 c 0 H 6 F Y The preparation of the compounds of this invention is accomplished by reacting fluorobenzyl indolin-2-ones with alkalimetal alkylsulphide, followed by acid hydrolysis to obtain the 7-(alkylthiobenzoyi)indolin-2-ones and hydrolyzing with an alkali-metal base to give the alkali-metal salt of the 2-a m i no-3-(a 1 kylth iobenzoyl) phenyl acetic acids. The following reaction sequence illustrates 25 the preparation of the alkali-metal salts of the compounds of Formula 1:

3 GB 2 105 708 A 3 H R2 R co 6- F Y R2 H R 1) Na a[ky[su[phide 0 2) H+ 6-S-bwe.ralkyt Formula 9 R2 exAm C=0 6-5-towera[kyt Formula la To obtain the free acid (R'=H) from the alkali metal salt, acetic acid is carefully added to an aqueous solution of the salt which causes the free acid to precipitate. The free acid is then separated by filtration, washed with water and dried. To obtain the ester (R'=iower alkyl), the alkali metal salt is treated in a suitable solvent such as dry dimethylformamide with a lower alkyl iodide. Water is added and the ester extracted from the mixture with a suitable solvent such as diethyl ether, dried over sodium sulphate and the solvent removed by evaporation.

The compounds of Formula 1 wherein Am is dimethylamino are prepared by reacting a 2-aminophenylacetic acid ester of Formula 1 wherein Am is -NH2 with formaldehyde and sodium cyanoborohyd ride in a solvent such as acetonitrile under mildly acidic conditions as provided by the use 10 of glacial acetic acid.

The invention may be put into practice in various ways and a number of specific embodiments will be described to illustrate the invention with reference to the accompanying preparations 1 to 10 of starting materials, Examples 1 to 8 of the compounds of the invention and Examples 9 to 11 of pharmaceutical compositions in accordance with the invention.

Preparation 1 7-(4-fluorobenzoyi)-3-methylthioindolin-2-one A solution of 42.2 g (0.196 mole) of 2-amino-4'-fluorobenzophenone in 2 litres of methylene chloride was cooled to -651C and 26.5 9 (0.198 mole) of ethyl methylthioacetate was added. A solution of 23.0 g (0.21 mole) of 95% tertiary butoxychloride in 50 mi of methylene chloride was added dropwise, keeping the temperature below - 651C. One hour after the addition was complete, 22,2 g (0.22 mol) of triethylamine was added dropwise and the mixture was allowed to warm to room temperature. The solution was concentrated to 700 mi and then washed with water. The organic solution was concentrated and the residue dissolved in 400 mI of methanol containing 30 mi of concentrated hydrochloric acid. The mixture was heated at reflux for one hour followed by cooling. The 25 mixture was allowed to stand overnight, the crystals collected and washed with methanol to yield 31.4 g (53%) as bright yellow solid, m.p. 165-167.50C.

Analysis:

Calculated for Cl,H1,N0JS: C, 63.77; H, 4.01; K4.65 Found: C, 63.58; H, 4.11; N, 4.67.

Preparations 2A to 2G Utilizing the procedure of Preparation 1 but substituting for 2-a m ino- 4' -f 1 uorobenzop he none, equal molar amounts of the following: 2-a m i no-4M1 uoro-4-m ethyl benzoph e none, 2-a m i no-4M1 uoro-5-m ethyl benzop he none, 4 GB 2 105 708 A 4 2-ami no-4'-f 1 uoro-6-methyl benzoph enone, 2-a m ino4'-f 1 uoro-4-chlorobenzophe none, 2 -a mi n o-4-fl uoro- 5-c h 1 o robe nzop he none, 2-a m! no-4'-fl u o ro-6-c h 1 o robe nzo ph e none, 2-a mi no-4'-f 1 uoro-5-methoxybenzophenone, 5 there are obtained:

(2N (2B) (2C) (213) (2C (2M (2G) 7-(4-fluorobenzoyl)-4-methy]-3-methylthioindolin-2-one, 7-(4fluorobenzoyi)-5-methyl-3-methylthioindolin-2-one, 7-(4-fluorobenzoyi)-6methyi-3-methylthioindolin-2-one, 7-(4-fluorobenzoyi)-4-chloro-3methyithioindolin-2-one, 7-(4-fluorobenzoyi)-5-chloro-3-methy[thioindolin2-one, 7-(4-fluorobenzoyl)-6-chloro-3-methyithioindolin-2-one, 7-(4fluorobenzoyl)-5-methoxy-3-methyithioindolin-2-one.

Preparation 3 15 7-(2-fluorobenzoyl)-3-methylthioindolin-2-one A solution of 86 g (0.4 mole) of 2-amino2'-fluorobenzophenone in 3 litres of methylene chloride was cooled to -651C and 54 9 (0.4 mole) of ethyl methy[thioacetate was added. A solution of 46 9 (0.42 mole) of 95% tertiary butoxychloride in 100 mi of methylene chloride was added dropwise keeping the temperature below -651C. One hour after the addition was complete, 41 9 (0.4 mole) of triethylamine was added dropwise and the mixture allowed to warm up to room temperature. The solution was concentrated to about 1400 mi and then washed with water. The organic solution was concentrated and the residue dissolved in 800 mi methanol containing 60 mi of concentrated hydrochloric acid. The mixture was heated at reflux for one hr. followed by cooling. The mixture stood overnight, then the crystals were collected and recrystallized from 20% aqueous ethanol to give 66 g (55% pale yellow needles, m.p. 147.0-148.50C.

Analysis:

Calculated for C1,1-112NO2FS: Found:

C, 63.77; H, 4.01; NA.65 C, 6 3.9 7; H, 4.19; M, 4.6 6.

Preparation 4 Utilizing the procedure of Preparation 3 but substitution for 2-a m i no- 2M 1 u orobenzophe none, 30 equal molar amounts of 2-amino-3'-fluorobenzophenone, there is obtained:

7-(3-fluorobenzoyl)-3methylthioindolin-2-one.

Preparation 5 7-(4-fluorobenzoyi)indolin-2-one This is the starting material for Example 1. A mixture of 40.0 g (0.133 mole) of 7-(4-fluorobenzoyi)-3-methyithioindolin-2-one and 40.0 9 (0.34 mole) of tin powder in one litre of 95% ethanol was heated to reflux and 100 mI of concentrated hydrochloric acid was added. The mixture was heated for 6 hrs., then filtered while hot. The filtrate was 40 cooled and the precipitate was collected and recrystallized from isopropyl alcohol to yield 24.5 9 (72%) as off-white needles, m.p. 185-1 87.01C.

Analysis:

Calculated for C1,1-11,1\102F: C, 70.58; H, 3.95; N, 5.49 Found: Q 7 0.80; H, 4.12; N, 5.5 1. 45 Preparations 6A to 6G Utilizing the procedure of Preparation 5 but substituting for 7-(4- fluorobenzoyi)-3-methyithioindolin-2-one, equal molar amounts of the following:

7-(4-fluorobenzoyi)-4-methyl-3-methylthioindolin-2-one, 7-(4-fluorobenzoyl)-5-methyi-3-methylthioindolin-2-one, 50 7-(4-fluorobenzoyl)-6-methyi-3-methyithioindolin-2-one, 7-(4-fluorobenzoyi)-4-chloro-3-methylthioindolin-2-one, 7-(4-fluorobenzoyi)-5-chloro-3-methylthioindolin2-one, 7-(4-fluorobenzoyi)-6-chloro-3-methy[thioindolin-2-one, 7-(4-fluorobenzoyl)-5-methoxy-3-methyithioindolin-2-one, 55 there are obtained:

(6A) 7-(4-fluorobenzoyl)-4-methylindolin-2-one, (6 B) 7 -(4-f 1 uorobe nzoyl)-5-methyl i ndol i n-2 -one, GB 2 105 708 A 5 WC) 7-Wf luorobenzoyi)-6-methylindol in-2one, WID) 7-(4-fluorobenzoyi)-4-chloroindolin-2-one, (6E) 7-Wfl uorobenzoyl)-5-ch 1 oroi ndol i n-2 -one, W) 7-(4-fluorobenzoyl)-6-chloroindolin-2-one, (60 7-Wfl uorobenzoyi)-5-methoxyindol i n-2-one. 5 Preparation 7 7-(2-fluorobenzoyi)-indolin-2-one A mixture of 60 g (0.2 mole) of 7-(2-fluorobenozyi)-3-methyithioindolin-2- one and 60 g (0.5 mol) of tin powder in one litre of 95% ethanol was heated to reflux and 150 mi of concentrated hydrochloric acid was added. Heating was continued for 18 hrs then the mixture was cooled and the precipitate was 10 collected by decanting the slurry from the remaining tin and filtering the slurry. The filter cake was recrystallized twice from absolute ethanol to give 31 g (60%) white needles, m.p. 209-21 O'C.

Analysis:

Calculated for C15H,,1M0217: C, 70.58; H, 3.95; N, 5.49 Found: C, 70.3 11; H, 4.08; N, 5.56. 15 Preparation 8 Utilizing the procedure of Preparation 7 but substituting for 7-(2- fluorobenzoyl)-3-methylthioindolin-2-one, equal molar amounts of the following:

7-(3-fluorobenzoyl)-3-methyithioindolin-2-one, there is obtained:

7-(3-fluorobenzoyi)-indoiin-2-one.

Preparation 9 Utilizing the procedure of Preparation 1 but substituting equal molar amounts of ethyl a(methyithio)propionate for ethyl methylthioacetate, there is obtained 7-(4-fluorobenzoyi)-3-methyi-3-methyithioindolin-2-one.

Preparation 10 Utilizing the procedure of Preparation 5 but substituting equal molar amount of 7-(4fluorobenzoyi)-3-methyi-3-methylthioindolin-2-one, there is obtained 7-(4-fluorobenzoyi)-3-methylindolin-2-one.

The reaction conditions employed for preparing the novel intermediates and compounds of the invention are more fully illustrated in the examples which follow.

Example 1

7-(4-methyithiobenzoyl)indolin-2-one (R 2 =R=H; lower alkyl =CH3) A solution of sodium methyl mercaptide, prepared from 400 m] of 3N sodium hydroxide and 24 g (0.5 mole) of methyl sulphide, was mixed with 25.5 g (0.1 mole) of 7-(4- fluorobenzoyi)indolin-2-one (see Preparation 5). The mixture was refluxed for 1.5 hr, cooled and acidified with caution since much methyl sulphide evolves rapidly. The resulting precipitate was collected and recrystallized twice from 40 benzene to give 17,8 g (70%) as yellow crystals, m.p. 167.0-11 69.01C.

Analysis:

Examples2Ato211 Calculated for Cj13NO2S: C, 67.82; H, 4.63; N, 4.94 Found: C, 67.65; H, 4.63; K 4.9 1.

Utilizing the procedure of Example 1 but substituting for 7-(4fluorobenzoyl)indolin-2-one, equal molar amounts of the following:

7-(4-fi uorobenzoyl)-4-m ethyl indo 1 in-2-on e, (see Preparation 6A) 7-(4-fluorobenzoyi)-5-methylindolin-2-one, (see Preparation 6M 7-(4-fluorobenzoyi)-6-methylindolin-2-one, (see Preparation 6C) 50 7-(4-fluorobenzoyi)-4-chloroindolin-2-one, (see Preparation 6M 7-(4-fluorobenzoyi)-5-chloroindolin-2-one, (see Preparation 6E) 7-(4-f 1 uorobenzoyl)-6-ch lo ro i ndo 1 in-2 -one, (see Preparation 6F) 7-(4-fi uo robe nzoyl)-5-methoxyi ndol i n-2-o ne, (see Preparation 6G) 7-(2-fluorobenzoyi)-indolin-2-one, (see Preparation 7) 55 7-(3-fluorobenzoyi)indolin-2-one, (see Preparation 8) there are obtained:

6 GB 2 105 708 A 6 7-(4-methylthiobenzoyl)-4-methylindolin-2-one, (Example 2A) 7-(4- methy[thiobenzoyi)-5-methylindolin-2-one, (Example 2B) 7-(4methy[thiobenzoyl)-6-methylindolin-2-one, (Example 2C) 7-(4methylthiobenzoyl)-4chloroindolin-2-one, (Example 2D) 7-(4methyfthiobenzoyi)-5chloroindolin-2-one, (Example 2E) 7-(4methylthiobenzoyi)-6-chloroindolin-2-one, (Example 2F) 7-(4methylthiobenzoyi)-5-methoxyindolin-2-one, (Example 2G) 7-(2methylthiobenzoyi)indolin2-one (Example 2H) 7-(3methyithiobenzoyi)indolin-2-one (Example 21).

Example 3A to 3C Utilizing the procedure of Example 1 but substituting for sodium methyl mercaptide, equal molar amounts of the following:

sodium ethyl m ercaptide, sodium isopropyimercaptide, sodium-n-buty[mercaptide, there are obtained the following:

7-(4-ethylthiobenzoyl)indolin-2-one, (Example 3A) 7-(4isopropy[thiobenzoyl)indolin-2-one, (Example 3B) 7-(4-n-butyithiobenzoyl)indolin-2-one (Example 3C).

Example 4

Sodium 2-a m i no-3-Wm ethylth iobe nzoyi) p h enyl acetic acid monohydrate A mixture of 5.2 g (0.018 mole) of 7-(4-methylthiobenzoyi)indolin-2-one (see Example 1) in 75 mi of 3N sodium hydroxide was heated at reflux for 20 hrs. The red solution was cooled and a yellow precipitate formed. The precipitate was collected by filtration and washed with a small amount of cold water and then triturated with tetrahydrofuran. The precipitate was again separated by filtration, dried, 25 and recrystallized from 95% ethanol to give 4.9 g (83%) of bright yellow needles, m.p. 244-2471C.

Analysis:

Examples5Ato5L Calculated for C,,^,NO,Si\la: C, 5 6.3 0; H, 4.7 2; N, 4.10 Found: C, 5 6.3 8; H, 4.6 2; N, 4.17.

Utilizing the procedure of Example 4 but substituting for 7 - (4-m ethylth iobenzoyl) i ndol i n-2 -one, equal molar amounts of the following:

7-(4-methyithlobenzoyl)-4methylindolin-2-one, (see Example 2A) 7(4-methylthiobenzoyl)-5-methylindolin-2-one, (see Examples 2B) 7-(4methylthiobenzoyl)-6-methylindolin-2-one, (see Example 2C) 7-(4methyithiobenzoyl)-4-chloroindolin-2-one, (see Example 2D) 7-(4methylthiobenzoyl)-5-chloroindolin-2-one, (see Example 2E) 7-(4methyithiobenzoyl)-6-chloroindolin-2-one, (see Example 2F) 7-(4methylthiobenzoyi)-5-methoxyindolin-2-one, (see Example 2G) 7-(2methyithiobenzoyl)indolin-2-one, (see Example 21-1) 7-(3-methyithiobenzoyi)indolin-2-one, (see Example 21) 7-(4ethyithiobenzoyl)indolin-2-one. (see Example 3A) 7-(4-isopropyithiobenzoyi)indoiin-2-one, (see Example 3B) 7-(4-nbutyithiobenzoyl)indolin-2-one, (see Example 3C) there are obtained, Sodium 2-a m i no-3 -(4-methy[thiobe nzoyl)-6-methyl phenyl acetic acid, (Example 5A) Sodium 2-amino-3-(4-methylthiobenzoyl)-5-methylphenylacetic acid, (Example 5B) Sodium 2-amino-3-(4-methyithiobenzoyl)-4methylphenylacetic acid, (Example 5C) Sodium 2-amino-3-(4methy[thiobenzoyl)-6-chlorophenylacetic acid, (Example 513) Sodium 2amino3-(4-methyithiobenzoyl)-5-chlorophenylacetic acid, (Example 5E) Sodium 2amino-3-(4-methylthiobenzoyl)-4-chlorophenylacetic acid, (Example 5F) Sodium 2-a m i no3-(4-methylth iobenzoyl)-5-methoxyp henyl acetic acid (Example 5G) Sodium 2-a mi no-3-(2-methyith iobenzoyl)-p henyl acetic acid, (Example 5H) Sodium 2-amino-3-(3-methyithiobenzoyi)-phenylacetic acid, (Example 51) Sodium 2-amino-3-(4-ethyithiobenzoyi)-phenylacetic acid, (Example 5J) Sodium 2-a m i no-3-(4-isopropylth iobe nzoyi) phenyl acetic acid, (Example 5K) Sodium 2-a mi no-3-(4-n-b utylthiobe nzoyi) phenyl acetic acid, (Example 5Q.

Example 6

7-(4-methyithiobenzoyi)-3-methylindolin-2-one Utilizing the procedure of Example 1 but substituting 7-(4-fluorobenzoyi)- 3-methylindolin-2-one 60 (see Preparation 10) for 7-(4-fluorobenzoyi)indolin2-one, the titled compound is obtained.

7 GB 2 105 708 A 7 Example 7 Sodium 2-amino-3-(4-methylthlobenzoyl)-a-methylphenylacetic acid A suspension of 7-(4-methyithiobenzoyl)-3-methyi-indolin-2-one (see Example 6) in 3N sodium hydroxide is refluxed under nitrogen, stripped of water under vacuum, and the product is isolated by 5 trituration with organic solvent.

Example 8 Ethyl 2-amino-3-(4-methyithiobenzoyi)phenylacetate Seventeen grams (0.05 mole) of sodium 2-a m i no-3-(4-methylth lobe nzoyi) p he nyl acetic acid monohydrate (see Example 4) are dissolved in approximately 150 mi of dimethylformamide and the solution treated with 33 9 ethyl iodide. The solution is stirred at room temperature for 2.5 hrs. and added to water and the mixture extracted several times with benzene. The combined benzene extracts are washed with dilute base and water, dried over sodium sulphate and concentrated to obtain the titled compound.

The present invention also contemplates novel compositions containing the compounds of the invention as active ingredients. Effective quantities of any of the foregoing pharmacological ly active 15 compounds may be administered to a living animal body in any one of various ways, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. In forming the novel 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 20 include starch, gelatin, glucose, magnesium carbonate, lactose and malt. Liquid compositions are also within the purview of this invention and 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 administered once daily or in multiple or divided 25 daily doses. The daily dosages may vary from 0.3 to 450 milligrams. Five to 25 milligrams appears optimum per unit dose.

It is only necessary that the active ingredient constitute an effective amount, i.e., such that a suitable effective dosage will be obtained consistent with the dosage form employed. The exact individual dosages as well as daily dosages will, of course, be determined according to standard 30 medical principles under the direction of a physician or veterinarian.

The active agents of the invention may be combined with other pharmacologically active agents, or with buffers, antacids or the like, for administration and the production of the active agent in the composition may be varied widely.

The following are examples of pharmaceutical compositions formed in accordance with this 35 invention.

Examples 9A to 9D Capsules Capsules of 5 mg. (Example 9A), 25 mg. (Example 913), and 50 mg. (Example 9C) of active ingredient per capsule are prepared. With the higher amounts of active ingredient, adjustment maybe 40 made in the amount of lactose.

Typical blend for encapsulation Per capsule, mg.

Active ingredient 5.0 Lactose 29.6.7 45 Starch 129.0 Magnesium stearate 4.3 Tota 1 435.0 mg.

follows:

Additional capsule formulations preferably contain a higher dosage of active ingredient and are as Example 9D

Ingredients Per capsule, mg.

Active ingredient 25.0 Lactose 306.5 Starch 99.2 55 Magnesium stearate 4.3 Total 435.0 mg.

8 GB 2 105 708 A 8 In each of Examples 9A to 9D the selected active ingredients are uniformly blended with lactose, starch, and magnesium stearate and the blend is encapsulated.

Example 10

Tablets

A typical formulation for a tablet containing 5.0 mg. of active ingredient per tablet follows. The 5 formulation may be used for other strengths of active ingredient by adjustment of weight of dicalcium phosphate.

Per tablet, mg.

(1) Active ingredient 5.0 (2) Corn starch 13.6 10 (3) Corn starch (paste) 3.4 (4) Lactose 79.2 (5) Dicalcium phosphate 68.0 (6) Calcium stearate 0,9 170.1 mg. 15 The procedure for making the tablets is to uniformly blend ingredients 1, 2, 4 and 5. Ingredient 3 is formed into a 10 per cent paste in water. The blend is granulated with the starch paste and the wet mass is passed through an eight mesh screen. The wet granulation is dried and sized through a twelve mesh screen. The dried granules are blended with the calcium stearate and pressed.

Example 11 20

Injectable-2% sterile solutions Per cc Active ingredient 20 mg.

Preservative, e.g., chlorobutanol 0.5% weight/voiume 25 Water for injection q.s.

The procedure is to prepare the solution, clarify it by filtration, and fill it into vials, which are then sealed and autoclaved.

Claims

1. A compound having the formula:

wherein; cation, CHRCOOR' R2-9 C=0 - S-toweratkyt Formula 1 R represents a hydrogen atom or a lower alkyl group, R' represents a hydrogen atom or a lower alkyl group or a pharmaceutically acceptable metal R 2 represents a hydrogen or a halogen atom or a lower alkyl or lower alkoxy group and Am represents a primary amino (-NH2), methylamino or dimethylamino group.

2. 2-Amino-3-(3-methyithiobenzoyi)-phenylacetic acid and pharmaceutically acceptable esters and salts thereof.

3. Sodium 2-amino-3-(4-methylthiobenzoyi)-phenylacetic acid monohydrate.

4. A compound as claimed in claim 1 and as specifically described with reference to Example 4, 5A to 5L, 7 or 8.

5. A compound as claimed in claim 1, 2, 3 or 4 for use in alleviating inflammation in a living animal body.

6. A compound as claimed in claim 1, 2, 3 or 4 for use in alleviating pain in a living animal body. 45

7. A compound as claimed in claim 1, 2, 3 or 4 for use in platelet aggregation in a warm-blooded animal.

9 GB 2 105 708 A 9

8. A therapeutic pharmaceutical composition suitable for alleviating inflammation and pain and inhibiting blood platelet aggregation in a living animal body comprising an effective amount of a compound having the formula:

H R 2-Q C=0 6-S[owera[kyl wherein; R represents a hydrogen atom or a loweralkyl group, R' represents a hydrogen atom or a loweralkyl group or a pharmaceutically acceptable metal R' represents a hydrogen or a halogen atom or a loweralkyl or lower alkoxy group and Am represents a primary amino (-NH,), methylamino or dimethylamino group and a pharmaceutically acceptable carrier or diluent.

9. A composition as claimed in claim 8 in which the compound is present in an amount in the range 0.1 to 150 milligrams.

10. A composition as claimed in claim 8 or claim 9 in which compound is 2amino-3-(4- methylthiobenzoyl) phenylacetic acid.

11. A composition as claimed in claim 8 or claim 9 in which compound is sodium 2-amino-3-(4 methyithiobenzoyi)-phenyi-acetic acid monohydrate.

12. A pharmaceutical composition as claimed in claim 8 substantially as specifically described herein with reference to Example 9, 10 or 11.

13. 7-(S-loweralkyithiobenzoyi) indolin-2-ones having the formula cation, 1 R 2 P:::LR 0 &0 H S-[owera[kyl wherein; R represents a hydrogen atom or a lower alkyl group, R' represents a hydrogen atom or a lower alkyl group or a pharmaceutically acceptable metal cation, and R 2 represents a hydrogen or a halogen atom or a lower alkyl or lower alkoxy group.

14. 7-(4-Methyithiobenzoyl) indolin-2-one.

15. 7-(4-Methyithiobenzoyi)-4-methylindolin-2-one.

16. 7-(4-M ethylth i obe nzoyl)-5 -methyl i ndol in-2 -one.

17. 7-(4-Methylthiobenzoyi)-6methylindolin-2-one.

18. 7-(4-Methyithiobenzoyl)-4-chloroindolin-2-one.

19. 7-(4-Methyithiobenzoyl)-5-chloroindolin-2-one.

20. 7-(4Methylthiobenzoyi)-6-chloroindolin-2-one.

21. 7-(4-Methylthiobenzoyl)-5-methoxyindolin-2-one.

22. 7-(2-Methyithiobenzoyl) indolin-2-one.

23. 7-(3-Methyithiobenzoyi) indolin-2-one.

24. 7-(4-Ethyithiobenzoyi) indolin-2-one.

25. 7-(4-1 sop ropylth iobenzoyl) indolin-2-one.

26. 7-(4-n-Butyithiobenzo1) indolin-2-one.

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1983. Published by the Patent Office, 25 Southampton Buildings, London, WC2A l AY, from which copies may be obtained