FI74457B - FOERFARANDE FOER FRAMSTAELLNING AV 2-AMINO-3- (ALKYLTIOBENZOYL) -PHENYLETTIKSYROR. - Google Patents

Description

775 ^ 71 ANNOUNCEMENT ΠΛΑ ^ η [β] (11> UTLÄGGNINGSSKRIFT / 4 4 O f ^ (45) * "Γ

^ "V

(51) Kv.lk.Vint.Cl4 C 07 c 1 ^ 9 / ^ 3, C 07 D 209/3 ^

SUOMI FINLAND

(Fl) (21) Patent application - Patentansökning 802282 (22) Application date - Ansökningsdag 18.07-80

National Board of Patents and Registration (23) Start date - Giitighetsdag 18.07.80

Patent- och registerstyrelsen (41) TuNut jU | kiseksi_B |, vit 0ffentiig 02.02.81 (44) Date of publication and date of publication. - 30.10.87

Ansökan utlagd och utl.skriften publicerad (86) Kv. application - Int. trap (32) (33) (31) Claim claimed - Begärd priontet 01. 08.79 USA (US) 063029 (71) AH Robins Company, Incorporated, 1 ^ 07 Cummings Drive, Richmond, Virginia, USA (72) David Allan Walsh, Richmond, Virginia,

Dwight Allen Shamblee, Richmond, Virginia, USA (7/4) Berggren Oy Ab (5A) Process for the preparation of 2-amino-3 '(α1-thiobenzoyl) -phenylacetic acids - Preparation of 2-amino-3_ ( The present invention relates to a process for the preparation of 2-amino-3- (alkylthiobenzoyl) phenylacetic acid for use as a medicament of the formula

COOR

2 Χ / Υ 2

R -H II

NH2 1 c = o

A

C 1-6 alkyl wherein r 1 is a hydrogen atom, lower alkyl or a pharmaceutically acceptable metal cation, and r is a hydrogen atom, halogen or lower alkyl.

2 74457

Certain 2-amino-3- (5- and 6-) benzoylphenylacetic acids in which the benzoyl moiety is substituted by lower alkyl, alkoxy, halogen, nitro and trifluoromethyl groups, and a process for their preparation and use are described in U.S. Pat. in Exam No. 4,045,576. The compounds of this invention cannot be prepared by the procedures described therein.

The novel compounds of formula I have valuable pharmacological properties and are useful as pharmaceuticals. The compounds have anti-inflammatory and analgesic activity and inhibit platelet aggregation in warm-blooded animals.

Certain new intermediates, 7- (S-lower allylthiobenzoyl-1i) indolin-2-ones, are represented by formula II:

R 2 _-- H

N → O

C = O H Π -4-S-lower alkyl in W 1 2] R is the same as defined above.

Anti-inflammatory activity was demonstrated in laboratory animals using a modification of the method of the Evans Blue Carrageenan Pleural Effusion Assay, Sancilio, L.F., J. Pharmacol. Exp. Ther. 168, 199-204 (1969).

The compounds of formula I as inhibitors of platelet aggregation illustrate this property by reducing platelet aggregation as described by Born, J. of Phys. 162, pages 67-69 (1972) and Evans et al., J. of Expt. Med. 1 ^ 8, 877-894 (1968). The rats were orally administered test drugs, and after 3 74457 hours, the rats were bled and flaked with plasma. Collagen was added to flake-rich plasma to cause flake accumulation and comparisons were made between control and treated samples.

The compounds of formula I also act as analgesics as determined by the Bradykinin analgesic test method, Dickerson et al., Life Sci. 4, 2063-2069 (1965), modified by Sancilio and Cheung, Fed. Proc. 35, 774 (1976).

It is therefore an object of the present invention to provide novel compounds and preparations. Yet another object is to provide a new method for treating a live animal, and in particular mammals, in order to alleviate inflammation and pain and to prevent platelet aggregation with minimal undesirable side effects. Additional purposes will be apparent to those skilled in the art, and yet other purposes will become apparent below.

In defining the symbols in the formulas present herein and where they occur elsewhere throughout this patent specification, the terms have the following meanings.

The term "lower alkyl" as used herein includes straight and branched chain radicals containing up to six and preferably up to four carbon atoms and is exemplified by groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl. -, tert-butyl, amyl, isoamyl and hexyl groups.

As mentioned herein, the term "halogen" means a Cl, F, Br and J tower.

4 74457

Typical pharmaceutically acceptable salts include sodium, potassium, calcium, magnesium, zinc, copper salts and hydrates thereof.

Compare 1 tests

Comparative experiments were performed with the following compounds to determine their pharmacological properties: a) sodium 2-amino-3- (4-methoxybenzoyl) -phenylacetic acid base hydrate, b) sodium 2-amino-3- (4-methyl-obenzoyl) -phenyl ethyl acetate monohydrate, c) indomethacin

The anti-inflammatory effects of sodium 2-amino-3- (4-methoxybenzoyl) phenylacetic acid hemihydrate, sodium 2-amino-3- (4-methylthiobenzoyl) phenylacetic acid monohydrate and indomethacin were studied in Evans-Blue-Carrageenan. bag fluid formation assay (Sancilio, LF, Jr., Pharmacol. Exp. Ther. 1, 68, 199-204 (1969)).

Fasted Charles River male albino rats weighing more than 250 g were used. Each control and experimental group consisted of six animals. Groups and animals were selected by random methods. The substances were administered by intraperitoneal intubation 1a (10 ml / kg) as a solution or suspension in 0.5% Tween-80 fluid. The control group was given a vehicle. One hour after administration, the rats were anesthetized with ether and 5 ml of a mildly irritating solution (0.075% Evans Blue and 0.5% Carrageenan) was administered to the pleura. Five hours later, the animals were killed with chloroform or carbon dioxide. Pleural fluids were collected and measured in calibrated centrifuge tubes. The results are shown in the following table and are expressed as the mean percentage reduction in pleural fluid volume compared to the control group. The reliability of the data was determined by the Dunnett's +/- experiment (J. Amer. Ass. 5J3: 1096-1121 (1955)).

5 74457

Substance Dose Lung Change Effect mg / kg, bag% (Indo PO fluid, = 1) ml + _ S. D.

Amendment - 6.4 + J, l

Na-2-amino-3- (4-methoxy-benzoyl) -phenylacetic acid hemi-4.0 6.2 + 0.3 -3 Λ hydrate 20.0 4.2 + 0.61 -3δί 0 .09 (0.04-0.21) in solution 100.0 3.9 + 0.5 -39,)

Na-2-amino-3- (4-methyl-thiobenzoyl-1i) phenyl-acetic acid 0.16 6.4 + 0.4 ° n monohydrate a 0.80 5.0 OM), 3-21 ° C 0.87 (0,34-2-25)

in solution 4.0 4.4j ^ 0.7 -3lJ

Indometa-0.16 6.1 + 0.7 -3 Λine 0.80 5.4 + 1.0 -16 i 1.00

in suspension 4.0 4.2 + 0.3 -35J

lp <0.05 amendment from group 74457

In a similar series of experiments, other compounds of the invention were individually compared to indomethacin. The experimental conditions were similar to those described above. The following results were obtained.

Substance Dose% change in fluid volume in mg / kg compared to control group

Na-2-amino-5-chloro-3- (4-methylthiobenzoyl) phenylacetic acid monohydrate 4.0 -43

Indomethacin 4.0 -40

Na-2-amino-3- (4-methylthiobenzoyl) phenylacetic acid monohydrate 4.0 -39.4

Indomethacin 4.0 -38.8

Na-2-amino-3- (4-methylthiobenzoyl) -5-fluorophenylacetic acid 4.0-28.0

Indomethacin 4.0 -33.0

Na-2-amino-3- (4-methylthiobenzoyl) -5-methylphenylacetic acid dihydrate 4.0-26.0

Indomethacin 4.0 -42.0 7 74457

In the experiment, a dose of 4 mg / kg of sodium 2-amino-3- (4-methoxy benzoyl) phenyl ethyl acetic acid hydrate did not significantly reduce the volume of pleural fluid compared to the control group with a p-value greater than 0.05. In contrast, a dose of 4 mg / kg of sodium 2-amino-3- (4-methylthiobenzoyl) phenylacetic acid monohydrate significantly (31%) reduced the volume of pleural fluid compared to the corresponding control group with a p-value below 0.05.

Analysis of the information in the table shows that: a) Sodium 2-amino-3- (4-methylthiobenzoyl) phenylacetic acid monohydrate is an effective anti-inflammatory drug at a dose of 4 mg / kg and is approximately as effective as indomethacin when using the Carrageenan pleural effusion test. The same applies to compounds of the formula I in which R is 5-CH, 5-Cl and 5-F.

3 b) Sodium 2-amino-3- (4-methoxy benzoyl) phenylacetic acid hemihydrate is not an effective anti-inflammatory drug at a dose of 4 mg / kg.

c) A comparison of the dose-response curves shows that sodium 2-amino-3- (4-methylthiobenzoyl) phenylacetic acid monohydrate is about 10 times more effective than sodium 2-amino-3- (4-methoxybenzoyl) phenylacetic acid hemihydrate when the Carrageenan pleural fluid formation test is used. The same applies to compounds of formula I wherein R is 5-CH 5 -Cl and 5-F.

O

methods of Preparation

The fluorobenzoylindolin-2-one starting materials used to prepare the compounds of this invention can be prepared by one or more of the methods described in U.S. Patent 4,045,576. One of the methods described therein begins by reacting 2-amino-4'-halobenzoylbenzophenone with 74457 with ethyl methylthioacetate, t-BuOCL and Et 2 N to give 7- (halobenzoyl) -3-methylthioindolin-2-ones, which are then reduced with Raney nickel 7- (halobenzoyl-1i) -3-indole To form -2-one. A variation of this procedure was also used, in which Raney nickel was replaced with tin powder in alcohol and concentrated hydrochloric acid. The following equation represents the preparation of 7- (fluorobenzoyl) -indole-2-οηΐ used in the preparation of the compounds of the invention:

2 2 R \ R \ H

x Cort: scH3 \ j ^^ nh2 + CH2 (sch ^ coor1 T ^ .o

C = O-^ c = O H

i. (1) t-BuOCl JL

ψ} @ -F

F 2 / Sn si HC1 YSA "

C = 0 H

(G} f 74457 The preparation of the compounds of this invention is completed by reacting fluorobenzoylindolin-2-ones with an alkali metal alkyl sulfide, followed by acid hydrolysis to give 7- (alkylthiobenzoyl) indolin-2-ones and hydrolyzing with an alkali metal base 2-amino-3-one. to obtain an alkali metal salt of - (alkylthiobenzoyl) phenylacetic acids The following reaction sequence describes the preparation of alkali metal salts of the compounds of formula I: H r2 \ _ ti

r2-KDI [--H

1) alkyl sulfide \ c = 0 H 2) H ^ 0

t C = 0 H

A r A

(j) -S-lower alkyl

✓Formula II NaOH

A ^ \ / CHRC00Na

A

q = o Formula Ia - S-lower alkyl

To obtain the free acid (R1 = H) from the alkali metal salt, acetic acid is carefully added to the aqueous salt solution, which causes the free acid to precipitate. The free acid is then filtered off, washed with water and dried. To obtain the ester (R 1 · = lower alkyl group), 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 is extracted from the mixture as a suitable solvent such as diethyl ether, dried over sodium sulfate and the solvent is removed by evaporation.

74457 το

The reaction conditions used to prepare the fluorobenzoylindolin-2-one starting materials are described in more detail in the following preparation methods.

Preparation 1 A solution of 7- (4-fluorobenzoyl) -3-methylthioindolin-2-one containing 42.2 g (0.196 mol) of 2-amino-4'-fluorobenzophenone in 2 liters of methylene chloride was cooled to -65 ° C. and 26.5 g (0.198 mol) of ethyl methylthioacetate were added. A solution of 23.0 g (0.21 mol) of 95% tertiary butoxychloride in 50 ml of methylene chloride was added dropwise keeping the temperature below -65 ° C. 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 ml and then washed with water. The organic solution was concentrated and the residue was dissolved in 400 ml of methanol containing 30 ml of concentrated hydrochloric acid. The mixture was refluxed for one hour, after which it was cooled. The mixture was allowed to stand overnight, the crystals were collected and washed with methanol to give 31.4 g (53%) of a bright yellow solid, m.p. 165 to 167.5 ° C.

Analysis: Calculated for C 16 H 12 NO 2 FSi C 63.77; H 4.01; N 4.65 experimentally C 63.58; H 4.11; N 4.67.

Preparation Method 2 Using the procedure of Preparation Method 1, but replacing 2-amino-4'-fluorobenzophenone with equal molar amounts of the following: 2-amino-4'-fluoro-4-methylbenzophenone, 2-amino-4'-fluoro-5-methylbenzophenone, 2-amino-4'-fluoro-6-methylbenzophenone, 2-amino-4'-fluoro-4-chlorobenzophenone, 2-amino-41-fluoro-5-chlorobenzophenone, 2-amino-4'-fluoro-6-chlorobenzophenone , 11-, 74457 gives: 7- (4-fluorobenzoyl) -4-methyl-3-methylthioindolin-2-one, 7- (4-fluorobenzoyl) -5-methyl-3-methylthioindolin-2-one, 7- ( 4-fluorobenzoyl) -6-methyl-3-methylthioindolin-2-one, 7- (4-fluorobenzoyl) -4-chloro-3-methylthioindolin-2-one, 7- (4-chlorobenzoyl) -5-chloro-3 -methylthioindolin-2-one, 7- (4-fluorobenzoyl) -6-chloro-3-methylthioindolin-2-one,

Preparation 3 7- (2-Fluorobenzoyl) -3-methylthioindolin-2-one A solution of 86 g (0.4 mol) of 2-amino-2'-fluorobenzophenone in 3 liters of methylene chloride was cooled to -65 ° C and 54 g (0.4 mol) of ethyl methylthioacetate were added. A solution of 46 g (0.42 mol) of 95 tertiary butoxychloride in 100 ml of methylene chloride was added dropwise keeping the temperature below -65 ° C. One hour after the end of the addition, 41 g (0.4 mol) of triethylamine were added dropwise and the mixture was allowed to warm to room temperature. The solution was concentrated to ca.

To 1400 ml and then washed with water. The organic solution was concentrated and the residue was dissolved in 800 ml of methanol containing 60 ml of concentrated hydrochloric acid. The mixture was refluxed for one hour, after which it was cooled. The mixture was allowed to stand overnight, after which the crystals were collected and recrystallized from 20% aqueous ethanol to give 66 g (55%) of pale yellow needles, m.p. 147.0 to 148.5 ° C.

Analysis: Calculated from C 63.77; H 4.01; N 4.65 experimentally C 63.97; H 4.19; N 4.66.

Preparation 4 Using the procedure of Preparation 3, but substituting an equal molar amount of 2-amino-3'-fluorobenzophenone for 2-amino-2'-fluorobenzophenone, 7- (3-fluorobenzoyl) -3-methylthioindolin-2-one is obtained.

Preparation 5 7- (4-Fluorobenzoyl) -indolin-2-one

A mixture of 40.0 g (0.133 mol) of 7- (4-fluorobenzoyl) -3-74457 methylthioindolin-2-one and 40.0 g (0.34 mol) of tin powder in one liter of 95% ethanol was heated to reflux. and 100 ml of concentrated hydrochloric acid were added. The mixture was heated for 6 hours, then filtered hot. The filtrate was cooled and the precipitate was collected and recrystallized from isopropyl alcohol to give 24.5 g (72%) of off-white needles, m.p. 185 to 187.0 ° C.

Analysis: Calculated for C 12 H 11 N 2 O 2 F 2 F: C, 70.58; H 3.95; N 5.49 experimentally C 70.80; H 4.12; N 5.51.

Preparation 6 Using the procedure of Preparation 5, but substituting equal molar amounts of 7- (4-fluorobenzoyl) -3-methylthioindolin-2-one for the following: 7- (4-fluorobenzoyl) -4-methyl-3-methylthioindolin-2-one, 7 - (4-fluorobenzoyl) -5-methyl-3-methylthioindolin-2-one, 7- (4-fluorobenzoyl) -6-methyl-3-methylthioindolin-2-one, 7- (4-fluorobenzoyl) -4-chloro -3-methylthioindolin-2-one, 7- (4-fluorobenzoyl) -5-chloro-3-methylthiodindolin-2-one, 7- (4-fluorobenzoyl) -6-chloro-3-methylthioindolin-2-one, are obtained : 7- (4-fluorobenzoyl) -4-methylindolin-2-one, 7- (4-fluorobenzoyl) -5-methylindolin-2-one, 7- (4-fluorobenzoyl) -6-methylindoline -2-one, 7- (4-fluorobenzoyl) -4-chloroindolin-2-one, 7- (4-fluorobenzoyl) -5-chloroindolin-2-one, 7- (4-fluorobenzoyl) -6 -chloroindole n-2-one,

Preparation 7 7- (2-Fluorobenzoyl) -indolin-2-one

A mixture of 60 g (δ, 2 mol) of 7- (2-fluorobenzoyl) -3-methylthioindolin-2-one and 60 g (0.5 mol) of tin powder in one liter of 95% ethanol was heated to reflux and 150 ml of concentrated hydrochloric acid were added. Heating was continued for 18 hours, after which the mixture was cooled and the precipitate was collected by decanting 13,745,57 of the slurry from the remaining tin and filtering the slurry. The filter cake was recrystallized twice from absolute ethanol to give 31 g (60%) of white needles, m.p. 209-210 ° C.

Analysis: Calculated for C 15 H 15 NO 2 F: C 70.58; H 3.95; N 5.49 experimentally C 70.31; H 4.08; N 5.56.

Preparation 8 Using the procedure of Preparation 7, but substituting an equal molar amount of 7- (2-fluorobenzoyl) -3-methylthioindolin-2-one for: 7- (3-fluorobenzoyl) -3-methylthioindolin-2-one, 7- (3 -fluoribentsoyyli) indole-2-one.

Preparation Method 9 Using the procedure of Preparation Method 1, but substituting an equal molar amount of ethyl α- (methylthio) propionate for ethyl methylthioacetate, 7- (4-fluorobenzoyl) -3-methyl-3-methylthioindolin-2-one is obtained.

Preparation 10 Using the procedure of Preparation 5, but substituting an equal molar amount of 7- (4-fluorobenzoyl) -3-methyl-3-methylthioindolin-2-one for 7- (4-fluorobenzoyl) -3-methylthioindolin-2-one, 7- (4-fluorobenzoyl) -3-methyl-Indolin-2-one.

The reaction conditions used to prepare the novel intermediates and compounds of the invention are more fully described in the following examples.

Example 1 7- (4-Methylthiobenzoyl) -indolin-2-one

To a solution of sodium methyl mercaptide prepared from 400 ml of 3N sodium hydroxide and 24 g (0.5 mol) of methyl sulfide was added 25.5 g (0.1 mol) of 7- (4-fluorobenzo-14 74457) yl. ) indole-2-one. The mixture was refluxed for 1.5 hours, cooled and acidified (warning: abundant methyl sulfide develops rapidly). The resulting precipitate was collected and recrystallized twice from benzene to give 17.3 g (70%) of yellow crystals, m.p. 167.0 to 169.0 ° C.

Analysis: Calculated for C 16 H 13 NO 2 S: C, 67.82; H 4.63; N 4.94 experimentally C 67.65; Il 4.63; N 4.91.

Example 2 Using the procedure of Example 1, but substituting equal molar amounts of 7- (4-fluorobenzoyl) indolin-2-one for: 7- (4-fluorobenzoyl) -4-methylindolin-2-one, 7- { 4-fluorobenzoyl) -5-methylindolin-2-one, 7- (4-fluorobenzoyl) -6-methylindolin-2-one, 7- (4-fluorobenzoyl) -4-chloroindolin-2-one , 7- (4-fluorobenzoyl) -5-chloroindolin-2-one, 7- (4-fluorobenzoyl) -6-chloroindolin-2-one, 7- (2-fluorobenzoyl) indolin-2-one , 7- (3-fluorobenzoyl) -indolin-2-one, gives: 7- (4-methylthiobenzoyl) -4-methylindolin-2-one, 7- (4-methylthiobenzoyl) -5-methylindolin-2-one -one, 7- (4-methylthiobenzoyl) -6-methylindolin-2-one, 7- (4-methylthiobenzoyl) -4-chloroindolin-2-one, 7- (4-methylthiobenzoyl) -5-chloro -indolin-2-one, 7- (4-methylthiobenzoyl) -6-chloroindolin-2-one, 7- (2-methylthiobenzoyl) -indolin-2-one, 7- (3-methylthiobenzoyl) -indolin-2-one -one.

Example 3 Using the procedure of Example 1, but substituting equal molar amounts of sodium methyl mercaptide for: sodium ethyl mercaptide, sodium isopropyl mercaptide, sodium n-butyl mercaptide, the following is obtained: 74457 15 7- (4-ethylthiobenzoyl) indolin-2-one, 7- (4 -isopropylthiobenzoyl) -indolin-2-one, 7- (4-n-butylthiobenzoyl) -indolin-2-one.

Example 4

Sodium 2-amino-3- (4-methylthiobenzoyl) -phenylacetic acid monohydrate

A mixture of 5.2 g (0.018 mol) of 7- (4-methylthiobenzoyl) -indolin-2-one in 75 ml of 3N sodium hydroxide was refluxed for 20 hours. 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 in tetrahydrofuran. The precipitate was again filtered off, dried and recrystallized from 95% ethanol to give 4.9 g (83%) of bright yellow needles, m.p. 244-247 ° C.

Analysis: Calculated for C 18 H 19 NO 2 SNa: C, 56.30; H 4.72; N 4.10 experimentally C 56.38; H 4.62; N 4.17.

Example 5 Using the procedure of Example 4, but substituting equal molar amounts of 7- (4-methylthiobenzoyl) indolin-2-one for: 7- (4-methylthiobenzoyl) -4-methylindolin-2-one, 7- (4-methylthiobenzoyl) -6-methylindolin-2-one, 7- (4-methylthiobenzoyl) -4-chloroindolin-2-one, 7- (4-methylthiobenzoyl) -6-chloroindolin-2-one 2-one, 7- (2-methylthiobenzoyl) indolin-2-one, 7- (3-methylthiobenzoyl) indolin-2-one, 7- (4-ethylthiobenzoyl) indolin-2-one, 7- (4 -isopropylthiobenzoyl) -indolin-2-one, 7- (4-n-butylthiobenzoyl) -indolin-2-one, gives sodium 2-amino-3- (4-methylthiobenzoyl) -6-methylphenylacetic acid, 16 74457 sodium -2-Amino-3- (4-methylthiobenzoyl) -4-methylphenylacetic acid, sodium 2-amino-3- (4-methylthiobenzoyl) -6-chlorophenylacetic acid, sodium 2- Amino-3- (4-methylthiobenzoyl) -4-chlorophenylacetic acid, sodium 2-amino-3- (2-methylthiobenzoyl) -phenylacetic acid, sodium 2-amino-3- ( 3-methyl-obenzo yyl) -phenylacetic acid, sodium 2-amino-3- (4-ethylthiobenzoyl) -phenylacetic acid, sodium 2-amino-3- (4-isopropylthiobenzoyl) -phenylacetic acid, sodium 2-Amino-3- (4-n-butylthiobenzoyl) phenylacetic acid.

Example 6 7- (4-Methylthiobenzoyl) -3-methylindole Using the procedure of Example 1, but substituting 7- (4-fluorobenzoyl) -indolin-2-one 7- (4-fluorobenzoyl-3-methyl) - indolin-2-one 11a gives the title compound.

Example 7

Sodium 2-amino-3- (4-methyl-obenzoyl) -methyl-phenyl-acetic acid

A suspension of 7- (4-methylthiobenzoyl) -3-methyldiol! in-2-one in 3-n sodium hydroxide, refluxed under nitrogen, distilling off water in vacuo and isolating the product by trituration in an organic solvent.

17 74457

Example 8

Ethyl 2-amino-3- (4-methylthiobenzoyl) phenyl acetate 17 g (0.05 mol) of sodium 2-amino-3- (4-methylthiobenzoyl) phenylacetic acid monohydrate are dissolved in approximately 150 ml of dimethylformamide and the solution is treated with 33 g of ethyl iodide. The solution is stirred at room temperature for 2.5 hours and added to water and the mixture is extracted several times with benzene. The combined benzene extracts are washed with dilute base and water, dried over sodium sulfate and concentrated to give the title compound.

Example 9

Sodium 2-amino-3- (4-methylthiobenzyl) -5-fluorophenylacetic acid Using the procedure of Example 4, but starting from 7- (4-methylindenzoyl) -5-fluoroindoline-2 -one was obtained as sodium 2-amino-3- (4-methylthiobenzoyl) -5-fluorophenylacetic acid as a yellow powder, m.p. 241-244 C. Example 10

Sodium 2-amino-3- (4-methylthiobenzoyl) -5-methylphenylacetic acid Using the procedure of Example 4, but starting from 7- (4-methylthiobenzoyl) -5-methylindolin-2- onion, sodium 2-amino-3- (4-methylthiobenzoyl) -5-methylphenylacetic acid was obtained in the form of an orange-yellow powder, m.p. 225-260 ° C.

Example 11

Sodium 2-amino-3- (4-methylthiobenzoyl) -5-chlorophenylacetic acid Using the procedure of Example 4, but starting from 7- (4-methylthiobenzoyl-5-chloroindoline) 2-one, gave 2-amino-3- (4-methylthiobenzoyl) -5-chloro phenylacetic acid as a yellow solid, mp 259-2600 ° C.

74457 18 Prescription and Form of Administration This invention also relates to novel preparations containing the compounds of the invention as active ingredients. Effective amounts of any of the above pharmacologically active compounds may be administered to a living animal body by any of a variety of routes, for example, orally such as 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 formulations of this invention, the active ingredient is incorporated into a suitable carrier, typically a pharmaceutical carrier. Suitable pharmaceutical carriers useful in forming the compositions of this invention include starch, gelatin, glucose, magnesium carbonate, lactose, malt, etc. Liquid preparations are also within the scope of this invention and suitable liquid pharmaceutical carriers include ethyl alcohol, propylene glycol, glycol, glycol.

The pharmacologically active compounds can be advantageously used in unit doses of 0.1 to 150 milligrams. The unit dose may be administered once daily or in multiple or divided daily doses. The daily dose can range from 0.3 to 450 mg. 5-25 mg proves to be optimal per unit dose.

It is only necessary that the active ingredient form an effective amount, i.e., so as to obtain a suitable effective dose consistent with the dosage form employed. Accurate individual doses as well as daily doses will, of course, be determined in accordance with standard medical principles under the supervision of a physician or veterinarian.

The active ingredients of the invention may be combined with other pharmacologically active substances or buffers, acid-binding agents, etc., for administration to a patient, and the ratio of active substance in the preparation may be varied widely.

The following are examples of preparations formed in accordance with this invention: 1. Capsules

Capsules containing 5 mg, 25 mg and 50 mg of active ingredient per capsule are prepared. With larger amounts of active ingredient, the adjustment can be performed in the amount of lactose.

Typical mixture Per capsule for encapsulation mg_

Active ingredient 5.0

Lactose 296.7 Of starch 129.0

Magnesium stearate 4.3

A total of 435.0 mg

Other capsule recipes preferably contain a higher dose of active ingredient and are as follows:

Ingredients Per capsule, mg

Active ingredient 25.0

Lactose 306.5 Of starch 99.2

Magnesium stearate 4.3

A total of 435.0 mg

In all cases, the selected ingredient is uniformly mixed with lactose, starch and magnesium stearate and the mixture is encapsulated.

2. Tablets

The following is a typical recipe for a tablet containing 5.0 mg of active ingredient per tablet. The prescription can be used for other strengths of the active ingredient by adjusting the weight of the dicalcium phosphate.

20 7 4 4 5 7

Per tablet, mg (1) Active ingredient 5.0 (2) Maize starch 13.6 (3) Maize starch (pasta) 3.4 (4) Lactose 79.2 (5) Dicalcium phosphate 68.0 (6) Calcium stearate 0.9 170.1 mg

Mix evenly 1, 2, 4 and 5. Prepare 3 to 10% pasta in water. Granulate the mixture with starch paste and pass the moist mass through an eight-mesh sieve. The wet granule slab is dried and screened through a twelve mesh screen. The dried granules are mixed with calcium hydrate and compressed.

3. Sterile injectable 2% solutions 3

Per cm

Active ingredient 20 mg Preservative, eg chlorobutanol 0.5% w / v

Brown water q.s.

Prepare the solution, clarify by filtration, fill into glass flasks, seal and autoclave.

Various modifications and equivalents will be apparent to those skilled in the art and may be made to the compounds, preparations and methods of this invention without departing from its spirit or scope, and it is therefore to be understood that the invention is limited only by the appended claims.

Claims (6)

21 74457 Patent Requirements A process for the preparation of 2-amino-3- (alkylthiobenzoyl) phenylacetic acid for use as a medicament of the formula 2-amino-3- (alkyl-thiobenzoyl) phenyl-acetic acid Wherein R is a hydrogen atom, a lower alkyl or a pharmaceutically acceptable metal cation and R is a hydrogen atom, a halogen or a lower alkyl, characterized in that the compound of formula 2 R. H in H 11 c = o H __-S-lower alkyl 2 wherein R is as defined above, is hydrolysed with an alkali metal base and, if desired, the resulting alkali metal salt of formula I is converted to the free acid, optionally alkylated with an alkali metal salt of formula I to a compound of formula I wherein R is lower alkyl. Process according to Claim 1, characterized in that 2-amino-3- (4-methylthiobenzoyl) -phenylacetic acid is prepared. Process according to Claim 1, characterized in that sodium 2-amino-3- (4-methylthiobenzoyl) phenylacetic acid monohydrate is prepared. An intermediate for the preparation of 2-amino-3- (alkylthiobenzoyl) -phenylacetic acid of the formula -CH COOR rZ-Oc-nh2 I c = o I "- S-ali al a alkyl wherein R is a hydrogen atom, lower alkyl or a pharmaceutically acceptable metal cation and R is a hydrogen atom, halogen or lower alkyl, characterized in that the intermediate is a compound of formula 2 R 1 H 2 or -HH C = 0 H 11 f --- S-lower kyl i 2 where R has the same meaning as above 23 7 4 4 5 7 Intermediate according to Claim 4, characterized in that it is 7- (4-methylthiobenzoyl) -indolin-2-one. A process for the preparation of 7- (alkylthiobenzoyl) -indolin-2-one having the formula 2 H ΝΛ I h ° C = 0 M II ---— S-lower alkyl wherein 2 R is a hydrogen atom, halogen or lower alkyl, characterized in that the compound of formula 2. H c = o H - F 2 wherein R is as defined above, is reacted with an alkali metal sulfide followed by acid hydrolysis. 74457 24