NO150080B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-AMINO-3- (ALKYLTHIOBENZOYL) -PHENYLEDOIC ACID DERIVATIVES - Google Patents

Description

The present invention relates to an analogous process for the production of certain new therapeutically active 2-amino-3-benzoylphenylacetic acids with alkylthio substitution on the benzoyl group, and their metal salts, which are suitable for use in pharmaceutical preparations.

Certain 2-amino-3-(5- and 6-)-benzoylphenylacetic acids whose benzoyl group is substituted with lower alkyl, halogen, nitro and trifluoromethyl and methods for their preparation and use are disclosed in U.S. Pat. patent 4 045 576. The compounds produced according to the present invention cannot be produced by the methods specified there.

The present invention relates more specifically to manufacturing. none of 2-amino-3-(alkylthiobenzoyl)-phenylacetic acids

and metal salts thereof, with the formula:

where

R is hydrogen or a pharmaceutically acceptable metal cation, and

R 2 is hydrogen, halogen or lower alkyl.

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

Certain new intermediates, the 7-(S-lower alkylthiobenzoyl)-indolin-2-ones, have the formula:

where R 2 is as stated above.

The anti-inflammatory activity was demonstrated in laboratory animals using a modification of the Evans Blue Carrageenan Pleural Effusion Assay of Sancilio,

LF, J. Pharmacol. Exp. Ther. 168, 199-204 (1969). The compounds of formula I as inhibitors of platelet aggregation show this property by reducing platelet aggregation as described by Born, J. of Phys. 162, 67-68 (1962) and Evans et al, J. of Expt. With. 128, 877-894 (1968). Rats were administered orally with experimental drugs, and after 2 hours the rats were bled, and a platelet-rich plasma was retained. 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 I also act as analgesics as determined by the Bradykinin Analgesic Test method according to Dickerson et al, Life Sci. 4, 2063-2069 (1965) as modified by Sancilio and Cheung, Fed. Pro. 35, 774 (1976).

It is therefore an aim of the present invention to provide new therapeutically active compounds for the treatment of living animal bodies, and in particular mammalian bodies to alleviate inflammation and pain, and inhibit platelet aggregation with a minimum of unwanted side effects.

The method compounds include the compounds of formula I.

In the definition of the symbols in the formulas, the expressions have the following meaning.

The term "lower alkyl" is used to include straight-chain and branched groups with up to 6 carbon atoms, preferably no more than 4 carbon atoms, and exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, amyl, isoamyl and hexyl.

The term "halogen" is used to denote chlorine, fluorine, bromine and iodine.

Examples of pharmaceutically acceptable salts are the sodium, potassium, calcium, magnesium, zinc and copper salts, and the hydrates thereof.

The fluorobenzoylindolin-2-ones used as starting materials in the present method can be prepared by one or more of the methods described in US patent 4,045,576. A method indicated there begins with the reaction of 2-amino-4'-halobenzoylbenzophenone with ethyl-methylthioacetate, t-BuOCl and Et^N to give 7-(halobenzoyl)-3-methylthioindolin-2-ones which are then reduced with Raney nickel to form the 7-(halobenzoyl)-3-indolin-2-ones. A modification of this method was used in which Raney nickel was replaced by tin powder in alcohol and concentrated hydrochloric acid. The following equation illustrates the preparation of 7-(fluorobenzoyl)-indolin-2-ones used to prepare the process compounds:

The preparation of the process compounds is by reacting fluorobenzoyl-indolin-2-ones with alkali metal alkyl sulfide, followed by acid hydrolysis to obtain the 7-(alkylthio-benzoyl)-indolin-2-ones which are hydrolyzed with alkali metal base to obtain the alkali metal salts of 2 -amino-3-(alkylthio-benzoyl)-phenylacetic acids. The following reaction scheme illustrates the preparation of the alkali metal salts of the compounds of formula I:

To obtain the free acid (R<1> = H) from the alkali metal salt, acetic acid is carefully added to an aqueous solution of the salt, causing the free acid to precipitate. The free acid is then separated by filtration, washed with water and dried. Example 1 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 heated under reflux 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 with tetrahydrofuran. The precipitate was again separated by filtration, dried and recrystallized from 95% ethanol, whereby 4.9 g (83%) of bright yellow needles with m.p. 244-247 C. Analysis: Calculated for C16<H1>6N04SNa: C 56.30; H 4.72; N 4.10

Found: C 56.38; H 4.62; N 4.17

Example 2

By using the method in example 1, but by replacing 7-(4-methylthiobenzoyl)-indolin-2-one with an equimolar amount of the following compounds: 7-(4-methylthiobenzoyl)-5-methylindolin-2-one/ 7-(4-methylthiobenzoyl)-5-chloroindolin-2-one,

7-(4-methylthiobenzoyl)-5-fluoroindolin-2-one,

obtained respectively: sodium 2-amino-3-(4-methylthiobenzoyl)-5-methylphenyl-acetic acid, m.p. 225-260°C,

sodium 2-amino-3-(4-methylthiobenzoyl)-5-chlorophenyl-acetic acid, m.p. 259-260°C,

sodium 2-amino-3-(4-methylthiobenzoyl)-5-fluorophenyl-acetic acid, m.p. 241-244°C.

The reaction conditions used for the preparation of the fluoro-benzoylindolin-2-one starting materials are illustrated more particularly in the following preparation methods.

Production of starting materials

Method 1

7-(4-methylthiobenzoyl)-indolin-2-one

A solution of sodium methyl mercaptide, prepared from 400 ml of 3N sodium hydroxide and 24 g (0.5 mol) of methyl sulfide, was mixed with 25.5 g (0.1 mol) of 7-(4-fluorobenzoyl)-indolin-2-one . The mixture was refluxed for 1.5 hours, cooled and acidified (caution, much methyl sulphide is rapidly developed). The precipitate formed was collected and recrystallized twice from benzene to give 17.8 g (70%) as yellow crystals, m.p. 167.0-169.0°C.

Analysis: Calculated for C16H13<N>02S: C 67.82; H 4.63; N 4.94

Found: C 67.65; H 4.63; N 4.91.

Method 2

7-(4-fluorobenzoyl)-3-methylthioindolin-2-one

A solution of 42.2 g (0.196 mol) of 2-amino-4'-fluoro-benzophenone in 2 L of methylene chloride was cooled to -65°C, and

26.5 g (0.198 mol) of ethyl methyl thioacetate was added. A solution of 23.0 g (0.21 mol) of 95% t-butoxychloride in 50 ml of methylene chloride was added dropwise, keeping the temperature below -65°C. 1 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 evaporated to 700 ml and then washed with water. The organic solution was concentrated and the residue dissolved in 400 ml of methanol containing 30 ml of concentrated hydrochloric acid. The mixture was heated under reflux for 1 hour followed by cooling. The mixture was allowed to stand overnight, the crystals were collected and washed with methanol to give 31.4. g (53%) as a bright yellow solid with m.p. 165-167.5°C.

Analysis: Calculated for C 2 H NO 2 FS: C 63.77; H 4.01; N 4.65

Found: C 63.58; H 4.11; N 4.67

Method 3

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

A solution of 86 g (0.4 mol) of 2-amino-2'-fluorobenzophenone in 3 L of methylene chloride was cooled to -65°C, and 54 g (0.4 mol) of ethyl methylthioacetate was added. A solution of 46 g (0.42 mol) of 95% t-butoxychloride in 100 ml of methylene chloride was added dropwise while maintaining the temperature below

-65°C. 1 hour after the addition was finished, 41 g (0.4 mol) of triethylamine was added dropwise, and the mixture was allowed to warm to room temperature. The resolution was

evaporated to approx. 1400 ml and then washed with water. The organic solution was evaporated, and the residue was dissolved in 800 ml of methanol containing 60 ml of concentrated hydrochloric acid. The mixture was heated under reflux for 1 hour followed by cooling. The mixture stood overnight, then the crystals were collected and recrystallized from 20% aqueous ethanol, whereby 66 g (55%) pale yellow needles with m.p. 147.0-148.5°C.

Analysis: Calculated for C16<H>12<N0>2FS: C 63.77; H 4.01; N 4.65

Found: C 63.97; H 4.19; N 4.66

Method 4

7-(4-fluorobenzoyl)-indolin-2-one

A mixture of 40.0 g (0.133 mol) 7-(4-fluorobenzoyl)-3-methylthioindolin-2-one and 40.0 g (0.34 mol) tin powder in 1 liter of 95% ethanol was heated under reflux , and 100 ml of concentrated hydrochloric acid was added. The mixture was heated for 6 hours and then filtered while hot. The filtrate was cooled, and the precipitate was collected and recrystallized from isopropyl alcohol, whereby 24.5 g (72%) of off-white needles with m.p. 185-187.0°C.

Analysis: Calculated for C15<H>10N02F: C 70.58; H 3.95; N 5.49

Found: C 70.80; H 4.12; N 5.51

Method 5 7-(2-fluorobenzoyl)-indolin-2-one

A mixture of 60 g (0.2 mol) 7-(2-fluorobenzoyl)-3-methylthioindolin-2-one and 60 g (0.5 mol) tin powder in 1 liter 95% ethanol was heated under reflux, and 150 ml of concentrated hydrochloric acid was added. Heating was continued for 18 hours, then the mixture was cooled and the precipitate was collected by decanting the slurry from the remaining tin and filtering the slurry. The filter cake was recrystallized twice from absolute ethanol, whereby 31 g (60%) of white needles with m.p. 209-210°C.

Analysis: Calculated for C15H10N02F: C 70.58; H 3.95; N 5.49

Found: C 70.31; H 4.08; N 5.56

Fasted male Charles River albino rats weighing over 250 g were used. Each control and experimental group consisted of 6 animals. The groups and animals were selected by random methods. The compounds were administered by intra-gastric intubation (10 ml/kg) as a solution or a suspension in 0.5% Tween^80. The control group received the medium. 1 hour after administration of the compounds, the rats were treated with ether and 5 ml of a mild irritant solution (0.075% Evans Blue and 0.5% carrageenan) was administered intra-pleurally. 5 hours later, the animals were euthanized with chloroform or carbon dioxide. The pleural fluids were collected and measured in calibrated centrifuge tubes.

The results are shown in the following table and are expressed as the average percentage reduction in the volume of pleural fluid compared to that in the control group. "Pleural Effusion Tests" (anti-inflammatory) by the method indicated on page 2, lines 10-13 of the description, gave the following results:

Effective amounts of the pharmacologically active method compounds can be administered to a living animal body in a number of different ways, e.g. 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. When preparing preparations, the active ingredient is incorporated into a suitable carrier, e.g. a pharmaceutical carrier. Suitable pharmaceutical carriers useful in the preparation of the preparations containing the process compounds include starch, gelatin, glucose, magnesium carbonate, lactose, malt and the like. For liquid preparations, suitable liquid pharmaceutical carriers including ethyl alcohol, propylene glycol, glycerol, glucose syrup and the like are used.

The pharmacologically active compounds produced according to the invention can advantageously be used in a unit dose of from 0.1 to 150 mg. The unit dose may be administered once daily or in multiple or divided daily doses. The daily dose can vary from 0.3 to 450 mg. 5 - 25 mg seems to

be optimal per unit dose.

It is only necessary that the active ingredient constitutes an effective amount, i.e. so that a suitable effective dose is obtained uniformly in the dosage form used. The exact individual dose as well as the daily doses will of course have to be determined according to normal medical principles under the guidance of a doctor or veterinarian.

The active process compounds can be combined with other pharmacologically active agents, or with buffers, antacids and the like, for administration, and the amount of the active agent in the preparation can vary greatly.

Claims (1)

Analogous procedure in the preparation of therapeutically active compounds with the general formula: wherein R"<*>" is hydrogen or a pharmaceutically acceptable metal cation, and R 2 is hydrogen, halogen or lower alkyl, characterized in that a compound with the formula: where R 2 is as indicated above, is hydrolyzed with an alkali metal base, and if the free acid is desired, the obtained metal salt of formula I is neutralized with an acid to transfer R"*" to hydrogen.