DK155936B - METHOD OF ANALOGY FOR THE PREPARATION OF 2-AMINO-3- (HALOGENBENZOYL) -METHYLPHENYL ACID ACID ACIDS OR ALKYL ESTERS OR METAL SALTS THEREOF - Google Patents

Description

in

DK 155936 B

The present invention relates to an analogous process for the preparation of novel 2-amino-3- (halo-benzoyl) methylphenylacetic acids or alkyl esters or metal salts thereof.

Certain 2-amino-3- (5 and 6) benzoylphenylacetic acids with various substituents in the benzyl and phenyl group and methods for their preparation and use are described in U.S. Patent No. 4,045,576. The compounds of this patent are not methylphenylacetic acids or derivatives thereof.

U.S. Patent 4,221,716 discloses a process for preparing 7-acylindolin-2-ones which are intermediates in the preparation of the compounds of the present invention.

More particularly, the invention relates to an analog promotion

Procedure for Preparation of 2-Amino-3- (Halogenobenzoyl) - Methylphenylacetic Acids or Alkyl Esters or Metal Salts of Formula I

20 ClfeCOOR

CH3 rC_) I

Wherein R is selected from hydrogen, lower alkyl and a pharmaceutically acceptable metal cation, Y is halogen and n is an integer of 1 to 3, and the process is characterized in that a 7-benzoylmethyl-indolin-2-one of the formula

DK 155936 B

2 Μδη

0 = C H

5 JL

wherein 10 Y and n are as defined above are hydrolyzed in aqueous basic solution to form a salt of an acid of formula I, optionally reacted with an acid to form a free acid of formula I, whereupon this free acid is optionally converted to a metal salt thereof optionally reacted in a suitable solvent having a lower alkyl halide to form an alkyl ester of formula I.

The novel compounds of the present invention have valuable pharmacological properties and are useful as 20 pharmaceutical agents. The compounds exhibit excellent anti-inflammatory and analgesic action in warm-blooded animals with minimal gastrointestinal toxicity.

In the definition of symbols in the formulas herein and where they otherwise appear in the description, the terms used 25 have the following meaning.

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

The term "halogen" includes chlorine, fluorine, bromine and iodine.

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

The 7-benzoylmethylindolin-2-ones of the formula

DK 155936 B

3

0 = C H

β n used as starting compounds can be prepared by 10 conventional methods, e.g. as disclosed in U.S. Patent Nos. 4,045,576 and 4,221,716.

In general, strong anti-inflammatory drugs have so far been shown to cause serious adverse effects in the form of bleeding and ulceration of the stomach when administered orally to animals in an amount in the effective range. The compounds of the invention have been found to have the advantage of a lower incidence of gastric irritation when administered in an amount in the effective range to reduce inflammation, as compared to 20 indomethacin and 2-amino-3- benzoylphenylacetic acids and their derivatives described in U.S. Patent No. 4,045,576.

For example, the compound prepared according to Example 2, sodium 2-amino-3- (4-chlorobenzoyl) -5-methylphenyl acetate, is found to be approx. 2 times as effective as indomethacin and sodium-2-amino-3-benzoylphenyl acetate, but exhibits approx. 1/4 of the irritating effect of indomethacin on the stomach and approx. 1/2 of the irritating effect of sodium 2-amino-3-benzoylphenyl acetate on the stomach. The compound prepared according to Example 2 is found to be approx. 1/2 times as effective as sodium 2-30-amino-3- (4-chlorobenzoyl) -5-fluorophenyl acetate, but surprisingly exhibits approx. 1/4 of this compound's irritating effect on the stomach.

The anti-inflammatory effect is demonstrated in laboratory animals using a modification of the "Evans 35 Blue-Carageenan Pleural Effusion Assay" according to L.F. Sancilio, J. Pharmacol. Exp. Ther. 168. 199-204 (1969).

4 I

DK 155936B

The gastric toxicity is determined by a modification of the method of Tsukada et al., Arzneim. Forsch. 28, 428-438 (1978).

The compounds of the invention also act as analgesics as determined by a modification of the method of Collier et al., Brit. J. Pharmacol. Chemother.

32, 295-310 (1968).

The compounds of the invention can be administered in any of various ways, e.g.

10 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 the preparation of compositions of the compounds, the active ingredient is incorporated into a suitable carrier, e.g. a pharmaceutical carrier.

Suitable pharmaceutical carriers which may be used to prepare the compositions are, for example, starch, gelatin, glucose, magnesium carbonate, lactose and malt. Liquid preparations are prepared by suitable liquid pharmaceutical carriers, e.g. ethyl alcohol, propylene glycol, glycerol and glucose syrup.

The pharmacologically active compounds can advantageously be used in a unit dosage of 0.1 to 150 mg. 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 to 25 mg seems to be optimal per day. unit dose.

It is only necessary that the active ingredient constitute an effective amount, ie. so that a suitable effective dosage is obtained corresponding to the dosage form used.

The exact individual dosages as well as the daily doses will, of course, be determined according to common medical principles by a physician or veterinarian.

The present active ingredients may be combined with other pharmacologically active agents or with buffers, antacids or the like for administration, and the proportion of the active ingredient in the composition may be varied within

DK 155936 B

5 limits.

The preparation of the compounds of the invention is further illustrated in the following examples.

Example 1

Preparation of sodium 2-amino-3- (4-fluorobenzoyl) -5-methylphenyl acetate monohydrate.

A mixture of 8.0 g (0.03 mol) of 7- (4-fluorobenzoyl) -5-methylindolin-2-one in 120 ml of 3N sodium hydroxide is heated to reflux for 16 hours. After dilution with water to 300 ml, the solution is titrated at a temperature of 50 ° C with concentrated hydrochloric acid to a pH of 8.2. The resulting orange solution is filtered and the resulting filtrate is cooled to 5 ° C and acidified to a pH of 4.5 with 15 glacial acetic acid. The resulting yellow solid is separated and washed with water and then dissolved in methylene chloride. Water is added and the mixture is titrated with dilute sodium bicarbonate solution until a pH of 7.0 is maintained. The aqueous layer is separated and concentrated by removing the water by azeotropic distillation with absolute ethyl alcohol. The resulting yellow powder is dissolved in isopropyl alcohol and 1 ml of water is added. After standing the mixture for 3 days, the resulting yellow solid is separated and dried at 25 ° C under high vacuum for 2 days to give 25 g (a 16.5% yield) of the title compound as a yellow powder with a yellow powder. mp 140-160 ° C.

Analysis for C 16 H 13 FN 2> 3 Na, H 2 O: C% H% N% Calc'd: 58.72 4.62 4.28 Found: 58.71 4.68 4.26

Example 2

Preparation of sodium 2-amino-3- (4-chlorobenzoyl) -5-methylphenyl acetate.

In the procedure of Example 1, a mixture of 11.5 g (0.04 mole) of 7- (4-chlorobenzoyl) -5

DK 155936 B

6 lin-2-one and 160 ml of 3N sodium hydroxide after recrystallization from water 2.5 g (18%) of the title compound as orange needles with m.p. 262 ° C.

Analysis for C ^ gH ^ClNO ^ Na: 5 C% H% N% Calc'd: 59.00 4.02 4.30 Found: 58.82 4.09 4.32

Example 3 Preparation of sodium 2-amino-3- (2,4-dichlorobenzoyl) -5-methylphenyl acetate.

In the procedure of Example 1, a mixture of 7- (2,4-dichlorobenzoyl) -5-methylindolin-2-one and 3N sodium hydroxide gives the above compound.

15

Example 4

Preparation of sodium 2-amino-3- (2,3,5-trichloro-benzoyl) -6-methylphenyl acetate.

In the procedure of Example 1, a mixture of 7- (2,3,5-trichlorobenzoyl) -4-methylindolin-2-one and 3N sodium hydroxide gives the above compound.

Example 5

Preparation of sodium 2-amino-3- (4-chlorobenzoyl) -25 -4-methylphenyl acetate.

In the procedure of Example 1, a mixture of 4-chlorobenzoyl-6-methylindolin-2-one and 3N sodium hydroxide gives the above compound.

Examples of compositions of the compounds of the present invention are given below.

7

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ISLAND

'First capsules

Capsules are prepared with 5, 25 and 50 mg of active ingredient per ml. capsule. At the higher levels of active ingredient, the amount of lactose can be changed.

5 Typical mixture for capsules Pr. capsule, mg of active ingredient 5.0 lactose 296.7 starch 129.0 magnesium stearate 4.3 total 435.0 mg

Other capsule preparations preferably have a higher dose of active ingredient and have the following composition: Ingredients Pr. capsule, mg of active ingredient 25.0 15 lactose 306.5 starch 99.2 magnesium stearate 4.3 total 435.0 mg In each case, the selected active ingredient is mixed uniformly with lactose, starch and magnesium stearate and the mixture is filled into capsules .

2. Tablets

A typical preparation for tablets containing 5.0 mg of active ingredient per day. tablet is given below.

The composition can be used with other strengths of active ingredient by changing the amount of dicalcium phosphate.

Pr. tablet, mg (1) active ingredient 5.0 (2) corn starch 13.6 (3) corn starch (paste) 3.4 (4) lactose 79.2 (5) dicalcium phosphate 68.0 (6) calcium stearate 0.9 a total of 170.1 mg and 1, 2, 4 and 5 are mixed evenly. 3 is prepared as a 10% paste in water. The mixture is granulated with starch

. DK 155936 B

8 paste and the wet mass is passed through an 8 mesh sieve.

The wet granules are dried and sieved through a 12 mesh sieve. The dried granules are mixed with calcium stearate and pressed.

3. Injectable 2% sterile solution.

_ 3

Pr. cm active ingredient 20 mg of preservative, e.g.

chlorobutanol 0.5% (w / v) water for injection q.s.

The solution is prepared, clarified by filtration, filled into ampoules, sealed and autoclaved.

Claims (1)

DK 155936B O Analogous process for the preparation of 2-amino-3- (halo-benzoyl) -methylphenylacetic acids or alkyl esters or metal salts thereof of the formula I 5 and a pharmaceutically acceptable metal cation, Y is halogen, and n is an integer from 1 to 3, characterized in that a 7-benzoylmethylindolin-20 -2-one of the formula 0 = CH (YJ n wherein Y and n have the above, is hydrolyzed in aqueous basic solution to form a salt of an acid of formula I, optionally reacted with an acid to form a free acid of formula I, and then this free acid is optionally converted to a metal salt thereof, which optionally reacting in a suitable solvent 35 having a lower alkyl halide to form an alkyl ester of formula I.