FI73970C - FOERFARANDE FOER FRAMSTAELLNING AV PHARMACEUTISKT AKTIVA 2-AMINO-3- (HALOBENSOYL) -METHYL-PHENYL ETHYL OCH ESTRAR OCH SALTER DAERAV. - Google Patents

Description

1 73970

This invention relates to a process for the preparation of certain novel 2-amino-3- (halobenzoyl) methylphenylacetic acids and their alkyl esters and metal salts. preparation.

Certain 2-amino-3- (5- and 6) benzoylphenylacetic acids having various substituents on the benzoyl and phenyl moieties and methods for their preparation and use are disclosed in U.S. Patent 4,045,576. The compounds of this U.S. patent are not methyltenylacetic acids or derivatives thereof.

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

The invention therefore relates to a process for the preparation of pharmaceutically active 2-amino-3- (halobenzoyl) methylphenylacetic acids or their esters or salts of the formula: CH-COOR / / 2 CHr. Q j '' '(/ XNH2 1 c = o I.

: O; <Y »wherein R is a hydrogen atom, a lower alkyl group or a pharmaceutically acceptable cation, Y is a halogen atom and n is an integer from 1 to 3.

The novel compounds of this invention have valuable pharmacological properties and are useful as pharmaceuticals. The compounds have excellent anti-inflammatory and analgesic activity in homogeneous animals with minimal gastrointestinal toxicity.

The term "lower alkyl" as used herein includes straight chained and branched chain radicals having up to six carbon atoms, preferably up to four carbon atoms, and exemplified by groups such as methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary. butyl, amyl, isoamyl and hexyl groups.

The term "halogen" as used herein includes chlorine, fluorine, bromine and iodine atoms.

Typical pharmaceutically acceptable metal cations include sodium, potassium, calcium, magnesium, zinc, aluminum, copper and hydrates thereof.

The compounds of formula I are prepared in such a way that 7-benzoyl-methyl-indolin-2-one of the formula -3-6-f

o = c H

I Oi (v> n ^ where Y and n have the same meaning as above are hydrolyzed in basic aqueous solution to form a salt of formula I, optionally acidified to form the corresponding acid and optionally converted to the metal salt, which if desired is reacted with an alkyl halide in a suitable solvent to form an alkyl ester.

The hydrolysis is preferably carried out at reflux temperature and ambient pressure.

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The starting compounds of formula II can be prepared by conventional methods, such as those described in the aforementioned U.S. Patents 4,045,576 and 4,221,716.

The preparation of the compounds of this invention is further illustrated by 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) -4,73970 5-methylindolin-2-one in 120 ml of 3-N sodium hydroxide was heated at reflux for 16 hours. After diluting the mixture to 300 ml with water, the solution was titrated at 50 ° C with concentrated hydrochloric acid to pH 8.2. The resulting orange solution was filtered and the resulting filtrate was cooled to 5 ° C and acidified to pH 4.5 with glacial acetic acid. The resulting yellow solid was collected and washed with water and then dissolved in methylene chloride. Water was added and the mixture was titrated with dilute sodium bicarbonate solution until pH 7.0 was maintained. The aqueous layer was separated and concentrated by azeotroping the water off with absolute ethyl alcohol. The resulting yellow powder was dissolved in isopropyl alcohol and one ml of water was added. After standing for 3 days, the resulting yellow solid was collected and dried at 25 ° C under high vacuum for 2 days to give 1.6 g (16.5% yield) of the title compound as a yellow powder, m.p. 160 ° C.

Analysis: Calculated from the formula C 18 H 28 FNO 3 Na * H 2 O: ^ 58.72; H 4.62; N 4.28 found C 58.71; H 4.68; N 4.26 Example 2

Preparation of sodium 2-amino-3- (4-chlorobenzoyl) -5-methylphenylacetate___

Following the procedure of Example 1, a mixture of 11.5 g (0.04 mol) of 7- (4-chlorobenzoyl) -5-methylindolin-2-one and 160 ml of 3-N sodium hydroxide gave, after recrystallization, 2 g of water. .5 g (18%) of the title compound as orange needles, m.p. 262 ° C.

Analysis: Calculated from the formula C 1-6 -H-, H 4.02; N 4.30 Found C 58.42; H 4.09; N 4.32

Example 3

Preparation of sodium 2-amino-3- (2,4-dichlorobenzoyl) -5-methylphenyl acetate_ 73970

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

Example 4

Preparation of sodium 2-amino-3- (2,3,5-trichlorobenzoyl) -6-methylphenyl acetate

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

Example 5

Preparation of sodium 2-amino-3- (4-chlorobenzoyl) -4-methylphenylacetate__

Following the procedure of Example 1, a mixture of 4-chloro-benzoyl-6-methyl-indolin-2-one and 3-N-sodium hydroxide affords the title compound.

In general, prior to this, strong anti-inflammatory drugs have been found to produce serious side effects, such as gastric bleeding and ulceration, when administered orally to animals in an effective amount. The compounds of this invention have been found to have the advantage of being found to reduce the incidence of abdominal irritation when administered in an amount effective to reduce inflammation compared to indomethacin and 2-amino-3-benzoylphenylacetic acids and their derivatives disclosed in U.S. Patent 4,045,576. sodium 2-amino-3- (4-chlorobenzoyl) -5-methylphenylacetate was found to be approximately twice as potent as indomethacin and sodium 2-amino-3-benzoylphenylacetate, but showed approximately 1/4 as much gastric irritation than indomethacin and about 1/2 as much abdominal irritation as sodium 2-amino-3-benzoyl-phenylacetate. The compound of Example 2 was found to have about 1/2 the potency of sodium 2-amino-3- (4-chlorobenzoyl) -5-fluorophenyl acetate, but surprisingly showed about 1/4 as much stomach irritation as this compound.

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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 (1968).

Gastric toxicity was determined by a modification of the method of Tsukada et al., Arzneim.

Forsch. 28: 428-438 (1978).

The compounds of this invention also function as analgesics as prescribed by a modification of the method of Collier et al., Brit. J. Pharmacol. Chemother. 32: 295-310 (1968).

Drug Formulation and Administration The present invention also contemplates novel formulations containing the compounds of the invention as active ingredients. Effective amounts of any of the aforementioned pharmacologically active compounds may be administered to a living animal body by any means, for example orally, such 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 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, glycerin, glycerin.

The pharmacologically active compounds can be advantageously used in unit doses of 0.1 to 150 milligrams. The unit dose of 73970 may be administered once daily or in multiple or divided daily doses. The daily dose can vary between 0. 3-450 mg. 5-25 mg proves to be optimal per unit dose.

It is only necessary that the active ingredient constitute an effective amount, i.e., such that a suitable effective dose is obtained in accordance with the dosage form employed. The exact individual doses as well as the daily doses will, of course, be determined according to standard pharmacological principles under the guidance of a physician or veterinarian.

The active agents of the invention may be combined with other pharmacologically active agents or buffers, acid scavengers, and the like for administration to a patient, and the amount of active agent in the mixture may be varied widely.

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

1. Capsules

Capsules are prepared containing 5 mg, 25 mg and 50 mg of active ingredient per capsule. With higher amounts of active ingredient, a check can be made on the amount of lactose.

Typical encapsulated Per capsule, mixture__ _mg_

Active ingredient 5.0

Lactose 296.7 Of starch 129.0

Magnesium stearate 4.3

A total of 435.0 mg

Supplementary capsule prescriptions preferably contain a higher dose of active ingredient and are as follows: 73970

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 either case, the selected active ingredient is 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 checking the weight of the dicalcium phosphate.

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 1, 2, 4 and 5 evenly. Prepare 3 to 10% pasta in water. Granulate the mixture with starch paste and pass the wet mass through an 8 mesh screen. The wet granulate is dried and sieved through a 12 mesh screen. The dry granules are mixed with calcium stearate and compressed into tablets.

3. Injectable 2% sterile solutions per 3 cm

Active ingredient 20 mg Preservative, e.g. chlorobutanol 0.5% w / v Water for injection q.s.

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Prepare the solution, clarify by filtration, fill into bottles, 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 (7)

73970 A process for the preparation of pharmaceutically active 2-amino-3- (halobenzoyl) methylphenylacetic acids or their esters or salts of the formula: wherein R is a hydrogen atom , a lower alkyl group or a pharmaceutically acceptable cation, Y is a halogen atom and n is an integer from 1 to 3, characterized in that 7-benzoyl-methylindolin-2-one of the formula CH3-f0] h 0 = CH έ ( Y) n wherein Y and n are as defined above is hydrolysed in basic aqueous solution to form a salt of formula I, optionally acidified to form the corresponding acid and optionally converted to the metal salt, which if desired is reacted with an alkyl halide in a suitable solvent to form an alkyl ester. Process according to Claim 1, characterized in that 2-amino-3- (4-fluorobenzoyl) -5-methylphenylacetic acid is prepared. 73970 Process according to Claim 1, characterized in that sodium 2-amino-3- (4-fluorobenzoyl) -5-methylphenylacetate monohydrate is prepared. Process according to Claim 1, characterized in that 2-amino-3- (4-chlorobenzoyl) -5-methylphenylacetic acid is prepared. Process according to Claim 1, characterized in that sodium 2-amino-3- (4-chlorobenzoyl) -5-methylphenylacetate is prepared. A process for the preparation of a pharmaceutically active compound 2-amino-3- (halobenzoyl) -methyl-phenylacetyl or an ester or a salt of the formulation (CH_COOR U nh2 ip) in halogen and in 1-3, 7-benzoyl-methyl-indolin-2-one with the formula "3-61 i". i 0 = CH <Y) n ^ II