DK154136B - METHOD OF ANALOGUE FOR THE PREPARATION OF 2-AMINO-3-BENZOYLPHENYLACETAMIDES - Google Patents

Description

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The present invention relates to an analogous process for the preparation of certain novel 2-amino-3-benzoylphenylacetamides with pharmacological properties. The compounds are anti-inflammatory, antipyretic, analgesic and platelet aggregation inhibitory and at the same time exhibit minimal undesirable side effects of gastric mucosa irritation following oral administration to live animals, including humans.

2-Amino-3-benzoylphenylacetic acids, esters and metal salts thereof with anti-inflammatory activity and platelet aggregation inhibitory properties are known from U.S. Patent No. 4,045,576.

From South African Patent Specification No. 68/4682, generic benzoylphenylacetamides with several different substituents are known in undetermined positions on the phenyl nucleus. However, none of the compounds specifically described therein are amino-phenylacetamides.

In general, strong anti-inflammatory drugs have so far been shown to produce severe adverse reactions to gastric bleeding and gastric ulcer when administered orally to animals within the effective dosing range. Therefore, it should be considered surprising when the compounds prepared by the process of the present invention have now been found to have the particular advantage of presenting extremely low incidence of stomach irritation when administered within that range. , which is effective in reducing or reducing inflammation, compared to indomethacin (1- (4-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid) and those of U.S. Patent No. 4,045,576 described slightly less irritating 2-amino-3-benzoylphenylacetic acids.

Accordingly, the present invention relates to an analogous process for the preparation of novel 2-amino-3-benzoylphenylacetamides of the general formula

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2

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CH0-C-NH0 oc ™ 5 J-- T NH0 c = o wherein Y is hydrogen or halogen and n is an integer from 1 to 3 inclusive.

The novel compounds of formula (I) prepared by the process of the invention have valuable pharmacological properties and, when administered internally in effective amount of alleviate or reduce inflammation, alleviate pain in animals suffering from it, inhibit platelet aggregation, and fight temperature rise. in living animal bodies, while exhibiting minimal side effects compared to certain other potent anti-inflammatory agents. By way of illustration of the anti-inflammatory activity obtained simultaneously with minimal side effects, reference can be made to the compound prepared according to Example 3, namely 2-amino-3- (4-chlorobenzoyl) phenylacetamide, which has been found to offer approximately the same force or strength as indomethacin, but only to induce approx.

1/100 as much stomach irritation as indomethacin.

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The stomach irritant effect is determined by a modification of that of Tsukada et al. in Arzneim.Forsch. 28, 428--438 (1978). Male rats weighing between 200 and 350 g are used. The doses are expressed as free acid or free base. After killing the rats, their 30 stomach ulcers are examined. The results are listed in Table I using the following value scale:

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Value Description 0 No lesions 1 Few (1-3) small ulcers with diameter <3 mm 5 2 Many small ulcers 3 Few (2-3) large ulcers with diameter> 3 mm or length> 4-5 mm · 4 Many large ulcers 10

The results in Table I show that compound B is only approx. 0.16 times as stomach irritant as indomethacin, and compound D is about as irritating as B, while compound A is only approx. 1/10 as irritating as the corresponding ethyl ester, compound C.

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TABLE I

Gastric irritation

Toxic effect

Dose Sum of (95% reliable-

Compound (mg / kg) N value number Value level)

Control 0 8 0/8 0 0

Indomethacin 1.0 8 2/8 0.38 ± 0.74 1.0 3.0 8 1/8 0.25 ± 0.71 6.0 8 7/8 1.38 ± 0.74 9.0 8 7/8 1.88 ± 0.84

Conn. B 15.0 8 2/8 0.63 ± 1.41 0.16 45.0 8 1/8 0.13 ± 0.35 (approximate) 135.0 8 3/8 0.50 ± 0.76

Control 0 8 0/8 0 0

Indomethacin 1.0 8 1/8 0.13 ± 0.35 1.0 3.0 8 5/8 1.00 ± 0.93 6.0 8 5/8 0.88 in 0.84 9.0 8 6/8 1.50 ± 1.20

Conn. D 3.0 8 4/8 0.63 ± 0.74 0.93 9.0 8 7/8 1.15 ± 0.71 (0.47 - 2.41) 27.0 8 8/8 2.50 ± 1, 07

Control 0 7 0/7 0 0

Conn. A 6.0 7 0/7 0 1.0 15.0 7 1/7 0.14 ± 0.38 45.0 7 3/7 1.14 ± 1.68 135.0 7 7/7 3.57 ± 0.79

Conn. C 1.0 70/7 0 9.99 3.0 7 4/7 1.29 ± 1.25 (6.37 - 16.11) 6.0 7 6/7 1.71 ± 1.11 9.0 7 7/7 3 , 14 ± 0.90

Compound A: 2-Amino-3-benzoyl-phenylacetamide Compound B: 2-Amino-3- (4-chlorobenzoyl) phenylacetamide Compound C: Ethyl-2-amino-3-benzoylphenyl acetate Compound D: Sodium 2-amino-3- (4-chlorobenzoyl) phenyl acetate

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p

Furthermore, the compound of Example 1, 2-amino-3-benzoyl-phenylacetamide has been found to be approx. 8 times more effective as an anti-inflammatory agent than the corresponding 4-amino-3-benzoyl-phenylacetamide, while at the same time showing only 5 / 10th as much stomach irritation as the corresponding compound of U.S. Patent No. 4,045,576. , ethyl 2-amino-3-benzoylphenyl acetate.

The anti-inflammatory activity has been demonstrated in laboratory animals using modification of withdrawal 10 or leakage into the mesothelioma of Evans blue dye in the carrageenan as described by L.F. Sancilio in J. Pharmacol. Exp. Ther. 168, pp. 199-204 (1969).

The test results are shown in Table II below: 6

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TABLE II

Leakage in mesothelioma

Dose of lung wash

Compound (mg / kg) N (ml ± SD) Strength

Control 0 6 5.82 ± 0.35 0

Indomethacin 0.16 ± 5.84 ± 0.73 1.0 0.80 6 5.33 ± 0.53 4.0 6 3.97 ± 0.38

Conn. B 0.8 6 5.12 ± 0.50 0.79 4.0 6 4.25 ± 0.53 (0.41 - 1.82) 20.0 6 3.60 ± 0.30

Control 0 6 7.7 ± 0.53 0

Phenylbutazone 4.0 6 7.2 ± 0.77 1.0 20.0 6 6.7 + 0.60 100.0 6 5.1 ± 0.43

Conn. D 0.16 6 6.5 ± 0.40 94.5 0.80 6 5.5 ± 0.49 (49.7 - 209.9) 4.0 6 4.7 ± 0.42

Control 0 6 6.9 + 0.22 0

Phenylbutazone 10.0 6 6.5 + 0.49 1 31.6 6 4.9 ± 0.30 100.0 6 3.5 ± 0.17

Indomethacin 0.31 6 6.5 ± 0.44 26.9 1.00 6 5.3 ± 0.35 (15.3 - 43.5) 3.16 6 4.6 + 0.30

Compound B: 2-Amino-3- (4-chlorobenzoyl) phenylacetamide Compound D: Sodium 2-amino-3- (4-chlorobenzoyl) phenylacetate

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The compounds of formula (I) are found to inhibit platelet aggregation by that of Born in Journal of Physiology 162, pages 67-68 (1962) and Evans et al. in the Journal of Expt. With 5 pages 877-894 (1968) 5 test method described. The tested drugs are administered to rats and after 2 hours blood is drawn from the rats and platelet rich plasma is obtained. The collagen is added to the plate-rich plasma to induce plate aggregation, and comparisons are made between an untreated control and samples obtained from the drug-treated animals.

The compounds of formula (I) also act as analgesics as determined by the Bradykinin analgesic test method of Dickerson et al. in Life Sci. Volume 4, pages 2063-2069 (1965) as modified by Sancilio and 15 Cheung in the Fed. Proc. 35, page 774 (1976).

The antipyretic activity of the compounds is demonstrated by the lowering of the febrile response in hyperthermic animals without affecting the rectal temperature of normothermic animals. Hyperthermic response produced by subcutaneous injection of beer yeast in rats is overcome by oral administration of only as little as 4-8 mg / kg of the compounds of formula (I) and no significant change in rectal temperature in normothermic rats is observed.

Accordingly, the novel compounds prepared by the method of the invention serve, in particular, to treat live animals and especially mammals by administering medicaments containing these active compounds for the purpose of relieving inflammation and pain, inhibiting platelet aggregation, and treating fever. -30 pray with a minimum of undesirable side effects in the gastrointestinal tract.

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

The compounds of formula (I) are prepared by the process of the invention, characterized in that a 2-amino-3-benzoyl-α- (alkyl- or phenylthio) -phenyl-acetamide of formula 8

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SR3 I 9

CH.CNIL

s 9 ^ du c = o, 0 (Y) n

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wherein n and Y have the above meanings and R is C 1-6 alkyl or phenyl is reduced.

To illustrate the preparation of compounds of formula (I), the following reaction scheme, which includes the above reaction, is used: [f) l + R3SCH_.CNH_1) t-BuOCl

J UH .. 2, 2 s) Et3K

pn · 2 ir worm Ij.X

C = 0 ^ 7non ^ ca -70 C.

molds] IV methylene chloride solution | (Y | Ng) SR3 Γ I 0 (Y) n chl: nh2 o 25 O C ^ ych2-C-NH2 in NH2 Raney Ni „J = ° (THF) i = 0 2

ί ^ Λΐ formula I- formula I

Wherein Y and n are as defined above and R is C 1-6 alkyl or phenyl.

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The preparation of the compounds of formula (II) used as an intermediate is illustrated in more detail below. Generally, these intermediates are prepared by first reacting an appropriate 2-aminobenzophenone with 5 tert.butyl hypochlorite and an appropriate thioacetamide in the cold (-60 ° C to -70 ° C) followed by addition of triethylamine.

The intermediates of formula (II) are reduced by Raney nickel to compounds of formula (I) in solvent such as tetrahydrofuran and isolated by removing the solvent and crystallizing.

Preparation 1 2 »(2-Propyl thio) acetamide 15 To a mixture of 46.7 g (0.5 mole) of 2-chloroacetamide in 20 ml of absolute ethyl alcohol is added in a slow stream a solution of 38.1 g (0.5 mole) of 2-propanethiol in 100 ml of absolute ethyl alcohol and 40 g of 50% aqueous sodium hydroxide. The mixture is heated to reflux for 1 hour, then filtered. The filtrate is concentrated under reduced pressure, the residue is dissolved in methylene chloride and the solution is dried with magnesium sulfate. The mixture is filtered and the filtrate is concentrated again. Upon standing, the syrupy residue crystallizes out. Recrystallization from isopropyl ether 25 gives 59.0 g (89%) of white plates melting at 52-54 ° C. N: C = 45.08%, H = 8.32% N = 10.51% Found: C = 45.05%, H = 8.32% N * 10.55 % 30 35

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Preparation 2 2- (1-Propyithio) acetamide

Using the method described in Preparation 1, but using an equal molar amount of 1-propanethiol instead of 2-propanethiol, 61.2 g (92%) of the title compound are obtained. The white crystals melt at 49.5-51.0 ° C.

N: C = 45.08%, H = 8.32% N = 10.51% Found: C = 44.97%, H = 8.24% N = 10, 40%

Preparation 3 2-Amino-3-benzoyl-α- (methylthio) phenylacetamide

To a cold (-70 ° C) solution of 19.7 g (0.10 mol) of 2-amino-benzophenone in 300 ml of methylene chloride under nitrogen atmosphere is added a solution of 11.5 g (0.10 mol) of 95% 20 tert.butyl hypochlorite in 30 ml of methylene chloride followed 10 minutes by a solution of 10.5 g (0.1 mole) of methyl thioacetamide in 300 ml of tetrahydrofuran. The temperature is maintained at or below -55 ° C during these additions. After an additional 1 hour at -60 ° C, the mixture is allowed to warm to room temperature and the precipitate is collected by filtration.

The precipitate is slurried in 200 ml of methylene chloride and 11 g (0.11 mol) of triethylamine is added. The mixture is stirred for 5 minutes. The solution is washed twice with 100 ml of water and the organic phase is dried with magnesium sulfate and concentrated under reduced pressure. The residue is washed with diethyl ether and dried to give 13.0 g (43%) of a pale yellow powder, mp 153-155 ° C.

Analysis: Calculated for δ = 3.98%, H = 5.37% N = 9.33% Found: C = 63.64%, H = 5.39% N = 9.25% 11

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Preparation 4 2-Amino-3- (4-chlorobenzoyl) -g- (phenylthio) phenylacetamide

To a cold (-70 ° C) solution of 34.6 g (0.15 mol) of 5 2- 'amino-4'-chlorobenzophenone in 500 ml of methylene chloride is added 17.3 g (0.15 mol) of 95% tert.Butyl hypochlorite followed 10 minutes by the addition of a solution of 25.0 g (0.15 mol) of phenylthioacetamide in 400 ml of tetrahydrofuran added over a period of 20 minutes.

The temperature is maintained at -64 ° C or below during these additions. After 2 hours, 20 g (0.2 mole) of triethylamine are added and the mixture is allowed to warm to room temperature. The mixture is concentrated and the residue partitioned between water and methylene chloride. Material insoluble in any of these two phases is collected by filtration, washed with 20% aqueous ethanol solution and dried to give 36 g (61%) of a pale yellow powder, mp 189-191 ° C. Analysis: Calculated for C 21 H 17 N 2 ° 2 SC1: C = 63'55 ^ H ~ 4/32% N = 7.06% Found: C = 63.73%, H = 4.3 4 N = 7.16%

Preparation. 5 2-Amino-3-benzoyl-α- (phenylthio) phenylacetamide

To a cold (-70 ° C) solution of 68.75 g (0.349 mole) of 2-amine benzophenone in 1.5 ml of methylene chloride under nitrogen atmosphere is added 39.1 g (0.360 mole) of tert.butyl hypochlorite in 100 ml of methylene chloride. After stirring for 10 minutes, a solution of 59.1 g (0.354 mol) of α- (phenylthio) acetamide in 1.5 liters of tetrahydrofuran is added. The mixture is stirred for 1.25 hours at -65 ° C, 37.5 g (0.371 mol) of triethylamine is added and the solution is allowed to warm to room temperature. The reaction mixture is extracted with several portions of water and the organic layer is dried 12

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with anhydrous sodium sulfate. Yield 57% of theory. Recrystallized from methylene chloride / diethyl ether / hexane, the compound melts at 153-154 ° C.

Analysis: Calculated for C = 9.59%, H = 5.01% N = 7.73% Found: C = 69.33%, H = 5.00% N = 7.76% Preparation 6 2 -amino-3- (4-fluorobenzoyl) -α- (n-propylthio) phenylacetamide

A solution of 21.5 g (0.1 mole) of 4'-fluoro-amino-benzophenone in 400 ml of methylene chloride is cooled to -70 ° C, and 11.5 g (0.1 mole) of 95% is added. tert.Butyl hypochlorite over a period of 15 minutes, keeping the temperature below -66 ° C. To this solution is added a solution of 13.3 g of 2-n-propylthioacetamide in 50 ml of methylene chloride over a period of 10 minutes. The solution is stirred for 20 µl at -65 to -70 ° C, then allowed to warm to 0 ° C, at which time 10.2 g (0.1 mole) of triethylamine is added. The solution is stirred for 10 minutes and then washed with ether. The organic solution is dried with magnesium sulfate. After concentration under reduced pressure, the residue crystallizes from isopropyl alcohol and dried to give 19.5 g (56%) of yellow crystals melting at 140-142 ° C.

Analysis: Calculated for C 13 H 19 N 2 O 2 F: C = 62.41%, H = 5.53% N = 8.09% Found: C = 62.34%, H = 5.58% N = 8 , 04% 35

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Preparation 7 In the same manner as stated above in Preparation 4, 2-amino-3- (2-fluorobenzoyl) -α- (phenylthio) phenylacetamide, 2-amino-3- (2,4-dichlorobenzoyl) -α- (phenylthio) are prepared. ) phenylacetamide and '2-amino-3- (2,4-difluorobenzoyl) -a- (phenylthio) phenylacetamide, from phenylthioacetamide, tert-butyl hypochlorite and 2-amino-2' -fluorobenzophenone, 2-amino-2 ', 4'-dichlorobenzophenone and 2-amino-2', 4'-difluorobenzophenone.

Preparation 8 2-Amino-3- (2,4-dichlorobenzoyl) -g- (propylthio) phenylacetamide To a -70 ° C cooled mixture of 13.3 g (0.05 mole) of 2-amino-2 ', 4'-dichlorobenzophenone, 6.7 g (0.05 mole) of 2- (1-propylthio) acetamide and 300 ml of methylene chloride over a period of 40 minutes drop 5.8 g (0.05 mole) of 95% tert. hypochlorite. The mixture is maintained for a further 2 hours at -70 ° C, 20 and then 5.1 g (0.05 mole) of triethylamine is added dropwise. The mixture is allowed to warm to room temperature and washed with water.

The organic layer is evaporated to a yellow crystalline residue. The residue is washed with isopropyl ether and recrystallized from isopropyl alcohol to give 12.8 g (65%) of 25 yellow powder, mp 195.0-197.5 ° C.

Analysis: Calculated for C18 H18 N2 O2 SC12: C = 54.41%, H = 4.57% N = 7.05% Found: C = 54.33%, H = 4.56% N = 7.11%

Preparation 9 2-Amino-3- (2-fluorobenzoyl) -α- (propylthio) phenylacetamide

In the procedure of Example 8, 16.1 g (0.075 mole) of 2-amino-2'-fluorobenzophenone, 0.075 mole of 2- (1-35-propylthio) acetamide and 10.0 g (0.075 mole) of 95% tert are reacted. butyl hypochlorite in methylene chloride. Add 8.0 g (0.08)

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mole) triethylamine and the mixture is washed and evaporated. The residue is recrystallized from isopropyl alcohol to give 10.6 g (41%) of yellow solid, mp 157-159 ° C.

Analysis calculated for C ^ gH ^ g gC C SF: C = 62.41%, H = 5.53% N = 8.09% Found C = 62.62%, H = 5.53% N = 8 Example 1 2-Amino-3-benzoyl-phenylacetamide

To a stirred solution of 9.7 g (0.032 mol) of 2-amino-3-benzoyl-α- (methylthio) phenylacetamide in 100 ml of tetrahydrofuran is added 80 g of wet Raney nickel (wash three times with water and three times with tetrahydrofuran).

After 10 minutes, the mixture is filtered to remove Raney nickel and the filtrate is concentrated under vacuum. The residue is crystallized from isopropyl alcohol to give 6.0 g (73%) of yellow needles, mp 178.5-180.0 ° C.

Analysis: Calculated for c15 H14 N2 ° 2: C = 70'85% H = 5 / 55¾ N = 11.0% found: C = 70.53%, H = 5.53% N = 11.04%

Example 2 2-Amino-3- (4-chlorobenzoyl) phenylacetamide To a stirred solution of 28.5 g (0.077 mol) of 2-amino-3- (4-chlorobenzoyl) -a- (phenylthio) phenylacetamide in 1 liter of tetrahydrofuran Add 230 g of wet Raney nickel (washed three times with water and three times with tetrahydrofuran). After 15 minutes, the mixture is filtered, 35 and the filtrate concentrated under reduced pressure, which 15

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yields 17.4 g (84%) of yellow crystalline solid. Recrystallization from isopropyl alcohol followed by recrystallization twice from absolute ethanol gives yellow needles, mp 212-215 ° C.

Analysis: Calculated for C ^ --H₂C ^Cl: C = 62.40%, H = 4.54% N = 9.70% Found: C = 62.76%, H = 4.58% N = 9.83% Example 3 2-Amino-3- (4-fluorobenzoyl) phenylacetamide

A solution of 24.2 g (0.07 mol) of 2-amino-3- (4-fluorobenzoyl) -a- (n-propylthio) phenylacetamide in 300 ml of tetrahydrofuran is treated with 250 g of wet Raney nickel (washed three times with water and three times with tetrahydrofuran). The mixture is stirred for 1 hour and then filtered.

The filtrate is concentrated in vacuo and the residue is recrystallized from 95% ethyl alcohol to give 14.8 g (78%) of yellow needles, melting at 184-186 ° C.

Analysis: Calculated for C15H13W2 ° 2E ': C = 66.17%, H = 4.81% N = 10.29% Found: C = 66.32%, H = 4.81% • N = 10.48% 25

Example 4

Amino-3- (2,4-dichlorobenzoyl) phenylacetamide

A slurry of 8.0 g (0.02 mol) of 2-amino-3- (2,4-dichlorobenzoyl) -α- (propylthio) phenylacetamide in 300 ml of tetrahydrofuran is treated with 60 g of wet Raney nickel (washed with water and titrated to constant pH 7 with acetic acid, washed 35 16

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with water again and then washed 3 times with tetrahydrofuran) for 20 minutes. The mixture is filtered and the filtrate is evaporated to a yellow crystalline residue. The residue is triturated with hot isopropyl ether and the solid is collected and dried to give 5.8 g (89%) of yellow powder, mp 219-220.5 ° C.

Analysis calculated for; C = 55.75%, H = 3.74%, N = 8.67% found C = 55.90%, H = 3.79% N = 8.72%

Example 5 2-Amino-3- (2-fluorobenzoyl) phenylacetamide

Using the procedure of Example 4, 8.0 g (0.023 mol) of 2-amino-3- (2-fluorobenzoyl) -α- (propyl thio) phenylacetamide is treated with 65 g of wet Raney nickel in 150 ml of tetrahydrofuran. After filtration and evaporation of the filtrate, the residue is recrystallized from isopropyl ether to give 4.6 g (73%) of yellow crystals, mp 199.0 to 20.0 0.0 ° C.

Analysis calculated for C = 66.17%, H = 4.81% N = 10.29% Found C = 66.16%, H = 4.81% N = 10.42%

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Preparation and administration.

The novel active compounds prepared by the process of the invention are prepared in various formulations. Effective amounts of any of the above pharmacologically active compounds can be administered to live animals in any of a variety of ways, e.g. oral such as in the form of capsules or tablets, parenterally such as in the form of sterile solutions or suspensions and in some cases intravenously in the form of sterile solutions. In preparing such agents, a compound prepared by the process of the invention is incorporated as an active ingredient into a suitable carrier which may be an pharmaceutical carrier for illustration. Suitable pharmaceutical carriers which may be used in the construction of such preparations include starch, gelatin, glucose, magnesium carbonate, lactose, malt and the like. Liquid agents may also be used in the preparation of such active compound-containing formulations prepared by the process of the invention, and suitable liquid pharmaceutical carriers include, for example, ethyl alcohol, propylene glycol, glycerol, glucose syrup and the like.

Advantageously, the pharmacologically active compounds can be used in unit dosage form containing from 0.1 to 250 mg or even more of the active compound, depending on the size of the animal. For example, if in the case of a large animal such as a horse, tablets containing 5QO-1QOQ mg of active ingredient may be required. The unit dose can be administered an appropriate number of times daily so that the daily dosage can range from 0.3 to 450 mg. It seems "5-25 mg is optimal per day. unit dose.

Deb is only required that the active ingredient be an effective amount, ie. such that a suitable effective dosage is obtained in accordance with the dosage form used. The exact individual doses as well as the daily dosages will of course be determined according to standard medical principles under way.

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The compounds prepared by the process of the invention for use as active agents can be combined with other pharmacologically active agents or with buffers, antacids or the like for administration in appropriate form, and the proportion of active ingredient in such agents can be widely varied.

The following examples serve to illustrate the various forms of preparation in which the compounds prepared by the process of the invention may conveniently be included.

1. Capsules

Capsules containing 5 mg, 25 mg and 50 mg of active ingredient per ml are prepared, respectively. capsule. With the higher amounts of active ingredient, adjustments to the amount of active substance can be made by controlling the amount of lactose.

Typical mixture for Pr. capsule capsules___ mg_

Active Ingredient 5.0 20

Lactose 296.7

Starch 129.0

Magnesium stearate 4.3

Total 435.0 mg 25

Further capsule preparations preferably contain a higher dosage of active ingredient and are as follows:

Ingredients Pr. capsule _ mg_ 30 Active ingredient 25.0

Lactose 306.5

Starch 99.2

Magnesium stearate 4.3

Total 435.0 mg 35

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19 In each case, uniform mixing of the selected active substance with lactose, starch and magnesium stearate is made, and the mixture is filled into capsule.

2 »Tablets 5 A typical preparation for a tablet containing 5 mg of active substance per day. tablet is as follows. The composition may be used at other active ingredient strengths by adjusting the weight of dicalcium phosphate accordingly.

10 Pr · tablet, mg (1) Active ingredient 5.0 (2) Corn starch 13.6 (3) Corn starch (paste) 3.4 (4) Lactose 79.2 15 (5) Dicalcium phosphate 68.0 (6) Calcium stearate 0.9.1 mg

Components 1, 2, 4 and 5 are mixed evenly.

Component # 3 is prepared as a 10% paste in water.

The mixture is granulated with the starch paste and the wet mass is passed through a 8 mesh mesh screen (US sieve series). The wet granulate is dried and sieved through a 12 mesh screen mesh (US sieve series).

25 The dried granules with the calcium stearate and pressed into tablets, 3, 2% injectable sterile solutions.

3

Pr. cm 3Q Active substance 20 mg

Preservative, e.g. chlorobutanol 0.5% w / v

Water for injection 35 0 20

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The solution is prepared, clarified by filtration and filled into vials, which are sealed and autoclaved.

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Claims (5)

An analogous process for the preparation of 2-amino-3-benzoylphenylacetamides of the general formula 510 IICH-jC-NEL · NH + 1 2 (I) 10 c = o 15 wherein Y is hydrogen or halogen and n is 1, 2 or 3, characterized in that a 2-amino-3-benzoyl-α- (alkyl or phenylthio) phenylacetamide of the general formula SR3 20 in I9 CHCNH, vC I 'Wi C = 0 II), Y) n 30 wherein n and Y have the meanings given above and R is C 1-6 alkyl or phenyl is reduced. Process according to claim 1, characterized in that 2-amino-3-benzoyl-phenylacetamide is prepared. Process according to claim 1, characterized in that 2-amino-3- (4-chlorobenzoyl) phenylacetamide is prepared. O DK 154136 B Process according to claim 1, characterized in that 2-amino-3- (4-fluorobenzoyl) phenylacetamide is prepared. 5 10 15 20 25 30 35