CH646138A5 - AMINO-2-BENZOYL-3-PHENYLACETAMIDES AND THEIR CYCLIC APPROVALS USEFUL AS MEDICINAL PRODUCTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. - Google Patents

Description

The present invention relates to novel amino-2-benzoyl-3-phenylacetamides and their cyclic counterparts useful as medicaments and pharmaceutical compositions containing them. The compounds of the invention are medicaments useful in particular as anti-inflammatory, antipyretic, analgesic and inhibitors of the agglutination of blood platelets, which produce a minimum of undesirable side effects of gastric irritation when they are administered orally. to living things.

U.S. Patent No. 4,045,576 describes amino-2-benzoyl-3-phenylacetic acids as well as esters and metal salts derived therefrom which have anti-inflammatory activity and inhibitory properties. agglutination of blood platelets.

South African Patent No. 68/4682 describes benzoyl-phenylacetamides having various substituents at positions

2

of the phenyl radical. None of the compounds described therein are aminophenylacetamides.

In general, it is known that the known potent anti-inflammatory drugs cause serious side effects of gastric hemorrhage and gastric ulcers when administered orally to living beings at an effective dose. The compounds of the invention have the advantage of having very little gastric irritation effect when administered at a dose which is effective in reducing inflammation compared to indomethacin and of being less irritating than amino-2-benzoyl-3-phenylacetic acids described in the aforementioned United States patent.

The compounds of the invention are amino-2-benzoyl-3-phenyl-acetamides corresponding to the following formula:

C = o where

R represents a hydrogen atom or an alkyl radical Q to C8;

R1 and R2 represent a hydrogen atom or an alkyl radical Cj to C8, cycloalkyl, phenyl or phenyl substituted by an alkyl radical Cj to C8, alkoxy C! at C8, halo, nitro or trifluoromethyl, 35 or R1 and R2 together with the adjacent nitrogen atom form a heterocyclic radical;

X represents a hydrogen atom or a Ct to C8 alkyl, Q to C8 alkoxy, halo or trifluoromethyl radical;

Y represents a hydrogen atom or an alkyl radical Q to C8, 40 alkoxy Cj to C8, halo, trifluoromethyl, alkylthio Cj to C8, alkyloxythio C! to C8 or alkyldioxythio Cx to Cs; Am represents a primary amino radical (—NH2), methylamino or dimethylamino; and n is 1,2 or 3.

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The new compounds of formula I have interesting pharmacological properties which make them useful when they are administered internally to relieve inflammation, to relieve pain, to inhibit the agglutination of blood-born platelets and to combat temperature rise, with minimal side effects compared to some other powerful anti-inflammatory agents.

The anti-inflammatory activity accompanied by minimal side effects is illustrated by the compound of Example 3, that is to say 55 amino-2- (4-chloro benzoyl) -3-pheaylacetamide which s' is shown to have approximately the same activity as indomethacin,

but only cause gastric irritation equal to 1/100 that of indomethacin.

The anti-inflammatory activity was demonstrated on the ani-60 laboratory ailments according to a modification of the pleural effusion test. With carrageenan and Evans blue by Sancilio, L.F., "J. Phar-macol. Exp. Ther. ", 168,199-204 (1969).

The compounds of formula I inhibit the agglutination of platelets in the test described by Born, "J. of Phys. ”, 162, p. 67-68 (1962) and 65 Evans et al., “J. of Expt. med. ”, 128, 877-894 (1968). According to this test, the drugs to be studied are administered to rats and 2 hours later the rats are bled to obtain a plasma rich in platelets. Collagen is added to the platelet-rich plasma to cause clumping

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nation of platelets and comparisons are made between control and treated samples.

The compounds of formula I also behave as analgesics according to the dradykinin analgesia test of Dickerson et al., "Life Sci.", 4.2063-2069 (1965) modified by Sancilio and Cheung, "Fed. Proc. ”, 35, IIA (1976).

The antipyretic activity of the compounds of formula I is manifested by a lowering of the febrile response of animals in hyperthermia without modification of the rectal temperature of animals at normal temperature. The hyperthermia response caused by the subcutaneous injection of brewer's yeast to rats is inhibited by oral administration of as little as 4 to 8 mg / kg of the compounds of formula I without being observed significant change in rectal temperature of rats at normal temperature.

The invention also relates to therapeutic compositions for treating living beings and in particular mammals to relieve inflammation and pain, inhibit the agglutination of blood platelets and combat fever with a minimum of undesirable side effects in terms of stomach and intestine.

In the present description, the term lower alkyl designates straight or branched radicals containing up to 8 carbon atoms 5 such as methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, hexyl, heptyle and octyl. The term lower alkoxy denotes -O-lower alkyl radicals.

The term halo denotes in the present description radicals fluoro, chloro, bromo or iodo and preferably fluoro, chloro and io bromo.

The term cycloalkyl denotes in the present description essentially cycloalkyl radicals comprising 3 to 12 carbon atoms inclusive such as cyclopropyl, cyclobu-tyle, cyclopentyl, cyclohexyl, cycloheptyl and the like. Heterocyclic radiols are radicals such as morpholino, pyrroli-dinyl-1, piperidino, piperazinyl-1 and the like.

The invention will now be described in detail.

The compounds of formula I can be prepared according to reactions comprising the following reaction sequence:

3 "12 + R SCHRCNR R

Formula III

formula IV

1) t-BuOCl

2) Et3N

*

(rv - 70 ° C. in methylene chloride)

SR

I 0

1 "'12

CRCNR R

Neither of

C = 0 (THF)

Formula II

Raneyy

"12 ^ CHR-C-NR R

Formula I

where R, R1, R2, X, Y and n have the same definition as above, except that Y cannot represent a lower alkylthio radical or the corresponding oxides and R3 represents a lower alkyl or phenyl radical. In addition, the compounds where Y represents an -S-alkyl radical are prepared from the compounds of formula I where Y represents a fluoro radical according to the following reaction sequence:

0 0

and the compounds where Y represents a lower alkyloxythio or lower alkyldioxythio radical can be prepared by reacting compounds where Y represents a lower alkylthio radical with one or two moles of sodium metaperiodate or metachloroperbenzoic acid according to the following reaction sequence:

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4

D

"12 CHR-C-NR R

/

vAm

NalO,

C = 0

Ö

m d 2 CHR-C-NR R

Am

C = 0

S-lower alkyl

3-lower alkyl or 2NaIO.

4

To prepare the compounds of formula I where Am is a dimethylamino radical, the corresponding 2-amino compound can be reacted with sodium cyanoborohydride, formaldehyde, acetonitrile and acetic acid.

The preparation of the intermediate compounds of formula II is described in more detail in preparations 6 to 15. In general, to prepare these intermediates, the appropriate amino-2-benzophenones are first reacted with tert.-butyl hypochlorite. and the appropriate thioacetamide when cold (-60 to -70 ° C) and then triethylamine is added.

The intermediates of formula II are reduced with Ra-ney nickel to obtain the compounds of formula I (where Y does not represent a lower alkylthio radical) in a solvent such as tetrahydrofuran and is isolated by elimination of the solvent and crystallization . In such a reduction, Raney nickel would react on the S-lower alkyl radical.

BR19 J: 16-3 PTJ16-3b 646138 Preparation 1:

(Methyl-2-acetyl) -4 morpholine

A mixture of 40.2 g (0.3 mol) of ethyl methylthioacetate and 130 g (1.5 mol) of morpholine is heated at reflux for 70 h. By fractional distillation under reduced pressure, 45 g (86%) of product are obtained. E. 104-105 ° C / 0.05 mmHg after a second distillation.

Theoretical analysis for C7H13N02S:

Calculated: C 47.98 H 7.48 N7.99%

Found: C 47.55 H 7.59 N 8.18%

Preparation 2:

Methylthio-2-N-methylacetamide

A mixture of 134 g (1.0 mol) of ethyl methylthioacetate and 310 g (10.0 mol) of methylamine is heated in a bomb at 150 ° C. for 72 h. The excess amine and the ethanol produced are distilled off and the remaining fluid syrup is distilled to obtain 112 g (94%) of the desired compound in the form of a colorless liquid. E. 76-78 ° C / 0.4 mmHg.

Theoretical analysis for C4H9NOS:

Calculated: C 40.31 H 7.61 N 11.75%

Found: C 39.78 H 7.69 N 11.88%

Preparation 3:

Methylthio-2-N, N-dimethylacetamide

A mixture of 134 g (1.0 mol) of ethyl methylthioacetate and 360 g (8.0 mol) of dimethylamine is heated in a bomb at 150 ° C. for 90 h. The excess amine and the ethanol produced are distilled off and the residue is distilled to obtain 129 g (97%) of the desired compound in the form of a clear colorless liquid. E. 76-77 ° C /

0.5 mmHg.

Theoretical analysis for CsH ^ NOS:

Calculated: C 45.08 H 8.32 N 10.51%

Found: C 43.88 H 8.41 N 10.60%

Preparation 4:

Isopropylthio-2-acetamide

To a mixture of 46.7 g (0.5 mol) of chloro-2-acetamide in 200 ml of absolute ethanol is slowly added a solution of 38.1 g (0.5 mol) of propanethiol-2 in 100 ml absolute ethanol and 40 g of 50% aqueous sodium hydroxide. The mixture is heated at reflux for 1 h and then filtered. The filtrate is concentrated under reduced pressure; the residue is dissolved in methylene chloride and the solution is dried over magnesium sulfate. The mixture is filtered and the filtrate is concentrated again. A syrupy residue crystallizes on standing. By recrystallization from isopropyl ether, 59.0 g (89%) of small white tables are obtained, melting at 52-54 ° C.

Theoretical analysis for C5HnNOS:

ss Calculated: C 45.08 H 8.32 N 10.51%

Found: C 45.05 H 8.32 N 10.55%

Preparation 5:

g ,, Propylthio-2-acetamide

According to the procedure of preparation 4 but replacing propanethiol-2 with an equimolecular amount of propanethiol-

1, 61.2 g (92%) of the desired compound are obtained. The white crystals melt at 49.5-51.0 ° C.

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Theoretical analysis for CsHuNOS:

Calculated: C 45.08 H 8.32 N 10.51%

Found: C 44.97 H 8.24 N 10.40%

n 2

CHR-C-NR R

C = 0

^ Am

S- lower alkyl

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Preparation 6:

Amino-2-benzoyl-3-chloro-5-a- (methylthio) phenylacetamide

To a cold solution (—70 ° C) of 12.77 g (0.055 mol) of amino-2-chloro-5-benzophenone in 300 ml of methylene chloride under nitrogen atmosphere, 6.0 g ( 0.0552 mol) of tert.-butyl hypochlorite in 20 ml of methylene chloride. After another 15 min of stirring, a suspension of 5.8 g (0.055 mol) of a- (methylthio) acetamide is added in 150 ml of methylene chloride. The mixture is stirred at -65 ° C for 1 h. 5.6 g (0.055 mol) of triethylamine are 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 over magnesium sulfate. The solution is concentrated in vacuo to about 200 ml and the product crystallizes as a yellow solid. Mp 173.5-174.5 ° C. The yield is 6.86 g (37.3%).

Theoretical analysis for C16H15N202SC1:

Calculated: C 57.40 H 4.52 N 8.37%

Find; C 57.38 H 4.50 N 8.51%

Preparation 7:

Amino-2-benzoyl-3-a- (methylthio) phenylacetamide

To a cold solution (-70 ° C) of 19.7 g (0.10 mol) of amino-2-benzophenone in 300 ml of methylene chloride under nitrogen atmosphere, a solution of 11.5 g is added (0.10 mol) of 95% tert.-butyl hypochlorite in 30 ml of methylene chloride and then, after 10 min, a solution of 10.5 g (0.1 mol) of methylthioacetamide in 300 ml of tetrahydrofuran. During these additions, the temperature is maintained at -5 ° C or below. After again

1 h at -60 ° C, the mixture is allowed to warm to room temperature and the precipitate is collected by filtration. The precipitate is suspended in 200 ml of methylene chloride and added

II g (0.11 mol) of triethylamine. The mixture is stirred for 5 min. The solution is washed twice with 100 ml of water and the organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The residue is washed with ethyl ether and dried to obtain 13.0 g (43%) of a light yellow powder. F. 153-155 ° C.

Theoretical analysis for C16H, 6N202S:

Calculated: C 63.98 H 5.37 N9.33%

Found: C 63.64 H 5.39 N9.25%

Preparation 8:

Amino-2- (chloro-4-benzoyl) -3-a- (phenylthio) phenylacetamide

To a cold solution (—70 ° C) of 34.6 g (0.15 mol) of amino-2-chloro-4'-benzophenone in 500 ml of methylene chloride, 17.3 g (0, 15 mol) of tert.-butyl hypochlorite at 95% then, after 10 min, a solution of 25.0 g (0.15 mol) of phenylthioacetamide in 400 ml of tetrahydrofuran is added over 20 min. The temperature is maintained at -64 ° C or below during these additions. After 2 h, 20 g (0.2 mol) of triethylamine are added and the mixture is allowed to warm to room temperature. The mixture is concentrated and the residue is partitioned between water and methylene chloride. The insoluble material in the two phases is collected by filtration, washed with 20% aqueous ether and dried to obtain 36 g (61%) of a light yellow powder. F. 189-19rC. Theoretical analysis for C21H17N202SC1:

Calculated: C 63.55 H 4.32 N 7.06%

Found: C 63.73 H 4.36 N 7.16%

Preparation 9:

[(Amino-2-benzoyl-3-phenyl) -2-methylthio-2-acetyl] -4-morpholine

To a cold solution (—65 ° C) of 9.9 g (0.05 mol) of amino-2-benzophenone and 8.8 g (0.05 mol) of (a-methylthio) acetyl-4- morpho-line in 200 ml of methylene chloride, a solution of 5.8 g (0.05 mol) of 95% tert.-butyl hypochlorite in 20 ml of methylene chloride is added dropwise. After another 1 h at -60 ° C, 5.1 g (0.05 mol) of triethylamine is added and the mixture is allowed to warm to room temperature. The solution is washed twice with 100 ml of water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on 600 g of silica gel, eluting first with isopropyl ether and then with 10% acetone in isopropyl ether. The eluate is concentrated, the residue is dissolved in 150 ml of ethanol and the solution is poured into 400 ml of water. The undissolved solid is collected and crystallized from ethyl ether and then dried. The yield is 12.3 g (62%) of yellow crystals. Mp 119-121 ° C.

Theoretical analysis for C20H22N2O3S:

Calculated: C 64.84 H 5.99 N7.56%

Found: C 65.01 H 5.99 N7.57%

Preparation 10:

Amino-2-benzoyl-3-chloro-5-a- [(chloro-4-phenyl) thio] phenylacetamide

To a cold solution (—70 ° C) of 20 g (0.0863 mol) of amino-2-chloro-5-benzophenone in 500 ml of methylene chloride under nitrogen atmosphere, a solution of 9 is added, 48 g (0.088 mol) of tert.-butyl hypochlorite in 50 ml of methylene chloride. After another 15 minutes of stirring, a solution of 17.35 g (0.0863 mol) of a- (chloro-4-phenylthio) acetamide in 500 ml of a mixture of tetrahydrofuran and chloride chloride is added. methylene. The mixture is stirred at -70 ° C for 2 h, 8.72 g (0.0863 mol) of triethylamine are added and the stirred solution is allowed to warm to room temperature for 2 h. The reaction mixture is extracted with several portions of water and the organic layer is dried over magnesium sulfate. The volume of liquid is reduced to about 500 ml. 500 ml of methylene chloride are added to precipitate the product which, after filtration and drying, weighs 16.62 g (44.7%). The yellow solid melts at 198-200 ° C.

Theoretical analysis for C21H16N202SC12:

Calculated: C 58.48 H 3.74 N 6.49%

Found: C 58.49 H 3.77 N 6.67%

Preparation 11:

Amino-2-benzoyl-3-chloro-5-a- (phenylthio) phenylacetamide

To a cold solution (—70 ° C) of 80.72 g (0.349 mol) of amino-2-chloro-5-benzophenone in 1.5 l of methylene chloride, under nitrogen atmosphere, 39 is added, 1 g (0.360 mol) of tert.-butyl hypochlorite in 100 ml of methylene chloride. After 10 min of stirring, a solution of 59.1 g (0.354 mol) of a- (phenylthio) acetamide in 1.5 l of tetrahydrofuran is added. The mixture was stirred for 1.25 h at -65 ° C, 37.5 g (0.371 mol) of triethylamine was added and the solution was allowed to warm to room temperature. The reaction mixture is extracted with several portions of water and the organic layer is dried over anhydrous sodium sulfate. The solution is concentrated in vacuo and a yellow solid is precipitated which is recrystallized from acetonitrile to obtain a yellow crystalline solid. Mp 190-191 ° C (decomposition).

Theoretical analysis for C21H17N202SC1:

Calculated: C 63.55 H 4.32 N 7.06%

Found: C 63.62 H 4.29 N 7.08%

Preparation 12:

Amino-2-benzoyl-3-a- (phenylthio jphenylacetamide

According to the procedure of Preparation 11, but by replacing amino-2-chloro-5-benzophenone with an equimole-circular amount of amino-2-benzophenone, the desired compound is obtained with a yield of 57%. After recrystallization from a mixture of methylene chloride, ethyl ether and hexane, the compound melts at 153-154 ° C.

Theoretical analysis for C2iH18N202S:

Calculated: C 69.59 H 5.01 N 7.73%

Found: C 69.33 H 5.00 N 7.76%

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Preparation 13:

Amino-2-ben: oyl-3-a- (methylthio) -N-methylphenylacetamide

Cool a solution of 29.6 g (0.15 mol) of amino-2-benzophenone in 350 ml of methylene chloride to -70 ° C. and add 17.9 g (0.15 mol) of methylthio- 2-N-methylacetamide in 20 ml of methylene chloride. A solution of 17.2 g (0.15 mol) of 95% tert.-butyl hypochlorite in 30 ml of methylene chloride is added dropwise to the mixture cooled to -70 ° C. The temperature is maintained at -65 ° C or below for 1.5 h and then rapidly added 15.1 g (0.15 mol) of triethylamine. The solution is allowed to warm to room temperature and washed with water. The organic solution is concentrated and the residue crystallizes by mixing with isopropyl ether. The solid is recrystallized from isopropyl alcohol to obtain 31 g (65%) of yellow needles. Mp 149-150 ° C.

Theoretical analysis for C17HisN20ìS:

Calculated: C 64.94 H 5.77 'N8.91%

Found: C 65.24 H 5.83 N 8.99%

Preparation 14:

Amino-2-benzoyl-3-a- (methylthio) -N, N-dimethylphenylacetamide

Cool a solution of 29.6 g (0.15 mol) of amino-2-benzophenone in 350 ml of methylene chloride to -70 ° C. and add 20.0 g (0.15 mol) of methylthio- 2-N, N-dimethylacetamide. A solution of 17.2 g (0.15 mol) of 95% tert.-butyl hypochlorite in 30 ml of methylene chloride is added dropwise to the mixture cooled to -70 ° C. The temperature is maintained at -65 ° C or below for 1.5 h and then rapidly added 15.1 g (0.15 mol) of triethylamine. The solution is allowed to warm to room temperature and washed with water. The organic solution is concentrated and the residue crystallizes by mixing with isopropyl ether. The solid is recrystallized from isopropyl alcohol to obtain 39.8 g (81%) of brilliant yellow crystals. F. 153-155 ° C.

Theoretical analysis for CI8H20N2O2S:

Calculated: C 65.83 H 6.14 N 8.53%

Found: C 65.87 H 6.15 N 8.52%

Preparation 15:

Amino-2- (fluoro-4-benzoyl) -3-a- (propylthio) phenylacetamide

A solution of 21.5 g (0.1 mol) of fluoro-4'-amino-2-benzophenone in 400 ml of methylene chloride is cooled to -70 ° C. and 11.5 g (0) are added over 15 min. , 1 mol) of tert.-butyl hypochlorite at 95% while maintaining the temperature below - 66 ° C. To this solution is added a solution of 13.3 g of propylthioacetamide in 50 ml of methylene chloride in 10 min. The solution is stirred for 1 h between -65 and -70 ° C then allowed to warm to 0 ° C and then 10.2 g (0.1 mol) of triethylamine is added. The solution is stirred for 10 min and then washed with water. The organic solution is dried over magnesium sulfate. After concentration under reduced pressure, the residue is crystallized from isopropyl alcohol and dried to obtain 19.5 g (56%) of yellow crystals, melting at 140-142 ° C.

Theoretical analysis for C18H19N202SF:

Calculated: C 62.41 H 5.53 N 8.09%

Found: C 62.34 H 5.58 N 8.04%

Preparation 16:

As described in preparation 8, tert-butyl hypochlorite and amino-2-fluoro-2'-benzophenone, ramino-2-trifluoromethyl-4'-benzo are prepared from phenylthioacetamide -phenone, amino-2-dichloro-2 ', 4'-benzophenone or amino-2-difluoro-2', 4'-benzophenone, ramino-2- (fiuoro-2-benzoyl) -3 -a- (phenylthio) phenylacetamide, ramino-2- (trifluoromethyl-4-ben-zoyl) -3-a- (phenylthio) phenylacetamide, amino-2- (2,4-dichloro-2,4-benzoyl) -3-a - (phenylthio) phenylacetamide and amino-2 (2,4-difluoro-benzoyl) -3-a- (phenylthio) phenylacetamide.

Preparation 17:

Amino-2-benzoyl-3-chloro-5-a- (methylthio) -N-methylphenyl-acetamide

To a solution of 38.3 g (0.166 mol) of amino-2-chloro-5-benzo-phenone in 11 of methylene chloride cooled to -70 ° C. under a nitrogen atmosphere, 18.05 g is added ( 0.167 mol) of tert.-butyl hypochlorite. The solution is stirred for 15 min and then a solution of 20.3 g (0.171 mol) of methylthio-2-N-methylacetamide in 100 ml of methylene chloride is added. The solution was stirred at -70 ° C for 2 h, and 25 ml of triethylamine was added. The solution is allowed to warm to room temperature with stirring, then extracted with water and the organic layer is dried with magnesium sulfate. The solution is concentrated to approximately 400 ml, ether is added and the mixture is placed in the refrigerator at approximately 0 ° C. overnight. The solid which has crystallized is dried under high vacuum for approximately 4 h at 50 ° C. The product weighs 31.56 g (54.6%) and melts at 170-171 ° C. Theoretical analysis for C17H17N202SC1:

Calculated: C 58.53 H 4.91 N8.03%

Found: C 58.68 H 4.91 N 8.13%

Preparation 18:

Benzoyl-3-methylamino-2-a- (methylthio) phenylacetamide

To prepare this compound, use the procedure of Preparation 7, replacing Famino-2-benzophenone with an equimolecular amount of methylamino-2-benzophenone.

Example 1:

Amino-2-benzoyl-3-chloro-5-phenylacetamide

A mixture of 21.34 g (0.0639 mol) of amino-2-benzoyl-3-chloro-5-a- (methyl-thio) phenylacetamide and an excess of nickel is stirred at room temperature for 45 min. Raney in a mixture of 900 ml of absolute ethanol and 200 ml of dimethylformamide. The mixture is filtered on celite to remove the Raney nickel. The solvent is removed under vacuum to obtain a yellow solid which, after recrystallization, melts at 213.5-215.0 ° C (decompostion).

Theoretical analysis for C15H13N203C1:

Calculated: C 62.40 H 4.54 N9.70%

Found: C 62.35 H 4.58 N9.74%

Example 2:

Amino-2-benzoyl-3-phenylacetamide

To a stirred solution of 9.7 g (0.032 mol) of amino-2-benzoyl-3-a-methylthio) phenylacetamide in 100 ml of tetrahydrofuran, 80 g of wet Raney nickel (washed three times with water and three times with tetrahydrofuran). After 10 min, the mixture is filtered to remove the Raney nickel and the filtrate is concentrated in vacuo. The residue is crystallized from isopropyl alcohol to obtain 6.0 g (73%) of yellow needles. Mp 178.5-180.0 ° C.

Theoretical analysis for Ci 5H14N202:

Calculated: C 70.85 H 5.55 N 11.02%

Found: C 70.53 H 5.53 NI 1.04%

Example 3:

Amino-2- (chloro-4-benzoyl) -3-phenylacetamide

To a stirred solution of 28.5 g (0.077 mol) of amino-2- (chloro-4-benzoyl) -3-a- (phenylthio) phenylacetamide in 11 of tetrahydrofuran, 230 g of wet Raney nickel ( washed three times with water and three times with tetrahydrofuran). After 15 min the mixture is filtered and the filtrate is concentrated under reduced pressure to obtain 14.4 g (84%) of a yellow crystalline solid. By recrystallization from isopropyl alcohol and then two recrystallizations from absolute ethanol, yellow needles are obtained. Mp 212-215 ° C.

Theoretical analysis for C15H13N202C1:

Calculated: C 62.40 H 4.54 N9.70%

Found: C 62.76 H 4.58 N9.83%

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Example 4:

[(Amino-2-benzoyl-3-phenyl) -2-acetyl] -4-morpholine

To a stirred solution of 18.5 g (0.05 mol) of [(amino-2-benzoyl-3-phenyl) -2-methylthio-2-acetyl] -4-morpholine in 300 ml of tetrahydrofuran, the following is added 150 g of wet Raney nickel. After 15 min, the mixture is filtered and the filtrate is concentrated under reduced pressure. After recrystallization of the residue from isopropyl alcohol, 13.3 g (82%) of brilliant yellow crystals are obtained. Mp 156.5-158.5 ° C.

Theoretical analysis for C19H20N2O3:

Calculated: C 70.35 H 6.22 N 8.64%

Found: C 70.24 H 6.21 N 8.63%

Example 5:

Amino-2-benzoyl-3-N-methylphenylacetamide

A solution of 22.5 g (0.072 mol) of amino-2-benzoyl-3-a- (methylthio) -N-methylphenylacetamide in 400 ml of tetrahydrofuran is treated with 160 g of wet Raney nickel (washed three times with water and three times with tetrahydrofuran) for 10 min. The mixture is filtered and the filtrate is concentrated. The residue is crystallized from isopropyl alcohol to obtain 17.2 g (89%) of yellow needles. Mp 145-146 ° C.

Theoretical analysis for C16Hi6N202:

Calculated: C 71.62 H 6.01 N 10.44%

Found: C 71.76 H 6.05 N 10.52%

Example 6:

Amino-2-benzoyl-3-N, N-dimethylphenylacetamide

A solution of 33.0 g (0.1 mol) of amino-2-benzoyl-3-a- (methylthio) -N, N-dimethylphenylacetamide in 500 ml of tetrahydrofuran is treated with 240 g of wet Raney nickel ( washed three times with water and three times with tetrahydrofuran) for 10 min. The mixture is filtered and the filtrate is concentrated. The residue is crystallized from isopropyl alcohol to obtain 27.2 g (96%) of yellow needles. Mp 123-124 ° C.

Theoretical analysis for C17H18N202:

Calculated: C 72.32 H 6.43 N9.92%

Found: C 72.34 H 6.42 N9.98%

Example 7:

Amino-2- (fluoro-4-benzoyl) -3-phenylacetamide

A solution of 24.2 g (0.07 mol) of amino-2- (fluoro-4-benzoyl) -3-a- (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 h and filtered. The filtrate is concentrated in vacuo and the residue is recrystallized from 95% ethanol to obtain 14.8 g (78%) of yellow needles, melting at 184-186 ° C.

Theoretical analysis for C! 5Hi3N202F:

Calculated: C 66.17 H 4.81 N 10.29%

Found: C 66.32 H 4.81 N 10.48%

Example 8:

As described in Example 2, amino-2- (fluoro-2-benzoyl) -3-phenylacetamide, Famino-2- (dichloro-2,4-benzoyl) -3-phenylacetamide, amino -2- (difluoro-2,4-benzoyl) -3-phenyl-acetamide and ramino-2- (trifluoromethyl-4-benzoyl) -3-phenyl-acetamide from amino-2- (fluoro-2- benzoyl) -3-a- (phenylthio) -phenylacetamide, amino-2- (2,4-dichloro-benzoyl) -3-a- (phenylthio) -phenylacetamide, ramino-2- (difluoro-2,4- benzoyl) -3-a- (phenylthio) -phenylacetamide and ramino-2- (trifluoromethyl-4-benzoyl) -3-a- (phenylthio) phenylacetamide.

Example 9:

Amino-2- (methylthio-4-benzoyl) -3-phenylacetamide

To prepare this compound, Pamino-2- (fluoro-4-) is refluxed.

benzoyl) -3-phenylacetamide with excess sodium methanethiolate in ethanol and isolated appropriately.

Example 10:

5 Amino-2- (oxomethylthio-4-benzoyl) -3-phenylacetamide

To prepare this compound, 1 mol of amino-2- (methylthio-4-benzoyl) -3-phenylacetamide is reacted with 1 mol of sodium metaperio-date and is isolated appropriately.

10 Example 11:

Amino-2- (dioxymethylthio-4-benzoyl) -3-phenylacetamide

To prepare this compound, 1 mol of amino-2- (methylthio-4-benzoyl) -3-phenylacetamide is reacted with 2 mol of sodium metaperio-date and is isolated appropriately.

Example 12:

Amino-2-benzoyl-3-chloro-5-N-methylphenylacetamide

A solution of 28.33 g (0.081 mol) of amino-2-benzoyl-20 3-chloro-5-a- (methylthio) -N-methylacetamide in 11 of tetrahydrofuran is treated with an excess of Raney nickel with ordinary temperature for 2 h. The solution is filtered on celite. The Raney nickel residue is washed with acetone and the washing liquid is filtered. The combined organic filtrates are dried over magnesium sulfate and concentrated to about 300 ml. An excess of ether is added and the solution is allowed to stand at room temperature for 1 h and then refrigerated overnight. The yellow solid collected and dried weighs 20.94 g (85.68%) and melts at 179-180 ° C.

Theoretical analysis for Ci6H15N202C1:

Calculated: Found:

C 63.48 C 63.44

H 4.99 H 4.99

N 9.25% N 9.27%

Example 13:

^ Benzoyl-3-methylamino-2-phenylacetamide

To obtain this compound, use the procedure of Example 2, replacing amino-2-benzoyl-3-a- (methylthio) -phenylacetamide with benzoyl-3-methylamino-2-a- (methylthio). phenylacetamide.

40

Example 14:

Benzoyl-3-dimethylamino-2-phenylacetamide

A solution of 12.7 g (0.05 mol) of amino-2-benzoyl-3-phenylacetamide in 150 ml of acetonitrile is treated four times with 16 ml 45 (0.2 mol) of formalin at 37%, 6.4 g (0.1 mol) of sodium cyanoborohydride and 2 ml of glacial acetic acid with a stirring period of 15 min between each treatment. The mixture is finally poured into dilute sodium hydroxide and extracted three times with ethyl ether. The ethereal extracts are combined, dried over sul-50, magnesium fate and concentrated. The product is isolated by column chromatography.

The invention also relates to pharmaceutical compositions containing as active ingredient the compounds of the invention. Effective amounts of any of the pharmacologically active compounds of the invention can be administered to a living being in a variety of ways, such as orally in the form of capsules or tablets, parenterally in the form of solutions or sterile suspensions and in some cases intravenously in the form of sterile solutions.

To prepare the new compositions of the invention, the active ingredient is incorporated into an appropriate vehicle such as a pharmaceutical vehicle. Suitable pharmaceutical vehicles useful for preparing the compositions of the invention are starch, gelatin, glucose, magnesium carbonate, lactose, malt and si-65 mil. The compositions of the invention may also be liquid and suitable liquid pharmaceutical carriers are ethyl alcohol, propylene glycol, glycerin, glucose syrup and the like.

646138

The active compounds can advantageously be used. In all cases, the pharmacological active ingredient is uniformly mixed in the form of unit doses containing 0.1 to with lactose, starch and magnesium stearate and 2 is introduced, 50 mg or more of active ingredient depending on the weight of the subject in which capsules.

administers them. For example, a large animal, such as a horse, may require tablets containing 500 to 1000 mg of active ingredient. Unit doses can be administered appropriately several times a day to obtain a daily dosage of between 0.3 and 450 mg. The optimum unit doses appear to be 5 A typical composition for preparing tablets containing

to "25 mg. of 5> 0 mg of active ingredient is shown below. The

It is sufficient that the active ingredient is present in an effective amount, 10 comPos'tion with other concentrations of active ingredient per mo-that is to say that one obtains an effective dosage with the form dification of the weight of phosphate dicalcic.

of administration used. The specific dosages can be determined according to conventional medical principles by a doctor or a veterinarian.

The active agents of the invention can be combined with other pharmacologically active agents or with buffers, antacids and the like to administer them, and the proportions of the active ingredients in such compositions can vary widely.

Examples of compositions according to the invention are given below.

Per tablet (mg)

1) active ingredient 5.0

2) corn starch 13.6

3) corn starch 3.4

4) lactose 79.2

5) dicalcium phosphate 68.0

6) calcium stearate 0.9

170.1

1. Capsules

Capsules containing 5 mg, 25 mg or 50 mg of active ingredient are prepared. For the high amounts of active ingredient, 1, 2, 4 and 5 are mixed uniformly. The amount of lactose is prepared 3 under the form. 25 of a 10% job in 1 water. We granulate the mixture with

Typical mixture for capsule Per capsule (mg) starch paste and the wet mass is passed through a ta-

active ingredient 5.0 n "5 of 2.38 mm mesh size. The moist granules are dried

lactose 296 7 des and they are passed through a sieve of 1.41 mm mesh opening,

starch 129.0 The dry granules are mixed with the calcium stearate and

magnesium stearate 4.3 30 Pnme-

Total 435.0

Another composition for capsules preferably containing a larger amount of active ingredient is as follows: 3 sterile solutions for injection at 2%

Ingredients Per capsule (mg) Per milliliter active ingredient 25.0 35 active ingredient 20 mg lactose 306.5 preservative, for example chlorobutanol 0.5% w / v starch 99.2 water for injection q.s.

magnesium stearate 4.3 Qn prepares the solution, it is clarified by filtration, it is condi-

Total 435.0 is in vials, closed and autoclaved.

R

Claims (4)

646138 CLAIMS 1. Compounds, characterized in that they correspond to formula I: or R represents a hydrogen atom or an alkyl radical Cx to C8; R1 and R2 represent a hydrogen atom or a Ct to C8 alkyl, cycloalkyl, phenyl or phenyl radical substituted by a Ct to C8 alkyl, Ct to C8 alkoxy, halo, nitro or trifluoromethyl radical, or R1 and R2 form together with l 'nitrogen atom adjacent a heterocyclic radical; X represents a hydrogen atom or an alkyl radical Cj to C8, alkoxy Q to Cs, halo or trifluoromethyl; Y represents a hydrogen atom or an alkyl radical Cj to C8, alkoxy Q to C8, halo, trifluoromethyl, alkylthio Cl to C8, alkyloxythio Cj to C8 or alkyldioxythio Q to C8; Am represents a primary amino (—NH2), methyl-amino or dimethylamino radical, and n is 1, 2 or 3. 2. Compounds according to claim 1, characterized in that they consist of ramino-2-benzoyl-3-chloro-5-phenylacetamide, Famino-2-benzoyl-3-phenylacetamide, amino-2- (chloro- 4-benzoyl) -3-phenylacetamide, [(amino-2-benzoyl-3-phenyl) -2-acetyl] -4-mor-pholine, rammo-2-benzoyl-3-N-methylphenylacetamide, amino -2-benzoyl-3-N, N-dimethylphenylacetamide, amino-2- (fluoro-4-benzoyl) -3-phenylacetamido or amino-2-benzoyl-3-chloro-5-N-methylphenylacetamide. 3. Pharmaceutical compositions useful in particular as anti-inflammatories, antipyretics, inhibitors of the agglutination of blood platelets and analgesics, characterized in that they contain at least one compound according to one of claims 1 or 2. 4. Compositions according to claim 3 for oral or parenteral administration in the form of unit doses preferably containing 0.1 to 250 mg of active ingredient.