LU82797A1 - NOVEL 2-AMINO-BENZOYL-3 PHENYLACETAMIDES AND THEIR CYCLIC HOMOLOGUES USEFUL AS MEDICAMENTS AND THERAPEUTIC COMPOSITIONS AND PHARMACEUTICAL FORMS CONTAINING THEM - Google Patents

Description

„“ * * ”* 1

The present invention relates to novel 2-amino-3-benzoylphenylacetamides and their cyclic counterparts useful as medicaments and therapeutic compositions and pharmaceutical forms containing them. The compounds of the invention are medicaments useful in particular as anti-inflammatories, antipyretics, analgesics and inhibitors of blood platelet agglutination, which produce a minimum of undesirable side effects of gastric irritation when administered. orally to living things.

10 U.S. Patent No. 4,045,576 V.

describes 2-amino-3-benzoyl-phenylacetic acids as well as esters and metal salts derived therefrom which have anti-inflammatory activity and properties of inhibition of the agglutination of blood platelets.

South African Patent No. 68/4682 describes benzoylphenylacetamides having various substituents at unspecified positions of the phenyl radical. None of the compounds described therein are aminophenylacetamides.

In general, it is known that 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 2-amino-3-benzoyl-phenylacetic acids described in the aforementioned United States patent.

The compounds of the invention are 2-amino-3-benzoylphenylacetamides corresponding to the following formula: 30 R 0 R1

I II

CH-C-N0 \ r2

x ~ t I

^ 5ϊϊ; γ · '' χΝΑπι ^? -0 (formula I), Α • JH w ”-. > 2 "where R represents a hyrogen atom or a lower alkyl radical, 1 2 R and R represent a hydrogen atom or a lower alkyl, cycloalkyl, phenyl, or phenyl radical substituted by a lower alkyl, lower alkoxy radical, halo, nitro or 5-trifluoro-methyl, or R * · and R together with the adjacent nitrogen atom form a heterocyclic radical; X represents a hydrogen atom or a lower alkyl, lower alkoxy, halo or trifluoro-methyl radical; Y represents a hydrogen atom or a lower alkyl, lower alkoxy, halo, trifluororaethyl, lower alkylthio, lower alkyloxythio or lower alkyldioxythio radical; Am represents a primary amino, methylamino or dimethylamino radical and n is equal to 1, 2 or 3.

The new compounds of formula I have interesting pharmacological properties which make them useful when administered internally to relieve inflammation, to relieve pain, to inhibit the agglutination of blood platelets and to combat an increase in temperature, 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 amino-2 (4-chloro-benzoyl) -3 phenylacetamide which has been found 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% in laboratory animals according to a modification of the pleural effusion test with carrageenan and Evans blue by Sancilio, L. F., J. Pharmacol. Exp. Ther. 168. 199-204 (1969), 30 Compounds of formula I inhibit agglutination. platelets in the test described by Born; J, of Phys. 162, pp 67-68 (1962) and 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 two hours later the rats are bled to obtain plasma rich in platelets. Collagen is added to the platelet-rich plasma to cause agglutination of the platelets and comparisons are made between lesser samples and treated samples.

_ * 3

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, 774 (1976).

5 The antipyretic activity of the compounds of formula I

manifests itself 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 there is a significant change in the rectal temperature of rats at normal temperature.

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

In the present description, the term "lower alkyl" designates straight or branched radicals containing up to 8 carbon atoms such as the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl radicals, pentyl, isopentyl, hexyl, heptyle and octyl. The term "lower alkoxy" denotes -0-lower alkyl radicals.

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

The term "cycloalkyl" denotes in the present description essentially cycloalkyl radicals containing 3 to 12 carbon atoms inclusive such as cyclo-propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Heterocyclic radicals are radicals such as morpholino, pyrrolidinyl-1, piperidino, piperazinyl-1 and the like.

The invention will now be described in detail.

% - ·.

4

The compounds of formula I can be prepared according to reactions comprising the following reaction sequence: x— (Çjl + rW®V 1) t-BuOClj

5 ^ m 2) And-N

I Formula III ^ | (jv - 70 ° C. in chloride / V formula IV of methylene) (Y / ^ v n 3 io sr I 8! 2 °

, bRCm R - cbr-c-hrV

--oL Ύ 15 I Ni de Raney y. ‘C = 0 (THF) ^ C '°

| Formula II / γ Formula I

0 aP

"A 1 2 where R, R, R, X, Y and n have the same definition as above, except that Y cannot represent a lower alkylthio radical 3 or the corresponding oxides and R represents a radical lower alkyl or phenyl. 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 25 _ CHR-G-NR1R2 _, CHR-C- NRlR2 OC oc _ NaS-lower alkyl „_

v — U y L <* “U

0 »to» F xS-lower alkyl 5 and the compounds where Y represents a lower alkyloxy-thio or lower alkyldioxythio radical can be prepared by reaction of compounds where Y represents a lower alkylthio radical with one or two moles of sodium metaperiodate or d metachloroperbenzoic acid according to 5 the following reaction sequence: O 0

h 1 2 "12 _ CHR-C-NRR CHR-G-NRR

Ö _, (Y

Μ NalO, 1 ^ 10 G = 0 C = 0 JL Λ o [Γ ~) Ί S-lower alkyl S-lower alkyl 15 '0

"12 .., CHR-C-NR R

© k y Am, C = 0? 20 or 2NaI0 ^ —S "a ^ y ^ e lower 0

In order 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 2-amino benzophenones are first reacted with tert-butyl hypochlorite and the appropriate thioacetamide when cold (-60 to -70%) and then triethylamine is added.

6 *

The intermediates of formula II are reduced with Raney 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 removal of the solvent and crystallization. In such a reduction, Raney nickel would react on the lower S-alky] e radical.

Preparation 1 (2-methylthio acetyl) -4 morpholine.

A mixture of 10.40.2 g (0.3 mole) of ethyl methylthioacetate and 130 g (1.5 mole) of morpholine is heated at reflux for 70 hours. 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 C ^ H ^ NOjS: 047.98; H = 7.48; N = 7.99% 15 found: 047.55; H = 7.59; N. = 8.18%

Preparation 2 Methylthio-2 N-methylacetamide.

A mixture of 134 g (1.0 mole) of ethyl methylthioacetate and 31010 g (10.0 moles) of methylamine is heated in a bomb at 150 ° C. for 72 hours. 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 C ^ H ^ NOS: 0 = 40.31; H = 7.61; N = 11.75% found: 039.78; H = 7.69; 011.88% 'Preparation 3 Methylthio-2 N.N-dimethylacetamide.

A mixture of 134 g (1.0 mole) of ethyl methylthioacetate and 360 g (8.0 moles) of dimethylamine is heated in a bomb at 150 ° C. for 90 hours. 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 C ^ H ^ NOS: 045.08; H = 8.32; N = 10.51% 35 found: 043.88; H = 8.41; N = 10.60% "7

Preparation 4 Isopropylthio-2 acetamide To a mixture of 46.7 g (0.5 mole) of 2-chloro acetamide in 200 ml of absolute ethanol is slowly added a solution 5 of 38.1 g (0.5 mole) of propanethiol-2 in 100 ml of absolute ethanol and 40 g of 50% aqueous sodium hydroxide. The mixture is heated at reflux for one hour 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 G ^ H ^^ NOS: C = 45.08; H = 8.32; N = 10.51% 15 found: C = 45.05; H = 8.32; N = 10.55%

Preparation 5 Propylthio-2 acetamide.

According to the procedure of preparation 4 but by 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.

Theoretical analysis for C ^ H ^ NOS: C = 45.08; H = 8.32; N = 10.51% found: C = 44.97; H = 8.24; N = 10.40%

Preparation 6 25 Amino-2-benzoyl-3 chloro-5 a- (methvlthio) phenylacetamide.

To a cold solution (-70 ° C) of 12.77 g (0.055 mole) of 2-amino-5-chloro-benzophenone in 300 ml of methylene chloride under nitrogen atmosphere, 6.0 g (0, 0552 mol) of tert-butyl hypochlo-rite in 20 ml of methylene chloride. After another 3P 15 minutes of stirring, a suspension of 5.8 g (0.055 mole) of a- (methylthio) acetamide in 150 ml of methylene chloride is added. The mixture is stirred at -65 ° C for one hour. 5.6 g (0.055 mole) 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 sot.s ss form of a yellow solid F. 173.5-174.5 ° C. The yield is 6.86 g (37.3%).

AT 8 *

Theoretical analysis for C ^ gH ^^ C ^ SCl; 0 = 57.40; 11 = 4.52; N = 8.37% found: 0 = 57.38; H = 4.50; N = 8.51%

Preparation 7

Amino-2 benzoyl-3 a- (raéthYlthio) phenylacétaïTiide 5 A cold solution (-70 ° C) of 19.7 g (0.10 mole) of amino-2 benzophenone in 300 ml of methylene chloride under atmosphere d nitrogen, a solution of 11.5 g (0.10 mole) of 95% tert-butyl hypochlorite in 30 ml of methylene chloride is added and then, after 10 minutes, a solution of 10.5 g (0 , 1 mole)> 10 of methylthioacetamide in 300 ml of tetrahydrofuran. During these additions the temperature is maintained at -55 ° C or below. After another hour 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 11 g (0.11 mole) of triethylamine are added. The mixture is stirred for 5 minutes. 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 was washed with ethyl ether and dried to obtain 13.0 g (43%) of a light yellow powder; Mp 153-155 ° C.

Theoretical analysis for ^^ g ^ g ^ 202S: 0 = 63.98; H = 5.37; N = 9.33% found: C = 63.64; H = 5.39; N = 9.25%

Preparation 8

Amino-2 (4-chloro benzoyl) -3 a- (phenylthio) phenvlacetamide.

To a cold solution (-70 ° C) of 34.6 g (0.15 mol) - 2-amino-chloro-4 'benzophenone in 500 ml of methylene chloride, 17.3 g (0, 15 mol) of 95% tert-butyl hypochlorite and then, after 10 minutes, a solution of 25.0 g (0.15 mole) of phenylthioacetamide in 400 ml of tetrahydrofuran is added over 20 minutes. The temperature is maintained at -64 ° C or below during these additions. After two 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 is partitioned between water and methylene chloride.

The insoluble material in the two phases is collected by filtration, washed with 20% aqueous ethanol and dried 9 r to obtain 36 g (61%) of a light yellow powder; Mp 189-191 ° C. Theoretical analysis for: C = 63.55; H = 4.32; N = 7.06% found: 0 = 63.73; H = 4.36; N = 7.16%

Preparation 9 5 [(Amin.o-2 benzoyl-3 phenvD-2 methvlthio-2 acetyll-4 morpholine.

To a cold solution (-65 ° C) of 9.9 g (0.05 mole) of 2-amino benzophenone and 8.8 g (0.05 mole) of (a-methylthio) acetyl ~ 4 morpholine in 200 ml of methylene chloride, a solution of 5.8 g (0.05 mole) of 95% tert-butyl hypochlorite in 20 ml of methylene chloride is added dropwise. After another hour at -60 ° C, 5.1 g (0.05 mole) 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, first eluting 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 ^ 20 ^ 22 ^ 2 ^ 3 ^ 'C = 64.84; H = 5.99; N = 7.56% found: C = 65, Ol; H = 5.99; N = 7.57%

Preparation 10 25 Amino-2-benzoyl-3 chloro-5 a - [(4-chloro-phenyl) -thio1phenylacetamide.

To a cold solution (-70 ° C) of 20 g (0.0863 mole) of 2-amino-5-chloro-benzophenone in 500 ml of methylene chloride under nitrogen atmosphere, a solution of 9.48 g is added. (0.088 mole) tert-butyl hyprochlorite in 50 ml of methylene chloride.

After a further 15 minutes of stirring, a solution of 17.35 g (0.0863 mole) of a- (chloro-4-phenylthio) acetamide in 500 ml of a mixture of tetrahydrofuran and chloride is added. methylene. The mixture was stirred at -70 ° C for 2 hours, 8.72 g (0.0863 mole) of triethylamine was added and the stirred solution was allowed to warm to room temperature for two hours. 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.

5 Theoretical analysis for C2i®i6N2 ° 2SC12: c = ^> 48; H = 3.74; N = 6.49% found: 0 = 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 mole) of 2-amino-5-chloro-benzophenone in 1.5 liters of methylene chloride, under nitrogen atmosphere, 39.1 is added. g (0.360 mole) of tert-butyl hypochlorite in 100 ml of methylene chloride. After 10 minutes of stirring, a solution of 59.1 g (0.354 mol) of a- (phenylthio) acetamide in 1.5 liters of tetrahydro-furan is added. The mixture is stirred for 1.25 hours at -65 ° C, 37.5 g (0.371 mole) 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 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: C = 63.55; H = 4.32; N = 7.06% found: C = 63.62; H = 4.29; N = 7, Q8% 25 Preparation 12

2-amino-3-benzoyl a- (phenylthio) phenylacetamide.

According to the procedure of Preparation 11, but replacing the 2-amino-5-chloro-benzophenone by an equi-molar amount of 2-amino-benzophenone, the desired compound 30 is obtained with a yield of 57 7. After recrystallization from a mixture of methylene chloride, ethyl ether and hexane, the compound melts at 153-154 ° C.

Theoretical analysis for ^ 21 ^ 18 ^ 2 ^ 2 ^ '^ = 69.59; H = 5.01; N = 7.73 7a found: C = 69.33; H = 5.00; N = 7.76% 11

Preparation 13

2-amino-3-benzoyl a- (methylthio) N-methylphenylacetamide.

A solution of 29.6 g (0.15 mole) of 2-amino benzophenone in 350 ml of 5-methylene chloride is cooled to -70 ° C. and 17.9 g (0.15 mole) of 2-methylthio N-methylacetamide in 20 ml of methylene chloride. A solution of 17.2 g (0.15 mole) of 95% tert-butyl hypochlorite in 30 ml of methylene chloride is added dropwise to the mixture cooled to -70 ° G. The temperature is maintained at -65 ° C or below for 1.5 hours and then rapidly added 15.1 g (0.15 mole) 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 ai-15 yellow guilles; Mp 149-150 ° C.

Theoretical analysis for C ^ H ^ g ^ O ^ S: C = 64.94; H = 5.77; N = 8.91% found: 0 = 65.24; H = 5.83; N = 8.99%

Preparation 14

2-amino-3-benzoyl a- (methylthio) N.N-dimethylphenylacetamide.

A solution of 29.6 g (0.15 mole) of 2-amino benzophenone in 350 ml of methylene chloride is cooled to -70 ° C. and 20.0 g (0.15 mole) of methylthio- are added. 2 N, N-dimé-thylacêtamide. A solution of 17.2 g (0.15 mole) 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 hours and then 15.1 g (0.15 mole) of triethylamine are quickly added. 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; E. 153-155 ° C.

Theoretical analysis for ^ 3 ^ 20 ^ 2 ^ 2 ^ C = 65.83; H = 6.14; N = 8.53% found: 0 = 65.87; H = 6.15; N = 8.52% 12 *

Preparation 15

Amino-2 (4-fluoro benzovD-3 a- (propvlthio) phenylacetamide.

A solution of 21.5 g (0.1 mole) of 4-fluoro-2 'amino-2-benzophenone in 400 ml of methylene chloride is cooled to -70 ° C. and 11.5 g (0, 1 mole) of 95% tert-butyl hypochlorite 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 over 10 minutes. The solution is stirred for one hour between -65 and -70 ° C then allowed to warm to 0 ° C and then 10.2 g (0.1 mole) of triethylamine is added. The solution is stirred for 10 minutes 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 C ^ gEj, 2N2O2SF: 0 = 62.41; H = 5.53; N = 8.09% found: 0 = 62.34; H = 5.58; N = 8.04 7a

Preparation 16

As described in Preparation 8, phenylthioacetamide, tert-butyl hypochlorite and 2-amino-2-fluoro-benzophenone, 2-amino-trifluoromethyl-4 'benzophenone are prepared from phenylthioacetamide. 1'-amino-2-dichloro-2 ', 4' benzophenone or 2-amino difluoro-2 ', 4' benzophenone, amino-2 (2-fluoro-benzoyl) -3 a- (phenylthio) phenylacetamide, l amino-2 (4-trifluoromethyl ben-25 zoyl) -3 a (phenylthio) phenylacetamide, amino-2 (2,4-dichloro ben-zoyl) -3 a- (phenylthio) phenylacetamide and amino-2 (2,4-difluOro benzoyl) -3 a- (phenylthio) phenylacetamide.

Preparation 17

Amino-2 benzoyl-3 chloro-5 "- (methylthio) N-methylphenylacetamide.

30.05.05 g (0.167 mole) is added to a solution of 38.3 g (0.166 mole) of 2-amino-5 chloro-benzophenone in 1 liter of methylene chloride cooled to -70 ° C. under a nitrogen atmosphere ) tert-butyl hypochlorite. The solution is stirred for 15 minutes and then a solution of 20.3 g (0.171 mol) of methyl-35 thio-2 N-methylacetamide in 100 ml of methylene chloride is added. The solution is stirred at -70 ° C for 2 hours, and 25 ml of 13 triethylamine is 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 about 400 ml, ether is added and the refrigerator is placed at about 0 ° C overnight. The solid which has crystallized is dried under high vacuum for about 4 hours at 50 ° C. The product weighs 31.56 g (54.6%) and melts at 170-171 ° C.

Theoretical analysis for: C = 58.53; £ [= 4.91; N = 8.03% found: 0 = 58.68; H-4.91; N-8.13% 10 Preparation 18 t

Benzoyl-3 methvlamino-2 a- (methylthio) phenylacetamide.

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

15 Example 1

2-amino-3-benzoyl-5-chloro-phenylacetamide.

A mixture of 21.34 g (0.0639 mole) of 2-amino-3-benzoyl-5-chloro-5 (methylthio) phenylacetamide and an excess of Raney nickel in a mixture is stirred at room temperature for 45 minutes. 900 ml of absolute ethanol and 200 ml of dimethylfor-mamide. The mixture is filtered on celite to remove the Raney nickel. The solvent is removed in vacuo to obtain a yellow solid which, after recrystallization, melts at 213.5-215.0 ° C (decomposition). Theoretical analysis for; 0 = 62.40; H = 4.54; N = 9.70% 25 found: C = 62.35 N = 4.58; N = 9.74%

Example 2

2-amino-3-benzoyl phenylacetamide.

80 g of wet Raney nickel (washed three times) are added to a stirred solution of 9.7 g (0.032 mole) of 2-no-3-benzoyl-3-methylthio) phenylacetamide in 100 ml of tetra-30 hydrofuran. with water and three times with tetrahydrofuran). After 10 minutes, the mixture is filtered to remove the Raney nickel and the filtrate is concentrated under vacuum. The residue is crystallized from isopropyl alcohol to obtain 6.0 g (73%) of yellow needles. F. 178.5-35 180.0 ° G.

Theoretical analysis for ^ 5 ^ 4 ^ 2 ^ 21 ^ = 70.85; H = 5.55; N = 11.02% found: 0 = 70.53; H = 5.53; N = ll, 04% 14

Example 3

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

To a stirred solution of 28.5 g (0.077 mol) of ami-no-2 (4-chloro-benzoyl) -3 a- (phenylthio) phenylacetamide in 1 liter 5 of tetrahydrofuran, 230 g of wet Raney nickel is added (washed three times with water and three times with tetrahydrofuran). After 15 minutes, 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 etanol, yellow needles are obtained; Mp 212-215 ° C.

Theoretical analysis for: C = 62.40; H = 4.54; N = 9.7Q% found: 0 = 62.76; H = 4.58; N = 9.83%

Example 4 15 [(2-Amino-3-benzoylphenyl) -2 acetyl] -4 morpholine.

To a stirred solution of 18.5 g (0.05 mole) of [(2-amino-3-benzoyl-phenyl) -2-methylthio-acetyl] -4 morpholine in 300 ml of tetrahydrofuran, 150 g of Raney nickel is added wet. After 15 minutes, 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 C ^ H ^ O.}: 0 = 70.35; H = 6.22; N = 8.64% found: 0 = 70.24; H = 6.21; N = 8.63% 25 Example 5

2-amino-3-benzoyl N-methylphenylacetamide.

A solution of 22.5 g (0.072 mole) of 2-amino-3-benzoyl a- (methylthio) N-methylphenylacetamide in 400 ml of tetrahydrofuran is treated with 160 g of wet Raney nickel 30 (washed three times with water and three times with tetrahydrofuran) for 10 minutes. 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 ^] _ 6 ^ 16 ^ 2 ° 2: 6 * 71.62; H = 6, .01; N = 10.44% 35 found: 0 = 71.76; H = 6.05; N = 10.52% 15 a). *

Example 6

Amino-2 benzoyl-3 N.N-dimethylphenylacetamide.

A solution of 33.0 g (0.1 mole) of 2-amino-3-benzoyl a- (methylthio) Ν, Ν-dimethylphenylacetamide in 5500 ml of tetrahydrofuran is treated with 240 g of wet Raney nickel (washed three once with water and three times with tetrahydrofuran) for 10 minutes. 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.

10 Theoretical analysis for ^ 7Hxg ^ 2 ° 2: c = 72.32; H = 6.43; 11 = 9.92% found: C = 72.34; H = 6.42; N = 9.98%

Example 7

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

A solution of 24.2 g (0.07 mole) of amino-2 (4-fluoro-benzoyl) -3 a- (propylthio) phenylacetamide in 300 ml of tetrahydrofuran is treated with 250 g of wet Raney nickel (washed 3 times with water and 3 times with tetrahydrofuran). The mixture is stirred for one hour 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 = 66.17; H = 4.81; N = 10.29% found; 0 = 66.32; H = 4.81; N = 10.48%

Example 8

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

Example 9

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

To prepare this compound, friend no-2 (4-fluoro-benzoyl) -3 phenylacetamide is refluxed with an excess of sodium methane thiolate in ethanol and is isolated as appropriate.

16

Example 10

Amino-2 (4-oxymethylthio benzoyl) -3 phenylacetamide.

To prepare this compound, a mole of 2-amino (4-methylthio-benzoyl) -3-phenylacetamide is reacted with a mole of 5-sodium metaperiodate and is isolated as appropriate.

Example 11

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

To prepare this compound, one mole of 2-amino (4-methylthio-benzoyl) -3-phenylacetamide is reacted with 2 moles of sodium metaperiodate and isolated appropriately.

Example 12

2-amino-3-benzoyl-5-chloro N-methylphenylacetamide.

A solution of 28.33 g (0.081 mole) of 2-amino-3-benzoyl-5 chloro-5- (methylthio) N-methylacetamide in 1 liter of tetrahydrofuran is treated with an excess of Raney nickel at room temperature for 2 hours. 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.

Excess ether is added and the solution is allowed to stand at room temperature for one hour 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 Gx6Hi5N2 ° 2C1: c = Ö3 ^ 48; H = 4.99; N = 9.25% 25 found: 0 = 63.44; H = 4.99; N = 9.27% 'Example 13

Benzoyl-3 methylamino-2 phenylacetamide.

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

Example 14

Benzoyl-3 dimethylamino-2 phenylacetamide.

A solution of 12.7 g (0.05 mol) of 2-amino-3-benzoyl-phenylacetamide in 150 ml of acetonitrile is treated 4 times with 16 ml (0.2 mol) of 37% formalin, 6, 4 g (0.1 mole) of sodium cyanoborohydride and 2 ml of glacial acetic aid with a period of agitation 1 17 of 15 minutes 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 magnesium sulfate and concentrated. The product is isolated by column chromatography.

The invention also relates to therapeutic compositions and pharmaceutical forms containing as active ingredient the compounds of the invention. Effective amounts of any of the pharmacologically active compounds of the invention may be administered to a living being in a variety of ways, for example, 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 the like. 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.

The pharmacologically active compounds can advantageously be used as unit doses containing from 0.1 to 2.50 mg or more of active ingredient depending on the weight of the subject to whom they are administered. For example, a large animal, such as a horse, may require tablets containing 500 to 1,000 mg of active ingredient. Unit doses may conveniently be administered several times a day to obtain a daily dosage of between 0.3 and 450 mg. The optimal unit doses appear to be 5 to 25 mg.

It is sufficient that the active ingredient is present in an effective amount, i.e. an effective dosage is obtained with the form of administration used. The specific dosages can be determined according to conventional medical principles by a doctor or a veterinarian.

‘18" "

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

Examples of compositions according to the invention are given below.

1. Capsules.

Capsules containing 5 mg, 25 mg or 50 mg of active ingredient are prepared. For high amounts of ingredient. 10 active, the amount of lactose is changed.

Typical capsule mix Per capsule (mg) active ingredient 5.0 lactose 296.7 starch 129.0 15 magnesium stearate 4.3

Total 435.0

Another composition for capsules preferably containing a larger amount of active ingredient is as follows: 20 Ingredients Per capsule (mg) active ingredient 25.0 lactose 306.5 starch 99.2 magnesium stearate 4.3 25 Total 435.0, In all cases, the active ingredient is mixed uniformly with lactose, starch and magnesium stearate and introduced into capsules.

2. Tablets A typical composition for preparing tablets containing 5.0 mg of active ingredient is shown below. The composition can be used with other concentrations of active ingredient by modifying the weight of the dicalcium phosphate.

35 "19 Λ" "·

Per tablet (mg) (1) active ingredient 5.0 (2) corn starch 13.6 (3) corn starch (poison) 3.4 (4) lactose 79.2 5 (5) dicalcium phosphate 68.0 (6) calcium stearate 0.9 170.1

1, 2, 4 and 5 are mixed uniformly. 3 are prepared in the form of a 10% paste in water. The mixture "10 is granulated with the starch paste and the wet mass is passed through a sieve with a 2.38 mm mesh opening. The wet granules are dried and passed through a 1.41 mm mesh opening sieve. The dry granules are mixed with the calcium stearate and compressed.

15 3. Sterile solutions for injection at 2%.

per ml

Active ingredient 20 mg preservative, for example chlorobutanol 0.5% w / v water for injection q.s.

The solution is prepared, clarified by filtration, conditioned in bottles, closed and autoclaved.

Of course, various modifications can be made by those skilled in the art to the devices or methods which have just been described solely by way of nonlimiting examples without departing from the scope of the invention.

Claims (5)

1. New compounds, characterized in that they correspond to the formula R 0 E1 '"^> CH-CN„ x — UI r ^ Am Po / ··, 10 + j— where R represents a hydrogen atom or a lower alkyl radical, 1 2 R and R represent a hydrogen atom or a lower alkyl, cycloalkyl, phenyl or phenyl radical substituted by a lower alkyl, lower alkoxy, halo, nitro or trifluoromethyl radical, or • 1 2 15. and R together with the adjacent nitrogen atom form a heterocyclic radical, X represents a hydrogen atom or a lower alkyl, lower alkoxy, halo or trifluoromethyl radical, Y represents a hydrogen atom or a lower alkyl, lower alkoxy radical , halogeno, trifluoromethyl, lower alkylthio, lower alkyloxythio, or lower alkyldioxythio, Am represents a primary aminoamethyl or dimethylamino radical and n is 1, 2 or 3. 2. Compounds according to claim 1, characterized in that they consist of 2-amino-3-benzoyl-5-chloro-phenylacetamide, 2-amino-3-benzoyl-phenylacetamide, 2-amino (4-chloro-benzoyl) -3% 25 phenylacetamide, [(2-amino-3-benzoyl-phenyl) -2 acetyl] -4 morpholine, 2-amino-3-benzoyl-3-ethylphenylacetamide, 2-amino-3-benzoyl, N- dimethylphenylacetamide, 2-amino (4-fluoro-benzoyl) -3 phenylacetamide or 2-amino-3-benzoyl-5-chloro-N-methylphenylacetamide. 3. New drugs useful in particular as anti-inflammatory drugs, antipyretics, inhibitors of the agglutination of blood platelets and analgesics, characterized in that they contain at least one compound according to claim 1 or 2, 4. Pharmaceutical compositions, characterized in that they contain as active ingredient at least one of the medicaments according to claim 3. ": η 5, Pharmaceutical forms of oral or parenteral administration of the therapeutic compositions according to claim 4, preferably in the form of unit doses containing 0.1 to 250 mg of active ingredient. "H