CH626806A5 - 2-Amino-3-(-5- and -6-)benzoylphenylacetic acid derivatives and process for preparing them - Google Patents

Description

The present invention relates to novel amino acids.

2-Benzoyl-3- (5- and -6) -phenylacetics, their esters and their salts of the invention relates in particular to amino-2-phenyl acids

alkali and alkaline earth metals, process for their preparation and acetics, their esters and their metal salts corresponding to the formula pharmaceutical compositions containing them. general:

CHRCOOR

(i)

and

CHRCOO

R '

(I-A)

wherein R is a hydrogen atom or a lower alkyl group, R1 is a hydrogen atom, an alkali or alkaline earth metal cation or a lower alkyl group, R2 is a hydrogen or halogen atom or a lower alkoxy group, X is a hydrogen or halogen atom or a lower alkyl group,

nitro or trifluoromethyl, Y is a hydrogen or halogen atom or a lower alkyl group, nitro or trifluoromethyl and Am is a primary amino group (—NH2), methylamino or dimethylamino, with the additional condition that in benzoyl derivatives -3 and -5, R1 cannot be a hydrogen atom when Y and R2 are hydrogen atoms and Am a NH2 group, and R3 is an alkaline earth metal, preferably calcium or magnesium.

The preferred alkali metal salts of formula I are the sodium and potassium salts. The salts are endowed with anti-inflammatory activity and are useful intermediates for the preparation of the esters of formula I.

The new compounds of formula I and I-A have interesting pharmacological properties and are useful as pharmaceutical agents. The compounds are endowed with anti-inflammatory activity, lower the blood cholesterol contents in rats in a state of hyperlipemia and inhibit the agglomeration of 50 platelets.

Anti-inflammatory activity is demonstrated by a modification of the Evans blue / carrageenan pleural effusion test described by Sancilio, L.F., in "J. Pharmacol. Exp. Ther. ", 168,

pp. 199-204 (1969).

55 The subject of the invention is therefore new compounds and the pharmaceutical compositions which contain them with a view to relieving inflammation, reducing cholesterol levels and inhibiting the agglomeration of platelets with a minimum of undesirable side effects.

60

In the definition of the symbols in formula I and the formulas below, the terms used in the present description have the following meanings:

The term lower alkyl is used to designate radicals with a straight or branched chain up to and including C6, preferably up to C4, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, amyl, isoamyl and hexyl. The term lower alkoxy corresponds to the formula —O — lower alkyl.

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The term halogen is used to denote a halogen having preferably, but not necessarily, an atomic weight less than 80.

Substituents which can be attached to the mono- or disubstituted benzoyl radical can be halogens or lower alkyl, nitro or trifluoromethyl groups or mixtures thereof, said mono- and disubstituted benzoyl groups including, but not limited to, benzoyl (lower alkyl) groups , halobenzoyl such as chloro-benzoyl, bromobenzoyl and fluorobenzoyl, nitrobenzoyl and trifluoromethylbenzoyl, 3,5-dichloro benzoyl, 2,4-dichloro-benzoyl, 3-trifluoromethyl-4-chloro-benzoyl, 2,4-dimethyl, 3,5-dimethyl benzoyl, 3-nitro-4-chloro-benzoyl, 2-methyl-4-chloro-benzoyl, 3-methoxy-4-chloro-benzoyl, or 3,4-methylenedioxy benzoyl.

The term benzoyl is understood below to denote the unsubstituted benzoyl radical and the mono- and disubstituted benzoyl radicals.

The invention also relates to a process for the preparation of benzoyl-3- (5- and -6) -phenylacetic acids of formula I above in which R is a hydrogen atom, or a lower alkyl group, R1 is a hydrogen atom, R2 is a hydrogen or halogen atom or a lower alkoxy group, X is a hydrogen or halogen atom or a lower alkyl group nitro or trifluoromethyl, Y is a hydrogen atom or halogen or a lower alkyl, nitro or trifluoromethyl group and Am is NH2methylamino or dimethylamino, and their salts and esters.

According to the invention, the 2-amino-benzoyl-3- (5- and -6) -phenylacetic acids are prepared from suitable substituted aminobenzophenones of general formula:

/ = \ 9

. w.

• R

in which X, Y and R2 are as defined above with an α-methylthioacetic ester of formula CHR (SCH3) COOR1 in which

R is as defined above and R1 is a lower alkyl group, and tert-butyl hypochlorite to obtain a compound of general formula:

cr (sch3) coor

1

XI

in which X, Y, R, R1 and R2 are as defined above, which is hydrolyzed without isolating it with an acid to obtain a benzoyl-4- (5- or -7) -methylthio-3 indolinone -2 of general formula:

r

-sch

3 XII

20

at)

h in which X, Y, R and R2 are as defined above; Compound XII is treated with Raney nickel under a nitrogen atmosphere to obtain the benzoylindolinone of general formula:

X

II

^ ao h

wherein X, Y, R and R2 are as defined above, and indolinone II is hydrolyzed in an aqueous base and acidified with a weak organic acid or a dilute inorganic acid.

The above reaction sequence is illustrated by the reaction scheme below:

+ chr (sch3) c00r t-BuOCl

CR (SCH3) COOR

.SCH.

H

Nor of Raney

XII

5

626806

II

/ V

chrcooh

wherein X, Y, R, R1 and R2 are as defined above.

The hydrolysis of indolinone-2 of formula II is carried out in an aqueous base, for example a 3N sodium hydroxide solution, for approximately 1 h to 1 h. The hydrolysis can be carried out in an inert atmosphere using nitrogen. The hydrolysis mixture can be filtered to separate the insoluble substances in the base and the basic solution can be adjusted to pH 6-7 by the addition of an acid.

weak organic, such as acetic acid, or a dilute inorganic acid, such as hydrochloric acid. When the compound I is 2-amino-5-benzoylphenylacetic acid, the product can easily be recrystallized from an appropriate solvent. When Compound I is a 2-amino-3-benzoylphenylacetic acid, recrystallization may result in partial cyclization to 7-benzoyl-indolinone-2. Therefore, in the preparation of a 2-amino-3-benzoylphenylacetic acid of formula I, the product is not usually recrystallized and is isolated by carefully acidifying the basic filtered hydrolysis mixture.

Preferably, the lower alkyl esters of formula I are prepared from the acids which are converted to the alkali metal salt, preferably the sodium or potassium salt, which are isolated, dried and reacted. in a suitable solvent, for example dimethylformamide, with an alkyl halide, preferably an alkyl iodide, to give the desired ester.

The compound of formula I in which Am is a dimethylamino group is prepared by reaction of the 2-amino benzoylphenylacetic acid of formula I in which Am is an amino group with formaldehyde and sodium cyanoborohydride in a solvent such as l acetonitrile under mild acid conditions, for example using glacial acetic acid.

The 5-benzolin-indolinones-2 can also be prepared by reacting an indolinone-2 of formula III with a benzoyl chloride in the presence of aluminum chloride, as indicated by the diagram below:

Indolinones-2 of formula III are commercially available or they can be prepared by methods known in the art, for example that described by Wenkert et al., "J. Am. Chem. Soc. ”, 81, pp. 3763-3768 (1959).

Benzoyl-7-indolinones-2 can be prepared by the following reactions:

H

I

NHs

IV

_CH2 — C-CH3

.1) oh 2) h +

c2H5OH

HCl

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I

h +, 03

h +, o3

The starting amino-2 indolinones-2 of formula IV can be prepared by suitable methods known in the art such as those described by Baumgarten et al., "J. Am. Chem. Soc. ”, 82, pp. 3977-3982 (1960). The 1-amino-indolinone-2 of formula IV is reacted with a phenylacetone to obtain a (α-methyl-phenethylidene-imino) -1 indolinone-2 of formula V which is cyclized in ethanolic hydrochloric acid in < x- (2-methyl-phenyl-3 40 indolyl-7) to obtain a acetamido-2 benzoyl-3 ethyl phenylacetate of formula VII which is cyclized in an inorganic acid diluted in benzoyl-7 indolinone-2 of formula II .

It is also possible to hydrolyze an oc- (2-methyl-3-phenyl-indolyl-7) ethyl acetate of formula VI in aqueous basic solutions of a- (2-methyl-phenyl-3 indolyl-7) acetic acid of formula VIII that it is treated with ozone in acetic solution to obtain a 2-acetamido-3-benzoyl-phenylacetic acid of formula IX. The acid is cyclized to benzoyl-7 indoIinone-3 of formula II by a dilute acid which hydrolyzes the amido-2 function. 50

The compounds of formula II in which R2 is a methoxy group can be prepared by catalytic reduction of 7-carboxy-5-methoxy-isatin, a known compound obtained by a modification of the process described by Cragoe, E. J. et al. in "J. Org. Chem. ”, 18, p. 561 (1953), in 7-carboxy-5-methoxy-2-indolinone and reaction of the latter 55 compound with phenyllithium.

The compounds of formula II in which R2 is a chlorine atom can be prepared by reaction of the known 5-chloro-indolinone-2 with benzoyl chloride in the presence of aluminum chloride.

The following examples illustrate the invention without, however, limiting its scope. Examples 1 to 27 describe the preparation of indolinones of formula II and Examples 28 to 55 describe the preparation of benzoylphenylacetic acids of formula I.

Example 1:

Preparation of benzoyl-7 chloro-5 indolinone-2.

A mixture of 162.5 g (1.08 mol) of benzoyl chloride and 260 g (1.80 mol) of aluminum chloride is treated, heated to

200 ° C with stirring, with 65 g (0.360 mol) of chloro-5 indolinone-2. The mixture is stirred for 15 min and poured onto ice. The resulting precipitate is triturated with boiling water, then with chloroform. The chloroform solution is washed with 5% sodium bicarbonate, then with water, dried over sodium sulfate and the solvent is removed to obtain approximately 55 g of a bright solid. This substance is then triturated with hot methanol and the methanol is evaporated in vacuo to obtain approximately 20 g of a yellow solid substance. The extraction of a benzene solution of this substance makes it possible to separate the starting 5-chloro-indolinone-2 which may be present and, after washing with water and drying and evaporating the benzene, 3 g of a gray substance are obtained. blue. Trituration of this substance with methanol at room temperature gives a residue which is recrystallized from methanol. 2.5 g of a solid identified with the desired product are obtained, mp 186-187 ° C.

Elementary analysis for ClsH10ClNO2:

Calculated: C 66.31 H 3.71 N 5.16%

Found: C 66.27 H 3.83 N 5.07%

Example 2:

Preparation of 5-methoxy-7-benzoyl-indolinone-2.

A suspension of 1.0 g (4.9 mmol) of 5-methoxy-7-carboxy-2 indolinone-2 in 20 ml of tetrahydrofuran is treated dropwise with 12 ml of a commercial solution of 2.3M phenyllithium (0.28 mol) in an ether / benzene mixture. After stirring for 2 h, the reaction mixture is poured into water and it is extracted several times with ethyl ether and benzene. The combined extracts are washed with water, dried over sodium sulfate and concentrated in a rotary evaporator to obtain a solid residue which is recrystallized from a hydro-acetone mixture. 250 mg (yield 21%) of a yellow powder are obtained, mp 154 ° C.

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Elementary analysis for Cl6H13N03:

Calculated: C 71.90 H 4.90 N 5.24%

Found: C 71.72 H 5.15 N 5.13%

Example 3:

Preparation of 4-benzoyl-3-methylthio-indolinone-2.

A solution of 30.0 g (0.152 mol) of 3-amino benzophenone in 600 ml of methylene chloride is cooled to -8 ° C. in a dry ice / acetone bath and treated dropwise under an atmosphere of nitrogen with a solution of 16.5 g (0.152 mol) of tert-butyl hy-pochlorite in 60 ml of methylene chloride. When the addition is complete, the thin layer chromatography shows, after 1 hour, that there is no more starting material. A solution of 20.2 g (0.152 mol) of ethyl α-methylthioacetate in 60 ml of methylene chloride is added dropwise and the stirring is continued at −78 ° C. for 2 h. A solution of 15.4 g (0.152 mol) of triethylamine in 60 ml of methylene chloride is added dropwise at -78 ° C and the reaction mixture is allowed to warm to room temperature with stirring for 16 h (overnight ). The dark brown solution is treated with 100 ml of 3N hydrochloric acid and stirred for 3 h at room temperature. After 15 to 30 min, it begins to precipitate a brown solid. 18.5 g of a solid are obtained by filtration, mp 224-228 ° C (decomposition). The layers of the filtrate are separated, the organic phase is dried over magnesium sulphate, evaporated under reduced pressure and the residue is triturated in 25 g of isopropyl ether. The gummy solid is triturated in cold methanol to obtain 8.3 g of product, mp 222-225 ° C (decomposition). The total yield is 26.8 g (62%). A 7.0 g sample is recrystallized from methanol and 5.6 g of product is obtained, mp 235-237 ° C (decomposition).

Elementary analysis for C16H13N02S:

Calculated: C 67.823 H 4.625 N 4.943%

Found: C 67.86 H 4.71 N 4.85%

Example 4:

Preparation of (4-chloro-benzoyl) -7 methylthio-3 indolinone-2.

A solution of 23.1 g (0.1 mol) of 2-amino-chloro-4 'benzophenone in 400 ml of methylene chloride is cooled to -65 ° C. and treated dropwise with 12.4 g (0 , 1 mol) of tert-butyl hypochlorite. After 15 min, 13.4 g (0.1 mol) of ethyl α-methylthioacetate are added dropwise while maintaining the temperature at -65 ° C. After 1 h, 10.1 g (0.1 mol) of triethylamine is added and the reaction mixture is allowed to return to room temperature. Water is then added to the solution and concentrated. The residue is taken up in methanol, the solution is brought to reflux, IN hydrochloric acid is added and the resulting mixture is continued to reflux overnight. The mixture is cooled, the resulting precipitate is filtered and recrystallized from toluene to obtain 10 g (33% yield) of a cream-colored solid, mp 186-188 ° C.

Elementary analysis for C16H12CIN02S:

Calculated: C 60.47 H 3.81 N4.41%

Found: C 60.29 H 3.76 N 4.43%

Example 5:

Preparation of 7-benzoyl-3-methyl-3-methylthio-indolinone-2.

A stirred solution of 3.94 g (0.02 mol) of 2-amino benzophenone in methylene chloride is treated at -65 ° C with 2.16 g (0.02 mol) of tert-butyl hypochlorite. After 15 min, 2.96 g of ethyl α-methylthiopropionate are added dropwise and the stirring is continued for 1 h. At the end of this time, 2.02 g (0.02 mol) of triethylamine is added dropwise and the reaction solution is allowed to warm to ambient temperature. It is then treated with IN hydrochloric acid and stirred for

15 min. The methylene chloride solution is then separated and concentrated in vacuo. The yellow oily residue is triturated with isopropyl ether and 3 g (51%) of a yellow solid are separated by filtration. After recrystallization from absolute ethanol, a cream-colored solid is obtained, mp 135-137 ° C.

Elementary analysis for CinHlsN02S:

Calculated: C 68.66 H 5.08 N 4.71%

Found: C 68.54 H 5.08 N 4.63%

Example 6:

Preparation of benzoyl-7 methylthio-3 indolinone-2.

A solution of 300 g (1.52 mol) of 2-amino benzophenone in 41 of methylene chloride is cooled to -40 ° C. and then treated with 204 g (1.52 mol) of α-methylthioacetate. ethyl dissolved in methylene chloride. The reaction mixture was cooled to -65 ° C and treated dropwise with 50 ml of a solution of 164 g (1.52 mol) of tert-butyl hypochlorite in methylene chloride. When the addition is complete, the stirring is continued for 2 h at -70 ° C. The solution is then treated with 182 g (1.8 mol) of triethylamine and allowed to return to room temperature overnight. The methylene chloride solution is washed twice with ice-cold water, then dried over sodium sulfate and the dried solution is concentrated under reduced pressure until a yellow oil is obtained. The oil is taken up in 1.51 methanol, treated with 11 IN hydrochloric acid and heated at reflux for 2 h. After cooling in an ice bath, filtration and drying, 343 g (yield 79.9%) of crude product are obtained. By means of two recrystallizations from toluene, creamy white flakes, F 130 ° C, are obtained.

Elementary analysis for C16H13N02S:

Calculated: C 67.82 H 4.62 N 4.97%

Found: C 68.06 H 4.68 N 4.87%

Example 7:

Preparation of benzoyl-4 indolinone-2.

A stirred suspension of 7.0 g (0.0248 mol) of 4-benzoyl-3-methylthio-2-indolinone-2 in 400 ml of tetrahydrofuran is treated in portions under a nitrogen atmosphere with 35.0 g of 2 Vi Raney nickel h. The reaction mixture is stirred for A h when the addition is complete and the catalyst is filtered off. The filtration cake is washed well with tetrahydrofuran and methylene chloride and the filtrate is evaporated under reduced pressure. 5.6 g of residue are obtained which are recrystallized from methanol to obtain 4.45 g (yield 76%) of product, mp 210.5-212 ° C.

Elementary analysis for C15Hl iN02:

Calculated: C 75.937 H 4.673 N 5.904%

Found: C 75.85 H 4.59 N5.92%

Example 8:

Preparation of (4-chloroyl benzoyl) -7 indolinone-2.

A stirred solution of 9 g (0.028 mol) of (4-chloro-benzoyl) -7-methylthio-2-indolinone-2 in 180 ml of tetrahydrofuran is treated in 2 h with 45 g of a commercial Raney nickel aqueous suspension. The mixture is filtered when the addition is complete. A drop of concentrated HCl is added to the filtrate which removes the coloring, then the resulting solution is evaporated under the vacuum of the water pump to obtain a cream-colored substance. Recrystallization from toluene gives pink needles (yield 93%); the substance sintered at 177 ° C and melts at 186 ° C.

Elementary analysis for ClsH10ClNO2:

Calculated: C 66.31 H 3.71 N 5.16%

Found: C 65.97 H 3.56 N5, ll%

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626806

Example 9:

Preparation of benzoyl-7 methyl-3 indolinone-2.

A stirred solution of 8 g (0.027 mol) of 7-benzoyl-3-methyl-3-methylthio-2-indolinone-2 in 80 ml of tetrahydrofuran is treated in a nitrogen atmosphere over 2 hours with 40 g of a commercial Raney nickel mixture. /water. At the end of this period, the mixture is filtered and the residue is washed thoroughly with tetrahydrofuran. A drop of concentrated HCl is added to the filtrate and the dark orange solution turns pale yellow. The solution is evaporated under vacuum to obtain a yellow oil which crystallizes on sowing. The substance is recrystallized from a toluene / petroleum ether mixture to obtain 6.0 g (89% yield) of a white crystalline solid, mp 125-127 ° C.

Elementary analysis for C16H13NOî:

Calculated: C 76.43 H 5.22 N5.57%

Found: C 76.38 H 5.22 N 5.52%

Example 10:

Preparation of (4-fluorobenzoyl) -7-indolinone-2.

A stirred suspension of 12.3 g (0.41 mol) of 7- (4-fluorobenzoyl) -3-methylthio-indolinone-2 in 250 ml of tetrahydrofuran is treated for 2 h with 60 g of an aqueous nickel suspension of commercial Raney. The mixture is then filtered under a nitrogen atmosphere and the residue is washed with tetrahydrofuran and methylene chloride. The filtrate is treated with a few drops of concentrated hydrochloric acid and then concentrated under reduced pressure to give 9.5 g (91%) of 7- (4-fluorobenzoyl) indoli-none-2.

Example 11:

2-amino-3-benzoyl-5-chloro-phenylacetic acid hemihydrate.

A mixture of 1.5 g (0.055 mol) of chloro-5-benzoyl-7 indolinone-2 in 35 ml of 3N sodium hydroxide is heated at reflux for 45 min and the resulting solution is filtered and diluted with an equal volume of water. The solution is then slowly neutralized with glacial acetic acid. The resulting yellow-green precipitate is filtered off and dried in a drying gun (without heating). 1.0 g (yield: 63%) of the compound is obtained, mp 85 at 87 ° C.

Elementary analysis for Ct SH12 ClN03 ViHz O:

Calculated: C 60.31 H 4.39 N 4.69%

Found: C 60.59 H 4.09 N 4.65%

Example 12:

Amino-2 benzoyl-3 methoxy-5phenylacetate sodium sesquihydrate.

A suspension of 75 mg (0.27 mol) of 5-methoxy-7-benzoyl-indolinone-2 in 5 ml of 3N sodium hydroxide is heated at reflux for 2 A h. The resulting orange-yellow solution is cooled, diluted with several times its volume of water; filtered and saturated with sodium chloride. The solution is then passed slowly through a polyethylene column (0 6.35 mm x 20.32 cm) containing a polymeric adsorbent sold under the name Amberlite XAD-2. The column is then washed with a saturated sodium chloride solution to separate all of the residual base. While attempts are made to wash off the sodium chloride, the desired product, however, also begins to elute (as observed by following its characteristic yellow color). A number of fractions are collected to ensure separation of all of the sodium chloride and, when the color begins to fade in the eluate, the column is finally swept with a methanol / acetone mixture. Evaporation of this organic solution gives, with a yield of 80%, a yellow solid which decomposes above 265 ° C; the nuclear magnetic resonance spectrum confirms that the product crystallizes with 1.5 mol of water.

Elementary analysis for C16H1ANOi, 1.5H20:

Calculated: C 57.49 H 5.126 N 4.19%

Found: C 57.63 H 4.90 N 4.25%

Example 13:

2-Amino-3-benzoyl phenylacetate sodium dihydrate.

A mixture of 2.6 g of 2-amino-3-benzoyl-phenylacetic acid and 0.1 mol of sodium hydroxide in 25 ml of water is stirred for approximately 10 min and then heated to reflux under a nitrogen atmosphere. . The reaction mixture is then cooled and filtered. The filtrate is evaporated to about 2 ml, filtered again and a large volume of acetone is added to the filtrate to precipitate the product in the form of bright yellow needles. Yield 70%.

Elementary analysis for ClsH16NOsNa, 2 H20:

Calculated: C 57.51 H 5.15 N 4.47%

Found: C 58.22 H 4.62 N 4.47%

Example 14:

2-Amino-3-benzoyl ethyl phenylacetate.

A solution of 2.5 g (0.009 mol) of 2-amino-3-benzoyl-phenylacetate in 25 ml of anhydrous dimethylformamide is treated with 5.0 g (0.035 mol) of methyl iodide. The mixture is stirred for 2 h at room temperature using a magnetic stirrer. The mixture is diluted with water and the aqueous solution is extracted several times with ethyl ether. The combined extracts are washed with water, dried over sodium sulfate and concentrated in vacuo to obtain a yellow solid. Recrystallized from absolute ethanol and 1.7 g (yield 61.0%) of yellow needles are obtained, mp 77-78 ° C.

Elementary analysis for CnHlnN03:

Calculated: C 72.07 H 6.05 N4.94%

Found: C 72.33 H 5.83 N 5.07%

Example 15:

Amino-2-benzoyl-3 methyl phenylacetate.

A solution of 4.0 g (0.014 mol) of 2-amino-3-benzoyl phenylacetate in 100 ml of anhydrous dimethylformamide is treated with 8.0 g (0.057 mol) of methyl iodide. After stirring for 2 h, the solution is poured into water and the aqueous solution is extracted several times with ethyl ether. The combined extracts are washed with water, dried over sodium sulfate and concentrated in vacuo to obtain a yellow oil. The oil is recrystallized from an ice-cold hydromethanol solution to obtain 3.5 g (90% yield) of a yellow solid, mp 52-54 ° C.

Elementary analysis for C16HlsN03:

Calculated: C 71.36 H 5.61 N 5.20%

Found: C 71.51 H 5.63 N 5.27%

Example 16:

Dimethylamino-2-benzoyl-3 methyl phenylacetate.

A stirred solution of 4.6 g (0.0165 mol) of 2-amino-3-benzoyl-3-phenylacetate and 13.2 ml (0.165 mol) of 37% for-maldehyde in 66 ml of acetonitrile is treated with 3.14 g (0.0495 mol) of sodium cyanoborohydride. 1.65 ml of acetic acid crystallizable over 10 min are added and the stirring is continued for 2 h at room temperature. A further 1.65 ml of glacial acetic acid is added and the mixture is further stirred for a weekend (approximately 65 h). The mixture is diluted with ether and the ethereal solution is washed successively with a 3N potassium hydroxide solution and with water, dried over sodium sulfate and concentrated in vacuo to give 1.0 g (18% ) a yellow oil. A portion of this oil is subjected to molecular distillation to obtain an analytical sample.

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Elementary analysis for ClsH19N03:

Calculated: C 72.71 H 6.44 N 4.71%

Found: C 72.33 H 6.26 N4.99%

Example 17:

2-Dimethylamino-3-benzoylphenylacetic acid.

A mixture of 500 mg (1.85 mmol) of 2-dimethylamino-3-benzoyl-phenylacetate and 15 ml of 3N sodium hydroxide is heated at reflux for 1 h under nitrogen. The reaction mixture is cooled and filtered and diluted with an equal volume of water and neutralized with glacial acetic acid. The precipitate formed cannot be recrystallized and it is therefore dissolved in benzene and the solution is passed through a column of magnesium silicate. Eluted with a benzene / acetone mixture to obtain 300 mg of product; after recrystallization from a benzene / isooctane mixture, mp 144-146 ° C.

Elementary analysis for Cx 1H1 nN03:

Calculated: C 72.07 H 6.05 N4.94%

Found: C 72.32 H 6.09 N 4.85%

Example 18:

Amino-2 benzoyl-6phenylacetate sodium hydrate.

A suspension of 4.5 g (0.0190 mol) of 4-benzoyl-indolinone-2 in 200 ml of 3N sodium hydroxide is heated for 4 hours under a nitrogen atmosphere. The volume of water is reduced by about half and the solution is saturated with sodium chloride. The solution is chromatographed on an ion exchange column containing 230 ml (wet volume) of Amberlite XAD-2 in distilled water. The product precipitates at the top of the column, but dissolves as the column is eluted with distilled water. The fractions containing the product are collected and combined and the solvent is separated under reduced pressure to obtain 4.6 g of solid. By recrystallization from a methanol / ether mixture, 0.91 g of a yellow solid is obtained, m 256.5-258.5 ° C (decomposition). The filtrate is evaporated under reduced pressure and the residue is dissolved in hot isopropyl alcohol, adding a small amount of water. The hot solution is filtered to separate a suspended solid. The filtrate is inoculated and placed in the freezer for 12 h. A pale yellow solid separates which is collected by filtration and 2.84 g (yield 50.3%) of product of 254.5-256 ° C. (decomposition) are obtained. A portion of the crude product is dried under high vacuum at room temperature.

Elementary analysis for C15H14NaN04:

Calculated: C 61.017 H 4.779 N 4.74%

Found: C 60.63 H 4.50 N 4.71%

Example 19:

Amino-2 (4-chloro benzoyl) -3 sodium phenylacetate hydrate.

A mixture of 3.5 g (0.0125 mol) of 2-amino acid (p-chlorobenzoyl) -3 phenylacetic acid in aqueous solution containing 0.5 g (0.0125 mol) of sodium hydroxide, cooled and filtered. The filtrate is concentrated to an oily consistency and poured into a large volume of acetone. A yellow precipitate separates which is collected and identified with the desired product by its nuclear magnetic resonance spectrum. 2.6 g (product 67%) are obtained; after recrystallization from an ethanol / ethyl ether mixture, M 265 ° C (decomposition).

Elementary analysis for C1SH13 ClN04Na:

Calculated: C 54.64 H 3.97 N 4.24%

Found: C 55.61 H 3.68 N 4.31%

Example 20:

Amino-2 benzoyl-3 x-methylphenylacetate sodium hydrate.

Heating under reflux under a nitrogen atmosphere for 18 h a suspension of 9 g (0.036 mol) of 7-benzoyl-3-methyl-2-indolinone in 100 ml of 3N sodium hydroxide. The mixture is filtered and evaporated under the vacuum of the water pump to obtain a gummy mixture of sodium hydroxide, water and the product. The mixture is triturated in boiling isopropyl alcohol and filtered. The isopropyl solution is cooled and filtered to separate a bright yellow product. 4.0 g of the product are obtained, m 218 ° C (decomposition).

Elementary analysis for CieH14N03Na:

Calculated: C 57.31 H 5.41 N 4.18%

Found: C 57.69 H 5.12 N 4.27%

Example 21:

Amino-2 benzoyl-3 phenylacetate potassium hydrate.

A solution of 4.0 g (0.015 mol) of 2-amino-3-benzoyl-phenylacetic acid in 40 ml of tetrahydrofuran is treated with 5.06 g (0.045 mol) of a 50% potassium hydroxide solution; a precipitate immediately separates. The cold solution is stirred (ice bath) for 1 h under a nitrogen atmosphere and filtered. The dried product is recrystallized from an ethanol / isopropyl ether mixture to obtain 3.5 g (72% yield) of the product in the form of long yellow needles.

Elementary analysis for ClsH12N03K, HzO:

Calculated: C 57.85 H 4.53 N 4.50%

Found: C 57.78 H 4.47 N 4.62%

Example 22:

Is heated under reflux for Vi h a mixture of 1.0 g (0.004 mol) of (methylenedioxy-3,4-benzoyl) -5 indolinone-2 and 30 ml of 3N sodium hydroxide. The reaction mixture is cooled, acidified to pH 6 with 3N hydrochloric acid and the weakly acidic solution is extracted with chloroform. The chloroform extracts are dried over magnesium sulfate and concentrated until a solid is obtained. By recrystallization from aqueous ethanol, 2-amino acid (methylenedioxy-3,4-benzoyl) -5 phenylacetic is obtained.

Example 23:

2-amino acid (3,4-dimethoxy benzoyl) -5phenylacetic.

When the (methylenedioxy-3,4-benzoyl) -5 indolinone-2 is replaced in the process of Example 25 by an equi-molecular amount of (dimethoxy-3,4-benzoyl) -5 indolinone-2, 2-amino acid (3,4-dimethoxy benzoyl) -5 phenylacetic is obtained.

Example 24:

2-amino acid (3,4-dichloro benzoyl) -5 phenylacetic.

When the (methylenedioxy-3,4-benzoyl) -5 indolinone-2 is replaced in the process of Example 25 by an equi-molecular amount of (dichloro-3,4-benzoyl) -5 indolinone-2, 2-amino acid (3,4-dichloro-benzoyl) -5 phenylacetic is obtained.

Example 25:

2-amino acid (3-methoxy-4-chloro-benzoyl) -5phenylacetic.

When the (methylenedioxy-3,4-benzoyl) -5 indolinone-2 is replaced in the process of Example 25 by an equi-molecular amount of (methoxy-3-chloro-4 benzoyl) -5 indolinone-2, 2-amino acid (3-methoxy-4-chloro-benzoyl) -5 phenylacetic is obtained.

The alkali metal salts prepared as described in the examples above are isolated in hydrated forms. They can be dehydrated in vacuo and stored in anhydrous form away from moisture.

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Example 26:

Preparation of 2-amino-3-benzoyl magnesium phenylacetate trihydrate.

oc <-

Mg2 +, 3H20

c = o

An aqueous solution of 6.36 g (0.02 mol) of 2-amino-3-benzoylphenylacetic acid is treated with an aqueous solution of 0.01 mol of magnesium chloride. A precipitate is immediately formed. After stirring for 15 min, the brilliant yellow precipitate is filtered and dried. Yield 4.06 g, mp 150-190 ° C.

Elementary analysis for C30H30N2O9Mg:

Calculated: C 61.40 H 5.15 N 4.77%

Found: C 61.18 H 5.19 N 4.72%

Example 27:

Preparation of 2-amino-3-benzoyl phenylacetate dihy-draté calcium.

ch2-c = o

A solution of 5 g (approximately 0.02 mol) of 2-amino-3-benzoylphenylacetic acid in 50 ml of water is treated with 1.2 g (approximately 0.01 mol) of calcium chloride in 10 ml of 'water. A precipitate is immediately formed which is stirred for a further 15 min and then filtered. Recrystallized from aqueous ethanol. And we obtain bright yellow needles, F 160 ° C- »glass 240 ° C (decomposition).

Elementary analysis for C30H28N2OsCa:

Calculated: C 60.91 H 4.85 N 4.60%

Found: C 60.70 H 4.92 N 4.72%

Example 28:

Preparation of (p-chlorobenzoyl) -3-benzoylamino-2phenylacetic acid.

(Formula at the top of the next column)

An ethanolic solution of 4.8 g (0.02 mol) of 2-benzoylamino-3-p-chlorobenzoyl-3-phenylacetate in 250 ml of ethanol is treated with 8 ml of 50% NaOH diluted in 250 ml of water (0.04 mol of NaOH). This mixture is then heated under reflux for 25 min, the ethanol is then evaporated from the light orange solution and the residue is diluted with another 250 ml of water. This mixture is extracted several times with ethyl ether to separate any neutral products, the aqueous solution is acidified to obtain a white precipitate which is filtered and dried. 3.8 g (yield 84%) of the product are obtained, mp 218-220 ° C.

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Elementary analysis for C22H16CIN0 ^:

Calculated: C 67.10 H 4.10 N3.56%

Found: C 67.39 H 4.22 N3.44%

Example 29:

Salt (1: 1) of 2-amino thiazole of 2-amino-3-benzoylphenylacetic acid solvated (1: 1) with benzene.

Ca2 +, 2H20

C6H6

A suspension of 9.5 g (0.037 mol) of 2-amino-3-benzoyl-phenylacetic acid in isopropyl alcohol is treated with a solution of 3.7 g (0.037 mol) of 2-amino thiazole in isopropyl alcohol. The mixture is stirred for 15 min until a yellow solution is formed. The solution is evaporated and the residue is recrystallized from benzene to obtain the desired salt. Yield 82%, M 84-87 ° C.

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Elementary analysis for C2iHZ3N303S: Calculated: C 66.49 H 5.35 N9.69% Found: C 65.70 H 5.33 N9.89%

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Example 30:

Preparation of sodium amino-2 (4-fluoro benzoyl) -3phenylacetate monohydrate.

• ch.

NH,

c = 0

I

f

A solution of 1 g (0.0036 mol) of 4-fluoro-benzoyl) -7-amino-2-phenylacetic acid in 10 ml of THF is treated with 0.7 g (0.009 mol) of a 50% NaOH solution. % and stirred under nitrogen for 15 min before a yellow precipitate forms. The mixture is cooled in an ice bath for 2 h while continuing to stir. The precipitate is separated by filtration and dried in air. Recrystallized from a THF / H2O mixture to obtain 150 mg (20% yield) of the product, M 240-250 ° C (decomposition).

Elementary analysis for C1SH11FN03Na:

Calculated: C 61.02 H 3.76 N 4.74%

Calculated: C 57.51 H 4.18 N 4.47%

(for monohydrate)

Found: C 58.23 H 3.81 N 4.53%

Example 31:

Preparation of ethyl amino-2 (4-chloro benzoyl) -3phenylacetate.

o-c-h nh,

c = 0

<Ù

j,

14 g of a very impure sample of 2-amino-4-chloro-3-benzoyl-phenylacetic acid are dissolved in about 150 ml of DMF and then treated with 30 g of ethylene iodide. The solution is then stirred at room temperature for 2 h. The solution is added to water and the mixture is extracted several times with benzene. The benzene layer is washed with a dilute base and with water. It is dried over Na2SO4 and evaporated to obtain an oil which crystallizes by trituration with petroleum ether (30-60 ° C). By recrystallization from ethanol, 11.6 g of yellow needles are obtained, mp 101-102 ° C.

Elementary analysis for ClnHl6ClN03:

Calculated: C 64.26 H 5.08 N 4.41%

Found: C 65.14 H 5.06 N 4.51%

Example 32:

Preparation of dihy-draté calcium amino-2-benzoyl-3-phenylacetate.

A stirred solution of 5 g of sodium amino-2-benzoyl-3-phenylacetate monohydrate (0.02 mol) in 50 ml of water is treated with 1.2 g of calcium chloride (0.01 mol) in 10 ml of water. A precipitate forms immediately which is separated after 15 min of additional stirring. Recrystallized from an ethanol / water mixture to obtain yellow needles, M 160-240 ° C (decomposition).

Elementary analysis for ^ - 3S 2O% Bcc:

Calculated: C 60.91 H 4.85 N 4.60%

Found: C 60.70 H 4.92 N 4.72%

Example 33:

Preparation of sodium amino-2-benzoyl-3-phenylacetate hydrate.

A solution of 111 g of amino-2-benzoyl-3-phenylacetic acid in 777 ml of tetrahydrofuran is treated with 31.3 g of a sodium hydroxide solution (50%). The sodium salt begins to precipitate after 15 min. After 3 hours of stirring in an ice bath, the sodium salt is separated and dried. 64.0 g, mp 245-252 ° C. are obtained. The salt is recrystallized by adding 1 g of salt to 10 ml of hot isopropyl ether. After refrigeration for several hours, the salt is separated and air dried. The recrystallized salt (90% recovery) melts at 254-255.5 ° C.

Elementary analysis for Cl5H14N04Na:

Calculated: .C 61.02 H 4.78 N 4.74%

Found: C 60.19 H 4.89 N 4.56%

The invention also relates to new pharmaceutical compositions containing the compounds according to the invention as active ingredient.

Effective amounts of any of the foregoing active compounds may be administered to a living animal by various routes, for example orally in the form of capsules or tablets, parenterally in the form of sterile solutions or suspensions and, in some cases, by intravenously in the form of sterile solutions. To form the compositions of the invention, the active ingredient is incorporated into an appropriate support, for example a pharmaceutical support. Suitable pharmaceutical carriers useful for preparing the compositions of the invention include starch, gelatin, glucose, magnesium carbonate, lactose, malt, etc. Liquid compositions also form part of the invention; pharmaceutically acceptable liquid carriers include ethyl alcohol, propylene glycol, glycerol, glucose syrup, etc.

The parhacologically active compounds can advantageously be used in a unit dose of 0.1 to 150 mg. The unit dose can be administered daily an appropriate number of times so that the daily dose can vary from 0.3 to 450 mg. An optimal amount is 25 mg per unit dose.

A few examples of compositions prepared according to the invention are described below by way of illustration.

1. Capsules:

5 mg, 25 mg and 50 mg active ingredient capsules are prepared per capsule, respectively.

Ingredient

Quantity per capsule

Active ingredient

Lactose

Starch

Magnesium stearate

5.0 mg 296.7 mg 129.0 mg 4.3 mg

Total 435.0 mg

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Another capsule formula containing a higher dose. The ingredients 1,2,4 and 5 are mixed uniformly. The active ingredient is prepared as follows: ingredient 3 in the form of a paste at 10% in the water. The mixture is granulated with the starch paste and the wet mass is passed through a sieve of 2.38 mm of mesh opening. The granulated mass is dried and passed through a sieve with 1.68 mm of mesh opening. The dried granules are mixed with the calcium stearate and pressed into tablets.

10 3. Injectable solutions:

In each case, the active ingredient is uniformly mixed. N sterile solutions at 2% of the following composition are prepared:

chosen with lactose, starch and magnesium stearate and the mixture is put into capsules.

2. Tablets:

A characteristic composition is given below for tablets containing 5.0 mg of active ingredient. The formula can be used for other active ingredient concentrations by adjusting the amounts of dicalcium phosphate.

Ingredient

Quantity per capsule

Active ingredient

Lactose

Starch

Magnesium stearate

25.0 mg 306.5 mg 99.2 mg 4.3 mg

Total 435.0 mg

Ingredient

Quantity per ml

Active ingredient Preservative, e.g. chlorobutanol Water for injection

20 mg

0.5% by weight by volume q.s.

Ingredient

Quantity per shelf

Active ingredient, 1 Corn starch, 2 Corn starch (paste), 3 Lactose, 4

Dicalcium phosphate, 5 Calcium stearate, 6

5.0 mg 13.6 mg 3.4 mg 79.2 mg 68.0 mg 0.9 mg

Total 170.1 mg

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

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It is understood that the invention is not limited to the preferred embodiments described above by way of illustration, and that a person skilled in the art can make various modifications and various modifications without however being depart from the scope and spirit of the invention.

Claims (8)

626806 CHRCOOR CLAIMS , 1 0 II and • CHRCOO R ~ (I-A) wherein R is a hydrogen atom or a lower alkyl group, R1 is a hydrogen atom, an alkali metal cation or a lower alkyl group, R2 is a hydrogen or halogen atom or a lower alkoxy group , X is a hydrogen or halogen atom or a lower alkyl group, nitro or trifluoromethyl, Y is a hydrogen or halogen atom or a lower alkyl group, nitro or trifluoromethyl, and Am is a primary amino group , methylamino or dimethylamino, with the additional condition that, in the benzoyl-3- and -5 derivatives, R1 cannot be a hydrogen atom when Y and R2 are hydrogen atoms, and Am a NH2 group, and R3 is an alkaline earth metal. 1. Derivatives of amino-2-benzoyl-3- (5- and -6) -phenylacetic acids, characterized in that they correspond to the general formula: 2. Derivatives according to claim 1, characterized in that R3 is calcium or magnesium. 3 626806 c) treating compound XII with Raney nickel under a nitrogen atmosphere to obtain the benzoylindolinone of general formula: ■ R (not) H in which X, Y, R and R2 are as defined above, and d) hydrolysing indolinone II in an aqueous base and acidifying with a weak organic acid or a dilute inorganic acid. 4. Method according to claim 3, characterized in that the compound obtained is transformed into its alkali or alkaline-earth metal salt. 3. Process for the production of amino-2-benzoyl-3- (5-and -6) -phenylacetic acids of general formula I according to claim 1, in which R is a hydrogen atom or a lower alkyl group, R1 is a hydrogen atom, R2 is a hydrogen or halogen atom or a lower alkoxy group, X is a atom Hydrogen or halogen or a lower alkyl group, nitro or trifluoromethyl, Y is a hydrogen atom or a lower alkyl group, nitro or trifluoromethyl and Am is a group —NH2, characterized in that it comprises following steps: a) reacting suitable substituted aminobenzophenones of general formula: 40 in which X, Y and R2 are as defined above with an α-methylthioacetic ester of formula CHR (SCH3) COOR1 in which R is as defined above and R1 is a lower alkyl group, and with tert-butyl hypochlorite to obtain a compound of general formula: CR (SCH3) COOR (XI) wherein X, Y, R, R1 and R2 are as defined above; 55 b) hydrolyzing without isolating the compound XI with an acid to obtain a benzoyl-4- (5- or -7) -methylthio-3-indolinone-2 of general formula: wherein X, Y, R and R2 are as defined above; SCH. (XII) 5. Method according to claim 3 or 4, characterized in that the acid or the alkaline salt obtained is treated with a halide of an alkaline earth metal, preferably calcium or magnesium, to obtain the corresponding salt of alkaline earth metal. 6. Process for the preparation of esters of formula I according to claim 1 in which R! is lower alkyl, characterized in that an alkali metal salt according to claims 3 and 4 is prepared, and in that the alkali metal salt obtained is reacted with a lower alkyl halide to form the corresponding ester . 7. Process for the preparation of a compound of formula I, according to claim 1, in which Am is a dimethylamino group, characterized in that an acid of formula I in which Am is an amino group is prepared according to the method of claim 3 and reacted with formaldehyde and sodium cyanoborohydride. 8. Pharmaceutical composition, characterized in that it contains a compound according to claim 1.