LU81068A1 - GLYCINAMIDE DERIVATIVES, THEIR PREPARATION AND USE, AS WELL AS COMPOSITIONS CONTAINING THOSE DERIVATIVES - Google Patents

Description

** A * * - r \ 3. * _.

'Λ k. * f MEMORY DESCRIPTION filed in support of the PATENT * INVENTION request in the name of the public limited company known as: "Continental Pharma" for: "Derivatives of ia glycinamide, their preparation and use, as well as compositions containing these derivatives".

Inventors: RONCUCCI Romeo - GILLET Claude - CORDI Alexis -MARTENS Mark - ROBA Joseph - NIEBES Paul - LAMBELIN Georges.

The present invention relates to derivatives of 2-aminoacetamide commonly called glycinamide as well as the i: salts of these compounds.

I r 5 These compounds correspond to the general formula I: r2r4. 0/1 1 1 ^ / / R - (CEJ -CN-CH -C ^ (I) / // 2 n 13 2 \ / 7 / R NH „i / f / '/ · in this formula: R1 represents a methyl group, C3-C10 alkenyl radical, 5 6 5 OR group, or COOR group, R being hydrogen, an alcohol protecting group, such as a benzyl, trimethylsilyl, tetrahydropyranyl group, or form with the alcohol of the alcohol function a ketal, acetal or - g ester group having an alkyl group C 1 -C 4, and R being hydrogen or an alkyl radical C - 4 -C 4 unsubstituted or substituted in particular by one or more phenyl groups; R2 and R3 represent simultaneously or independently of each other hydrogen or a linear or branched C 1 -C 4 alkyl radical; R 4 represents hydrogen or an alkyl group C ^ -C ^ linear or branched, an acyl group, an acyloxy group or a carboxamidomethyl group / na the value from 2 to 16.

In general, "alcohol protecting group" should be understood to mean one of the groups mentioned in chapter 3, page 95 et seq. Of the book entitled "Protective Groups in Organic Chemistry" edited by J.F.W. McOmie Plenum Press 1973.

Advantageously, if in formula I n is equal to 2 or 5, R1 cannot be a CH3 radical if R2, R3 and R4 are simultaneously hydrogen "

If the derivative of formula I is in the form of addition salts with acids, it can be transformed, according to usual methods, into the free base or into salts with other acids.

The most commonly used salts are acid addition salts, in particular non-toxic acid addition salts, pharmaceutically usable, formed with suitable inorganic acids, for example hydrochloric acid, T cIviT * Fil V * Ί fm ω Λΐι Ί 1 <r »-i Λ ar> VïAcn) inr η <-π in on a oac nm Λοο / ί" 'Λ',, 't "' · 'phatic, aromatic, araliphatic or heterocyclic , carbo-xylic or sulphonic, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malican, tartric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, hy - hydroxybenzoic, salicylic, phenylacetic, mandeligue, embonig, methanesulphonic, ethanesulphonic, panthotenic, toluenesulphonic, sulphanilic, cyclohexylaminosulphonic, stearic, alginic, beta-hydroxypropionic, beta-hydroxybutyronic, galactic. These salts can also be derived from natural or unnatural amino acids, such as lysine, glycine, arginine, ornithirte, asparagine, glutamine, 1 '/ alanine, valine, threonine, serine, leucine, cysteine, etc.

Examples of derivatives according to the invention are: 2-n.pentylaminoacetamide 2-n .hexylaminoacetamide 2-n.nonylaminoacetamide 2-n.octadecylaminoacetamide 2-n.octadecen-9-ylaminoacetamide 2-n. ^ -hydroxyhexylaminoacetamide 2-n. ^ -hydroxÿbutylaminoacetamide 5- (carboxamidomethyl) methyl amino hexanoate 7- (carboxaminomethyl) methyl amino octanoate 2-n.dodecylaminoacetamide.

The compounds of the invention exhibit good pharmaceutical activity./ in particular a peripheral peripheral vasodilator activity, antispasmodic, antiplatelet agent, inhibitor of lipolysis / of cholesterol synthesis and of collagen degradation, and a nootropic activity, i.e. d. a memory boosting effect, a reduction in sleep disturbances and a reduction in the harmful effects of alcohol taken in doses ^

The active compounds of the invention can be administered in combination with various pharmaceutical excipients and this, orally or parenterally.

For oral administration, dragees, granules, tablets, capsules, solutions, syrups, emulsions or suspensions containing additives or excipients conventional in galenic pharmacy will be used. For parenteral administration, use a liquid such as sterile water or an oil such as peanut oil or ethyl oleate.

These active compounds can be used alone or in combination with other active products having a similar or different activity.

In general, the derivatives according to the invention can be prepared by following the basic scheme below: 4 SX + Y-CH2 ~ CONH2 - ^ R-NR -CH -CONH2 in which X and Y are Δ different from each other and are an NHR group, a halogen atom, in particular chlorine, an OH group or an outgoing group of the tosyle, mesyle, R ^ COO ", NR 'R" R "' + type , PR, R "R" '+, SR' R "+, 0H2 +, ΟΝ- *, R100 ~, H0 ~, R'SO. 2, N2 +, N3, N02 in which R ', R "and R'" may be the same or different and represent.

linear or branched C ^ -C ^ alkyl radicals, X or Y representing 4 1 2312 3 4

an NHR group .; R represents R - (CH2) -CR R and R, R, R and R

have the meaning given above.

According to a first preferred embodiment of this general process, the reaction, on which it is based, is carried out between an amine and chloroacetamide according to the scheme: 0 O / r-NH + Cl-CH -C: <^ - > R-NH-CH -C ^ / '4 NH_' 4 Z ^ * NH0 /// R -2 R 2 \ / R2 1 I 14 where R represents R - (CH) -C and where R to R and n have the meaning 4 n | -,

R

cation given in general formula I.

This reaction is carried out in an organic solvent such as alcohols such as methanol, ethanol, isopropanol or in a chlorinated solvent such as chloroform or dichloromethane. The reaction can take place at an ordinary temperature or advantageously at a higher temperature such as the reflux temperature of the solvent used. An organic or inorganic base is preferably added to the reaction mixture. In the case of an inorganic base, for example, an alkali or alkaline earth metal carbonate or bicarbonate or an alkali or alkaline earth metal hydroxide or else finely pulverized lime will be chosen. In the case of an organic base, for example, pyridine, triethylamine, N-dimethylanilme will be chosen.

A variant of this process consists in starting from an ester of η ^ η chloroacetic acid CICH ^ COOR or R is a lower alkyl group C ^ -C ^ linear or branched or a benzyl group.

When the coupling of the two reagents is carried out, the ester function is transformed into an amide function by aminolysis.

Generally, this aminolysis takes place in an organic solvent such as ether, dioxane, tetrahydrofuran, chloroform, dichloromethane or in water.

In the present case, the amine used will be ammonia which will be introduced into the ester solution by bubbling gaseous ammonia or by adding a dilute aqueous solution.

Advantageously, the reaction will be carried out under acid catalysis; 1 ^ acid will then be for example dilute hydrochloric acid or chlo /

Lewis able to carry out this catalysis. The reaction will take place at room temperature or preferably with slight heating and with stirring.

The isolation of the product is carried out conventionally in organic chemistry by crystallization, by sublimation, by distillation or by column chromatography.

. According to a second preferred embodiment of this process, this one is carried out according to the reaction represented by the following diagram: R4 o 0 RX + HN-CH -C ^} RN-CH -C ^ "NH2 r4 NH2 R2 1 1 1 ^ 4 where R represents the radical R - (CEL) .- Ç and where R a R and z ^ i 3

R

n have the meaning given in general formula I.

X represents a halogen or an leaving group of the tosyle, mesyle, R'COCT, NR'R "R", +, PR, R "Rm +, SR'R" +, OHR, +, 0H2 +, CN ~, R 'type 00 ~, H0 ~, R'S02 “, N2 +, N", N02 ~ in lesguels R ', R "and R'" may be the same or different and represent linear or branched C ^ -C ^ alkyl radicals.

The reaction can be carried out in an organic solvent such as chloroform, dichloromethane, in an alcohol such as methanol or ethanol, in a saturated or aromatic hydrocarbon such as petroleum ether, benzene, toluene.

The reaction takes place either at room temperature or at a temperature between 0 ° C and the reflux temperature of the solvent. Advantageously, the reaction can be carried out in the presence of an organic base such as triethvlamine, pyridine, or K-dimethylaniline or an inorganic base such as hydroy /

/ W

xides, carbonates and bicarbonates of alkali or alkaline earth metals or of finely pulverized lime.

The products are isolated and purified by crystallization, by sublimation, by distillation or by column chromatography.

A variant of this process consists in using as reactant a glycine ester of formula: 0 HN-CH.-C ^ '_

R 4 ^ OR

4 where R has the meaning given in general formula I and where 7 R represents a linear or branched C 1 -C 4 lower alkyl radical or a benzyl group. The ester function is subsequently transformed into an amide function according to the method detailed in connection with the first embodiment described above.

The process according to the invention can advantageously be applied using the corresponding nitrile according to the scheme: 4 H3 ° t 4 RX + Y-CH CN -y R-NR -CH -CN —R-MR -CH -CCNH.

ώ Z L · 4 in which X, Y, R and R have the abovementioned meanings.

According to a first embodiment of this variant, R2 4 i 1 14 an amine R-NH-R where R represents R (CH0) -C and where R to R * and n 2 η J 3

R

have the meaning given in the general formula I are reacted with 2-hydroxyacetonitrile. The nitrile obtained is then hydrolyzed in an acidic or basic medium according to the scheme described ^ / ex-apres: / / 4 _4

f H 0+ I

R-NH-R4 + HO-CH -CN - * R-N-CH CN - "R-N-C ^ -C ^" HH2

The amine is condensed on 2-hydroxyacetonitrile in an organic solvent such as chloroform, dichloromethane, methanol, ethanol ... The reaction can be carried out: at a temperature between 0 ° C and the reflux temperature of the selected solvent. Advantageously, an acid such as hydrochloric acid or any other mineral or organic acid will be brought into contact with the reactants.

The final hydrolysis will be carried out with a mineral acid such as hydrochloric acid or sulfuric acid, working under temperature and concentration conditions such that the hydrolysis stops at the amide stage; advantageously, the hydrolysis can be carried out with 96% sulfuric acid at normal temperature or with a base such as sodium or potassium hydroxide which may contain 6 to 12% of hydrogen peroxide.

The products are isolated and purified conventionally by crystallization, by sublimation, by distillation or by column chromatography.

According to a second embodiment of this variant, it is applied according to the diagram: RX + H2N-CH2-CSN -> RNH-CH2 ~ C = N --J H30 + or h2o / oh "1 ^ 0 RNH-CH„ - C <^ ^ nh2 .. In this particular way of proceeding, H „N-CH is reacted with a compound RX where R represents a radical / / 1 - y -R2 1 I l 3, R - (CH ^ ) -C and where R to R and n have the meaning given in "" s general formula I where X represents a halogen or an leaving group of the tosyle, mesyle, R'COO ", HR1R" R "'" t, PR1R "R, SR'R ', +, OHR' *, 0H2 +, CN, R'00, HO, R'S02, N2 +, H3, N02 in which R ', R" and Rm may be the same or different and represent linear or branched C ^ -C alkyl radicals The final step in the reaction sequence is the hydrolysis of the nitrile group.

This sequence of reactions is carried out in an organic solvent such as alcohols, chlorinated solvents, saturated or unsaturated, aliphatic or aromatic hydrocarbons. It occurs at chamber temperature or at a temperature between 00C and the reflux temperature of the chosen solvent.

The hydrolysis of the nitrile to amine takes place in an acidic or basic medium and in a conventional manner the hydrolysis takes place with 96% sulfuric acid at normal temperature or with an aqueous solution of sodium hydroxide which can contain 6 to 12% hydrogen peroxide.

A second process consists in the hydrogenolysis of a sydno-nimine according to the reaction scheme described below: I R _ - 0 j '? -s? H Z H2. R-HH-CH -C-NH + HH / i N - · C-NH- Cat / /! · Ν '2 f, R2 1 l i 3 R represents the radical R - (CH_) -C where R to R and n have the 2 n r

R

. meaning given in formula I and where Z is an anion.

The sydnonimine is synthesized according to methods well documented in the literature; its hydrogenolysis leads to a 2-aminoacetamide.

The catalyst used can be palladium on activated carbon, nickel, platinum oxide. Generally, the catalyst belongs to the group of transition metals, their oxides or their sulfides.

The reaction solvent can advantageously be methanol, ethanol, petroleum ether or any organic solvent which is inert under the conditions of the reaction. The reaction will usually take place at room temperature, but the temperature may be adapted to the reactivity of the molecule.

At the end of the reaction, the product will be separated from the catalyst by filtration and purified as described above.

A third method consists in reacting an aldehyde 8 8 2 R CHO or a ketone R COR with 2-aminoacetamide and in reducing the imine thus formed according to the scheme described below: R 8 H / cat.

R CHO + H NCH C ^ - * R -CH = N-CH -CC "- * 2 2 nh2 ^ nh2 R -CH HNCH ^ CÇ · ™ 2 8 i ^ l

In this scheme / R represents a group R (CH2) n where R

and n have the meaning given in the general formula I. pf / 1

These reactions are carried out in organic solvents such as alcohols such as methanol or ethanol, or chlorinated solvents such as chloroform or dichloromethane or in aliphatic hydrocarbons such as pentane or petroleum ether.

These reactions can be carried out at temperatures between 0 ° C and the boiling point of the solvent, preferably at the reflux temperature of the solvent.

The product is isolated and purified as described above.

A variant of this process consists of starting from a glycine ester of general formula: H.N-CH COOR7

^ Z I

where R represents a linear or branched C ^ -C ^ lower alkyl group or a benzyl group.

The ester function is then subsequently transformed into an amide according to the method detailed in connection with the first embodiment of the first basic process.

A fourth method consists in treating a minimium salt adequately substituted by cyanide ions; ' the resulting product is then hydrolyzed. The scheme of this reaction is as follows: R +

R-N = CH + + WCN - »^ N-CH -CN -y ^ 0 or H ^ O / OH

! 4 s. * 4 v> N — CH -C <R NH2 • · R2 1 —1 14.

R represents the radical R (CH2) n_C e '* - ^ to R and n have the sxgnifr- * 3 cation given in the general formula I, Z represents an anion such as an anion of sulphate halide, of tetrafluoroborate or of perchlorate and W represents an inorganic cation such as Na +, K +, Li +, / _ + _ +. . . ___________ _________ // i ammonium or a cation of other ammonium salts substituted by C ^ -C ^ alkyl chains, these chains being unsubstituted or substituted by one or more aromatic rings, in particular phenyl rings.

The starting imine salt can be prepared according to the methods well described in the literature, in particular, by reaction of formaldehyde with a primary or secondary amine RNH2 or RNHR4 under the conditions required to carry out a Mannich reaction.

The condensation between the iminium salt and the cyanide takes place in a non-protic organic solvent such as chloroform or dichloromethane, in esters, cyclic or not, or in saturated or unsaturated hydrocarbons. The reaction will take place at normal temperature, but, depending on the speed of the reaction, the temperature may be increased or decreased.

The hydrolysis of the nitri obtained will take place in an acidic or basic medium so as to obtain the amide and not the acid. Conventionally, such hydrolysis can be carried out with 96% sulfuric acid at normal temperature or with an aqueous solution of sodium hydroxide which may contain 6 to 12% of hydrogen peroxide.

The isolation and purification of the products is carried out as described above.

A fifth process can be carried out according to the diagram: r-nh2 + o = c-cci3 - * r-n = ch-cci3 - --- ¾. r-nh-ch2-cci3

H

H3 ° / 0 NH ^ 3 /

RNH-CH-C * - = * - RNH-CH -COOH J

NH? / 1 / * · * '' V ·., · '

By this particular way of proceeding, the trichloroacetaldehyde is condensed on an amine RNH ^ where R represents R2 the radical R1- (CHJ -C and where R1 to R3 and n have the meaning 2 n | ‘3.

R

• given in general formula I.

e 'The condensation takes place partially under acid catalysis.

The formation of imine is advantageously carried out in a solvent immiscible with water. A solvent commonly used to carry out such a reaction is: benzene; however any other solvent which has the properties described above may be suitable. In general, the reaction is carried out at reflux of the solvent but, however, the reaction / can be carried out at any temperature between 0 ° C. and the reflux temperature of the solvent. The imine obtained is then reduced in a conventional manner and well documented in the literature, taking care however to preserve the trichloromethyl group.

The conversion ’of the trichloromethyl group to the car-boxvle group is generally carried out in water with 95% sulfuric acid; in some cases, it may be advantageous to use nitric acid in place of sulfuric acid. This reaction. occurs between 0 ° C and 100 ° C.

The acid obtained is then converted into amide in a conventional manner in organic chemistry.

Isolation and purification are carried out by crystallization, by sublimation, by distillation or by column chromatography. ,

A sixth process can be carried out according to the diagram: /

RX

02N-CH2-C00H —5> H2N-CH2-COOH> RNH-CH2COOH -Ÿ RNH-CH2CONH2.

According to this procedure, the nitro group of the nitroacetigue acid is reduced under conditions such that only the nitro group is selectively transformed into an amine without touching the carboxyl group. This reaction is particularly well documented in the literature (cf. Houben-Weyl : Methoden der organischen Chemie, 4th Aufl., Band 11/1 p 431 and following).

The amine is then alkylated by the reagent RX where R represents R2 1 I - i 3 ...

radical R - (CH „) -C and where R to R and n have the meaning 2 n I

R3 given in general formula I and where X represents a halogen - + or an leaving group of the tosyle, mesyle, R'COO, NR'R "R '", PR'R ,, R ,,, t SR'RM type +, OHR, +, 0H2 +, CN ~, R'OO ”, HO, R'S02, N2 +, N3, N02 ~ in which R ', R" and R' "may be the same or different and represent alkyl radicals C ^ -C ^ linear or branched.

This alkylation reaction of an amine is classified in organic chemistry and is carried out under the conditions described for the second embodiment of the first basic process.

The carboxylic acid is then converted into an amide in a conventional manner.

The purification is carried out according to the method described in the Λ 1 processes above. / d

A variant of this process consists in reacting 2-aminoacetigue acid, commonly called glycine, with an aldehyde of formu-le R CHO or a ketone R COR under the conditions described in the third process. The imine is then reduced to amine in a conventional manner (see the reference to Houben-Weyl above) then the carboxy-league acid is transformed into an amide according to well-documented methods.

The diagram is then as follows:

B

H N-CH COOH R ~ CH °} R8CH = N-CH „COOH

2 2 d 2.

Q Z

R-NH-CH -Cr "« - R CH NH-CH COOH

NH2

A seventh process can be carried out according to the diagram:

0 O

He îi

H-C-C-OH + RNH- '- * R-N = C-C00H - * RNH-CH -COOH

H 1 RNH-CH2-CONH2

This process consists in converting glyoxylic acid into imine by bringing it into contact with an amine of general formula RNH2 where R represents the radical R2 1 1 1 3 'R - (CH2) -C and where R to R and n have the meaning given in 11 R3 the general formula I.

This reaction is advantageously carried out in an acid medium in a solvent and removing the water as soon as it forms. The imine obtained is then conventionally reduced using conditions such that the carboxyl group remains intact. Numerous journals have been devoted to reactions of this type (see for example Houben-Weyl: Methoden der organischen Chemie, 4 Auf1.2 /

Band 11/1, p.341 and following). The carboxylic acid is then converted to the amide according to conventional methods. The reaction product is then isolated and purified according to the procedures described in the preceding methods.

According to an eighth process according to the invention, a glycanide of formula II: R-NH-CH ^ -C-r (II) nh r2; 1 1 12 3 where R represents a radical R ~ (CH „) -C and where R, R, R and n have 2 n | 3 R t the meaning given in the general formula I, is treated by a compound R ^ X where R ^ has the meaning given above and where X is a halogen atom or an outgoing group of the tosyle, mesyl, R'COO type -, NR, R "R ,,, + / PR'R''R", +, SR'R "+, OHR, +, 0H2 +, CN ~, R'00, HO, R1S02, N2 + 'N3' N ° 2 ^ in which R ', R "and R'" may be the same or different and represent linear or branched C ^ -C ^ alkyl radicals.

Advantageously, the reaction will take place in an organic solvent such as an alcohol, a chlorinated solvent, a nitrile, an aliphatic hydrocarbon or not, saturated or not.

The reaction will take place at normal temperature or at reflux temperature of the solvent. A basic catalysis can advantageously be considered. The base will then be mineral (sodium or potassium hydroxide) or organic such as pyridine, triethylamine or N-dimethylaniline.

The reaction product is isolated and purified as described above.

/ / ·

Below are given detailed examples of the preparation of some glycinamide derivatives according to the invention.

These examples are mainly intended to further illustrate the particular characteristics of the methods according to the invention.

Example 1.

Synthesis of 2-n.octadécvlaminoacétamide.

0 NaHCO

CH, T (CHJ -NH, + CICH-CQ -5 · j l Ll Δ £ ^ Nh2 CH - (CHJ.-NH-CH, -C £ j tu XNH2

In a 500 ml Erlenmeyer flask fitted with a condenser and a magnetic stirrer, 21.6 g of octadecylamine (0.08 mole), 7.48 g of chloroacetamide (0.08 mole) are mixed at room temperature. and 7.4 g of sodium bicarbonate in 350 ml of ethanol. This melan | ge is brought to reflux for 16 hours. After the solution has cooled, the solid is filtered and the solution is evaporated.

The residue from evaporation and the previously filtered solid are combined and recrystallized from cyclohexane. Sublimation -3 at 120-140 ° under 5.10 mm Hg followed by a new recrystallization in cyclohexane allows 3.5 g of an analytically pure product to be obtained.

F (° C) 102.5-103.5 °. 13% discount "

C H N analysis

calc.% 73.56 12.96 8.57 found.% 73.4 12.7 8.55 /

Example 2.

Synthesis of 2-n.hexylaminoacetamide.

O NaHCO 0 CH - (CH „) -NH + Cl-CH -C ^ - ^ CH _- (CH) _-NH-CH0-C ^ 3 2 5 2 NH2 3 2 5 2 ^ NH2

In a 500 ml Erlenmeyer flask fitted with a condenser and a magnetic stirrer, 11 g of hexylamine (0.11 mole), 10 g of chloroacetamide (0.107 mole) and 9.9 are mixed at room temperature. g of sodium bicarbonate (0.118 mole) in 200 ml of ethanol. This mixture is brought to reflux for 24 hours. After cooling, the sodium chloride is filtered, and washed with 50 ml of ethanol.

The combined filtrates are evaporated and the white solid obtained is recrystallized once in 140 ml of cyclohexane, once in 120 ml of acetone / finally in a minimum of ethyl acetate. The _3 product thus obtained is sublimed at 120 ° / 3.10 mm and recrystallized once again from 110 ml of cyclohexane.

Rdt. 6.7 g (40%) F (° C): 62-63.

C H N analysis

Hold. % 60.72 11.46 17.71 tr. % 60.60 11.2 17.4

Example 3.

Synthesis of methyl 5- (carboxamidomethyl) amino hexanoate Μ Θ n _ ^ ° NaHCO / CHo0C- (CH_) c-NH_Cl ^ + C1CH -C ^ - ^ / "Λ CH.-OC- (CH-) -NH -CH „-C ^ T il 3 2 5 2 nh2 /

In a 250 ml Erlenmeyer flask fitted with a condenser and a magnetic stirrer, 22 g of the hydrochloride of the 6-amino acid caproic acid methyl ester (0.121 mole) are mixed with 21 g of sodium bicarbonate (0.250 M) in 200 ml of isopropanol. This mixture is brought to reflux for 1 hour and then 11.22 g of chloroacetamide (0.120 M) are added thereto at room temperature.

The suspension is stirred for 4 days at normal temperature, the precipitate obtained is filtered, washed with 50 ml of boiling ethanol and the combined filtrates are evaporated. The residue is chromatographed on 1000 g of silica, eluting with a methanol-ether mixture (4/6). The product is collected between the 25th and 58th fraction of 50 ml. It is finally purified by dissolution in isopropanol and saturation of the solution thus obtained with HCl. Additional recrystallization from isopropanol gives 5.4 g of an analytically pure product (Yield 18.5%).

F (° C): 160

C H N analysis

% cal. 45.28 8.02 11.73% tr. 45.00 8.05 11.73

Example 4. j a) Synthesis of docecylaminoacetonitrile.

01oHocNHo + H0-CH-CN -7 0η -H, -NH-CH -CN

12 25 2 2 12 25 2

In a 500 ml flask fitted with a magnetic stirrer, 4.56 g of hydroxyacetonitrile (0.08 mole) is mixed at room temperature with 16.3 g of dodecylamine (0.088 M) in 250 ml / /.

methanol. The mixture is left to stand for 16 hours at normal temperature and the methanol is evaporated. The liquid obtained is -2 distilled under 10 mm of mercury. The fraction distilling between 106 and 116 ° crystallizes after cooling.

P (° C) 28-29. Rdt. 15.2 g (85%).

b) Synthesis of 2-n.dodecylaminoacetamide.

H2S04

C., ËLc-NH-CH -CN ^ *> CnNH-CEL-CC

12 25 2 A 12 25 2 ^ NH

15.2 g of (dodecylamino) acetonitrile (0.068 mole) dissolved in 20 ml of ethanol, were added dropwise to 2.5 ml of E 2 SO 4 in 25 ml of ethanol cooled in ice. The white precipitate which forms is filtered and dried (19 g of dodecylamino acetonitrile hydrogen sulfate). This product is added little by little in a 250 ml flask to 60 cc of H ^ SO ^ cc. This solution is brought to 100 ° for 1.30 h. After cooling, it is added dropwise to 400 ml of ethanol cooled in ice. The white precipitate which forms is filtered and recrystallized from ethanol. Yid: 14.5 g (73%). F (° C): 190 °

C H N analysis

% wedge. 49.38 9.47 8.22% tr. 49.30 9.55 8.15

Example 5.

a) Synthesis of hexylaminoacetonitrile.

C ^ IL-NEL + H-O-CH —CN -> CcH. _NH-CH „-CN + H„ 0 / b 16 Z Z b 16 Z 2 d - 21 - 4 ”

Mixed in a 100 ml / 5.7 g of hydroxy-acetonitrile (0.1 mol) flask with 11 g of hexylamine (0.11 mol) dissolved in 10 ml of MeOH. The temperature rises quickly during mixing. The solution is left to stand for 24 hours. The MeOH is evaporated and the liquid obtained is distilled at 72 ° under 0.8 mm. Yid: 11.4 g (81.5%).

b) Synthesis of 2-n.hexylaminoacetamide.

11.2 g of hexylamino acetonitrile (81 mM) are added dropwise to 30 ml of H ^ O ^ cc diluted in 30 ml of ethanol cooled in ice. As soon as the addition is complete, the ethanol is evaporated! and 40 ml of H 2 SO 4 are added to the white solid obtained. This so-2 4 lution is heated for 1 hour at 100 ° C, it is then cooled and added dropwise to 200 ml of ethanol cooled in ice * The white precipitate forms is filtered and washed with 50 ml of ethanol. Rdt. 14.4 g (70%) - F (° C): 151-152 °

C H N analysis

% wedge. 37.49 7.87 10.93% tr. 37.80 7.80 10.90

The table given below groups the typical compounds of the invention with their melting point, thus guiding the conditions for recrystallization. / j ^ Λ

Table 2 4

RR

1 I f R - (CH „) -C - N-CH0-Cf 2n“ 3 2 NH2! „1 4„ 2 „3! . solvent for R ^ R R R S n F <° C> crystallization I. j. ; 1; CH3 h H H I 3 46.1 (1/2 ^ 0) cyclohexane I j I 2 ’j CH ^ H H H 4 62-63 cyclohexane 3 i CH ^ Η Η Η Ί 13-13.5 cyclohexane, AcOEt

j I

4 ICH H H H 16 102.5-103.5 cyclohexane, AcOEt I 3 5 CH (CH „) -CH = CH H H H 7 88-89 cyclohexane, AcOEt 3 2 7 1 6 HO i H! H H 5 85 AcOEt! ! .! ! 7 i HO! H! H! H 3 117-121 EtOH (l) I 1! !

Io · I

i it · 1 day! : 8 CH 0-C 'H: H H 4 160 .EtOH (1): 1 3 i; : 1

! i ° i 1: I

i! tf I 1 t ·! I 9 iCH 0-C Η, H H 6: 166! Isopropanol (1) i: · 3,! 1; ; '; ! j 10ÎCH H H H 4, 151-152 jethanol (2)

: i i i I

11! CH_ H! H H 10! 190 I ethanol (2)

! 3 0: o i · I

• I ^ 0 1 121 CH -0-C -CH -C ^! H. H 4 116-117 isopropanol

3 2 NH_ I

2 I

! 13 HO ^ -CH -C ^ H H 5 115 isopropanol 2 NH0 i i "i! 14 CH — 0-C 1 -CH -C ;; H H 6 125! ethanol NH9 i! 1 - 15 HO -CH9-C ^ H H 3 160 1 isopropanol (1) x nh9 ~

U -: - LOJ -! - J

(1): hydrochloride / // (2): hydrogen sulphate \ Jf The peripheral vasodilator activity of the products of the invention was measured in the anesthetized dog, at the level of the femoral arterial circulation. For this purpose, the femoral artery, the collaterals of which have been ligated, is perfused at a constant rate by means of blood drawn from the aorta. The perfusion pressure, measured at the level of the femoral artery, therefore varies according to the resistance of the perfused territory. The products tested and the corresponding solvents are injected directly into the circuit, at a dose of 30 / Ag / kg. The blood flow being kept constant, a vasodilation is therefore measured by a decrease in the perfusion pressure. This is scored in relation to the action of papaverine, considered as a reference and injected once per group of 4 products. In case of interest, the products are tested at other doses under the same conditions.

The antispasmodic activity of the products of the invention was tested against the contractions of the guinea pig ileum induced by histamine and acetylcholine. These tests make it possible to highlight an antihistamine, anticholinergic or antispasmodic musculotropic activity. The response to the contracting agent (submaximal concentration) is repeated every 5 min before and after the injection of increasing amounts of the products tested -7 -4 (10 to 10 M). The various doses are spaced 20 min apart. or the time required to develop the maximum effect. We cal-. the percentage of inhibition under the influence of the products tested is calculated and the theoretical concentration producing 50% inhibition is determined graphically for each experiment. These tests made it possible to demonstrate that at least some of the compounds according to the invention exhibit an interesting antisDasmodigue activity. * / tf.

Behavioral examination demonstrates that at least some of the compounds according to the invention induce modifications in this behavior, such as sedation, analgesia or excitation.

The acute toxicity of the products of the invention was also determined after oral administration (gavage of a mucilage with 1% of tragacanth) to male mice (CD 1 strain, Charles River, fasting for 18 hours).

Groups of 5 mice are used and receive one of the following three doses: 300, 1000 and 3000 mg / kg. Optionally, other doses, lower or higher, are studied.

The behavior of the animals is studied 2 to 6 hours after administration, as well as after 24 hours or more if symptoms persist. The behavioral examination is carried out according to a method derived from that of Irwin (Gordon Research Conf. On Medicinal Chem.

133, 1959). Mortalities are recorded within 14 days of treatment. The DL_ ^ are calculated according to the method bü of Litchfield and Wilcoxon. (J. Pharmacol. Exp. Ther., 96, 99, 1949) and expressed in mg / kg.

The products of the invention are not very toxic. The DL ^ Q are in most cases located above 2000 mg / kg.

The bioohimic screening of the compounds of the invention was carried out in vitro according to the following procedures; 1) Inhibition of plaguettary aggregation.

* The turbidimetric method described by G.V.R. Born and M.J.

Cross (J. Physiol., 168, 178-195, 1973) is used. The platelet rich plasma is preincubated for 4 minutes before the introduction of the inducer (Thrombofax). Slight variations are recorded over a period of 10 minutes with an "Upchurch" aggregometer / The inhibition of the amplitudes of the maximum aggregation is measured.

In this test, in particular the compound n ° 2 of the table given * ‘above appeared to be active.

2) Inhibition of lipolysis.

. Epididymal fat is removed from fasting rats.

Fragments of adipose tissue (+ 150 mg) are incubated in the Krébs-Ringer buffer containing 3% of bovine serum albumin and the substance to be studied. A time zero sample is taken after a 30 minute incubation at 37 ° C. Norepinephrine is used to induce lipolysis. The level of free amino acids is measured after 20 minutes of incubation (Duncombe W.G., Clin.

Chim. Acta, 8 ^ 122, 1964).

In this test, in particular the compounds n ° s 1 and 2 of the table given above appeared to be active.

3) Inhibition of the biosynthesis of cholesterol.

Buffered rat liver homogenates are enriched with suitable cofactors. Aliquots are incubated for 60 minutes with 14 1- C acetate and the compound to be studied. After saponification of the medium, the sterols are extracted from petroleum ether and the dry residue is precipitated with digitonin in an alcohol-acetone solution. The C content of the precipitate dissolved in pyridine is measured by liquid scintillation counting according to the method described by N. Bûcher (J. Biol.Chem., 222, 1-15, 1956).

In this test, in particular the compound n ° 1 of the table given / above appeared to be active. - // 4) Inhibition of the capture of bioamines by synaptosomes.

Synaptosomes are isolated from rat brains after partial subcellular fractionation in a sucrose gradient (Gray R.G. and Whittaker V.P., J. Anat., S2_, 79, 1962).

GABA (Y -aminobutytic acid) is accumulated in synaptosomes by an uptake process for later use in the synaptic zone. GABA C uptake is a process dependent on sodium ions and temperature and occurs only in the tissues of the central nervous system. After a 5 minute preincubation with the drug, the synaptosomes are incubated with 14 C-GABA. The preparation is then filtered on a "Millipore" filter and the filters are washed with ice-cold buffer. The radioactivity of the filters is measured by liquid scintillation. The uptake is the difference between the radioactivity measured at 37 ° C and that measured at 0 ° C.

These tests have shown that in particular the compounds Nos. 7 and 8 of the table given above have been found to be active.

5) Activity of synaptosomal ATPase.

The activity of Na + / K + ATPase is determined by measuring the inorganic phosphate released by ATP. For this purpose, a colorimetric test is used after incubation in the medium according to Abdel-Latiff A.A., Smith J.P. and Ellington E.P. (Brain Research, 18, 441, 1970).

These tests have shown that, in particular, compound No. 4 of the table given above has been found to be active. / V

6) MAO activity in brain homogenates.

The activity of monoamines oxidases A and B is determined according to the method described by Christmas A.J. et al. (Br.J. Pharmacol., 14 45, 490, 1972) using C-tyramine as a substrate.

i ""

The radioisotopic assay of the reaction is based on the difference in the toluene in toluene of tyramine and of p-hydroxy-phenylacetigue acid (product of the reaction). The brain homogenate is preincubated with the drug and incubation begins with addition 14. „Of C-tyram. After extraction with toluene, an aliquot of the organic phase is taken and measured by counting by liquid scintillation.

These tests have shown that, in particular, compound No. 4 in the table given above has been found to be active.

7) Activity of glutamate decarboxylase in brain homogenates.

/ 14 Glutamic acid marks uniformly with C and is transformed 14 14 14 into CO and C-GABA. CO is absorbed by a basic solution of hyamine and its radioactivity is determined by liquid scintillation (Parker L., 1974, Methods in Enzymology. Ed.:

Fleischer S., Vol. XXXII, part. V, p 779). The incubation is carried out in a Warburg apparatus.

These tests have shown that, in particular, the compounds Nos. 1, 6 and 8 in the table given above have been found to be active.

8) Degradation of collagen.

After incubation at 37 ° C. of the collagen in the presence of collagenase in a medium buffered to pH 7.2, in the presence or in the absence of a drug, the amino acids released are demonstrated by colorimetric reaction with .the ninhydrin and absorbance measurement I

!

! m

These tests showed that, in particular, the compound n ° 2 of the table given above appeared to be active.

In conclusion, in general, the products of the invention inhibit the biosynthesis of cholesterol and the breakdown of collagen and activate GM) decarboxylase this mistletoe causes an increase in the level of GABA in the brain. In this regard, 2-n.pentylaminoacetamide is particularly remarkable. These products synthesized in the context of research into agonists and antagonists of the GABAergic system are of considerable therapeutic interest for preventing convulsions and epilepsy attacks, for treating certain types of nervous depression and for potentiating memory.

For the administration of the new compounds of the invention, r.

the daily dose will be 50 to 2000 mg, preferably it will be 100 to 1500 mg. The unit dose will be 200 to 500 mg.

The products of the invention can be used in various forms. The examples which follow are not limiting and relate to galenical formulations containing an active product designated by the letter A.

This active product is formed by one of the following compounds: 2-n-pentylaminoacetamide 2-n-hexylaminoacetamide 2-n-nonylaminoacetamide 2-n-octadecylaminoacetamide -.

2-n-octadecen-9-ylaminoacetamide f

2-n- & -hydroxyhexylaiainoacétamiâe A

7 methyl 2-n-O ^ -hydroxybutylaminoacetamide 5- (carboxamidomethyl) amino hexanoate methyl 7- (carboxamidomethyl) amino octanoate; 2-n.dodecylaminoacetamide ’v

Tablets.

At 300 mg

Aerosil 2 mg

Starch STA-RX 1500 18 mg

Calcium phosphate (CaHPO ^) 100 mg

Magnesium stearate 10 mg to 350 mg

Microcrystalline cellulose 70 mg

Auby-gel X 52 20 mg

Corn starch _ 50 mg

Magnesium stearate 10 mg A 1350 mg

Microcrystalline cellulose 100 mg

Starch STA-RX 1500 50 mg

Talc 15 mg Aerosil 5 mg To 300 mg

Magnesium stearate 10 mg Aerosil 5 mg /

Starch STA-RX 100 80 mg

Capsules A 300 mg

Starch STA-RX 1500 94 mg

Magnesium stearate 1 mg

Sodium lauryl sulfate 5 mg 350 mg

Microcrystalline cellulose 70 mg

Corn starch 30 mg

Peanut oil '0.01 mg

Sodium lauryl sulfate 5 mg A 3 00 mg

Sodium lauryl sulfate 5 mg

Microcrystalline cellulose 70 mg

Magnesium oxide 20 mg to 350 mg

Starch STA-RX 1500 100 mg

Magnesium stearate 1 mg „Sodium lauryl sulfate 9 mg

Microcrystalline cellulose 30 mg ^ f:

Claims (23)

2. RR 1 "Γ rJ" - (CH) -CN-CH- -C r (I) 2 n '3 2 NH0 R 2. As well as the salts of this derivative with non-toxic and pharmaceutically usable acids, in this formula: R represents a methyl group, a C -C alkenyl radical, a group i ό xu 5 6 5 pe OR or a COOR group, R being hydrogen, a protecting group for the alcohol function, such as a henzyl group, tri-methylsilyl, tetrahydropyranyl, or forms with the alcohol alcohol a ketal, acetal or ester group having a C 1 -C 4 alkyl group, g and R being hydrogen or a C 1 -C alkyl radical - C ^ unsubstituted or substituted in particular by one or more phenyl groups; 2 3. R and R representing simultaneously or independently of each other hydrogen or a linear or branched C ^ -C ^ alkyl radical; 4 R represents hydrogen, a linear or branched C 1 -C 4 alkyl group, an acyl group, an acyloxy group or a carboxa-midomethyl group, n being equal to a value from 2 to 16. 2. Derivative according to claim 1, characterized in that if, in formula I, n is equal to 2 or 5, R ^ cannot be a ra-2 3 4 dical CH if R, R and R are simultaneously hydrogen. , J “3, - Derivative according to either of claims 1 and 2, characterized in that, in formula I, R represents a group -------— T protecting group for the alcohol function , such as a benzyl, trimethylsilyl, tetrahydropyranyl group, or forms with the alcohol alcohol a ketal, acetal or ester group having an alkyl group 6 C ^ -C ^, and R being hydrogen or an alkyl radical C ^ -C ^ unsubstituted or substituted in particular by one or more phenyl groups. 4, - A derivative according to any one of claims 1 to 1. 2 3 4 3, characterized in that, in the formula I, R, R and R represent hydrogen and n is equal to 4, 8, 10, 12, 14 or 16. 5, - Derivative according to one any one of the preceding claims, characterized in that it is chosen from the group formed by the compounds: 2-n-pentylaminoacetamide 2-n-hexylaminoacetamide 2-n-nonylaminoacetamide 2-n-octadecylaminoacetamide 2-n-octadecen-9-ylaminoacetamide 2-nW-hydroxyhexylaminoacetamide 2 -n- Ci / -hydr oxybu ty lami noa c é tamid e 5- (carboxamidomethyl) methyl amino hexanoate 7- (carboxamidomethyl) methyl amino octanoate 2-n.docecylaminoacetamide. 6, - Glycinamide derivative of formula I as described above and in particular in the examples given. 7, - Process for the synthesis of glycinamide derivatives according to any one of Claims 1 to 6, characterized in that a compound of formula RX is reacted with a compound of formula. Y-CH ^ -CONH ^ or with an ester of the latter compound so as to ^ obtain the corresponding derivative, in these formulas X and Y are different from each other and are an NHR group ^, an atom of halogen, 'in particular chlorine, an OH group or an leaving group of the tosyle, mesyle, R'COO ~, NR'R ,, Rnïf, PR'R''R "' + / SR'R" +, OHR, +, OH +, CN ~ 4 "2 'R'00, HO, R'S02, N2 +, N3, N02 in which R', R" and R '". Can be identical or different and represent alkyl radicals C ^ -C ^ linear or branched, X or Y representing the group NHR4, R represents R - (CH ^ -CR R and R, R, R and R4 have the meanings given above. 8. Method according to claim 7, characterized in that a primary or secondary amine is reacted with 2-chloroacetamide or a corresponding ester, the latter then being subjected to aminolysis to obtain the glycinamide derivative. 9. Method according to claim 7, characterized in that reacts an alkane substituted by a halogen atom or by a group leaving the aforementioned type on la'2-aminoaceous-tamide or a corresponding ester, the latter being then subjected to an aminolysis of the ester function to obtain the corresponding glycinamide derivative. 10. A process for the synthesis of glycinamide derivatives according to any one of claims 1 to 6, characterized in that a compound of the formula R-NR4-CH2CN is submitted, in which R represents-1 2 3 is R - ( CH2) -CR R, on hydrolysis of the nitrile to amide, so as to form the corresponding derivative of glycinamide. 11.- A method according to claim 10, characterized in that a compound of formula RX is reacted with a compound of formula Y-CH2-CN until forming the intermediate compound of formula 4 R-NR -CH2 ~ CN and in that this intermediate compound * is then subjected to hydrolysis of the nitrile group into an amide group, X and Y having / the meanings given above. /// 12. Method according to claim 11, characterized in that a primary or secondary amine is reacted with hydroxyacetonitrile and in this gu * the intermediate product obtained is subjected to hydrolysis. 13. A method according to claim 11, characterized in that allcylated aminoacetonitrile by an alkyl derivative substituted by a halogen atom or by an leaving group of the tosyl, mesyl, R'COCf, NR ^ 'R' type "+, PR'R" R "'+, SR'R" +, OHR, +, OH2 +, CN ~, R * 00 ~, HO ", R1 SO ~, N_ +, N ~, NO ~ in which r ', R ”and R"' 2. i ό 2 may be the same or different and represent linear or branched C ^ -C ^ alkyl radicals and in that the intermediate compound RNH-Cï ^ -CN thus obtained is subjected to hydrolysis of the nitrile into an amide so as to obtain the corresponding derivative of glycinamide. 14. Process for the synthesis of glycinamide derivatives according to any one of claims 1 to 6, characterized in that the catalytic hydrogenation of the corresponding sydnonimine is carried out. 15. Process for the synthesis of glycinamide derivatives according to any one of claims 1 to 6, characterized in that a compound of formula R ^ (CH0) -CH = N-CH -CONH or a corresponding ester is subjected in laguelle R ^ and n have the meanings given above, to catalytic hydrogenation, this ester being subjected to hydrolysis to obtain the corresponding derivative of glycinamide. 16. The method of claim 15, characterized in that * 4 * that condenses an aldehyde on 2-aminoacetamide or on a corresponding „* ester, the latter then being subjected to an aminolysis of the ester function, and in that that the intermediate product 'formed is subjected to catalytic hydrogenation. / ly 17. Process for the synthesis of glycinamide derivatives according to any one of claims 1 to 6, characterized in that 4 subjects the compound of formula RR N-CI ^ -CN to hydrolysis, so as to transform the nitrile into amide. 18. The method of claim 17, characterized in that an iminium salt is reacted on a cyanide and in that the intermediate product obtained is subjected to hydrolysis, so as to transform the nitrile into an amide. 19. Process for the synthesis of glycinamide derivatives according to any one of claims 1 to 6, characterized in that gu'on 4 transforms a carboxylic acid of formula RR N-CH2-C00H into 1 corresponding amide. 20. The method of claim 19, characterized in that gu'ôn condenses trichloroacetaldehyde on a primary amine, the imine obtained is reduced to an amine, the tri-chloromethyl group is converted into a carboxyl group in an acid medium and the acid is transformed amyl carboxyl. 21. The method of claim 19, characterized in that nitroacetigue acid is reduced to glycine, the glycine is alkylated by an alkane substituted by a halogen atom or a group leaving the aforementioned type and the carboxylic acid obtained is turned into an amide. 22. Method according to claim 19, characterized in that glycine formed in particular by reduction of nitroacetigue acid is reacted with an aldehyde, the imine formed is t * reduced to amine and the carboxyl group is transformed into / 23. The method of claim 19, characterized in that glyoxylic acid is reacted with a primary amine, the resulting imine being reduced to amine and the carboxylic group being converted to amide. 24. A process for the synthesis of glycinamide derivatives according to any one of claims 1 to 6, characterized in that a 2-alkylaminoacetamide or a corresponding ester 4 4 is reacted with a compound of formula RX, in which R and X have the meanings given above, the ester being subjected to amino-lysis to obtain the corresponding derivative of glycinamide. 25. Process for the preparation of glycinamide derivatives, as described above, in particular in the attached examples. 26. Pharmaceutical composition, characterized in that it comprises at least one of the compounds of formula I or one of its salts, combined with one or more suitable pharmaceutical excipients or possibly with other therapeutic agents. 27. Composition according to Claim 26, characterized in that it is in the form of dragees, granules, tablets, capsules, solutions, syrups, emulsions or suspensions containing conventional additives or excipients in galenic pharmacy 28. Composition according to claim 26, characterized in that gu1 it comprises at least one of the derivatives according to formula I in solution, in particular in sterile water or in an oil such as peanut oil or ethyl oleate. "29.- Pharmaceutical composition as described above. 30.- A method of using the derivatives according to formula I, characterized in that they are administered at daily doses of 50 to 2000 mg, preferably from 10 to 1500 mg. fc ebyv-vi. ; % 0 po-c ^.> =, EU - * X b dx Λιλλ / τχοΙλχο X 1 / ΊΓΓν £> J, 0 3 / YHvXJtA -Λ ^ ^ 1 / Λ i.