LU85035A1 - AMIDE ACID AMIDE DERIVATIVES, PREPARATION AND USE THEREOF AS WELL AS COMPOSITIONS CONTAINING THESE DERIVATIVES - Google Patents

Description

% 2

The subject of the present invention is amino acid derivatives as well as the salts of these derivatives, their methods of preparation as well as pharmaceutical compositions containing at least one of these derivatives and their method of use.

The derivatives of the invention correspond to the general formula I: 10 R.? 2 Λ

> - (CH) „- C ^ I

R {"^ NH2 in which: 15 R represents: - a linear or branched alkyl radical C2, Cg, C4, Cg, c6" C7 'C8 * C9 * C10 * CH * C12 * - a linear or branched alkyl radical C2, Cg, substituted by a phenyl or phenoxy ring optionally substituted by one or two linear or branched alkyl radicals C ^, C ^, Cg, C4> by one or two linear or branched alkoxy radicals C ^ C2, Cg, C4 or by one or two ~ halogen atoms such as fluorine, chlorine or bromine; - a linear or branched acyl radical C ^, C2, Cg, C4 "Cg" * 25 .substituted by a phenyl ring optionally substituted by a or two linear or branched alkyl radicals Cj, C2 * C3 * C4 * by one or two linear or * branched alkoxy radicals Cj, C2, Cg, C4 or by one or two halogen atoms such as fluorine, chlorine or bromine; 30 represents: - hydrogen; - a linear or branched alkyl radical C2, Cg, C4, Cg, Cg, Γ C Γ C · ο ?, c8, tg, c10, - a linear or branched alkyl radical C2 , Cg, C4 substituted with 35 phenyl ring optionally substituted by one or two linear or branched alkyl radicals C ^ C2, Cg, C4, by one or two linear or branched alkoxy radicals C ^, C2, C-, C. or by one or two halogen atoms such than fluorine,% "3 chlorine or bromine; - A linear or branched acyl radical C ^, C2, C3, C4, c5 * C6 "C7 * C8" C9 "C10; * - a linear or branched acyl radical C ^, C2, C3, C4, 5 C5 substituted by a phenyl ring optionally substituted by one or two alkyl radicals. linear or branched Cj, C2, C3, C4, by one or two linear or branched alkoxy radicals C ^, C2, C3, C4 or by one or two halogen atoms such as fluorine, chlorine or bromine; 10 R2 represents hydrogen if n has the values 3, 4 or 5, if n has the value 1, R2 is represented by the formulas II, III or IV: 1 = · O "*’ OUfCV R3 ° 0CH2-

H

II III IV

In formula IV, R3 represents: - hydrogen; - - a linear or branched acyl radical C2, C3, C4, Cg; - A linear or branched acyl radical C ^, C2, C3 substituted by a phenyl nucleus optionally substituted by · "25 or two linear or branched alkyl radicals Cj, C2, C3, C ^, by one or two linear or branched alkoxy radicals Cp C2, C3, or by one or two halogen atoms such as fluorine, chlorine or bromine, as well as the salts of these compounds formed with pharmaceutically usable acids 3q.

According to a preferred form of the invention, the subject of the invention is compounds of formula I in which R represents; - a linear or branched Cg-Cg alkyl radical; a linear or branched C2-C4 alkyl radical substituted by a phenyl ring optionally substituted by a // 1 »4 methyl, methoxy radical or by a chlorine atom; a linear or branched Cg-C4 acyl radical substituted by a phenyl ring optionally substituted by a methyl or methoxy radical or by a chlorine atom; v 5 Rj represents: - 1‘hydrogen; - a linear or branched Cg-Cg alkyl radical; a linear or branched C 1 -C 4 alkyl radical substituted by a phenyl ring optionally substituted by a methyl or methoxy radical or by a chlorine atom; - a linear or branched C2-C8 acyl radical; - a linear or branched C2-C4 acyl radical substituted by a phenyl ring optionally substituted by a methyl or methoxy radical or by a chlorine atom; 15 R2 represents hydrogen and n has the value 3.

According to another preferred form of the invention, the subject of the invention is derivatives of formula I in which: R represents: 20 - a linear or branched alkyl radical Cg-Cg ·, - a linear or branched alkyl radical C2-C4 substituted by a phenyl ring optionally substituted by a methyl or methoxy radical or by a chlorine atom; a linear or branched C2-C4 acyl radical substituted by a phenyl ring optionally substituted by a methyl or methoxy radical or by a chlorine atom;

Rj represents: * - of 11 hydrogen; - a linear or branched alkyl radical Cg-Cg ·, 30 - a linear or branched alkyl radical C ^ C ^ substituted by a phenyl ring optionally substituted by a methyl or methoxy radical or by a chlorine atom; - a linear or branched C ^ -Cg acyl radical; - a linear or branched C2-C4 acyl radical, substituted by a phenyl ring optionally substituted by a 1 »5

methyl radical, methoxy or by a chlorine atom; n has the value 1 and R2 is represented by formulas II, III or IV

* <QC> V ζχ ^ ™ 2 '"

II H IV

III

10 in formula IV, R3 represents: - 11 hydrogen; - a linear or branched Cg-C ^ acyl radical; a linear or branched acyl radical Cj-C3, substituted by a phenyl ring, optionally substituted by a methyl, methoxy radical or by a chlorine atom.

A preferred class of products of formula I is that in which R represents: - a linear or branched alkyl radical Cg-Cg ·, - a linear or branched alkyl radical Cg-C ^ substituted by a phenyl ring; - a linear or branched Cg-C4 acyl radical substituted by a phenyl ring;

Rx and R2 represent hydrogen and n has the value 3. 25

Another preferred class of products of formula I is that in which R represents: a linear or branched C3-C6 alkyl radical; - a linear or branched Cg-C6 alkyl radical substituted by a phenyl ring; - A linear or branched acyl radical Cg-C ^ substituted by a phenyl ring R ^ represents hydrogen; n is 1 and Rg is represented by formula II.

\ »6

A third preferred class of products of formula I is that in which R represents: - a linear or branched Cg-Cg alkyl radical; - a linear or branched C2-C4 alkyl radical substituted by a phenyl ring; - a linear or branched C2 “C4 acyl radical substituted by a phenyl ring.

R1 represents hydrogen; • ^ n has the value 1 and R2 is represented by the formula III.

10

A fourth preferred class of products of formula I is that in which R represents: - a linear or branched Cg-Cg alkyl radical; - a linear or branched C2-C6 alkyl radical substituted by a phenyl ring; - a linear or branched acyl radical C2 ~ substituted by a phenyl ring; R ^ represents hydrogen; n has the value 1 and R2 is represented by formula IV 20 in which R3 represents: - 11 hydrogen; - a linear or branched C2-C5 acyl radical; - A linear or branched acyl radical C ^ -Cj substituted by a phenyl ring.

25

A fifth preferred class of products of formula I is that in which R represents: - a linear or branched Cg-Cg alkyl radical; - a linear or branched C2-C6 alkyl radical substituted by a phenyl ring; - a linear or branched C2-C ^ acyl radical substituted by a phenyl ring;

Rl and R2 represent hydrogen and n has the values 4 or 5.

// t 7

Examples of compounds according to the invention are: - an.butylami no-4-hydroxybenzenepropanamide, - an.hexylamino-4-hydroxybenzenepropanamide, - 4-hydroxy-a- (4-phenylbutyl) aminobenzenepropanamide, 5 - an.pentylaminobenzenepropanamide, - an.heptylamino-1H-indole-3-propanamide, - 4- (di-n.pentylamino) butanamide, - 4-n.pentylaminobutanamide, - 5-n.pentylaminopentanamide.

10

If the derivatives of formula I are in the form of addition salts with acids, they can be transformed, according to usual methods, into free bases or into addition salts with other acids.

15

The most commonly used salts are non-toxic, pharmaceutically usable acid addition salts formed with suitable inorganic acids, for example hydrochloric acid, sulfuric acid or phosphoric acid or with suitable organic acids, such as aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic, carboxylic or sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric acids , citric, ascorbic, glucuronic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranic, hydroxybenzoic, salicylic, phenylacetic, mandelic, methanesulfonic, ethanesulfonic, pantothenic, toluenesulfonic, nesulfonic alginic, ß-hydroxybutyric, oxalic, malonic, gaiactaric, galacturonic.

The compounds of formula I may have one or more asymmetric carbon atoms and are therefore likely to exist in the form of optical isomers, racemics or diastereoisomers; all these forms are part of the present invention. The optical isomers can be obtained by stereospecific or stereoselective synthesis or by resolution of the racemics according to conventional methods: for example, by formation of diastereoisomeric salts by the action of optically active acids such as tartaric, diacetyl-tartaric, tartranilic acids , dibenzoyltartrique, ditoluoyl-10 tartrique and separation of the mixture of diastereoisomers for example by fractional crystallization followed by the release of the optically active bases from these salts.

The active compounds of formula I can also be obtained using optically active starting materials. This is particularly the case for the derivatives of formula I in which n has the value 1; the starting materials are then preferably natural amino acids such as tyrosine, tryptophan and phenyl-alanine.

The derivatives of the invention can therefore be used either in the form of mixtures containing several diastereoisomers whatever the relative proportions thereof, or in the form of pairs of enantiomers in equal proportions (racemic mixture) or not, or also in k form optically pure compounds.

The products of the invention can be used in the treatment of neurological, psychiatric or cardiovascular conditions such as, for example, epilepsy, depression, dyskinesias such as Parkinson's disease, hypertension, hypotension, sleeping troubles, ...

Jf fti:

// I

i 9

The present invention also covers pharmaceutical compositions containing, as active ingredient, at least one compound of general formula I and / or a salt with a pharmaceutical excipient. These 5 compositions are presented so that they can be administered orally, rectally or parenterally.

The compositions for oral administration can be liquid or solid and presented in the form of tablets, dragees, coated tablets, capsules, granules, powders, syrups, suspensions or emulsions.

The dry oral forms include the additives and excipients generally used in galenic pharmacy.

These additives and excipients can be solid, powdery vehicles, such as, for example, lactose, sucrose, sorbitol, manitol, starch such as potato starch, starch corn, amylopectin, cellulose or gelatin, anti-friction agents such as magnesium stearate, calcium stearate, polyethylene glycol waxes or the like, disintegrating agents, binding agents, preservatives as well as colorants.

25

Such preparations can also be carried out so as to modulate over time the disintegration and, consequently, the duration of action of the active principle.

The aqueous suspensions, emulsions and oily solutions are made in the presence of sweetening agents, such as dextrose or glycerol, perfuming agents, such as vanillin and they may also contain thickening agents, wetting agents, preservatives and colorants.

AT

I10

The emulsions and oily solutions are made in an oil of vegetable or animal origin and may contain emulsifying, perfuming, dispersing, softening and antioxidant agents.

5

For parenteral administration, sterile water, an aqueous solution of polyvinylpyrrolidone, peanut oil, ethyl oleate, etc. are used as the vehicle, these aqueous or oily injectable solutions. may contain thickening, wetting, dispersing and gelling agents.

Rectal administration is in the form of suppositories or gels. The vehicle for suppositories 15 is cocoa butter or semisynthetic triglycerides. The gels are produced, for example, from water, carbopol and amines. These dosage forms may also contain other excipients such as preservatives.

The compounds of the invention are prepared according to methods which form part of the present invention and defined below. In cases where the processes give rise to the production of new intermediate compounds, these new compounds, as well as the processes which serve for their preparation, also form part of the present invention.

*

Method A.

According to this way of proceeding, the amine V is converted into the derivative of formula I:

R.? 2 R? 2 J

rN- (cH) -z - ^> - (ch> -c ^

Rf "Rj ^ n ^ NH2

35 v I

/! I <11 R, Rp R2 "n are as defined above and Z represents an amide function or a function which, by the action of an appropriate reagent, can be transformed into an amide function *, for example the carboxylic acid function (-CÛ0H), 5 the function ni tri 1e (-CN), the ester function (-C00R1) in which R 'represents an alkyl radical (C ^ -Cg) or a phenyl radical substituted in such a way that it activates the ester vis-à-vis the attack of a nucleophile,

^ NH

10 an amidine function (-C), an XNH0 halide function

/ 0 L

acid (C ^), where X represents a halogen such as chlorine or bromine or an anhydride function.

Z can also represent a precursor group of carboxylic acid such as, for example, the group / NS-trichloromethyl or an oxazoline (<Γ).

The transition from product V to product I, that is to say the conversion of an amide precursor to amide, takes place by conventional reactions which are very well documented in chemistry, for example: a) - conversion of a carboxylic acid as amide.

Several methods make it possible to carry out this chemical transformation.

For example, the carboxylic acid can be brought into the presence of the amine, the pyrolysis of the salt thus formed leads to the amide as does the action of a dehydrating agent such as P2 ^ 5 *

Another way of proceeding consists in transforming the carboxylic acid into an acid halide and then into an amide by the action of ammonia. The conversion of acid to acid halide is often accomplished without solvent with thionyl chloride, phosphorus pentachloride or phosphorus oxychloride. The corresponding bromides can also be used. In order for the reaction to be complete, it is often useful to heat the reaction mixture to a temperature between 50 and 150 ° C. If a solvent is useful for the course of the reaction, it will be an inert organic solvent such as hydrocarbons such as benzene, toluene or petroleum ether or ethers such as diethyl ether.

10

The reaction between the acid halide and ammonia is done by cooling the reaction mixture to a temperature between 0 ° C and -50 ° C, by introducing an excess of ammonia (at least 2 equivalents).

Conventionally, the acid chloride is added to the ammonia in solution, in an inert organic solvent such as those defined above or in solution in water. Another way of carrying out the reaction is to bubble a stream of ammonia in an acid chloride solution, cooled in a cooling bath.

Yet another way of proceeding is to react a carboxylic acid and ammonia in the presence of a coupling reagent as used, for example, in peptide synthesis. There are currently a large number of coupling reagents such as, for example, dicyclohexylcarbodiimide, N-ethyl-N‘-3-dimethylaminopropylcarbodiimide, phosphines,, phosphites, silicon or titanium tetrachloride.

b) - conversion of a nitrile into an amide.

The nitriles can be hydrolyzed to amides either in an acid medium or in a basic medium.

If the hydrolysis is carried out under acidic conditions, concentrated sulfuric acid, concentrated aqueous hydrochloric acid, formic acid in λ "· 13 in the absence of solvent, acetic acid in the presence of trifluoride may be used. boron. In most cases it is advantageous to heat the reaction mixture to temperatures up to 200 ° C.

Another way of converting a nitrile into an amide, in an acid medium, consists in treating said nitrile with hydrochloric acid in an alcohol such as ethanol. An intermediate iminoether is thus formed which thermally transforms into an amide.

If the hydrolysis is carried out under basic conditions, an aqueous solution of an alkali or alkaline earth metal hydroxide is used in this case. Advantageously, the presence of hydrogen peroxide facilitates the hydrolysis reaction. The Applicant has developed an original nitrile hydrolysis process which consists in adding to the equivalent of nitrile, 1 equivalent of cupric chloride and carrying out the reaction in an aqueous solution of alkali metal hydroxide at a pH close to 10 and this, at a temperature between 20 normal temperature and the reflux temperature of the reaction mixture.

Another very conventional basic hydrolysis method of nitriles is carried out using alkali metal hydroxide, preferably potassium hydroxide, in t-butanol.

c) - conversion of an ester into an amide.

The aminolysis of an ester is conventionally carried out either in water or in an inert organic solvent.

As an example of a solvent which can be used, there may be mentioned an aromatic hydrocarbon such as benzene or toluene, an aliphatic hydrocarbon such as hexane or petroleum ether, a halogenated hydrocarbon such as dichloromethane or chloroform.

"· 14

The presence of a strong base may be essential in the case of reaction with weakly basic or sterically hindered amines.

The above reaction can be carried out at a temperature between room temperature and the reflux temperature of the solvent.

d) - conversion of an amidine to an amide.

This reaction is mainly carried out by acid hydrolysis in an aqueous or alcoholic medium. The acid can be inorganic like hydrochloric acid or sulfuric or organic acid like acetic acid.

This reaction takes place at a temperature between room temperature and the reflux temperature of the reaction mixture.

e) - When group Z of the general formula represents a carboxylic acid precursor such as a trichloromethyl group or an oxazoline, the conversion to the carboxylic acid is carried out either in water or in an organic solvent i -not in the presence of acid. By an inert organic solvent is meant a solvent such as an aromatic or aliphatic hydrocarbon, chlorinated or not such as, for example, ben-zene, toluene, chloroform, dichloromethane or an ether such as diethyl ether, tetrahydro -furanne or dioxane.

As the acid, a mineral acid is generally used, such as halogenated hydracids, sulfuric acid, concentrated or diluted, nitric acid, concentrated or diluted, phosphoric acid or an organic acid such as acetic acid. The reaction temperature is between 0 ° C and 150 ° C and preferably between 50 and 100 ° C.

In some cases, it may be advantageous not to carry out the direct transformation of Z into an amide

B

"" 15 (-C ^) but to transform one value of Z into ^ nh2 another before generating the amide function. The „5 processes allowing these transformations are well known in the literature and we will quickly review them: - transformation of an acid into an ester and vice versa. Esterification of an acid is a very general reaction which can occur in many ways.

Conventionally, the acid and the alcohol are reacted in the presence of an acid catalyst such as hydrochloric acid or sulfuric acid or p-toluenesulfonic acid. This reaction is advantageously carried out under anhydrous conditions and one of the reactants is used in large excess.

The solvent can be either one of the reactants or an inert organic solvent such as chlorinated hydrocarbons such as chloroform and carbon tetrachloride or an aromatic or aliphatic hydrocarbon such as benzene, toluene or petroleum ether. The temperature is between the normal temperature and the reflux temperature of the reaction mixture.

Another way of proceeding consists in distilling the water as soon as it is formed using an appropriate device. The reaction conditions are identical to those described above with the exception that one of the reactants must not be used in large excess.

The hydrolysis of the ester takes place under conditions similar to the esterification reaction but, in this case, one of the reagents, in this case * * 16 water, is used in very large excess. The catalysis and temperature conditions are the same as for esterification.

- transformation of a nitrile into an ester.

5 The transformation of a nitrile into an ester is done by opposing the nitrile to an alcohol in an acid medium. Many catalysts have been described, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, p-toluene sulfonic acid or naphthalenesulfonic acid. The alcohol can be used as a solvent or any other inert organic solvent such as chlorinated hydrocarbons or aliphatic or aromatic hydrocarbons. The reaction takes place at a temperature between the normal temperature and the reflux temperature of the solvent.

An intermediate iminoether is thus formed which is converted into an ester by hydrolysis.

20 - transformation of a nitrile into an acid. The hydrolysis of a nitrile to carboxylic acid takes place in an acid medium or in a basic medium. As the acid, a halogenated hydraide such as hydrochloric acid or hydrobromic acid or an oxacid such as sulfuric acid or nitric acid is generally used. As the base, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide is used. This hydrolysis occurs in water and at reflux for several hours.

17 - transformation of a nitrile into amidine.

The conversion of a nitrile to amidine is done * by reacting the nitrile with an amine.

It is often advantageous to activate one of the reactants so as to obtain the amidine with a better yield. An activated form of nitrile can be an iminoether or an iminohalogenide. The amine can be activated in the form of a salt with an alkali or alkaline earth metal.

Under these conditions, the amidines are obtained in good yields.

For a better understanding of the process, the main access routes to derivatives V are described below.

I. SYNTHESIS OF THE COMPOUND V.

1. The derivative V can be obtained at the expense of the product VI, by alkylation or acylation.

20 I 2

R - NH - (CH) n - Z ____R_X R

· \! 2

VI N - (CH) - Z

y n

-or * 2 E1 25 R, - HH - (CH) - Z "" S * V

1 n R, Rj, R,> and n have been defined previously however, * in this case, R ^ does not represent hydrogen. X represents a good nucleofuge such as a halogen, such as chlorine, bromine or iodine, a tosyl or mesyl group or an acyloxy group.

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 hydro-carbide such as petroleum ether, / 7 m 1 * * 18 benzene, toluene.

The reaction takes place either at room temperature or 2 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 triethylamine, pyridine or N-dimethylaniline or an inorganic base such as hydroxides, carbonates and bicarbonates of alkali or alkaline earth metals 4 or of lime finely sprayed.

10

A variant of this process is illustrated below: R? 2 Rn * 2

> - H + X - (CH) - Z -N - (CH) - Z

R (n R (n 15 1 1

It will be noted that the above reaction and the preceding reaction are 2 reactions for the alkylation or acylation of a secondary amine into a tertiary amine. It goes without saying that the operating conditions for these two reactions are entirely comparable.

If, in the desired product of the invention, R and R 1 represent an alkyl radical or if the substituent R 1 has been introduced by acylation of the amine, the amide formed must be reduced to amine. Many ~ methods are described for effecting such reduction; let us mention, by way of example, hydrogenation in the presence of Raney nickel or cupric chromite in inert solvents such as lower alcohols such as methanol or ethanol or alternatively acetic acid; reduction with lithium or aluminum hydride in ethers such as diethyl ether, tetrahydrofuran or dioxane.

35 It is obvious that in choosing the reduction conditions, care must be taken to preserve the functionality of the * ·

J

group Z.

2. A variant can be schematized as follows: R? R v R9 5 i NH R ^

HO- (CH) -CN Rf N- (CH) —Z

n - = - ► VII V (Z = CN).

R, R ^ and R2 are as defined above.

When na has the value 1, the derivative VII is a cyanohydrin which can be synthesized beforehand or formed in situ from an aldehyde (Rg-CHO) and an inorganic or organic cyanide such as sodium or potassium cyanide or 15 trimethylsilyl cyanide or alternatively an alkyla- luminium or alkylammonium cyanide.

The condensation of the amine on the cyanohydrin takes place in an inert organic solvent such as 2Q chlorinated hydrocarbons such as chloroform or dichloromethane or an aromatic or aliphatic hydrocarbon such as benzene, toluene or petroleum ether or a ether such as diethyl ether or dioxane. In order to obtain a good yield, it is sometimes advantageous to work at a temperature of between 20 ° C. and 120 ° C.

An acid catalyzes the reaction: we will choose, for example, a halogenated hydracid, such as hydrochloric acid or an oxacid such as sulfuric acid or an organic acid such as p-toluenesulfonic acid.

30

When na has the values 3, 4 or 5, the derivative VII is a hydroxynitri which can be obtained, for example, from a haloalcohol by substitution of the halogen atom by a mineral or organic cyanide such as those which have been cited above. This substitution reaction takes place in an inert organic solvent such as chlorinated hydrocarbons such as chloroform or dichloromethane or an RV 0 * 20 aromatic or aliphatic hydrocarbon such as benzene, toluene or petroleum ether or an ether such as diethyl ether or dioxane. This reaction advantageously takes place at a temperature between room temperature and the reflux temperature of the solution.

The reaction between an iminium VIII salt and a cyanide IX proceeds in the same way.

- 10 R \ © / H. R? 2 N = Cv + CN N- (CH) -CN hydrolysis

Rf "- 15

VIII IX

Rs? 2 N- (CH) n-Z --1 20 R, Rj, R £ and Z are as defined above and n is 1.

The addition of cyanide IX to the iminium salt VIII takes place in an inert organic solvent such as chlorinated hydrocarbons such as chloroform or dichloromethane or an aromatic or aliphatic hydrocarbon such as benzene, toluene or ether of oil. It is advantageous to work at a temperature between 0 ° C. and the reflux temperature of the solvent.

* Depending on the hydrolysis conditions, Z will be a carboxylic acid, an amide, an ester or an amidine.

= 3. A third variant which gives access to the derivative V when n has the value 1 is represented by the diagram which follows:

Base Θ

R? CH9Z -b-aJ.e ... ^ R CHZ -► N - CH - Z

K Rf i ^ N-OAlk K2

K

X XI XII V / "" 21 R, R ^, R2 and Z are as defined in the general formula and in the above processes while Alk represents a lower alkyl radical C ^ -C ^.

The derivative X is transformed into anion XI by a strong base 5 in an inert organic solvent. The base used can be an alcoholate, such as potassium t-butoxide, or an amide such as sodium or lithium amide, or a complex base, commonly called "Caubere base" and which is a mixture of amide and alcoholate. The organic solvent is an aromatic or aliphatic hydrocarbon, such as benzene, toluene or petroleum ether.

The reaction temperature can be between -20 ° C and the reflux temperature of the solvent depending on the reactivity of the substrate.

15. The anion of the derivative X is then placed in the presence of an O-alkylated derivative of the hydroxylamine XII so as to form the product V. This substitution reaction is carried out in an inert organic solvent and at a temperature of between -20 ° C and the reflux temperature of the solvent.

4. According to this way of proceeding, valid only in the case where Z represents the nitrile group (-CN) and when n has the value 1, the derivative V is obtained at the expense of an enamine XIII by addition of hydrocyanic acid.

R., H R? 2

- *; C = C. Jt + HCN - ”. - (CH) „- Z

R / R / '"5' 'R. 1

"X

30 XIII V (Z = CN)

R, R ^ and R ^ have the values defined above while R

That ^ NCH represents the substituent R ?.

D / C

K5

H

Λ "22 Hydrocyanic acid can be added as such or synthesized in situ. This addition reaction is carried out in an inert organic solvent, preferably slightly polar, such as chlorinated hydrocarbons such as chloroform or dichloromethane or also in acetonitrile and at a temperature between the temperature. ambient temperature and the reflux temperature of the solvent.

5. This process consists in the reduction of the double liai-10 its carbon-carbon of an α-cyanoenamine XIV.

R ΓΝ d = C ^ / R —reduction ^ \ N _ (CH) _ z R / R / "5 Rx 15 XIV V (Z = CN) R, R ^ and R ^ are as defined in the general formula, R.

n is 1 and CH represents the substituent R0.

20 L

The reduction of the carbon-carbon double bond is done. conventionally by hydrogenation in the presence of a catalyst belonging to the class of transition metals, their oxides or their sulfides and on an inert support. Mention may be made, as catalysts, of Raney nickel, platinum, platinum oxide or also palladium on carbon. The presence of solvent is desired and it is chosen from lower alcohols such as methanol or ethanol or from the group formed by glacial acetic acid and its simple esters. This reduction is carried out at ordinary pressure or at a pressure greater than this. The reduction can also be done by hydrides such as sodium borohydride, advantageously in the presence of a Lewis acid or by diborane in 23 φ i of solvents such as methanol, ethanol, diglyme, tetrahydrofuran or dioxane.

The reduction conditions must be chosen judiciously so as to preserve the nitrile group.

"5 Finally, note that recent literature describes very general access routes to α-cyanoenamines XIV (see J. Toye and L. Ghosez, J. Am. Chem. Soc., 1975, 97 (0), 2276-7 ).

6. Another access route to derivative V is characterized by the formation of an intermediate iminium salt XV from an amine and a carbonyl compound XVI.

The reduction of the iminium salt leads to the derivative V.

S? 2 R. © / R2

'NH + R, C- (CH) „. - Z - »-Z

15 R1 R1 <? H> n-l XV! χν R2 reduction

V

20! rx h \ N- (CH) n-z R1

V

'25

The condensation between the amine and the carbonyl derivative XVI is conventionally carried out in an inert organic solvent, * preferably immiscible with water such as benzene or toluene. Advantageously, the reaction is catalyzed by an organic or inorganic acid.

P-toluenesulfonic acid is very commonly used to play this catalytic role.

/ * * 24

The reduction takes place in the presence of hydrogen and a hydrogenation catalyst, such as platinum, platinum oxide or palladium on carbon in a solvent such as methanol, ethanol, ethyl acetate. or glacial acetic acid and this, at ordinary pressure and more advantageously at higher pressure, either by an alkali metal hydride such as sodium borohydride in a solvent such as methanol or aluminum hydride and lithium in a solvent such as ether 10 or tetrahydrofuran.

It goes without saying that the method of reduction of the minminium salt will be chosen so as to keep intact the functionality of group Z. By choosing the reagents differently, a variant of this process can be written which makes it possible to arrive at product V passing through intermediates carrying the same chemical functions as above.

V '2 H + V' Â '2

= 0 + R.NH- (CH) - Z ► C = rP- (CH) - Z

R / n Rr n 20 7 7

XVII XVIII. XIX

reduction

R I

6m: h

’'25 R7 RXCH> n-Z

R1 Ä 1 * 2 and Z have the meanings given above while the groups Rß and Ry have values

R

30 such that ^ CH is equivalent to R.

ν 'Λ «* 25

The condensation of the carbonyl derivative XVII on the amine XVIII and the reduction of the iminium salt XIX take place under the conditions already described.

The variant described above starting from the derivative XVIII is particularly advantageous when n has the value 1 and when Z represents the carboxyl function. In this case, in fact, the starting reagent is an optically active natural amino acid. The synthesis starting from this amino acid involves two chemical transformations: the substitution of the nitrogen atom on the one hand and the transformation of the carboxyl group into carboxamide, on the other hand. These 2 reactions can occur in any order, that is to say: we can first substitute the nitrogen atom then transform the carboxyl function into carboxamide or we can first synthesize the amide starting from the amino acid and then substituting the nitrogen atom for the amine function.

20 As the starting reagent is an optically active natural amino acid, it goes without saying that if it is desired to obtain an optically active derivative of formula I, the reagents used in these syntheses will be non-racemising and the reactions will be carried out in wagering non-racial conditions.

Amino acids being bifunctional molecules, it is obvious that, to avoid side reactions on the function which must not react, protective groups or intermediates commonly used in peptide synthesis are used.

Thus, for example, to transform an amino acid into α-aminoamide, one often goes through an intermediate 35 called "Leuchs anhydride", represented by the formula XX.

* i 26 h A ”

5 XX

This compound is conventionally obtained by the action of phosgene on the amino acid. This reaction takes place in inert organic solvents such as aromatic or aliphatic hydrocarbons (benzene, toluene petroleum ether, hexane, etc.) or such as ethers (diethyl ether, tetrahydrofuran, ___).

It is often advantageous to slightly heat the reaction mixture so as to activate the reaction.

Leuchs' anhydride is then converted to α-amino 15 by reaction of a concentrated ammonia solution. This reaction generally takes place at room temperature, but in some cases it may be advantageous to slightly heat the reaction mixture.

20 The scientific literature in the field of amino acids indicates numerous protective groups which can be used in peptide synthesis, (see for example "The peptides, Analysis, Synthesis, Bvology" "Vol. 3" Protection of Functional Groups in Peptide Synthesis ", Ed. E. Gross 25 and “3. Meienhofer, Academie Press, 1981). All of these protecting groups can be used in this case.

-P- II. SYNTHESIS OF COMPOUND VI.

Reagent VI which serves as a starting point for the first process for the synthesis of amino acids of the invention can be obtained in various ways.

1. A first synthetic route and its variant are to be compared to the alkylation or acylation of the secondary amine to the tertiary amine described in paragraph - i a. / 7 * <27 r2 r2

RX + H2N - (CH) n - Z - ^ R - NH - (CH) n - Z

VI

5 or R 2 R 2

RNH2 + X - (CH) n - Z - ^ R - NH - (CH) n - Z

VI

10 R, r2, Z and n are defined above while the nature of X was clarified in method 1.1.

The alkylation or acylation of a primary amine to a secondary amine occurs in the same manner and substantially under the same conditions as the alkylation and acylation of a secondary amine to a tertiary amine; the experimental conditions described in paragraph I.I., can easily be applied, successfully, to the reaction presently described.

2. The variants described in paragraphs 1.2 and 1.3 are also applicable to the synthesis of the derivative VI, but in this case, the amine used is a primary amine, that is to say, R 1 represents hydrogen.

The variants described under paragraph 1.6 are also applicable to the synthesis of derivative VI, but it should be noted that the intermediate products formed are then imines and no longer iminium salts.

The conditions for reducing imines are comparable to the conditions used for reducing iminium salts.

f / \ fi • i 28 3. According to this synthetic route, valid only when Z represents a carboxylic group (-C00H) and when n * has the value 1, a creatinine derivative XXI is placed in the presence of an aldehyde XXII, the product XXIII thus obtained-5 is then reduced and hydrolyzed to derivative VI.

f8

° T ~ \ ° MC H

H-N Jl-R + r8CH0 -►H-N N-R-

10 X T

nH reduction

XXI XXII XXIII

0 ch2r8 15 hydrolysis ^ RNH- (CH) n-Z ^ - H_N / \ VI (Z = C00H) Ik

nH

XXIV

In this scheme, R, R2 and Z have the values defined above while the substituent RgCH2 has the values of the radical R 1.

The condensation of aldehyde XXII on the heterocyclic compound XXI takes place in an inert organic solvent such as chlorinated hydrocarbons such as chloroform or dichloromethane, lower alcohols such as methanol or ethanol; aromatic or *, aliphatic hydrocarbons such as benzene, toluene or petroleum ether, aliphatic or cyclic ethers or even dimethylformamide.

The reaction temperature can be chosen over a wide range of temperatures, but this reaction is normally carried out at a temperature between room temperature and 100 ° C. The presence of base is essential for the course of the reaction. The base can be an inorganic base like the hydroxides of metals therein.

H

• * 29 alkaline or alkaline earth or organic such as pyrri-dine, triethylamine or the salt of a carboxylic acid such as sodium acetate.

4 "

The reduction of the carbon-carbon double bond of com-5 posed XXIII is conventionally done by hydrogenation in the presence of a catalyst belonging to the class of transition metals, their oxides or their sulfides and on an inert support. As catalysts, mention may be made of Raney nickel, platinum, platinum oxide or even palladium on carbon. The presence of solvent is desired and it is chosen from lower alcohols such as methanol or ethanol or also from the group formed by glacial acetic acid and its simple esters. This reduction is carried out at ordinary pressure or at a higher pressure. The reduction can also be done by hydrides such as sodium borohydride, advantageously in the presence of a Lewis acid or by diborane in solvents such as methanol, ethanol, diglyme, tetrahydrofuran or dioxane.

The hydrolysis of the derivative XXIV takes place in an aqueous medium or in an inert organic solvent. The presence of acid is essential to carry out this reaction.

The acid can be mineral like hydrochloric acid • '25 or sulfuric or organic acid like acetic acid or p-toluene sulfonic acid.

By changing the starting heterocycle, it is possible to arrive at the derivative VI while keeping the reaction sequence and the experimental conditions. It is thus possible to start from a hydan-toin XXV, a thiohydantoin XXVI, a dioxopipe-razine XXVII or a 2-thiono-5-oxo-thiazolidine XXVIII.

ί * 4 30 0 .0 J, ο M ri Λ'ί-Η ri

4 R-N NH R-N NH R-N.J R-N S

Y y i ï 5

XXV XXVI XXVII XXVIII

6. Another access route to product VI, also valid only when Z represents a carboxylic group 10 (-C00H) and when n has the value 1 uses an amine and an α-carbonylated aldehyde XXIX according to the scheme: 0 0

'N R SH

RNH2 + R2C-C-H -R-NH-CH-Z

15. R2 XXIX VI (Z = C00H) The redox amination of the glyoxalic compound XXIX is carried out either in aqueous solution or in an inert organic solvent chosen, for example, from chlorinated hydrocarbons such as chloroform or dichloromethane or among lower alcohols such as methanol or ethanol or among aromatic or aliphatic hydrocarbons such as benzene, toluene or petroleum ether. The reaction is generally carried out at a temperature between normal temperature and the reflux temperature of the solvent.

Advantageously, a thiol (R "SH) will be introduced into the reaction mixture as catalyst (R" represents a lower alkyl radical C 1 -C 4 or a phenyl ring).

iï * F!

NOT

* * 31

Process B.

This process consists in opening a lactam XXX under * the action of a base. Said lactam XXX is conventionally obtained from lactone XXXI according to the diagram: s 5 R2 - (- W0 _ ^ R2 (CH ^ / ° ï MNH2

10 XXXI R

XXX

^ 2 0 I c s * U

RNH- (CH) n xnh2

15. I

R, and n have been defined previously, M represents a monovalent cation, such as of an alkali metal.

The conversion of lactone to lactam takes place in an inert organic solvent, such as chlorinated solvents such as chloroform or dichloromethane, such as aromatic or aliphatic hydrocarbons such as benzene, toluene and the various fractions of ether of petroleum or like alcohols such as methanol or ethanol.

Other solvents may also be suitable, such as, for example, acetonitrile or water.

AT

This reaction generally takes place at a temperature between the chamber temperature and the reflux temperature of the solution. Advantageously, this reaction is carried out at reflux temperature.

/ / / i Λ * 32 The opening of the lactam under the action of an amide is carried out in an inert organic solvent such as ethers, alcohols, chlorinated solvents, hydrocarbons or in water. This reaction can take place at room temperature but advantageously it will be carried out at the reflux temperature of the solution.

Method C.

According to this process, an aldehyde and an amine are opposed to an isonitrile XXXII in the presence of a carboxylic acid.

R r 0 R „CH0 + \ - H -xN-CH-C-NHRq

2 "f R9N * c Ri L

XXXII L

15 R, R ^ and R £ are as defined above, Rg is a protective group replaceable by a hydrogen atom.

The condensation of the amine on the aldehyde takes place under the same general conditions as for the synthesis of imines.

These conditions have been described in section II.3.

The addition of isonitrile takes place in an inert organic solvent such as aromatic or aliphatic hydrocarbons such as benzene, toluene or petroleum ether or as chlorinated hydrocarbons such as chloroform or dichloromethane or as ethers, cyclic or not.

The temperature at which the reaction takes place is adapted to the reactivity of the reactants: if the reaction is strongly exothermic, it may be useful to cool the reaction mixture in an ice bath or in a cooling bath based, for example, on dry ice; if, on the other hand, the reaction is very slow, it may be necessary to increase the temperature until reflux.

* A variant of this process consists in first reacting the aldehyde and isonitrile XXXII and then in "opening the intermediate iminooxirane XXXIII with the amine: R-J-R9

r2cho + RgN = C-γς - "7 -J

H 1) HNRR-, 10 XXXIÏ. ..

L J 2) protection

XXXIII

XN - CH - 15 Rf k2 NH2

VI

The reaction between the aldehyde and isonitrile preferably takes place at a very low temperature (between -30 ° C and -100 ° C) and is advantageously catalyzed by a Lewis acid such as, for example, BF etherate -g. An ether, such as diethyl ether, meets the requirements of the reaction well. To avoid any trace of humidity, the reaction is carried out under a nitrogen or argon atmosphere. The opening of the imino-oxirane XXXIII is done by adding amine to the reaction mixture at low temperature and then gradually raising the temperature to room temperature.

By using an optically active amine to open the iminooxirane, it is possible to preferentially obtain one of the enantiomers of derivative VI with a non-negligible optical yield.

It should also be noted that iminooxirane XXXIII can be synthesized by oxidation of ketenimine XXXIV. The oxidizing agent commonly used is m-chloroperbenzoic acid (mCPBA).

â «« 34 m.CPBA __J-R9 R2CH = C = N - Rg -H / \

XXXIV XXXIII

5

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

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

AT

ff * "35

Example 1.

Synthesis of L-g-n.butylannno-4-hydroxybenzenepropanamide.

a) 500 ml of phosgene in solution are introduced into a 2 liter flask fitted with a condenser surmounted by a calcium chloride tube and a magnetic bar. 20% in toluene (1 mole). A suspension of L-tyrosine (45.3 g, 250 mMoles) in 750 ml of tetrahydrofuran is then added with stirring and the mixture is brought to 40 ° C. A light yellow solution is thus obtained which is allowed to return to room temperature, which causes precipitation. After 2 hours of stirring, the solution is evaporated, taken up 3 times in 250 ml of THF which is evaporated, then in 250 ml of hexane, the suspension is filtered, washed with pentane. The solid is dried under reduced pressure at 50 ° C.

YId: 97.8% (50.65 g).

b) 4.1 g of the Leuchs anhydride obtained previously (20 mM) are introduced into a 250 ml flask, which is dissolved in 100 ml of THF. To this solution is added 2 ml of 25% ammonia and the mixture is stirred at room temperature * for 3 hours. From the start of the reaction, a precipitate appears. It is filtered and recrystallized from acetonitrile.

25 F (° C): 148.5 Yield: 64% (2.3 g).

c) In a 1 liter bottle of Parr, we introduce

O

0.6 g of 10% Pd / C, 5 g of 3 A molecular sieve, 5.41 g of L-tyrosinamide (30 mM), 2.16 g of butanal (30 mM) 30 and 120 ml of absolute ethanol. The bottle is shaken under 40 psi of hydrogen for 4 hours. It is then filtered on Celite and the filtrate is evaporated under reduced pressure.

The residue is taken up in 100 ml of hot toluene, the light insoluble material is filtered and evaporated to dryness. The solid obtained is stirred overnight with pentane, filtered and dried. λ lip i \ * »36 F (° C): 106 Yield: 68% (4.85 g).

Elementary analysis: C H N

% calculated 66.1 8.5 11.9% found 66.0 8.5 11.6 5

Example 2.

* Synthesis of L-a-n.hexylamino-4-hydroxybenzene propanamide.

0.4 g is introduced into a 1 liter bottle of Parr

O

'' of 10% Pd / c, 2 g of 3 A molecular sieve, 3.6 g of 10 L -tyrosinamide, 2 g of hexanal and 100 ml of absolute ethanol. Stir overnight at room temperature under 40 psi of hydrogen. It is filtered on this dish and evaporated to dryness. The solid is recrystallized from acetonitrile.

F (° C): 137 Yield: 29.3% (1.55 g).

15 Elementary analysis: C H N

% calculated 68.2 9.2 10.6% found 68.4 9.2 10.9

Example 3.

20 Synthesis of L-4-hydroxy-a- (4-phenylbutyl) aminobenzenepropa-namide.

In a 1 liter bottle of Parr, introduce 0.8 g

O

»Of 10% Pd / C, 5 g of 3 A molecular sieve, 8.1 g of L -tyrosinamide (45 mM), 6.65 g of 4-phenylbutanal (0.45 mM)" as well as 150 ml This suspension is stirred overnight under 40 psi of hydrogen at room temperature.

Filtered on celite, evaporated to dryness and recrystallized "from toluene.

F (° C): 119 Yd: 76% (10.7 g).

30 Elementary analysis: C H N

% calculated 73.1 7.7 9.0% found 72.9 7.8 9.1

Example 4.

35 Synthesis of L-a-pentylaminobenzenepropanamide.

a) 5 g (16.7 mM) of N-benzyloxycarbonylphenylalanine yj / 'i (Z-phenylalanine) suspended in 25 ml of THF at - 15 ° C ßj iy • m 37 are added dropwise to 2 g (19, 5 mM) of N-methylmorpholine. When the temperature has returned to -15 ° C, 2.17 g (20 mM, 1.9 ml) of ethyl chloroformate is added quickly, taking care that the temperature does not rise above -5 ° C, a white precipitate is formed. The reaction medium is left to react for 2 minutes and 2 ml (26 mM) of 25% ammonia are added all at once. After 15 minutes of reaction at -15 ° C, the reaction mixture is allowed to return to room temperature.

10 A solid solidifies which dissolves almost completely by the addition of 10 ml of THF. Then poured onto a mixture of water and ice and the solid which forms is filtered and recrystallized from isopropanol. F (° C): 166 Yield: 93% (4.6 g).

15. b) 2.1 g (7 mM) of ZL-phenylalaninamide, 606 mg of pentanal (7 mM), 100 mg of Pd / C at 10%, 1 g of molecular sieve and 100 ml of ethanol are stirred for 5 hours at 60 ° C under 40 psi of hydrogen. Filtered on celite, evaporated to dryness, washed with pentane and recrystallized from heptane.

F (0C): 111 Yield: 90% (1.5 g).

* Elementary analysis: C H N

% calculated: 71.7 9.4 11.9 25% found: 71.8 9.4 12.0

Example 5.

Synthesis of L-a-n.heptylamino-1H-indole-3-propanamide.

a) 40 g (0.13 mol) of tBoc-L-tryptophan are dissolved in 33 ml of anhydrous THF and cooled to -15 ° C. 13 g (0.128 mol) of N-methylmorpholine are then added while keeping the temperature at -15 ° C. To this solution, 17 g (0.124 mol) of isobutyl chloroformate are added and the mixture is left to react for 2 minutes at -15 ° C. 13 ml of 25% ammonia are added, the mixture is left to react for 15 minutes at -15 ° C., then it is left to return to room temperature. It is poured onto a mixture of ice and water and extracted three times with ethyl acetate, dried over MgSO 4 and evaporated, the residue is recrystallized from an ethyl acetate / hexane mixture.

5 F (° C): 146.4 Yield: 83% (31.4 g) “b) 31.4 g (0.1 mole) of tBoc-L-tryptophanamide are added to 314 ml of a solution of hydrochloric acid 2.5 N in ethyl acetate, the clear solution sees a precipitate appear after a few minutes.

After 3 hours, the solid is filtered and recrystallized from an ethanol / ether mixture. The hydrochloride is released at 0 ° C. with a 1N NaOH solution up to pH 10, extracted with ethyl acetate and evaporated.

15 17 g of a slightly brown oil are obtained.

Yid; 82.2% (17 g).

c) 5 g (25 mM) of tryptophanamide, 2 g of 3 A molecular sieve, 500 mg of Pd / C at 10%, 3.5 ml of heptanal (26 mM) and 200 ml of ethanol are introduced into a bottle 20 Parr and hydrogenated under 40 psi for 6 hours at 60 ° C.

Filtered on celite, evaporated to dryness, dissolved in methanol and added tartaric acid until - acid pH. By addition of ether, a white precipitate is formed which is filtered. It is recrystallized from a methanol / ether mixture.

F (° C): 85-95 Yield: 38% (4.3 g)

Elementary analysis C H N h ^ O

*% calculated: 57.3 7.4 9.1 1.5% found: 57.4 7.2 9.0 1.8 30

Example 6.

Synthesis of 4- (di-n.pentylamino) butanamide.

9.5 g (52 mM) of 4-aminobutamide hydrobromide are dissolved in 300 ml of methanol, at 0 ° C. 35 g of 3 A molecular sieve are added 35, 35.83 g (0.416 mole) of ί (• 9 39 pentanal and 4.95 g (0.078 mole) of NaBHgCN. After 2 hours, the mixture is filtered and evaporated. methanol, the residue is dissolved in water and extracted with ether, the aqueous phase is basified with a 1N NaOH solution up to 5 pH 11, the oil which is formed is extracted with ether, the ethereal phases are dried with K2CO3, the ether is evaporated and 9.5 g of the product is distilled at 140-146 ° under 10 "^ mbar

YId: 75% (9.5 g).

Elementary analysis: C H N

10% calculated 69.3 12.4 11.5% found 69.3 12.5 11.5

Example 7.

Synthesis of 4-n.pentylaminobutanamide.

15 5g (41 mM) of 4-chlorobutanamide are dissolved in 19 ml • (0.165 mole) of pentanamine and stirred for 48 hours at room temperature. By addition of ether (100 ml) a precipitate is formed which is filtered and recrystallized twice from isopropanol.

20 F (° C): 187.

Elementary analysis: C H * N

% calculated: 51.7 10.1 13.4% found: 52.0 10.2 13.4 25 Example 8.

Synthesis of 5-n.pentylaminopentanamide.

a) A mixture of 4.5 g of 5-chloropentanenitri le (40 mM), 3.8 g (44 mM) of pentanamine, 3.7 g of sodium bicarbonate in 60 ml is brought to reflux for 48 hours. absolute ethanol. The sodium chloride formed is filtered and the filtrate is evaporated to dryness under vacuum to remove the excess pentanamine. The residual oil is dissolved in ether and added with ether HCl. A white precipitate is formed which is filtered.

35 F (° C): 207-209 Yield: 34% (2.78 g).

/ 7 // / ·: · * * 40 b) 2.78 g (13.6 mM) of 5-n.pentylamino-pentanenitrile hydrochloride are suspended in 3.4 ml of concentrated HCl and stirred at 5 ° C for 6 days. The clear solution obtained is poured onto 20 ml of isopropanol, the solid which crystallizes is filtered and washed with isopropanol.

F (° C): 216-217 Yield: 45.4% (1.55 g).

Elementary analysis: C H N

% calculated 53.9 10.4 12.5% found 54.2 10.5 12.6 10

Example 9.

Synthesis of L-3- (4 * -phenylacetyloxyphenyl) -2-butyl-friend nopropanamide.

1.5 g (6.64 mM) of 3- (4-hydroxyphenyl) -2-butylaminopropanamide in solution in a 50 ml flask fitted with a calcium chloride tube and a magnetic bar 15 ml of trifluoroacetic acid. At room temperature, 2 ml (13 mM) of phenylacetyl chloride are added and the mixture is stirred for 3 hours. The solution-20 tion is then evaporated to dryness under reduced pressure. The residue is taken up in dichloromethane and the hydrochloride is formed by adding ether saturated with hydrochloric acid. The hydrochloride is then recrystallized once from acetonitrile and once from isopropanol.

F (° C): 229 - (decomposition.) Yield: 40% (1.03 g).

Elementary analysis: C H N

% calculated 64.5 6.9 7.1% found 64.0 6.9 7.2 30

Tables I and II given below group together the derivatives of the above examples as well as other derivatives of the invention prepared according to the above methods.

All the compounds listed in Tables I and II give an elementary C.H.N. correct.

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CTi "—i T — I lll CO <T

ÿ t-ÿ - o LO to co en o here rH rH i — I i—! r — I C \ J * eu · • + -> eu

^ "O -P

_ ----. s_ ro _> +3 s-

3 CL ETJ

<O ro >> (- ~ r-

__J CU LO o CM CO

in “O VD CO CO CO _

_ o KD KD KD KD

o ‘OJ OJ CNJ C \ i T ^ CNJ

• ___J__ _ ______ / fl / / // "m 46

The products of the invention were subjected to a series of pharmacological tests, the methodology of which is described below.

5 DLj-q are calculated according to the method of Litchfield and Wilcoxon (J. Pharmacol. Exp. Ther. £ 6, 99, 1949) and expressed in mg / kg. The products are administered orally to mice. In general, the products of the invention have been found to be not very toxic.

10 The effect on behavior is studied using a method derived from that of S. Irwin (Gordon Res. Conf. On Médicinal Chem., 133, 1959). The substances, suspended in a mucilage containing 1% of tragacanth, are administered orally by means of an intragasric probe to groups of 5 male mice (CD1, Charles River strains, fasting for 18 hours).

The doses tested depending on the activity observed range from 3000 to 3 mg / kg.

The behavior is studied 2, 4, 6 and 24 hours after the treatment. Observation is extended if symptoms persist at this time. Mortalities are recorded during the 14 days following treatment.

None of the products tested induced abnormal behavior in the mouse or proved to be toxic.

In general, certain products of the invention are endowed with an anticonvulsant activity.

The anticonvulsant effect is examined with respect to tonic convulsions induced by bicuculline. The compounds of the invention are administered orally at a dose of 10 mg / kg, to twenty mice, three hours before the intravenous injection of bicuculline, at a dose of 0.7 mg / kg. The number of mice protected against tonic convulsions and death is noted.

* "47

CP 2081 (Compound # 2 in Table I) was further evaluated. In the inhibi- test. convulsions induced by bicucullin, ED5Q

is 3 mg / kg. At the dose of 300 mg / kg, the percentage of protection against convulsions induced by bicuculline is 75%.

”CP 2081 also has an antagonistic effect on convulsions induced by leptazole and by electroshock.

10

In humans, the compounds of the invention will be administered orally, at doses ranging from 50 mg to 4000 mg, intravenously, the doses will be from 5 mg to 400 mg.

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

This active product can be formed by one of the following compounds: 20 - an.butylamino-4-hydroxybenzene propanamide - an.hexylamino-4-hydroxybenzenepropanamide - 4-hydroxy-a- (4-phenylbutyl) aminobenzenepropanamide - an.pentylaminobenzenepropanamide - σ-η .heptylami no-1H-i ndole-3-propanamide 25 - 4- (di-n.pentylamino) butanamide - 4-n.pentylaminobutanamide - 5-n.pentylaminipentanamide.

Tablets.

30 A 600 mg starch Sta-Rx 1500 80 mg hydroxypropyl methylcellulose 20 mg aerosil 5 mg magnesium stearate 15 mg h1 • “.

48 A 100 mg corn starch 100 mg £ lactose 80 mg aerosil 5 mg 5 talc 5 mg magnesium stearate 10 mg Capsules A 50 mg 10 lactose 110 mg corn starch 20 mg gelatin 8 mg calcium stearate 12 mg 15 A 200 mg polyvinylpyrrolidone 10 mg corn starch 100 mg

Cutina HR 10 mg 20 Injectable I.M. or I.V.

A 20 mg sodium chloride 40 mg sodium acetate 6 mg distilled water for injectables ad 25 5 ml

Injectable I.M.

A 200 mg benzyl benzoate 1 g 30 oil for injection ad 5 ml

If too much.

A 5 g ammonium glycyrhizinate 0.5 g 35 tartaric acid 0.5 g nipasept 0.1 g L · • · 49 sucrose 70 g aroma 0.1 g water ad 100 ml 5 Solute.

A 2 g sorbitol 50 g glycerin 10 g mint essence 0.1 g 10 propylene glycol 10 g demineralized water ad 100 mg

Suppose you re.

A 500 mg 15 butylhydroxyanisol 10 mg semi-synthetic glycerides ad 3g

Rectal gel.

At 100 mg 20 carbomer 15 mg tri ethanol friend ne ad pH 5.4 purified water 5 g JY '// /

Claims (23)

5 Rv? 2 0> - (CH) -C ^ I Ri n vNH2 in which: 10. represents - a linear or branched alkyl radical C2, C3, C ^, Cg, Cg »Cy, Cg, Cg, C ^ g JC ^ 2 0U ^ 12 * - a linear or branched alkyl radical C2, C3, substituted by a phenyl or phenoxy nucleus optionally substituted by one or two linear or branched alkyl radicals C ^, C2, C3, C ^, by one or two linear or branched alkoxy radicals C ^, C2, C3, C ^ or by one or two halogen atoms, such as fluorine, chlorine or bromine, 20. a linear or branched acyl radical Cp C2> C3 , C ^, Cg substituted by a phenyl ring optionally substituted by one or two linear or branched alkyl radicals Cp C2, C3, C ^, by one or two linear or branched alkoxy radicals Cp C2, C3> C ^ or by one or two halogen atoms, such as fluorine, chlorine or bromine, represents ”- hydrogen, - a linear or branched alkyl radical C2, C3> Cp Cg, Cg, C7 'C8' C9 'C10 * 30. a linear or branched C2 alkyl radical, C3, Cp substituted by a phenyl nucleus optionally substituted by one or two linear or branched alkyl radicals Cp C2> C3> Cp by one or two linear or branched alkoxy radicals Cp ^ 2 * ^ 3 »ου By one or two atoms of halogen, such as fluorine, chlorine or bromine. r a linear or branched acyl radical Cp C2, C3, Cp Cg, V "" 51 C6 'C7S C8' C95 C10 '- a linear or branched acyl radical Cp C2, C3, Cp Cg, substituted by a phenyl ring optionally substituted by one or two linear or branched alkalines Cp 5 Cp Cp Cp by one or two linear or branched alkoxy radicals Cp C2, Cp Cp or. by one or two halogen atoms, such as fluorine, chlorine or bromine, R 2 represents hydrogen if n has the values' 3, 4 or 5, 10 if na has the value 1, R2 is represented by the formulas II, III or IV: O, OrT ™ 2 "R3 ° - 0-CH2- i5 w II H IV III • in formula IV, R3 represents - hydrogen, 20. a linear or branched acyl radical C2, C ^, Cp Cg, - a linear or branched acyl radical Cp C2, C3, substituted by a phenyl ring optionally substituted by one or two linear or branched alkyl radicals Cp C2, Cp C ^, by one or two linear or branched alkoxy radicals * 25 Cp Cp Cp C ^ or by one or two atoms d 'hal ogen, such as fluorine, chlorine or bromine, as well as the salts of these compounds formed with pharmaceutically usable acids. "* 52 3. Derivative according to claim 1, characterized in that, in the general formula I, R represents a linear or branched Cg-Cg alkyl radical. 5 4. A derivative according to claim 1, characterized in that ·, in formula I, R represents an alkyl radical C3 to C6 ’* 5. Derivative according to claim 1, characterized in that, in the general formula I, R ^ represents - hydrogen, - a linear or branched alkyl radical Cg-Cg, - a linear or branched alkyl radical C2 ~ C4 substituted by a phenyl ring optionally substituted by a methyl or methoxy radical or by a chlorine atom, - a linear or branched acyl radical C2-Cg, - a linear or branched acyl radical Cg-C ^ substituted by a phenyl nucleus optionally substituted by a methyl or methoxy radical or by a chlorine atom. 20 6. A derivative according to claim 1, characterized in that R ^ represents an alkyl radical C ^ -Cg or * an acyl radical C2 substituted by a phenyl ring itself optionally substituted by a Cl atom or by a methyl radical. 7. Derivative according to claim 1, characterized in that, if n = 1, R2 represents a group R30- ^ j> -CH2 in which Rg is an acyl radical C2 optionally substituted-30 by a phenyl ring or a radical unsubstituted acyl. f / i «* 53 8. Derivative according to claim 1, characterized in that it is chosen from the group formed by the compounds: - an.butylamino-4-hydroxybenzenepropanamide, 5 an.hexylamino-4-hydroxybenzene propanamide, - 4-hydroxy-a (4 -phenylbutyl) aminobenzenepropanamide, - an.pentylami nobenzenepropanami de, * - an.heptylamino-1H-indole-3-propanamide, - 4- (di-n.pentylami no) butanamide, 10 - 4-n.pentylaminobutanamide, - 5- n.pentylaminopentanamide. 9. Intermediate products, in particular for the preparation of the derivatives according to any one of the preceding claims, corresponding to the formula V r2 N- (CH) -Z Rf n 20 V in which R, R ^, R2j n Z have the meanings given above. * 10. Intermediate products, in particular for the preparation of the derivatives according to any one of the preceding claims, corresponding to the formula VI h R-NH- (CH) n-Z VI in which R, R ^, n and Z have the meanings given above. 11. Derivative as described above, in particular in the examples given in the description. IÎ «I 54 12. Process for the synthesis of derivatives according to any one of claims 1 to 11, characterized in that it λ consists in converting an amine of formula - R2 * _ RI 5 "N- (CH) n - Z into a compound correspondent of formula I, R, R ^, R ^ and n having the meanings given above, Z representing an amide function or a function convertible into an amide function, such as a carboxylic group, nitrile, ester -C00R *, in which R ′ is an alkyl radical or a phenyl radical substituted in such a way that it activates the ester against attack by a nucleophile, 15 ^ NH an amidine function of the -C type, a anhydride group, ^ m9 0 c an acid halide -C ** where X represents a halogen, ^ X such as chlorine or bromine, or a precursor group of carboxylic acid such as a trichloromethyl group or an oxa- zoli ne. A 13. Process for the synthesis of derivatives according to any one of claims 1 to 11, characterized in that a lactam of formula XXX ✓ 0-. R2- (CH) n \? "^ N" R XXX in which R, R2 and n have the meanings given above is reacted with an alkali metal amide MNH2 in which M is a cation of an alkali metal, so as to obtain the corresponding derivative of formula I. i (1 4 * 55 14. Process for the synthesis of derivatives according to any one of claims 1 to 11, characterized in that an aldehyde [^ CHO, an isonitrile RgN = C * and an amine RR ^ NH are reacted in the presence of a carboxylic acid, so as to obtain the corresponding derivative of formula I; in these formulas, R, R ^ and R2 have the meanings given above and Rg represents a protective group replaceable by hydrogen. 15. Process for the synthesis of derivatives according to any one of the claims from 1 to 11, characterized in that an iminooxirane XXXIII \ J-R is reacted. , s 0 XXXIII and an amine HNRR ^ so as to obtain the corresponding derivative 20 of formula I; in these formulas R, R ^ and R2 have the meanings given above and Rg represents a protective group replaceable by 11 hydrogen. - 25 16. Process for the preparation of derivatives corresponding to formula VI: I 2 "R - NH- (CH) - Z VI n 30 in which R, R2 · n and Z have the meanings given above, characterized in what it consists in carrying out one of the following reactions:? 2 * 2 RX + H_N - (CH) - Z .-> R - NH - (CH) - ZZ nn> 5 R? ) 2 l 2 RNH2 + X - (CH) - Z -> R - NH - (CH) n - Z d i \ 56 <fr CH R ^ Jggrolys ^ ^. . z. H-N N-R · = 5 \ / II - N-H J or o o il II TJ llqrr 10 RNH + R „C - C - H - °) R - NH - CH - Z 2 2 | R2 in which R, R2, Z have the meanings given above, RgCH2 has the values of R2 and R "represents an alkyl radical C ^ -C ^ or a phenyl ring, in these various reactions R can be replaced by R ^ for the preparation of compound R, - NH- (CH) - Z. 1 n 20 17. Process for the preparation of derivatives corresponding to the formula V: · '- RX * 2 N - (CH) ^ - Z 25 κζ a 5 in which R, R ^, R2 and Z have the meanings given above, characterized in that it consists in carrying out one of the following reactions: flÛ / 1: J \ 30 V 57 R0 Rv PL · t 2 RXN \ 1 2 R - NH - (CH) - Z _ 1 \ Æ - (CH) - Z n 7 / n -; 5 R \ ^ R \? 2 ü / NH + X - (CH) - Z -} NN - (CH) - Z ny xi Ri VR "RR v R * I2 \ \ i2" HO - (CH) - CN + XNH —- ^ XN - (CH) - Z R1 El / 10 x χ R2 R \? 2 XN - (CH) n - CN —.Îyarolrse y Nj - (CH) n - Z * ("R1 15 R R „CH_Z ÎaSe, R-tpHZ --i. L · - ÇH - ZZZZ / yi RR (j R0 \ 12 N - OAlk / R1 20 R, .HR R9 - 4 / \! 2 XC = C ^ .R + HCN - »^ N - (CH) n - ZX Xh E1 X 25 a. R CN Rv ^ 2 r- \ c = CX / R reduction ^ \ .H. (^,. Z XXX 30 El ou giΊ ih Π / * 2 E \ 5. CX Z - "- (CH) n - Z Ri ^ X (iH) n-l R1 ΐ R = 10" Λ lg. Pharmaceutical composition, characterized in that it "comprises at least one of the derivatives of formula I or one of its salts, combined with one or more pharmaceutically suitable excipients or optionally with other therapeutic agents. 15 19. Composition according to Claim 16, characterized in that it is in the form of dragees, tablets, capsules, tablets, granules, capsules, solutions, syrups, emulsions or suspensions containing conventional additives or excipients in galenic pharmacy. 20 20 · Composition according to claim 16, characterized in that it comprises at least one of the derivatives of formula I in solution in particular in sterile water or in an oil such as peanut oil or oleate 25 * d 'ethyl. 11 v 21 · Process for the use of the derivatives of formula I, characterized in that they are administered at doses of 50 mg to 4000 mg orally and from 5. mg to 400 mg * parenterally. * 30 V 22 · Method of using the derivatives according to formula I in the treatment of various forms of epilepsy, in the treatment of dyskinesias such as Parkinson's disease, in the treatment of mental disorders such as depression and sleep disorders. and in the treatment of certain cardiovascular disorders such as hypertension and hypotension. , SS Jdmt: Λ op ^ cL ·. / f, “0 4 $ d e 0_jdcoouj - fCcr ^ r j ilj \