LU85043A7 - AMIDE ACID AMIDE DERIVATIVES, PREPARATION AND USE THEREOF AS WELL AS COMPOSITIONS CONTAINING THESE DERIVATIVES - Google Patents

Description

The subject of the present invention is derivatives of ω-amino acids 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 present invention includes acid derivatives

ω -amines which correspond to the general formula I

10 κ

„> - <CH2) n-CC I

K1 * 2 as well as the salts of these compounds formed with pharmaceutically usable metals, acids or bases.

In the general formula I: R represents: - a linear or branched alkyl radical C2, C3, C ^, Cg, 20 Cg »Cy, Cg, Cg, ^ 10 * ^ 12 * - 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 Cj, C2 "C3, C4, by one or two linear or branched alkoxy radicals Cj, C2, C3, C ^, or by one or two halogen atoms such as fluorine, chlorine or bromine; - a linear or branched acyl radical C2, C3, C ^, Cg,

Cg substituted by a phenyl ring optionally substituted by one or two linear or branched alkyl radicals C ^, C2, C3, C ^, by one or two linear or branched alkoxy radicals C1, C2, C3, C ^, or by one or two halogen atoms such as fluorine, chlorine or bromine; / / · 1 '2.

Rj represents: - hydrogen; - a linear or branched acyl radical C2, C3, C ^, C5,

Cg »C7» C8 * C9 * ^ 10 * C11 »'5 - a linear or branched acyl radical C2, C3, C ^, Cg, C6 substituted by a phenyl ring 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, or by one or two halogen atoms such as fluorine, chlorine or bromine; R2 represents: - a hydroxyl group; - an alkoxy group RgO-, in which R3 is a linear or branched C radical, C2 or C ^ C alkyl radical - an amine group (-NH2); n has the values 3, 4 or 5;

According to a preferred form of the invention, this relates to compounds of formula I, in which: R represents: a linear or branched alkyl radical C2, C3, C4, Cg "C6, Cj, Cg, Cg , C1Q, Cjj, C12; - a linear or branched C2 * C3 alkyl radical, substituted by a phenyl or phenoxy ring optionally substituted by one or two linear or branched alkyl radicals Cj, C2 »C3, C ^, by one or two linear or branched alkoxy radicals C1, C2, C3, C ^, or par. one or two halogen atoms such as fluorine, chlorine or bromine; - a linear or branched acyl radical C2, C3, C ^, Cg,

Cg substituted by a phenyl ring 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 a or two halogen atoms such as fluorine, chlorine or bromine;

/ I

11 I! 3.

* / ··

R1 represents: “hydrogen; a linear or branched acyl radical C2, Cg, C4, Cg, ^ 6 »Cy, Cg, Cg, Cjq, Cjjî - 5 - a linear or branched acyl radical Cg, C ^, Cg,

Cg substituted by a phenyl ring optionally substituted: substituted by one or two linear or branched alkyl radicals C1 # C2, Cg, C4, by one or two linear or branched alkoxy radicals C ^, C2, Cg, C4 or by a .10 or two halogen atoms such as fluorine, chlorine or bromine; R2 represents: - a hydroxyl group; - an alkoxy group R3O-, in which Rg is a linear or branched Cj, C2 or Cg alkyl radical; - an amine group (-NH2); n has the values 3, 4 or 5; . - when R represents a dodecyl radical and hydrogen, R2 does not represent a hydroxyl radical, 20 - when na has the value 4 and when R2 represents a hydroxyl group and R ^ of hydrogen, R does not represent a radical n .butyl or n.octyl, - when na has the value 4 and when R2 represents an ethoxy group and Rj of hydrogen, R does not represent an ethyl or n.butyl radical, - when R represents a n.butyl radical, Rj of hydrogen and R2 a methoxy or hydroxyl radical, n does not have the value 3, - when R represents an i.propyl radical, hydrogen * and Rg. A hydroxyl radical, n does not have not the value 5.

He * /" ! 4 i

According to another preferred form of the invention, this relates to compounds of formula I in which: R represents: “- a linear or branched alkyl radical C2-C1Q; 5 - a linear or branched C2-C4 substituted alkyl radical; by a phenyl or phenoxy ring optionally substituted ’- by a methyl or methoxy radical or by a chlorine atom

Rj represents: 10 - hydrogen - a linear or branched acyl radical C2-C ^ - a linear or branched acyl radical C2-C6 substituted by a phenyl ring optionally substituted by a methyl or methoxy radical or by a chlorine atom; R2 represents: - a hydroxyl group - an alkoxy group RgO, in which R3 is a linear or branched alkyl radical Cj-Cg - an amine group; N has the values 3, 4 and 5 - when n has the value 4 and when R2 represents a hydroxyl group and R ^ of hydrogen, R does not represent an n-butyl or n-octyl radical; - when n has the value 4 and when R2 represents an ethoxy group and R ^ of hydrogen, R does not represent. not an ethyl or n.butyl radical; - when R represents an n.butyl radical, Rj of the hy-. drogene and R2 a methoxy or hydroxyl radical, n does not have the value 3; - when R represents an i.propyl radical, R ^ of the hydrogen gene and R2 a hydroxyl radical, n does not have the value 5.

// * In 5

According to another preferred form of the invention, the subject of the invention is derivatives of formula I in which: R represents: c - a linear or branched C2-Cg acyl radical substituted by a phenyl ring optionally substituted by a methyl radical or methoxy or a chlorine atom; ', Rj represents hydrogen; R2 represents: - a hydroxyl group; An alkoxy group RgO, in which Rg-is a linear or branched Cj-Cg alkyl radical; - an amine group; n has the values 3, 4 and 5.

A preferred class of products of formula I is that in which: R represents a linear or branched C2-C6 alkyl group;

Rj represents hydrogen; R'2 represents: - a hydroxyl group; - an alkoxy group RgO, in which Rg is a linear or branched Cj-Cg- alkyl radical, - an amine group; n has the values 3, 4 and 5; When n has the value 4 and when Rg represents a hydroxyl group and R1 of hydrogen, R does not represent an n.butyl or n.octyl radical; when n has the value 4 and when R2 represents an ethoxy group and Rj of hydrogen, R does not represent an ethyl or n.butyl radical; - when R represents an n.butyl radical, R ^ of hydrogen and R2 a methoxy or hydroxyl radical, n does not have the value 3; - when R represents a propyl radical, R ^ of hydrogen and R2 a hydroxyl radical, n does not have the value 5.

/ he / »*,» 1 6

Another preferred class of products of formula I is that in which: R represents: a linear or branched C2-C1Q alkyl group; 5 - a linear or branched C2-Cg acyl group substituted with a phenyl ring; R ^ represents hydrogen; 4 R2 represents: - a hydroxyl group; An alkoxy group R30, in which R3 is a linear or branched C ^ -C3 alkyl radical; n has the value 3; when R represents an n.butyl radical, R2 does not represent a methoxy or hydroxyl radical.

• A last preferred class of products of formula I is that in which: 1 represents:, - a linear or branched alkyl radical C2‘C10Î 20 - a linear or branched acyl radical C2-Cg substituted by a phenyl ring;

Rj represents hydrogen; R2 represents an amine group (-NB2); and n is 3.

25 "

Examples of compounds according to the invention are:. 4-n.pentylaminobutanamide - 5-n.pentylaminopentanamide 6-n.pentylaminohexanamide 30 4-n.pentylaminobutanoTque 5- (p.tolylacetylamino) pentanamide 6- n. Decylaminohexanamide 6 - [(2-p.chlorophenoxyethyl) amino] hexanamide 4 - [(Nn.hexyl-N-4-ch.lorophenylacetyl) aminojbutanamide 7 * ♦

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.

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 410, such as aliphatic, cycloaliphatic, araliphatic or heterocyclic, carboxylic or sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric acids, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, hydroxybenzoic, salicylic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, pantothenic, toluenesulfonic, sulfaniic, sulfonic, cyclohexylaminic β-hydroxyButyric, oxalic, malonic, galactaric, galacturonic.

"

In the case where R2 represents a hydroxyl group, the derivatives of the invention may exist in the form of either a zwitterion, or of metal salts or of addition salts with bases, non-toxic and pharmaceutically usable.

Λ

If derivatives of the invention in which R2 represents a hydroxyl group are obtained in the form of a salt, they can be converted into acid or into other salts according to conventional methods.

/ 1 8 * ·. ''

These salts can be derived from metals such as, for example sodium, potassium, lithium, calcium, magnesium, aluminum, iron, or can be addition salts with bases such as, for example, 5 ammonia or amines such as ethylamine, isopropylamine, ethanol friend, diethylamine, diethanolamine triethylamine, or basic amino acids, natural or not, such as lysine, arginine , Ornithine.

The compounds of formula I can have one or more asymmetric carbon atoms and are therefore likely to exist in the form of optical isomers, racemates or diastereoisomers; all these forms are part of the present invention.

15

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

The products of the invention can be used in the treatment of neurological, mental or cardiovascular disorders such as, for example, epilepsy, depression, dyskinesias such as Parkinson's disease, muscular spasticities of nervous origin, hypertension, hypotension, sleep disturbances, memory, • as well as anthelmintic and analgesic agents.

30

The present invention also covers pharmaceutical compositions containing, as active ingredient, at least one compound of general formula I or a salt, with an additive and / or an excipient used in galenic pharmacy.

il 35 • '· · 9

These compositions are prepared so that they can be administered orally, rectally or parenterally.

They can be solids, liquids or gels and can be presented, depending on the route of administration, in the form of powders, tablets, dragees, coated tablets, capsules, granules, syrups, suspensions, emulsions, solutions , suppositories or gels. These composi--. It may also include another therapeutic agent having similar or different activity to the products of the invention.

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.

20 Method A.

According to this procedure, product II is converted into the derivative of formula I: 25 *> - lCH2> n-Z - K1 K1 K2

II I

R, Rj, R2 and n are as defined above and Z represents a group which, by the action of an appropriate reagent, can be converted into an amide, carboxylic acid or ester function. Examples of these functions are, among others, the amide function, the carboxylic acid function, the nitrile function, the ester function (-C00R1, in which R 'represents either R3, specified above, or an alkyl or phenyl radical substituted in such a way that it activates the ester against attack by a nucleophile), the function / 1 4 '· 1 10 ^ NH \ amine (-CJ, the acid halide function ^ nh2 / ^ 0 5 (-C ^, where X represents a halogen such as chlorine, ^ v bromine or iodine), the anhydride function, the imidate function * (”c>. J or S ^ oupe N-carbonylimidazole .

^ NH 1 10 Z can also represent a carboxylic acid precursor group such as, for example, the trihalomethyl group (“CX3, in which X represents a chlorine, bromine or iodine atom), an oxazoline group, a hydroxymethylene group (-CH20H), a formyl group (-CHO) which may or may not be present in a protected form such as, for example, a dithioacetal, cyclic or not, an a, ß ^ dihydroxyalkyl or ÿjkënyl group (-CHOH -CHOH-R ^ or -CH = CH-R ^ in which R ^ represents a linear alkyl radical C ^ -Cgg), an acetyl group (-CO-CH ^),. A 1-hydroxyethyl group (-CHOH-CH ^), an acetonyl group (-CH2-C0-CH3), a 2-hydroxypropyl-1 group (-CHg-CHOH-CHg) or a halogen atom, such as chlorine, bromine or iodine.

The group -CH2-Z can also represent the group 25 B

-CH in which B, and B * may be equal or ^ B2 different from each other and represent a function chosen from the following series: nitrile, carboxylic, carba-30 or alkoxycarbonyl (-COOR ^, R ^ having the values given above ).

{(1 // /

It {Μ *, 11

The transition from product II to product I, that is to say the conversion of the group Z or -C ^ -Z into a group (-CORg) can be carried out by conventional reactions very well documented in chemistry, such as for example : 5 fa) - conversion of a carboxylic acid into an amide.

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

- For example, the carboxylic acid can be placed in the presence of ammonia, the pyrolysis of the salt thus formed leads to the amide as does the action of a dehydrating agent such as PgOg.

Another way of proceeding consists in transforming the carboxylic acid into an acid halide and then into an amide by the action of ammonia.

Yet another way of proceeding consists in reacting a carboxylic acid and ammonia in the presence of a coupling reagent as used in peptide synthesis such as, for example, dicyclohexylcarbodiimide, N-ethyl- N'-3-dimethylamino-propylcarbodiimide, phosphines, phosphites, silicon or titanium tetrachloride.

b) - Conversion of a nitrile into an amide or an acid. The nitriles can be hydrolyzed to an amide or an acid, either in an acid medium or in a basic medium.

If the hydrolysis is carried out under acidic conditions, it is possible to use concentrated sulfuric acid, aqueous concentrated hydrochloric acid, aqueous hydrochloric acid, nitric acid, formic acid in the absence of solvent , acetic acid in the presence of boron trifluoride.

- Another way to convert a nitrile into an amide, in an acid medium, consists in treating said nitrile

He !

If I

i \ * ’" "12 with hydrochloric acid in a cool al. like ethanol. An intermediate iminoether is thus formed which thermally transforms into an amide.

- If the hydrolysis is carried out under basic conditions, use will be made, for example, of potassium hydroxide in t.butanol or an aqueous solution of an alkali metal or alkali metal hydroxide. The »presence of hydrogen peroxide facilitates hydrolysis.

The nature of the group formed, an amide or a carbo-xyl group, essentially depends on the reaction conditions used.

c) Transformation of a nitrile into an ester.

This conversion takes place by opposing the nitrile to an alcohol in an acid medium. As the solvent, alcohol or any other inert solvent can be used.

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

D) Conversion of an ester into an amide.

The aminolysis of an ester is conventionally carried out by opposing the ammonia to the ester, either in water or in an inert organic solvent.

E) 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 acid or organic like acetic acid.

f) Conversion of an acid halide, an anhydride or an N-carbonylimidazolyl group into a carboxylic or alkoxycarbonyl acid group (-C00R3).

i 13

This transformation takes place easily by opposing product II to water to form the carbo-xyl group (hydrolysis reaction) or to an alcohol RgOH,

Rg being a linear or branched alkyl radical C ^ -Cg, 5 to form the alkoxycarbonyl group -COORg (alcoholysis reaction).

These reactions are carried out in the presence of an excess of water or alcohol or with a stoichiometric amount of these reagents in the presence of an inert solvent. The alcoholysis 10 is advantageously carried out in the presence of a catalyst such as an organic or inorganic acid or base.

g) When the group Z of formula II represents a carboxylic acid precursor such as a trihalomethyl group or an oxazoline, the conversion to the carboxylic acid is carried out either in water or in an inert organic solvent in the presence of 'acid.

As the acid, there is generally used a mineral acid such as halogenated hydracids, sulfuric acid, concentrated or diluted, nitric acid, concentrated or diluted, phosphoric acid or an organic acid such as acetic acid.

h) The conversion of the group -CHg-Z, representing the group 25 sh -CH> ^ g, in which and Bg have the values given above, into a carboxymethyl group is carried out by hydrolysis in basic or acid medium under identical conditions. â those described above for the hydrolysis of a nitrile, followed by a period of heating in an acid medium in order to decarboxylate the intermediate α-di-acid obtained.

i) Conversion of other precursor groups of the carboxylic acid group to a carboxylic group by oxidation.

This conversion especially concerns the intermediates 5 in which Z represents a group such as'. -CHgOHi -CHO; -CHOH-CH3; -CO-CH3; -CH2-CH0H-CH3; -CH2-C0-CH3, -CH = CH-R4 and -CHOH-CHOH-R ^ in which. R4 has the values defined above. It is conventionally carried out by means of a large number of oxidizing agents and according to a wide variety of well-known methods.

Oxidation takes place via several intermediates which can be isolated in certain cases and depending on the nature of the oxidizing agent, it takes place in water or in an inert organic solvent.

It goes without saying that the choice of oxidizing agent and of the reaction conditions will depend on the nature of the group Z and so as to keep the other groups present in molecule II in tact.

j) The transformation of an acid into an ester and vice versa. Esterification of an acid is a very general reaction that can occur in many ways.

25 - Conventionally, the acid and the alcohol are reacted in the presence of an acid catalyst. 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.

- Another way of proceeding consists in distilling the water as soon as it forms using an appropriate device. The reaction conditions are identical to those described above with the exception i

It is due to the fact that one of the reagents must not be used in large excess.

The hydrolysis of the ester takes place under conditions of acidic or basic catalysis, but in this case one of the reactants, in this case water, is used in very large excess.

k) The conversion of the group Z representing an alkoxycarbonyl group (-C00R '), a carboxylic group, its salt or its anion into an alkoxycarbonyl group (-COORg).

Depending on the nature of Z, this conversion can be carried out by esterification, as described in the preceding paragraph, by transesterification, by heating the derivative II containing the group --COOR 'in the presence of an excess of alcohol R ^ OH and d '' an acidic or basic catalyst, advantageously by continuously distilling off the alcohol R'OH formed, or by alkylation using the reagent WR3, in which 20 U represents an easily substitutable group such as halogen such as chlorine, bromine or iodine , a 0-mesyl group, 0-tosyl, a sulfate group (-0-S02-OR3), an acyloxy group (Rç-CO-O) or a hydroxyl group.

R3 represents a linear or branched alkyl group C ^ -C3 and R5 ^ presents an R3 or phenyl group.

The alkylation of the carboxylic group, its salt or its anion is normally carried out in an inert organic solvent in the presence of a weak inorganic base or preferably an organic base such as pyridine or triethylamine.

l) The conversion of Z, representing a halogen atom to a carboxylic acid group.

This conversion is conventionally carried out by trans-> "It 16 forming the halogenated product into an organometallic derivative, the treatment of which with carbon dioxide, followed by the hydrolysis of the intermediate formed, provides the carboxylic group. The metal used can be lithium, magnesium, zinc or manganese.

In order to avoid side reactions during this conversion, the functional group RRjN- present in. molecule II will be adequately protected.

For a better understanding of the process, the main access routes to derivative II are described below: 1. Derivative II can be obtained at the expense of products III or IV by alkylation or acylation according to the diagrams below .

R W R

R-NH- (CH2) n-Z —î -> - (CH2VZ

R1

III II

20

RrNH- (CH2) n-Z VILS

IV

25 in which R, Rj, Z, W and n have the values. defined above, but in the reagent RjW, the group R ^ does not represent hydrogen.

RW and RjW can also represent a ketene of

Rg 30 formula ^ C = C = 0, so that the group h 'V · CH-C0-, obtained after the acylation of derivatives III or R7 I 1 · · -' J 17 IV, corresponds as appropriate to a group R or Rj.

This alkylation or acylation reaction can be carried out in an inert organic solvent such as a chlorinated hydrocarbon, an alcohol or an aliphatic or aromatic hydrocarbon, chosen according to the nature of the reagent.

The reaction takes place at a temperature between 0 ° C and the reflux temperature of the solvent.

e

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 or of fine lime sprayed.

15

A variant of this process is illustrated below:

R R

> H + W- (CH2) n - Z - ^ D> - (CH2) n - Z

20 R1 R1

V VI II

R, R ^, W, Z and n have the values defined above.

The above reaction is similar to the alkylation reaction of derivatives III or IV described above, and it goes without saying that the operating conditions for these three reactions are completely comparable.

30

According to another variant of the process, derivative II can be synthesized by acylation of a primary amine with a carboxylic acid making use of phosgene as a coupling agent. Phosgene can be introduced i 18! * * in a solution of the amine and the carboxylic acid or it can be opposed to one of the two reactants and the intermediate formed thus is then opposed to the second reactant.

This variant in which the phosgene is reacted with amine IV, followed by the transformation of the intermediate isocyanate, is illustrated by the following diagram:

Cuckold

10 R1NH- (CH2) n-Z -0 = C = N- (CH2) n-Z

; IV

i!

! Rr-C00H

! 15 -5-► R8-C0-N- (CH2) n-Z

R1 in which Rj represents hydrogen, Z and n have the values specified above and the group ^ Rg-C0 corresponds to the group R as defined above.

According to another variant, the derivative II in which R represents an alkyl or substituted alkyl group as defined above, can be obtained by acylation of the derivatives III or IV, as described above, followed by a reduction of the amide obtained as an intermediate. Many methods are described for carrying out such a reduction, but it is obvious that in the choice of the I reaction conditions, care must be taken to preserve the functionality of group Z.

: 30 ! 2. Another access route to derivative II is characterized

* by the formation of an intermediate iminium salt VIII

from an amine and a carbonyl compound VII.

he * w 19

The reduction of the iminium salt leads to derivative II.

R? R © H

> H + H-C- (CH2) -Z -►> = <5 R1 <(™ 2> „- ΓΖ

'. VII

reduction 'r 10 RR> “(CH2) n“ 2 K1

II

15

The condensation between the amine and the carbonyl derivative VII takes place conventionally in an inert organic solvent, preferably immiscible with water. Advantageously, the reaction is catalyzed by a mineral or organic acid.

The reduction is carried out in a suitable solvent in a conventional manner using hydrogen in the presence of a hydrogenation catalyst, using an alkali metal hydride, using aluminum and lithium hydride or using of another reducing agent, but it goes without saying that the reduction method of the imine 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 carried out which allows to arrive at product II by passing through intermediates carrying the same chemical functions as above.

»» * F 20 R1

Rg u + Rq l

R> = 0 + RlNH- (cH2) n-Z R> A ^ CH2) n'Z

K10 Rlo Φ

'X

5 IX IV

*, Reduction i>

Rg

y "CH

10 Rli> (CH2> n‘Z

R1

II

15 R ^, Z and n have the meanings given above; demment while the groups Rg and R ^ 0 have

R5K

values such that the group CH is equivalent to R.

R10 ”20 The condensation of the carbonyl derivative with amine IV and the reduction of the iminium salt X take place under the conditions described above.

It should be noted that when represents hydrogen, the condensations described above lead to an imine of formula:

H R

R-N = C ^ or 9 ^ C = N- (CH9) -Z

<CH2> n-rZ Rli 30

XI XII

in which Rs Rg * Rio »Z and n have the values defined above. The conditions for synthesis 21 and reduction of imines XI and XII are completely comparable to those of synthesis and reduction of the iminium salts VIII and X.

5 3. Another route to the derivatives of formula II

* consists of the transformation of a product of formula XIII

by means of reagent XIV, according to the diagram below:

10 "> (CH2> n-W + MZ -"> (CH2> n-Z

R1 R1

XIII XIV II

R, Rj, W and n have the meanings given previously, M represents hydrogen or a metal such as lithium, sodium, potassium or magnesium and Z has the values given previously compatible with the envisaged reaction such that: a nitrile group, a trihalomethyl group or a cyclic or non-cyclic dithioacetal group.

The transformation of product XIII can be carried out according to different conventional methods, chosen according to the nature of W and Z. Some of these methods; are summarized below, by way of example *.

A) when Z represents a nitrile or trihalomethyl group, the reaction can be carried out in different; solvents such as for example water, a lower alcohol, dimethylformamide or in mixtures of solvents, miscible or not.

In several cases, it is advantageous to work in the presence of an organic base or a phase transfer catalyst.

// Μ * »22 b) when Z represents a cyclic dithioacetal group or not, the reaction takes place under anhydrous conditions at low temperature, in an inert solvent such as diethyl ether or tetrahydrofuran.

The product II is then obtained by deprotection of the formyl group by well known methods such as hydrolysis in an acid medium or by the action of mercuric salts.

4. Another access route to derivatives of formula II in which -CHoZ represents * the 1st group -CH ^ 1 consists of B2 in the alkylation of a derivative XV by means of reagent XVI according to the following scheme: K ^ Bi 'Bi> ("!,)„, - W + HC <1 —►> - (CH2) n., - CHv

Rf ά n 1 B2 Rx n A B2

20 XV XVI

R, Rp Bj, B2, W and n have the values given above, except for W which, in this case, does not represent a hydroxyl group.

25 m represents an alkali metal such as sodium, potassium or lithium.

This conventional reaction is generally carried out under an inert atmosphere and under anhydrous conditions using a solvent such as an alcohol or an aliphatic or aromatic hydrocarbon.

Method B.

This process consists in opening a lactam XVIII, under the action of a base or an acid. Said lactam / 1

n »I

23 XVIII is conventionally obtained from lactone XVII according to the scheme:

'' (CH2) n- / RNH2 (CH2) n-V

\ / "\ / Π

0 N

R MR2

XVII

XVIII

10

Rv .0> - (™ 2) η <

Rj n ^ R2 15 I (Rj = H) R, R2, M and n have the values defined above.

The conversion of lactone to lactam takes place in an inert organic solvent, advantageously at the reflux temperature of the reaction medium.

The opening of the lactam can be done under the action of ammonia, an amide, an alkoolate or an alkali metal hydroxide, or under the action of a mineral acid such as hydrochloric acid or sulfuric acid. It takes place in water or in an inert organic solvent such as an ether, an alcohol, an aliphatic, aromatic hydrocarbon or a chlorinated hydrocarbon.

30

It is obvious that the methods described for the synthesis of compound II can also apply to products in which group Z already has the value of the group as specified above and lead to! I * 1 24 thus directly to the products of the invention corresponding to the general formula I.

It goes without saying that for all the processes for the synthesis of the compounds of formulas I and II, as well as for those mentioned for the transformation of the group Z and Cl 2 -Z into a group -C, the reagents and the conditions The reaction groups are chosen so as to keep intact the functional groups already present in the molecule and which are not involved in the envisaged reaction.

Thus, in order to be able to carry out the synthesis of compounds I and II, it is sometimes necessary to use protective groups in order to preserve the functionality of the groups present in the starting molecule. The choice of experimental conditions will condition the choice of protecting groups which, as well as the methods of their introduction and the methods of deprotection, are well described in the literature.

»// 25 tl · |

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

The main purpose of these examples is to further illustrate the particular characteristics of the methods according to the invention.

Example 1.

Synthesis of 4-n.pentylaminobutanamide.

5 9 (0.041 m) of 4-chlorobutanamide are dissolved in 19 ml 10 (0.165 m) of pentanamine and stirred for 48 hours at room temperature. By the addition of ether (400 ml), a precipitate forms which is filtered and recrystallized twice from 1 sopropanol.

. F (° C): 187.

15 Elementary analysis: C H N

% calculated 51.7 10.1 13.4% found 52.0 10.2 13.4

Example 2.

20 Synthesis of 5-n.pentylaminopentanamide.

a) The mixture is refluxed for 48 hours, a mixture of 4.5 g of 5-chloropentanenitrile (0.040 m), 3.8 g (0.044 m) of pentanamine, 3.7 g of sodium bicarbonate in 60 ml of absolute ethanol. The sodium chloride formed is filtered and the trat wire 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 (5-n.pentyl-aminopentanenitrile hydrochloride).

30 F (° C): 207-209.

t · 26 "I b) 2.78 g (0.013 m) of 5-n.pentylamino-pentanenitri 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 5 which crystallizes is filtered and washed with 11isopropanol.

F (° C): 216-217

Elementary analysis: C H N

% calculated 53.9 10.4 12.5% found 54.2 10.5 12.6 10

Example 3.

Synthesis of 6-decylaminohexanamide.

4.5 g of 6-chlorohexanamide (0.030 m) are heated to reflux in 100 ml of ethanol containing 5.2 g of dcanamine (0.033 m) and 2.52 g of NaHCOg (0.033 m). After 2 days and 2 nights, the solution is cooled, filtered and evaporated; the solid is recrystallized twice from ethyl acetate. The solid obtained is dissolved in ethanol and added with ether / HCl; the new solid obtained is re-crystallized twice in isopropanol.

F (° C): 206.

Elementary analysis: C H N

% calculated 62.6. 11.5 9.1% found 63.0 11.7 9.3 25

Example 4.

Synthesis of 5- (p.tolylacetylamino) pentanamide.

To a solution of 0.7 g (0.017 m) of NaOH and 2 g of 5-aminopentanamide (0.017 m) in 10 ml of cooled water 27 ".

at 0 ° C., 2.9 g (0.017 m) of p-tolylacetyl chloride and a solution of 0.7 g of NaOH in 4 ml of water are added dropwise simultaneously. The suspension which has formed is stirred for one hour at room temperature. The solid is filtered off 1 - 5 and recrystallized twice from isopropanol.

F (° C): 206.

Elementary analysis: C H N

% calculated 67.7 8.1 11.3 10% found 67.8 8.1 11.3

Example 5.

Synthesis of 4-pentylaminobutanoic acid.

7.75 g of penta-15 nal (0.090 m), 7.73 g of gamma-aminobutanoic acid (0.075 m), 800 mg of 10% palladium on carbon, 5 g of sieve are introduced into a Parr bottle. mole-

O

3 A ring and 200 ml of absolute ethanol. The bottle is shaken under a hydrogen atmosphere for 18 hours.

The suspension is filtered and the filtrate is evaporated to dryness at 20 ° C. at reduced pressure. The solid is washed with ether, dissolved in a minimum of ethanol and added with ether.

The crystals obtained are recrystallized again in the same manner.

F (° C): 161-162.

25 Elementary analysis: C H N

% calculated 62.4 11.0 8.1% found 62.1 11.1 8.0

Example 6.

Synthesis of 6- [3- (3,4-dimethoxyphenyl) propanoylamino3-hexanamide.

To a solution of 2.6 g (0.020 m) of 6-aminohexanamide and 0.8 g of NaOH in 15 ml of water, cooled to 0 ° C, 4.6 g (0.02 m) of 3- (3,4- /

II, 28 dimethoxyphenyl) propanoyl and 2.4 g of NaOH in 20 ml of water. The suspension is stirred for 2 hours at room temperature. Then, the solid is filtered and recrystallized from 1 1 isopropanol.

F (° C): 137.

5 Elementary analysis: C H N

% calculated 63.3 8.1 8.7% found 63.2 8.2 8.6

Example 7.

10 Synthesis of 6-n.pentylaminohexanamide.

The mixture is refluxed for 4 days, a mixture of 5 g of 6-chlorohexanamide (0.033 m), 4.25 ml of pentanamine (0.037 m) and 2.8 g of sodium bicarbonate (0.034 m) in 100 ml of ethanol. Then, after the solution has cooled, the salts are filtered and the solvents are evaporated to dryness. The solidifying product is crystallized twice from ethyl acetate, dissolved in a minimum of methanol and added with ether / HCl. The solid which forms is filtered and dried.

20 F (° C): 190.5

Elementary analysis: C H N

% calculated 55.8 10.6 11.8% found 55.8 10.6 11.8 25 Example 8.

Synthesis of 4-n.hexylaminobutanamide.

a) The mixture is refluxed for 2 days, a mixture of 18.5 ml of 4-chlorobutanenitrile (0.2 m), 29.1 ml of hexan-amine (0.22 m) and 18.5 g of sodium bicarbonate 30 (0.22 m) in 500 ml of ethanol. Then, the suspension is cooled, the salts are filtered and the filtrate is evaporated. The residue is partitioned between water and dichloromethane. The dichloromethane phase is washed with / 1 \ · \ 29 water, dried over K2C03 and evaporated at room temperature. The excess hexanamine is evaporated under high vacuum and the residual oil is dissolved in anhydrous ether and added ether / HCl. ..The solid which appears 5 is filtered, dissolved in a minimum of methanol and added with anhydrous ether. The product thus obtained is used as is in the next step.

b) 4.2 g of 4-hexylaminobutanenitri 1e (0.02 m) are stirred for 4 days at 5 ° C. in 5 ml of concentrated HCl. Then! te, we pour this solution into 50 ml of ice-cold acetone.

The white solid which forms is recrystallized from 1 sopropanol.

F (° C): 194

15 Elementary analysis: C H N

% calculated 53.9 10.4 12.6% found 54.1 10.4 12.6

Example 9.

20 Synthesis of 4 - [(N-n.hexyl-N-4-chlorophenylacetyl) aminolbutanamide.

650 mg of 4-hexylaminobutanamide hydrochloride (0.003 m) are dissolved in 9.4 ml of N0Η 1 N at 10 ° C. To this solution is added dropwise 0.65 ml of 4-chlorophenylacetic acid chloride. An oil immediately appears and solidifies. After 2 hours of reaction, the oil is extracted with ether, the ethereal phase is washed with water and with 1N hydrochloric acid, dried over K2CO3 and evaporated. The residual solid is recrystallized from ethyl acetate.

F (° C): 105-106.

Elementary analysis: C H N

¾ calculated * 63.1 8.0 8.2% found 63.0 7.9 8.1 35 i; calculated for a content of 1.03% H2O.

h 30

Example 10.

Synthesis of 5-n.dodecylaminopentanamide.

a) 7.4 g of dodecan-amine (0.04 m), 4.23 g of 5-chloropentanenitrile (0.036 m) are heated at reflux for 2 days; 5 and 3.4 g of sodium bicarbonate (0.04 m) in 100 ml of ethanol. Then, the cooled solution is filtered and the filtrate evaporated. The residual oil is distilled under 0.25 mm Hg. The distilling fraction is collected at 170 ° C. It is dissolved in ethanol and added with ether / HCl. The precipitating solid is filtered and used without further purification in the next step.

b) 2 g of 5-dodecylaminopentanenitrile hydrochloride (0.007 m) are dissolved in 50 ml of acetic acid. This solution is saturated with dry hydrochloric acid and stirred at room temperature for 2 days.

The acetic acid is then evaporated, the solid taken up in ether is filtered and the solid recrystallized twice from isopropanol.

F (° C): 212.

Elementary analysis: C H N

% calculated 63.6 11.6 8.7% found 63.9 11.6 8.8 25/31

Example 11.

Synthesis of 4-n.pentylaminobutanamide.

a) A mixture of 18.5 ml of 4-chlorobutanenitrile (0.2 m), 19.1 g of pentanamine (0.22 m) and 18.5 g of bicarbonate is heated at reflux for 2 days. sodium (0.22 m) in 500 ml of ethanol. Then, the suspension is cooled, the salts are filtered and the filtrate is evaporated.

The residue is partitioned between water and dichloromethane.

The dichloromethane phase is washed with water, dried over 10 and evaporated to room temperature. The excess pentanamine is evaporated under high vacuum and the residual oil is dissolved in anhydrous ether and added with ether / HCl.

The solid which appears is filtered, dissolved in a minimum of methanol and added with anhydrous ether until an abundant precipitate is obtained, which is filtered and used as is in the following stage.

b) 3.1 g of 4-pentylaminobutanenitrile (0.02 m) are dissolved in 30 ml of glacial acetic acid and saturated with HCl 20 at room temperature.

After 24 hours of stirring, the acetic acid is evaporated and the residual solid is recrystallized from isopropanol.

F (° C): 187.5

Elementary analysis: C H N

25%. calculated 51.7 10.1 13.4% found 51.8 10.2 13.4

AT

Example 12

Synthesis of 4-n.pentylaminobutanamide.

2.76 g of 4-aminobutanamide hydrochloride (0.02 m), 1.9 g of pentanal (0.022 m), 100 mg of 10% Pd / C and 50 ml of liquid are introduced into a Parr bottle. ethanol.

r *

The bottle is shaken overnight under an atmosphere of hydrogen at room temperature. The catalyst is then filtered, the solvent is evaporated and the residue is solidified in ether. The solid obtained is recrystallized 3 times from isopropanol. / d? 32 F (° C): 186.5

Elementary analysis: C H N

% calculated 51.7 10.1 13.4 5% found 52.0 10.3 13.5

Example 13

Synthesis of 4-n. pentylaminobutanamide.

3.1 g of N-pentylpyrrolidone (0.02 m) are introduced into a 200 ml flask containing 3.9 g of sodium amide (0.1 m) suspended in 50 ml of toluene. The suspension is brought to reflux for 3 days, after which, 10 ml of H 2 O and sufficient 1 N HCl are added to make the solution acidic (pH 2). The aqueous phase is decanted and lyophilized. The residue is extracted with boiling isopropanol, the solid which crystallizes is filtered and recrystallized twice from isopropanol.

F (° C): 186

20 Elementary analysis: C H N

% calculated 51.7 10.1 13.4% found 51.4 10.0 13.7 25 Example 14

Synthesis of 4- (2-phenylethylamino) butanoic acid.

a) In a 1 liter flask cooled in an ice bath, 500 ml of toluene and 15.2 ml of pyrolidone (0.2 m) are introduced under nitrogen. To this solution, 9.6 g of sodium hydride (0.4 m) are added three times. After one hour of stirring at 0 ° C., the suspension is allowed to return to room temperature. 37.15 ml of 2-phenyl-1-bromoethane (0.27 m) are then added and the whole is brought to reflux for 12 hours.

After adding 100 ml of water the toluene phase is decanted and washed 3 times with water, dried over K2CO3 and evaporated; the residual oil is distilled under 10 mmHg.

The colorless liquid which is distilled at 175 ° C. is collected, which is identified as N- (2-phenylethyl) pyrrolidone.

*, · 33 b) 17.9 g of N- (2-phenylethyl) pyrroiidone (0.095 m) are brought to reflux in 25 ml of concentrated HCl for 20 hours. The solution is then evaporated to dryness and the residual solid is crystallized from methyl ethyl ketone.

5 F (° C): 149-150.

Elementary analysis: C H N

% calculated 59.1 7.4 5.8 10% found 59.2 7.5 5.7

Example 15.

Synthesis of the ethyl ester of 4- (2-phenylethylamino) butanoic acid.

1 g of 4- (2-phenylethylamino) butanoic acid hydrochloride (0.004 m) is brought to reflux for 1 hour in 10 ml of 5N ethanol / HCl. The solution is then evaporated to dryness and the solid obtained is recrystallized from methyl ethyl ketone.

F (eC) 206-207

Elementary analysis CH N

% calculated 61, 9 8.2 5.1 25% found 61.9 8.2 5.2

Table I given below groups 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 Table I give an elementary C.H.N. correct.

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

5 The DL5q are calculated according to the method of Lichtfield and Wilcoxon (J. Pharmacol. Exp. Ther. 96_, 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 intra-gastric tube to groups of 5 male mice fasted 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 mice. The numbers refer to the numbers given to the products in column 2 of Table I. In general, certain products of the invention are endowed with an anticonvulsant activity.

The anticonvulsant effect is examined against the 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 35 tonic convulsions and death is noted.

/! 46 1 *

In this test, products n ° 1, 5, 8, 10 and 13 were found to be particularly active and give a protection percentage equal to or greater than 55%.

5 CP 2081 (Compound 1 in Table I) was further evaluated. In the test for inhibition of convulsions induced by bicuculline, the ED5q is 3 mg / kg. At a 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.

Biochemical tests have demonstrated that certain products of the invention exhibit a GABA-mimetic effect.

This effect was examined in vitro using a method derived from that of C. Braestrup and M. Nielsen (Brain Research Bulletin, Vol 5, Suppl. 2, p. 681-684 (1980)).

A rat brain homogenate (without cerebellum), washed in order to remove the GABA (1 γ-aminobutanoic acid) present, is used to measure the binding to the receptor / * 1 3 47 ("binding") to using H-f1 unitrazepam in the presence and absence of increasing concentrations of the test products or of a reference product (in this case GABA).

5 The non-specific binding is determined in the presence of! Diazepam.

Incubation takes place for 60 minutes at 0 ° C, on a homogenate diluted 200 times *

After incubation, the samples are filtered and washed on Whatman GFB filters. After drying the filter at 60 ° for 20 minutes, the residual radioactivity is measured using a liquid scintillator in an appropriate medium.

Under these conditions, the product CP 2818 (compound n ° 16 15 of Table I) behaves like a GABA-mimetic, characterized by an ECcn ("Enhancement concentration 50%") _r bu _7 of 4.7.10 M compared to the ECgQ 8.2.10 M of GABA and by an efficiency identical to that of GABA.

CP 2818 was also evaluated in vitro in the test for binding of H-muscimol to synaptic membranes of rat brains. This test is specific for GABAergic receptors and makes it possible to demonstrate an agonist or antagonist effect at GABA receptors. These are directly linked to the benzodiazepine receptors.

The preparation of the synaptic membranes as well as the test 3 of binding of H-muscimol to the synaptic membranes are identical to those published by Enna S.J. and Snyder S.H.

in Brain Research 100, 81-97 (1978).

3 30 The specific binding value of H-muscimol to the membranes is obtained by making the difference between the binding of H-muscimol alone and of this binding in the presence of 10 μΜ of GABA.

Different concentrations of CP 2818 were used to determine the concentration of the product needed to k inhibit the binding of H-muscimol to membranes (IC 50) by 50%. For the CP 2818 an IC5Q of 2.5 x 10 "5 M was obtained. The IC5Q of the GABA in this system is 2.10" M.

The antagonistic effect with respect to convulsions induced by bicuculline, leptazole and by electroshock as well as the GABA-mimetic effect indicate that the compounds of the invention have pharmaceutical properties which make them specially indicated for the treatment of various forms of epilepsy and dyskinesias such as Parkinson's disease.

In addition, the activity of the products at the level of the central nervous system makes these compounds potentially of interest for the treatment of certain cardiovascular disorders such as hypertension and hypotension, for the treatment of mental disorders such as depression, memory and sleep disturbances, as well as analgesic agents.

Certain products of the invention also exhibit anthelmintic activity.

This activity is measured in rats, infested with Nippostrongylus Brasiliensis (stage L3).

The product to be tested is administered by esophageal tube, in the form of mucilage, 8 days after the infestation. The rats are sacrificed on the 12th day and the parasites are counted in the intestine. The., Results obtained are ex // ki ", 49 awarded in .percentage of efficiency compared to a control group.

In this test, the product CP 2081 (compound No. 1 of: Table I) has a percentage of effectiveness of 91 at the dose of 50 mg / kg.

In humans, the compounds of the invention will be administered orally, at doses ranging from 10.50 mg to 4000 mg intravenously, the doses will be 5 mg to 1000 mg.

The products of the invention can be used in various dosage 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 can be formed by one of the following compounds: 4- n.pentylaminobutanamide 20 5-n.pentylaminopentanamide 6-n .pentylami nohexanamide 4-n.pentylaminobutanoic acid 5- (p.tolylacetylamino) pentanamide 6- n.decylaminohexanamide 25 6 - [(2-p.chlorophenoxyethyl) amino] hexanamide 4 - [(Nn.hexyl-N-4- chlorophenylacetyl) friend no] butanami from.

It ‘50 '. *.

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At 600 mg starch Sta-Rx 1500 80 mg hydroxypropyl methylcellulose 20 mg 5 aerosil 5 mg magnesium stearate 15 mg At 100 mg corn starch 100 mg 10 lactose 80 mg aerosil 5 mg talc 5 mg magnesium stearate 10 mg 15 Capsules.

50 mg lactose 110 mg corn starch 20 mg 20 gelatin 8 mg calcium stearate 12 mg 200 mg polyvinylpyrrolidone10 mg 25 corn starch 100 mg

Cutina HR 10 mg

Injectable I, M. or I.V.

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AT

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A 5 g tartaric acid 0.5 g nipasept 0.1 g 10 sucrose 70 g flavor 0.1 g water ad 100 ml

Solution.

15 A 2 g sorbitol 50 g glycerin 10 g mint essence 0.1 g propylene glycol 10 g 20 demineralized water ad 100 ml

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A '500 mg butylhydroxyanisol 10 mg 25 semi-synthetic glycerides ad 3g

Rectal gel.

AT . 100 mg carbomer 15 mg 30 triethanolamine ad pH 5.4 purified water 5 g i

Claims (23)

1. Derivative of ω-amino acids of general formula I '5 R yO; N- (CH2) nc (I R1 R2 10 as well as their racemic mixtures or not, their optically pure isomers and the salts of these compounds formed with pharmaceu-tically usable acids, bases and metals, in which: R represents 15. a linear or branched alkyl radical C2, Cg, C ^, Cg, Cg, C7, Cg, Cg, C10, or Cj2> - a radical linear or branched alkyl Cg »Cg, C ^ substituted by a phenyl or phenoxy ring - which may be substituted by one or two linear or branched alkyl radicals C ^, Cg, Cg, C ^, by one or two linear alkoxy radicals or branched Cj, Cg, Cg, C ^, or by one or two halogen atoms, such as fluorine, chlorine or bromine, - a linear or branched acyl radical Cg, Cg, C ^, Cg, 25 Cg substituted by a phenyl ring optionally substituted by one or two linear or branched alkyl radicals C ^, Cg, Cg, C4, by one or two linear or branched alkoxy radicals C ^, Cg, Cg, C ^, or by one or two halogen atoms, such as fluorine, chlorine or bromine, R · ^ represents - hydrogen - a linear or branched acyl radical Cg, Cg, C ^, Cg, Cg,, 53 "· · . Cy, Cg, Cg, C10, Cjj, - a linear or branched acyl radical C2, Cg, C ^, Cg, Cg substituted by a phenyl ring optionally substituted by one or two linear or branched alkyl radicals 5 C ^, C2, Cg, C ^, by one or two linear or branched alkoxy radicals C ^, C2, Cg, C ^ or by one or two halogen atoms, such as fluorine, chlorine or bromine, R2 represents - a hydroxyl group 10. an alkoxy group RgO-, in which Rg is a linear or branched alkyl radical C ^, C2 or Cg, - an amine group n has the values 3, 4 or 5; 2. Derivative according to claim 1, characterized in that in formula I: R represents 15. a linear or branched alkyl radical C2, Cg, C4, Cg, Cg, C7, Cg, Cg, C1Q, C ^ or C12, - a linear or branched alkyl radical C2, Cg, C4 substituted by a phenyl or phenoxy nucleus - which can be substituted by one or two linear or branched alkyl radicals C ^, C2, Cg, C ^, by one or two alkoxy radicals linear or branched C ^, C2, Cg, C ^, or by one or two halogen atoms, such as fluorine, chlorine or * bromine, r - a linear or branched acyl radical C2, Cg, C ^, Cg, 25 Cg substituted by a phenyl ring optionally substituted by one or two linear or branched alkyl radicals C ^, C2, Cg, C ^, by one or two linear or branched alko xy radicals C ^, C2, Cg, C ^, or by one or two halogen atoms, such as fluorine, chlorine or bromine, R ^ represents - hydrogen - a linear or branched acyl radical C2, Cg, C ^, Cg, Cg, 54 * 1 S Cy, Cg, Cg, C jq, Cjj, - a linear or branched acyl radical C2, Cg, C ^, Cg, Cg substituted by a phenyl ring optionally substituted * by one or two linear or branched alkyl radicals 5 Cj, C2, Cg, C ^, by one or two linear or branched alkoxy radicals C ^, C2, Cg, or by one or two> halogen atoms, such as fluorine, chlorine or bromine, Rg represents - a hydroxyl group 10. an alkoxy group R3O-, in which Rg is a linear or branched alkyl radical C ^, C2 or Cg, - an amine group n has the values 3, 4 or 5; - when R represents a dodecyl radical and R1 of the hydro-gene, Rg does not represent a hydroxyl radical, - when na has the value 4 and when R2 represents a hydroxyl group and Rj of hydrogen, R does not represent a n.butyl or n.octyl radical, - when na has the value 4 and when R2 represents a group-20 ethoxy and R ^ of hydrogen, R does not represent an ethyl radical or n.butyl, - when R represents a n.butyl radical, hydrogen and R2 a methoxy or hydroxyl radical, n does not have the value 3, 25. when R represents an isopropyl radical, hydrogen and R2 a hydroxyl radical, n does not have the ; value 5. 3. Derivative according to any one of claims 1 30 and 2, characterized in that in formula I, R represents an alkyl radical C2-C1Q. 4. Derivative according to any one of claims 1 and 2, characterized in that, in formula I, R represents a Cg-Cg alkyl radical. h 55 5. Derivative according to any one of claims 1 and 2, characterized in that, in formula I, R represents an alkyl radical C6 “C12 * u 5 6. Derivative according to any one of claims 1 * and 2, characterized in that, in formula I, R is a Cg-C7 radical. * 7. Derivative according to any one of claims 1 10 ′ and 2, characterized in that, in formula I, R represents a C2-C4 alkyl radical substituted by a phe-nyl or phenoxy ring which themselves may be substituted by a methyl or methoxy radical or by a chlorine atom. 8. Derivative according to any one of claims 1 and 2, characterized in that, in formula I, R represents an acyl radical C 1 -C 4 substituted by a phenyl radical itself substituted by one or two methyl radicals or methoxy or by one or two chlorine or bromine atoms. 9. Derivative according to any one of claims 1 to 8, characterized in that, in formula I, Rj represents an acyl radical C2-Cg. 25 10. A derivative according to any one of claims 1 to 8, characterized in that, in formula I, R ^ represents an acyl radical Cg-Cjj ·! ' 11. Derivative according to any one of claims 1 to 8, characterized in that, in formula I, R ^ represents an acyl radical C2-C ^ substituted by a phenyl radical itself substituted by one or two methyl radicals or methoxy or with one or two chlorine or bromine atoms. * · * 56 12. Derivative according to any one of claims 1 to 8, characterized in that, in formula I, represents * hydrogen and R ,, represents an amino radical. N * 13. A derivative according to claim 1, characterized in 5 that it is chosen from the group formed by the corn- * posed: 4- n. pentylaminobutanamide 5- n.pentylaminopentanamide 6- n.pentylaminohexanamide 10 4-n.pentylaminobutanoic acid 5- (p.tolylacetylami no) 6- n.decylami nohexanamide pentanami 6 - [(2-p.chlorophënoxyethyl) friend no] hexanami of 4 - [(Nn.hexyl-N-4-chlorophenylacetyl) friend no] buta namide 15 14. Amine derivative, in particular for the preparation of "derivatives according to any one of the preceding claims 2o, characterized in that it corresponds to formula II:!> - <CH2> n - Z 11 R1 25 w · in which R, R ^ ret n have the meanings given above and Z is an amide function, a carboxylic acid function, a nitrile function, an ester function (COOR ', in which R' represents either Rg, specified above, either an alkyl or phenyl radical substituted in such a way that it activates the ester (i 57 with respect to the attack of a nucleophile), an amidine / ^ ΛΊΗ \ function, a halide function of acid (C ^ nh2 / * 5. (C /) where X represents a halogen such as chlorine, a XX bromine or iodine), an anhydride function, a function * / 0R3 \ imidate (-C) or the group N-carbonylimidazolyle, ^ NH f 10 Z can also represent a carboxylic acid precursor group such as the trihalomethyl group (-CX3, in which X represents an atom (chlorine, bromine or iodine), an oxazoline group, a hydroxy-methylene group (-CH20H), a formyl group (-CH0) which may or may not be present in a protected form such as a cyclic dithioacetal or not, an a, ß-dihydroxy-alkyl or alkenyl group ('-CHOH-CH0H-R4 or -CH = CH-R4, in which R4 represents a linear alkyl radical. C1-C gg) »an acetyl group (-CO-CH3), a 1-hydroxyethyl group (-CHOH-CH3), an acetonyl group (-CH2-C0-CH3), a 2-hydroxypropyl-1 group (- CH2-CH0H-CH3) or a halogen atom, such as chlorine, bromine or iodine, or the group -CH2-Z representing the group 25 J CH in which B ·· and Bo can be equal or ^ b2 different from each other and represent a function chosen from the following series: nitrile, carboxylic, carba-30-base or alkoxycarbonyl (-C00R3, R3 having the values given above) . / 58 V% 15. Process for the synthesis of derivatives according to any one of claims 1 to 13, characterized in that it consists in converting a derivative of formula II!> - <CH2> n - Z Π R1 * * into a corresponding compound of formula I, R, R ^ and n 10 having the meanings given above, Z representing a group which, by the action of an appropriate reagent, can be converted into an amide, carbo-xylic or alkoxycarbonyl function (- COORg), like the amide function, the carboxylic acid function, the nitrile function, the ester function (-C00R1, in which R 'represents either Rg, specified previously, or an alkyl or phenyl radical substituted in such a way that it activates the ester vis-à-vis the attack of a nu-cleophile), the amidine / ^ NH \ function, the dù \ C ^ mz 'function ^ .0 acid halide ((r, where X represents halogen "" X 25 such as chlorine, bromine or iodine), the an- ORg hydride function, the imidate function (-C ^) or the group - ^ NH - N-carbonylimidazole, Z can also represent a carboxylic acid precursor group such as the trihalomethyl group (-CXg, in which X represents a chlorine, bromine or iodine atom), an oxazoline group, a hydroxymethylene group (-CH2OH), a group formyl (-CH0) which may or may not be present in a protected form such as a cyclic dithioacetal or not, an α, β-dihydro-m * * 59 xyalkyl or alkenyl group (-CHOH-CHOH-R ^ or - CH = CH-R ^, in which R ^ represents a linear alkyl radical Οχ — Cgo) "an acetyl group (-C0-CH3), a 1-hydroxyethyl group (-CHOH-CH ^), an acetonyl group 1.5 (-CH ^ -CO-CH ^), a 2-hydroxypropyl-1 group (-CH2-CH0H-CH3) * or a halogen atom such as chlorine, bromine ~ or iodine, or the group - CH2-Z representing the group f CH ^ in which Bj and B2 can be equal or dif-10 ”L relative to each other and represent a function chosen from the following series: nitrile, carboxylic, carbamodel or alkoxycarbonyl (-C00R3, R3 aya nt the values given previously). 15 16. Process for the synthesis of derivatives according to any one of claims 1 to 13, characterized in that it consists in subjecting to an condensation reaction an amine of formula RNH- (CH2) nZ or R1NH- (CH2) nZ 20 with an alkylation or acylation reagent such as * Rc Rg * RW, R, W, ^ C = C = 0, RrC00H, ^ C = 0, or an amine RV Rl ° of formula ^ NH with a compound W - (CH2) n ~ Z or OHC-ÎCH ^^ - Z, 25 R1 optionally followed by a reduction of the intermediate amide, imine or iminium function obtained; in these z. 'formulas R, Rj and n having the meanings given s RR 30 above, the groups ^^ CH-CO, ^^ CH-CH9, Rr-C0, R7 "R7 ^ c 0 R9 Rd-CHa or CH obtained after condensation, followed by ο ί R K10 where appropriate a reduction, representing the group 35 R or Rj, W having the value of a chlorine, bromine or iodine atom, of a group such as 0- tosyle, 0-mesyle, sulphate, acyloxy or hydroxyl and Z having the meaning "60% J of the group Zf *, in which R? has the values specified above. 2 - 5 17. Process for the synthesis of derivatives according to one any of the claims 1 to 13, characterized in that a lactam of formula XVIII y »10» 0 (CH2) „- f V i R 15 XVIII in which R and n have the meanings given above, is converted into a derivative of formula I, under the action of a mineral acid or under the action of ammonia, an amide, a alcoholate or an alkali metal hydroxide. 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. 0 30 19. Composition according to Claim 18, characterized in that it is in the form of dragees, tablets, capsules, tablets, granules, capsules, solutions, syrups, emulsions, suspensions or gels containing conventional additives or excipients in pharmaceutical pharmaceuticals. // 61 Γ -, ί ί 20. Composition according to claim 18, 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 l 'ethyl oleate. 5 * 21. A method of using the derivatives of formula I, * m * characterized in that they are administered in doses of * 50 mg to 4000 mg by oral route and from 5 mg to 400 mg by parenteral route. 10 22. Method of using the derivatives according to formula I in the treatment of various forms of epilepsy, in the treatment of muscular spasticities of nervous origin, in the treatment of dyskinesias such as 15. Parkinson's disease, in the treatment of mental disorders such as depression, sleep disorders and memory impairment, in the treatment of certain cardiovascular disorders such as hyper- * tension and hypotension as well as analgesic and anthelmintic agents. Oc-i'r: ......... </ · Penches, i „r * λ nanc ûu g *» 1'- “'_JÛU-Pac5- ...... ff DsneB Ch description. .............. ',. .. ··: ·, ·. ··, ύ: ϋcation ', ao. · F *,; ; J, ·. \ \ Luxembourg, b \ i OCT. 1083 J * Le manda ·: iro: Vie Α5ε '^^