NL8302916A - DERIVATIVES OF OMEGA-AMINO ACIDS, THE PREPARATION AND USE THEREOF AND PREPARATIONS CONTAINING THESE DERIVATIVES. - Google Patents

Description

.99 · 0 · 31,998 1 i Derivatives of td-amino acids, their preparation and application and preparations containing these derivatives.

The Applicant mentions as inventors: A. CordijC.GilletjJ.RobajP.ITiebes; P. Janssens, de Varebeke and G. Lambelin. ,.

The present invention relates to derivatives of--amino acids, to the salts of these derivatives, to processes for their preparation, to pharmaceutical preparations containing at least one of these derivatives and to a process for their use.

The present invention includes the derivatives of amino acids corresponding to the general formula 1 as well as the salts of these compounds formed with metals, acids or bases which are pharmaceutically applicable.

In the general formula 1, 10 R represent a linear or branched alkyl radical with 2-12 carbon atoms; a straight or branched alkyl radical of 2 to 4 carbon atoms, which is substituted by a phenyl or phenoxy nucleus, which is optionally substituted by one or two straight or branched chain alkyl radicals with 1 to 4 C atoms, by one or two straight or branched chain alkoxy radicals 1 -15 4 C atoms or through one or two halogen atoms such as fluorine, chlorine or bromine atoms; a straight or branched acyl radical with 2-6 C atoms, which is substituted by a phenyl core, which is optionally substituted by one or two straight or branched alkyl radicals with 1-4 C atoms, by one or two straight or branched alkoxy radicals with 1-4 C atoms or through one or two halogen atoms such as fluorine, chlorine or bromine atoms;

R1 is a hydrogen atom; a straight or branched acyl radical with 2-11 C atoms; a straight or branched acyl radical with 2-6 C atoms, which is substituted by a phenyl core, optionally substituted by one or two straight or branched alkyl radicals with 1-4 C atoms, by one or two straight or branched alkoxy radicals with 1 to 4 carbon atoms or by one or two halogen atoms, such as fluorine, chlorine or bromine atoms; R2 is a hydroxyl group; An alkoxy group R30-, wherein R3 represents a straight or branched chain alkyl radical with 1-3 C atoms; an amino group (-NH2) for; and n has the values 3, 4 or 5 *

In a preferred embodiment, the invention relates to compounds of formula 1, wherein R is a straight or branched chain alkyl radical containing 2-12 carbon atoms; a straight or branched chain alkyl radical of 2-4 carbon atoms

8 * v * - \ ** A

0 ij ij <yr 2% * * substituted by a phenyl or phenoxy nucleus, which is optionally substituted by one or two straight or branched alkyl radicals with 1 -4 C atoms, by one or two straight or branched alkoxy radicals with 1 -4 C atoms or by one or two halogen atoms such as fluorine, chlorine 5 or bromine atoms; a straight or branched acyl radical with 2-6 C atoms, which is substituted by a phenyl core, which is optionally substituted by one or two straight or branched alkyl radicals with 1-4 C atoms, by one or two straight or branched alkoxy radicals with 1 -4 C atoms or by one or two halogen atoms such as fluorine, chlorine or bromine atoms;

Rj, a hydrogen atom; a straight or branched acyl radical with 2-11 C atoms; a straight or branched acyl radical with 2-6 C atoms, which is substituted by a phenyl core, which is optionally substituted by one or two straight or branched alkyl radicals with 1-4 C atoms, or by one or two straight or branched alkoxy radicals with 1-4 C atoms or by one or two halogen atoms, such as fluorine, chlorine or bromine atoms; R2 is a hydroxyl group; an alkoxy group R30-, wherein R3 represents a straight or branched chain alkyl radical with 1-3 C atoms; represents an amino group (-NH2); n has the values 3, 4 or 5; When R represents a dodecyl radical and R 1 represents a hydrogen atom, R 2 does not represent a hydroxyl radical, when n has the value 4, and when R 2 represents a hydroxyl group and R 1 represents a hydrogen atom, R represents no n-butyl or n-octyl radical for, when n has the value 4 and when R2 represents an ethoxy group and R1 represents a hydrogen atom, R does not represent an ethyl or n-butyl radical, when R represents an n-butyl radical, R1 represents a methoxy or hydroxyl group n does not have the value 3.35 when R represents an isopropyl radical, R] represents a hydrogen atom and R2 represents a hydroxyl radical, n does not have the value 5.

In another preferred embodiment, the invention relates to compounds of formula 1, wherein R is a straight or branched chain alkyl radical containing 2-10 C atoms; 40 a straight or branched alkyl radical with 2 to 4 C atoms, which is substituted by a phenyl or phenoxy nucleus, which is optionally substituted by a methyl or methoxy radical or by a chlorine atom, *; Κχ a hydrogen atom; 5 a straight or branched acyl radical with 2-11 C atoms; a straight or branched acyl radical with 2-6 C atoms, which is substituted by a phenyl core, which is optionally substituted by a methyl or methoxy radical or by a chlorine atom; R2 is a hydroxyl group; An alkoxy group R30-, wherein R3 represents a straight or branched chain alkyl radical with 1-3 C atoms; represents an amino group; n has the values 3, 4 and 5; when n has the value 4 and when R2 represents a hydroxyl group and R1 represents a hydrogen atom, R represents no n-butyl or n-octyl radical; when n has the value 4 and when R2 represents an ethoxy group and Rx represents a hydrogen atom, R does not represent an ethyl or n-butyl radical; When R represents an n-butyl radical, Rx represents a hydrogen atom and R2 represents a methoxy or hydroxyl radical, n does not have the value 3, when R represents an isopropyl radical, Rx represents a hydrogen atom and R2 represents a hydroxyl radical, n does not have the value 5.

According to another embodiment, the invention relates to derivatives of the formula 1, wherein R is a straight or branched acyl radical with 2-6 C atoms, which is substituted by a phenyl core, which is optionally substituted by a methyl or methoxy radical or a chlorine atom;

Rx represents a hydrogen atom; R2 is a hydroxyl group; an alkoxy group R30-, wherein R3 represents a straight or branched chain alkyl radical with 1-3 C atoms; represents an amino group; n has the values 3, 4 and 5.

A preferred class of compounds of the formula I are compounds of the formula 1 wherein R represents a straight or branched chain alkyl radical containing 2-10 carbon atoms;

Rx represents a hydrogen atom; R2 is a hydroxyl group; 40 an alkoxy group R30 - wherein R3 is a straight or branched chain alkyl radical? T r

v w ^ 'y i; J

4! t * with 1-3 C atoms; represents an amino group; n has the values 3, 4 and 5; when n has the value 4 and when R2 represents a hydroxyl group and R1 represents a hydrogen atom, R represents no n-butyl or n-octyl radical; when n has the value 4. and when R2 represents an ethoxy group and R1 represents a hydrogen atom, R represents no ethyl or n-butyl radical; When R represents an n-butyl radical, R 1 a hydrogen atom and R 2 represents a methoxy or hydroxyl radical, n does not have the value 3; when R represents an isopropyl radical, R 1 represents a hydrogen atom and R 2 represents a hydroxyl radical, n does not have the value 5.

Another preferred class of compounds of formula 1 are compounds of formula 1, wherein R is a straight or branched chain alkyl radical containing 2-10 C atoms; a straight or branched acyl radical with 2-6 C atoms, which is substituted by a phenyl nucleus; Rx represents a hydrogen atom; R2 is a hydroxyl group; an alkoxy radical R30-, wherein R3 represents a straight or branched alkyl radical containing 1-3 C atoms; n has the value 3, when R represents an n-butyl residue, R2 does not represent a methoxy or hydroxyl residue.

A further preferred class of compounds of the formula 1 are compounds of the formula 1, wherein R 30 is a straight or branched chain alkyl radical containing 2 to 10 carbon atoms; a straight or branched acyl radical with 2-6 C atoms, which is substituted by a phenyl nucleus;

R1 represents a hydrogen atom; R2 represents an amino group (-NH2); 35 and n has the value 3.

Examples of compounds according to the invention are: 4-n-pentylaminobutanamide 5-n-pentylaminopentanamide 6-n-pentylaminohexanamide 40 4-n-pentylaminobutanoic acid λ ί-Ί, Γ- .λ * 4 5 5- (p-tolylacetylamino) pentanamide # 6-n-decylaminohexanamide '6 - [(2-p-chlorophenoxyethyl) amino] hexanamide 4 - [(Nn-hexyl-N-4-chlorophenylacetyl) amino] butanamide.

When the derivatives of the formula I are in the form of addition salts with acids, they can be converted into free bases or addition salts of other acids by conventional methods.

The salts most commonly used are addition salts of pharmaceutically applicable, non-toxic acids, which are formed with suitable inorganic acids, for example hydrogen chloride, sulfuric or phosphoric acid, or with suitable organic acids, such as aliphatic acids, cycloaliphatic acids, aromatic acids , araliphatic or heterocyclic acids, carboxylic or sulfonic acids, for example formic, acetic, propionic, tartaric, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, glutamic, acid, benzoic acid, anthranilic acid, hydroxybenzoic acid, salicylic acid, phenylacetic acid, mandelic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, pantothenic acid, toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, 20 stearic acid, o-hydroxybutyric acid, oxalactyl butyric acid «

In the case where R 1 represents a hydroxyl group, the derivatives of the invention may be in the form of zwitterions or in the form of metal salts or addition salts with non-toxic and pharmaceutically applicable bases.

When the derivatives of the invention, wherein R 2 represents a hydroxyl group, have been obtained in the salt form, they can be converted to the acids or other salts by conventional methods.

These salts may be derived from metals such as, for example, sodium, potassium, lithium, calcium, magnesium, aluminum, iron, or may be addition salts with bases, such as, for example, ammonia or amines such as ethylamine, isopropylamine, ethanolamine, diethylamine, diethanolamine, triethylamine or natural or basic amino acids, such as lysine, arginine, ornithine.

The compounds of the formula I can contain one or more asymmetric carbon atoms and can therefore be in the form of optical isomers, racemic mixtures or diastereoisomers; all of these forms are part of the present invention.

The derivatives according to the invention can therefore take the form of J ». . * C ‘3 t -. ·; - · -:.

* * 6 mixtures containing various diastereoisomers in arbitrary proportions or in the form of pairs of enanthlomers, whether or not * in equal amounts (racemic mixture) or in the form of optically pure compounds.

The products according to the invention can be used in the treatment of neurological, psychological or cardiovascular disorders, such as, for example, epilepsy, depression, movement disorders such as Parkinson's disease, muscle spasms of a nervous nature, hypertension, hypotension, sleep disorders, memory disorders as well as anthelmintic and analgesic agents.

The present invention also includes pharmaceutical preparations which contain as active ingredient at least one compound of the general formula 1 or a salt thereof with an additive and / or a diluent, which is used in Galenus pharmaceutical manufacture.

These preparations are prepared in such a way that they can be administered orally, rectally or parenterally. They can be solids, liquids or gels and, depending on the route of administration, may be in the form of powders, tablets, dragees, coated tablets, capsules, granules, syrups, suspensions, emulsions, solutions, suppositories or gels. These compositions may also contain another therapeutic agent having an activity, which may or may not correspond to that of the products of the invention.

The compounds of the invention are prepared according to methods which are part of the present invention and are described below. In the case where the methods give rise to the formation of new intermediates, these new compounds as well as the methods for their preparation are part of the present invention.

30 Method A.

According to this mode of operation, the product of the formula II according to the reaction scheme of Fig. 1 is converted into the derivative of the formula 1, wherein R, R1, R2 and n have the above defined meaning and Z represents a group which, by action of a suitable reagent can be converted to an amide, carboxylic acid or ester function. Examples of these functions include the amide function, the carboxylic acid function, the nitrile function, the ester function (-C00R *, where R 'has the same meaning as the above-defined symbol R3 or represents an alkyl or phenyl radical substituted in such a way). 40, that the ester is activated with respect to a nucleophilic attack, the amidine function (group of formula 3), the acid halide function (group of the formula IV, wherein X represents a halogen atom such as a chlorine, bromine or iodine atom), the anhydride function, the imidate function (group of the formula 5) or the N-carbonylimidazole group. Z 5 may also represent a precursor group of a carboxylic acid, such as, for example, the trihalomethyl group (-CX3, wherein X represents a chlorine, bromine or iodine atom), an oxazoline group, a hydroxymethylene group (-CH2OH), a formyl group (-CH0) which may or may not be in protected form, such as, for example, a cyclic dithioacetal or not, an α, β-dihydroxyalkyl or alkenyl group (-CHOH-CHOH-R4 or -CH-CH-R4, in which R4 is a straight alkyl radical with 1-20 C atoms), an acetyl group (-CO-CH3), a 1-hydroxyethyl group (-CHOH-CH3), an acetonyl group (-CH2-CO-CH3), a 2-hydroxypropyl-1 group (-CH2-CHOH-CH3) or a halogen atom, such as a chlorine, bromine or iodine atom.

The group -CH2-Z may also represent the group of formula 6, wherein Βχ and B2 may be the same or different and represent a nitrile, carboxyl, carbamoyl and / or alkoxycarbonyl function (-COOR3, where R3 has the meaning given above possession).

The conversion of the product of the formula II into the product of the formula 1, ie the conversion of the group Z or -CH2-Z into a group (-COR2) can be carried out according to conventional reactions described in the literature such as, for example: a) Conversion of a carboxylic acid into an amide.

This chemical conversion can be carried out by various methods.

For example, the carboxylic acid can be contacted with ammonia, the pyrolysis of the salt thus formed leads to the amide as well as the action of a dewatering agent such as P2O5.

Another mode of operation consists of converting the carboxylic acid into an acid halide and then into the amide by the action of ammonia.

Another mode of operation is to convert a carboxylic acid and ammonia in the presence of a coupling reagent, such as is used in the synthesis of peptides, such as, for example, dicydohexylcarbodiimide, N-ethyl-N'-3-dimethylamino-propylcarbodiimide, phosphines , phosphites, silicon or titanium tetrachloride.

b) Conversion of a nitrile into an amide or acid.

The nitriles can be hydrolyzed in an acid or basic medium to an amide or acid. When the hydrolysis under acidic conditions · · r- λ -ï w «· ii * v

__J

In addition, concentrated sulfuric acid, concentrated hydrochloric acid aqueous solution, hydrobromic acid aqueous solution, nitric acid, formic acid in the absence of solvent, acetic acid in the presence of boron trifluoride can be used.

Another method of converting a nitrile to an amide in an acidic environment is to treat the nitrile with hydrogen chloride in an alcohol such as ethanol. Thus, as an intermediate, an imino ether is formed, which is thermally converted into the amide.

When the hydrolysis is carried out under basic conditions, for example, potassium hydroxide in tert-butanol or an aqueous solution of an alkali or alkaline earth metal hydroxide will be used. The presence of hydrogen peroxide facilitates hydrolysis. The nature of the group formed, an amide or a carboxylic acid group, depends mainly on the reaction conditions used.

c) Conversion of a nitrile into an ester.

This conversion is carried out with a nitrile and an alcoholic acid medium. As the solvent, alcohol or any other inert solvent can be used. An imino ether is thus formed as an intermediate product, which is converted into an ester by hydrolysis.

d) Conversion of an ester to an amide.

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

e) Conversion of an amidine to an amide.

This conversion is mainly performed by acidic hydrolysis in water or alcohol containing medium. The acid can be inorganic, such as hydrogen chloride or sulfuric acid, or organic, such as acetic acid.

f) Conversion of an acid halide, of an anhydride or of an N-carbonylimidazolyl group to a carboxylic acid or alkoxycarbonyl group (-COOR3).

This reaction proceeds easily with the product of formula II with water to form the carboxyl group (hydrolysis reaction) or with an alcohol R3OH, where R3 represents a straight or branched alkyl radical with 1-3 C atoms to form the alkoxycarbonyl group - COOR3 (alcoholysis reaction).

These reactions are carried out in the presence of an excess of 40 water or alcohol or with a stoichiometric amount of these

€> 9 9 1 1

9 Λ 4 reagents in the presence of an inert solvent. The alcoholysis is advantageously carried out in the presence of a catalyst such as an organic or inorganic acid or an organic or inorganic base.

G) When the group Z of the formula 2 represents a precursor group of a carboxylic acid, such as a trihalomethyl or an oxazoline group, the conversion to the carboxylic acid in water or in an inert organic solvent is carried out in the presence of acid. As the acid, an inorganic acid is generally used, such as the hydrogen halides, dilute or concentrated sulfuric acid, dilute or concentrated nitric acid, phosphoric acid or an organic acid such as acetic acid.

h) The conversion of the group -0¾-Z, corresponding to the group of the formula 6, wherein and B2 has the above meaning -15, In a carboxymethyl group is carried out by hydrolysis in acid or basic medium under conditions which are identical to the above conditions for the hydrolysis of a nitrile followed by a period of heating in an acid medium to decarboxylate the intermediate α-dicarboxylic acid obtained.

I) Conversion of other precursor groups of the carboxylic acid group into a carboxylic acid group by oxidation.

This conversion particularly concerns the intermediates of the formula 2, wherein Z is a group such as -CH 2 OH, -CHO, -CHOH-CH 3, -CO-CH 3, -CH 2 -CHOH-CH 3, -CH 2 -CO-CH 3, -CH -CH-R4 and represents CHOH-CHOH-R4, wherein R4 has the above defined meaning. This conversion is carried out in the usual manner using a considerable number of oxidizing agents and according to a large number of different known methods.

The oxidation proceeds through various intermediates, which can be isolated in certain cases and, depending on the nature of the oxidizing agent, the oxidation is carried out in water or an inert organic solvent.

It goes without saying that the choice of the oxidizing agent and of the reaction conditions will depend on the nature of the group * 35 Z and on the manner in which the other groups present in the molecule of the formula 2 are kept intact. The conversion of an acid into an ester and vice versa.

The esterification of an acid is a very general reaction, which can be carried out in various ways.

40 In the usual manner, the acid and alcohol are present when Q ~ A Γ '; "

Ö V V -J u * 'J

10 converted from an acidic catalyst. This reaction can advantageously be carried out under anhydrous conditions and one of the reaction materials is used in great excess.

The solvent can be one of the reaction materials or an inert organic solvent.

Another mode of operation is to distill water as soon as it is formed using a suitable device. The reaction conditions are identical to the reaction conditions described above, except that one of the reaction materials should not be used in excessive amounts.

The hydrolysis of the ester is carried out under acidic or basic catalytic conditions, but in this case one of the reaction materials, here water, is used in very large excess.

K) Conversion of the group Z, which represents an alkoxycarbonyl group (-C00R '), a carboxyl group, its salt or its anion into an alkoxycarbonyl group (-COOR3).

Depending on the nature of Z, this conversion may be carried out by esterification, as described in the previous paragraph, by transesterification, the derivative of the formula II containing the group -C00R * being heated in the presence of a excess alcohol R3OH and an acidic or basic catalyst, advantageously removing the alcohol R'OH formed continuously by distillation, or by alkylation using a reagent WR3, wherein W represents an easily replaceable group, such as a halogen atom, such as a chlorine, bromine or iodine atom, an O-mesyl, O-tosyl, sulfate group (-O-SO2-OR3), an acyloxy group (R5-CO-O) or a hydroxyl group. R3 represents a straight or branched chain alkyl group with 1-3 C atoms and R5 represents a group R3 or 30 a phenyl group. The alkylation of the carboxyl group, of its salt or of its anion is normally carried out in an inert organic solvent in the presence of a weak inorganic base or preferably in the presence of an organic base such as pyridine or triethylamine.

35 1) Conversion of the group Z, which represents a halogen atom, into a carboxylic acid group ·

This conversion is carried out in the usual manner by converting the halogenated product into an organometallic derivative,% whereby the treatment with carbon dioxide, followed by hydrolysis of the intermediate formed, yields the carboxyl group. It used O r 0

* 2 V ^ .λ v - -J

* fc 11 x metal can be lithium, magnesium, zinc or manganese.

In order to avoid side reactions during this conversion, the functional group aanwezige- present in the molecule of formula 2 is suitably protected.

For a better understanding of the method, the main methods of preparation of the derivative of the formula II are described below.

1. The derivative of the formula II can be obtained by using the products of the formula 7 or 8 by alkylation or acylation according to the reaction scheme of fig. 2, wherein R, Rx, Z, W and n are the have the above-defined meanings, but where in the reagent R] W the group Rx does not represent a hydrogen atom · BW and R] W may also represent a ketene of the formula 9, so that the group of the formula 10, which after acylation of the derivatives with the formula 7 or 8 15 is obtained, depending on which reagent used corresponds to a group R or Βχ. 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 an aromatic hydrocarbon selected depending on the nature of the reagent.

The conversion proceeds at a temperature between 0 ° C and the reflux temperature of the solvent. The reaction can advantageously be carried out in the presence of an organic base such as triethylamine, pyridine or N-dimethylaniline or an inorganic base such as the hydroxides, carbonates and hydrogen carbonates of alkali or alkaline earth metals or finely powdered lime.

A variant of this method is illustrated by the reaction scheme of Figure 3, wherein R, Rx, W, Z and n have the above defined meanings.

The above reaction corresponds to the above-described alkylation reaction of the derivatives of formula 7 or 8 and it goes without saying that the conditions used for these three reactions are quite similar.

In another variant of the method, the derivative of the formula II can be synthesized by acylation of a primary amine by a carboxylic acid, using phosgene as the coupling agent. The phosgene can be brought into a solution of the amine and of the carboxylic acid or it can be contacted with one of the two reaction materials and the intermediate thus formed is then contacted with the second reaction material.

40 This variant, in which the phosgene is brought into contact with the y * - "V Ά Λ ** ï Λ V» 12, amine of the formula 8, followed by the conversion of the isocyanate formed as intermediate, is illustrated. by the reaction scheme of Fig. 4, wherein R 1 represents a hydrogen atom, Z and n have the above meanings and the group Rg-CO corresponds to the group R * defined above

According to another variant, the derivative of the formula 2, wherein R represents an alkyl group which may or may not be substituted in the above-defined manner, can be obtained by acylation of the derivatives of the formula 7 or 8, as described above, followed by reduction of the intermediate amide obtained.

Numerous methods have been described for carrying out such a reduction, but it goes without saying that care must be taken in preserving the functionality of the group Z when selecting the reaction conditions.

2 · Another method of preparation of the derivative of the formula 2 is characterized by the formation of an iminium salt of the formula 14 as intermediate of an amine and a carbonyl compound of the formula 13. The reduction of the iminium salt leads to the derivative of the formula 2. (Compare the reaction scheme of Fig. 5).

The condensation of the amine and the carbonyl derivative of the formula 13 is carried out in an inert organic solvent, which is preferably immiscible with water, in the usual manner. Advantageously, the conversion is catalyzed by an inorganic or organic acid.

The reduction is carried out in the usual manner in a suitable solvent using hydrogen in the presence of a hydrogenation catalyst, using an alkali metal hydride, using the aluminum and lithium hydride, or using another reducing agent, but it goes without saying that the method of reducing the iminium salt will be chosen in such a way that the functionality of the group Z remains intact. In a different choice of the reaction materials, a variant of this process can be carried out, whereby the product of the formula II can be obtained, whereby no intermediates are formed which contain the same chemical functions as above. (Reaction scheme according to Fig. 6, wherein R 1, Z and n have the meanings given above, while the groups R 8 and R 20 have such a meaning that the group of formula 17 is R).

The condensation of the carbonyl derivative with the amine of the formula 8 and the reduction of the iminium salt of the formula 16 are carried out under the conditions described above.

VJ 8 13, It should be noted that when Κ, χ represents a hydrogen atom, the condensations described above lead to an imine of the formula 18 or 19, in which R, Rg, Rxo, Z and n have the meanings defined above . The conditions of synthesis and reduction of the imines of formulas 18 and 19 are completely comparable to those of the synthesis and reduction of iminium salts of formulas 14 and 16.

3. Another preparation method of the derivatives of formula 2 consists of the reaction of a product of formula 20 using the reagent of formula 21 according to the reaction scheme of Fig. 7, wherein R, Εχ, W and n are the have the above meanings, M represents a hydrogen atom or a metal atom such as lithium, sodium, potassium or magnesium and Z has the meanings given above which are compatible with the intended reaction, such as a nitrile, trihalomethyl group or an optionally cyclic dithioacetal group.

The reaction of the product of the formula V can be carried out by various conventional methods, depending on the nature of W and Z. Some of these methods are summarized below by way of example: 20 a) when Z represents a nitrile or trihalomethyl group , the conversion can be carried out in various solvents, such as, for example, water, a low-molecular alcohol, dimethylformamide or in mixtures of solvents which can be miscible or immiscible.

In many cases it is advantageous to operate in the presence of an organic base or a phase transfer catalyst.

b) when Z represents a cyclic dithioacetal group or not, the conversion proceeds under anhydrous conditions at low temperature in an inert solvent such as diethyl ether or tetrahydrofuran. The product of formula II is then obtained by removing the protecting group from the formyl group by known methods, such as hydrolysis in an acid medium or by the action of mercury salts.

4. Another method of preparing the derivatives of formula 2, wherein -CH 2 Z represents the group of formula 6, consists of alkylating a derivative of formula 22 using a reagent of formula 23 according to the reaction scheme of Fig. 8, wherein R, Ri, Βχ, B2, W and n have the meanings given above, except for the symbol W, which in this case may not represent a hydroxyl group.

40 M represents an alkali metal such as sodium, kaliun or lithith.

"- -» v "f * c, v 'l i ö 14

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

5 Method B.

This process consists of opening a lactam of the formula 25 under the action of a base or an acid. This lactam of formula 25 is conventionally obtained from the lactone of formula 24 according to the reaction scheme of Fig. 9, wherein R, R2, M and n have the above defined meanings. The conversion of the lactone to the lactam is carried out in an inert organic solvent, advantageously at the reflux temperature of the reaction medium. The opening of the lactam can be effected under the action of ammonia, an amide, an alcoholate or a hydroxide of an alkali metal or under the action of an inorganic acid such as hydrogen chloride or sulfuric acid. The opening proceeds in water or in an inert organic solvent, such as an ether, an alcohol, an aliphatic, aromatic and / or chlorinated hydrocarbon.

It will be clear that the described methods for the synthesis of the compound of the formula II can also be used in the products in which the group Z already has the meaning of the group of the formula 26, as above has been described and can thus lead directly to the products according to the invention corresponding to the general formula 1.

It goes without saying that for all the processes for the synthesis of the compounds of formulas 1 and 2 as well as for the processes mentioned for the conversion of the group Z and CH 2 -Z to a group of the formula 26, that the reaction materials and the reaction conditions are selected in such a way that the functional groups already present in the molecule remain intact and are not involved in the intended reaction.

Thus, in order to be able to carry out the synthesis of the compounds of formulas 1 and 2, it is sometimes necessary to use protecting groups in order to maintain the functionality of the groups present in the starting molecule. The choice of the experimental conditions will depend on the choice of the protecting groups, which have been described in the literature, as have the methods for introducing them and the methods for removing them.

Extensive examples of the preparation of some derivatives of the invention are given below. These examples are mainly intended to illustrate the particularly advantageous characteristic aspects of the methods according to the invention.

Example I.

Synthesis of 4-n-pentylaminobutanamide.

5 g (0.041 mol) of 4-chlorobutanamide are dissolved in 19 ml (0.165 mol) of pentanamine and stirred at ambient temperature for 48 hours. A precipitate is formed by adding ether (400 ml), which is filtered off and recrystallized twice in isopropanol.

Melting point: 187 ° C.

10 Elemental analysis: C Η N

calculated (wt%) 51.7 10.1 13.4 found (wt%) 52.0 10.2 13.4.

Example II.

Synthesis of 5-n-pentylaminopentane amide.

A) A mixture of 4.5 g of 5-chloropentanitrile (0.040 mol), 3.8 g (0.044 mol) of pentanamine and 3.7 g of sodium hydrogen carbonate in 60 ml of absolute ethanol is refluxed for 48 hours. The sodium chloride formed is filtered off and the filtrate is evaporated to dryness under reduced pressure to remove the excess pentanamine 20. The remaining oil is dissolved in ether and ether / HCl is added. A white precipitate is formed, which is filtered off (5-n-pentylaminopentanitrile hydrochloride).

Melting point: 207-209 ° C.

b) 2.78 g (0.013 mol) of 5-n-pentylaminopentanitrile 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 crystallized solid is filtered off and washed with isopropanol.

Melting point: 216-217 ° C

30 Elemental Analyzer: C Η N

calculated (wt. X) 53.9 10.4 12.5 found (wt.%) 54.2 10.5 12.6.

Example III.

Synthesis of 6-decylaminohexanamide.

4.5 g of 6-chlorhexanamide (0.030 mol) are heated to reflux in 100 ml of ethanol containing 5.2 g of decane amine (0.033 mol) and 2.52 g of NaHCO 3 (0.033 mol). After 2 days and 2 nights, the solution is cooled, filtered and evaporated, the solid recrystallized twice in ethyl acetate. The solid obtained is dissolved in ethanol and ether / HCl is added; de ~ o Cï '·] 6 16. recovered solid is recrystallized twice in isopropanol.

Melting point; 206 ° C.

Elemental Analysis: C · N

5 calculated (wt%) 62.6 11.5 9.1 found (wt%) 63.0 11.7 9.3.

Example IV.

Synthesis of 5- (p-tolylacetylamino) pentanamide.

To a solution of 0.7 g (0.017 mol) of NaOH and of 2 g of 5-amino-10 pentanamide (0.017 mol) in 10 ml of water cooled at 0 ° C, is added dropwise and at the same time 2.9 g (0.017 mol) of p tollacetyl chloride and a solution of 0.7 g of NaOH in 4 ml of water. The formed suspension is stirred at ambient temperature for one hour. The solid is filtered off and recrystallized twice in isopropanol.

Melting point: 206 ° C.

Elemental Analysis: C Η N

calculated (wt%) 67.7 8.1 11.3 found (wt%) 67.8 8.1 11.3.

Example V.

Synthesis of 4-pentylaminobutane carboxylic acid.

7.75 g of pentanol (0-090 mole), 7.73 g of gamma-aminobutanoic acid (0.075 mole), 800 mg of 10% by weight palladium on charcoal, 5 g of molecular sieves are added to a vessel according to Parr. of 3 l and 200 ml of absolute ethanol. The contents of the vessel are stirred under hydrogen atmosphere for 18 hours. The suspension is filtered and the filtrate is evaporated to dryness under reduced pressure at 20 ° C. The solid is washed with ether, dissolved in a minimal amount of ethanol and then ether. added. The crystals obtained are recrystallized in the same manner.

Melting point: 161-162 ° C.

Elemental Analysis: C Η N

calculated (wt%) 62.4 11.0 8.1 found (wt%) 62.1 11.1 8.0.

Example VI.

Synthesis of 6-f3- (3,4-dimethoxyphenyl) propanoylamino] hexane amide.

To a solution of 2.6 g (0.020 mol) of 6-aminohexanamide and 0.8 g of NaOH in 15 ml of water, cooled to 0 ° G, 4.6 g is added at the same time. (0.02 mol) 3- (3,4-dimethoxyphenyl) propanoyl chloride and 2.4 g NaOH in 20 ml water. The suspension is stirred at room temperature for 2 hours. The solid is then filtered off and recrystallized -?> 7 7- = 0 «" 1. ¾.!)? : U * .V ^ \ 17

• I

In isopropanol.

Melting point: 137 ° C.

Elemental Analysis: C Η N

calculated (wt. Z) 63.3 8.1 8.7 5 found (wt.%) 63.2 8.2 8.6.

Example VII.

Synthesis of 6-n-pentylaminohexanamide.

A mixture of 5 g of 6-chlorhexanamide (0.033 mol), 4.25 ml of pentanamine (0.037 mol) and 2.8 g of sodium hydrogen carbonate (0.034 mol) in 100 ml of ethanol is refluxed for 4 days. After cooling the solution, the salts are then filtered off and the solvents are evaporated until dry material is obtained. The product, which solidifies, is crystallized twice in ethyl acetate, dissolved in a minimal amount of ethanol and 15 ether / HCl is added. The solid formed is filtered and dried.

Melting point: 190.5eC.

Elemental Analysis: C Η N

calculated (wt. Z) 55.8 10.6 11.8. 20 found (wt.%) 55.8 10.6 11.8.

Example VIII.

Synthesis of 4-n-hexylaminobutanamide.

a) A mixture of 18.5 ml of 4-chlorobutanitrile (0.2 mol), 29.1 ml of hexanamine (0.22 mol) and 18.5 g of sodium hydrogen carbonate (0.22 mol) in 500 ml is heated refluxing ethanol for two days. The suspension is then cooled, the salts are filtered off and the filtrate is evaporated. The residue is partitioned between water and dichloromethane. The dichloromethane phase is washed with water, dried over K2CO3 and evaporated at room temperature. The excess hexanamine is evaporated under high vacuum and the residual oil is dissolved in anhydrous ether and ether / HCl is added. The solid formed is filtered off, dissolved in a minimal amount of methanol and added to anhydrous ether. The product thus obtained is used as such in the next step 35.

b) 4.2 g of 4-hexylaminobutanitrile (0.02 mol) are stirred in 5 ml of concentrated HCl at 5 ° C for 4 days. This solution is then poured into 50 ml of ice-cold acetone. The white solid formed is recrystallized from isopropanol.

40 Melting point: 194eC.

"3-3¼ 18

Elemental Analysis: C - Η N

calculated (wt%) 53.9 10.4 12.6 found (wt%) 54.1 10.4 12.6.

Example IX.

Synthesis of 4- [(N-n-hexyl-N-4-chlorophenylacetyl) amino] butanamide.

650 mg of 4-hexylaminobutanamide hydrochloride (0.003 mol) are dissolved in 9.4 ml of 1 N Κ0Η at 10 ° C. 0.65 ml of 4-chlorophenylacetic acid chloride are added dropwise to this solution. An oil immediately forms and solidifies. After a reaction of 2 hours ex-10, the oil is extracted with ether, the ether phase is washed with water and with 1 N hydrogen chloride, dried over K2CO3 and evaporated. The residual solid is recrystallized from ethyl acetate c

Melting point 105-106 ° C.

15 Elemental analysis; C Η N calculated (wt%) 63.1 8.0 8.2 found (wt%) 63.0 7.9 8.1.

Example X.

Synthesis of 5-n-dodecylaminopentane amide.

A) 7.4 g of dodecanamine (0.04 mol), 4.23 g of 5-chloropentanitrile (0.036 mol) and 3.4 g of sodium hydrogen carbonate (0.04 mol) in 100 ml of ethanol are heated for 2 days reflux. The cooled solution is then filtered and the filtrate is evaporated. The remaining oil is distilled under a pressure of 0.25 mm Hg. The fraktle which is distilled at 170 ° C is collected. This is dissolved in ethanol and ether / HCl is added. The solid which precipitates is filtered and used in the next step without further purification.

b) 2 g of 5-dodecylaminopentanitrile hydrochloride (0.007 mol) are dissolved in 50 ml of acetic acid. This solution is saturated with dry hydrogen chloride 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 is recrystallized twice in isopropanol.

35 Melting point: 212eC.

Elemental Analysis: C Η N

calculated (wt%) 63.6 11.6 8.7 found (wt%) 63.9 11.6 8.8.

Example XI.

40 Synthesis of 4-n-pentylaminobutanamide.

fi 'Z -> *' · -Ί

* .v '_ Λ to ·' ’* W.

A) A mixture of 18.5 ml of 4-chlorobutanitrile (0.2% mol), 19.1 g of pentanamine (0.22 mol) and 18.5 g of sodium hydrogen carbonate (0.22 mol) is heated. In 500 ml ethanol under reflux for 2 days. The suspension is then cooled, the salts are filtered off and the filtrate is evaporated. The residue is partitioned between water and dichloromethane. The dichloromethane phase is washed with water, dried over K2CO3 and evaporated at room temperature. The excess pentanamine was evaporated under a high vacuum and the residual oil was dissolved in anhydrous ether and ether / HCl was added. The solid formed is filtered off, dissolved in a minimal amount of methanol and anhydrous ether is added until a copious amount of precipitate is obtained, which is filtered off and used as such in the next step.

b) 3.1 g of 4-pentylaminobutanitrile (0.02 mol) are dissolved in 15 ml of glacial acetic acid and saturated with HCl at room temperature.

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

Melting point: 187.5 ° C.

Elemental Analysis: C Η N

Calculated (wt. Z) 51.7 10.1 13.4 found (wt. Z) 51.8 10.2 13.4.

Example XII.

Synthesis of 4-n-pentylaminobutanamide.

In a vessel according to Parr, 2.76 g of 4-aminobutanamide hydrochloride (0.02 mol), 1.9 g of pentanal (0.022 mol), 100 mg of Pd / C are added.

(1 wt% wt) and 50 ml ethanol. The contents of the vessel are stirred overnight under a hydrogen atmosphere at ambient temperature.

The catalyst is then filtered off, the solvent is evaporated and the residue is solidified in ether. The solid obtained is recrystallized three times in isopropanol.

Melting point: 186.5 ° C.

Elemental Analysis: C Η N

calculated (wt%) 51.7 10.1 13.4 found (wt Z) 52.0 10.3 13.5.

Example XIII.

Synthesis of 4-n-pentylaminobutanamide. 3.1 g of N-pentylpyrrolidone (0.02 mol) are placed in a 200 ml flask containing 3.9 g of sodium amide (0.1 mol) suspended in 50 ml of toluene. The suspension is kept under reflux for 3 days, after which 10 ml of H 2 O and a sufficient amount of 1N HCl are added to the mixture. acidify the solution (pH 2) The aqueous phase is decanted and lyophilized The residue is extracted with boiling isopropanol, the crystallized solid is filtered off and recrystallized twice in isopropanol · Melting point: 186 ° C.

Elemental Analysis: C Η N

calculated (wt%) 51.7 10.1 13.4 found (wt%) 51.4 10.0 13.7.

Example XIV.

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

a) In a 1 liter flask, which is cooled in an ice bath, 500 ml of toluene and 15.2 ml of pyrrolidone (0.2 mol) are added under nitrogen. To this solution, 9.6 g of sodium hydride (0.4 mol) are added in three portions. After stirring at 0 ° C for one hour, the suspension is allowed to return to room temperature. Then 37.15 ml of 2-phenyl-1-bromoethane (0.27 mol) are added and the whole is refluxed for 12 hours. After adding 100 ml of water, the toluene phase is decanted and washed three times with water, dried over K2CO3 and evaporated; the residual oil is distilled under a pressure of 10 mm Hg. The colorless liquid is collected, which distills at 175 ° C and is identified as N- (2-phenylethyl) -pyrrolidone.

b) 17.9 g of N- (2-phenylethyl) pyrrolidone (0.095 mol) are refluxed in 25 ml of concentrated HCl for 20 hours. The solution is then evaporated to dryness and the residual solid is crystallized in methyl ethyl ketone.

Melting point: 149-150eC.

Elemental Analysis: C Η N

calculated (wt%) 59.1 7.4 5.8 found (wt%) 59.2 7.5 5.7.

Example XV.

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

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

Melting point: 206-207 ° C.

Elemental Analysis: C Η N

calculated (wt%) 61.9 8.2 5.1 40 found (wt%) 61.9 8.2 5.2.

83 0 2 9 1 6 21

The following table lists the derivatives of the above-described examples, as well as other derivatives of the invention, which have been prepared by the above-described methods. A correct elemental analysis (C, H and 5 N) is obtained for all compounds listed in Table Δ.

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The products according to the invention have been subjected to a series. pharmacological tests, the method of which is described below *

The LD5Q values were calculated by the method of Licht-5 field and Wilcoxon (J. Pharmacol. Esp. Ther. 96, 99, 1949) and expressed in mg / kg. The products have been administered orally to mice. The products according to the invention generally appear to be little toxic. The effect on behavior has been studied using a method derived from the method of S. Irwin (Gordon Res. Conf. On 10 Medicinal Chem., 133, 1959). The substances suspended in a gum solution containing 1% by weight of tragacanth gum have been administered orally by gavage to groups of 5 male mice that had fasted for 18 hours.

The doses tested depending on the observed activity are between 3000 and 3 mg / kg.

The behavior is studied 2, 4, 6 and 24 hours after treatment. The observation continues when symptoms persist in this manner. Deaths are recorded over the 14 days following treatment. None of the tested products cause an ab-20 normal behavior in the mouse. The numbers used correspond to the numbers of the products shown in Table A.

Certain products according to the invention generally have an anticonvulsant effect. The anticonvulsant effect is investigated on the basis of tonic convulsions induced by bicuculline. The compounds of the invention are administered to 20 mice orally at a dose of 0.7 mg / kg at a dose of 0.7 mg / kg 3 hours before the intravenous injection with bicuculline. The number of mice protected from the tonic convulsions and the number of dead mice are noted.

In this test, products Nos. 1, 5, 8, 10 and 13 are found to be particularly effective and to provide a protection percentage of 55% or more.

Compound CF 2081 (Compound No. 1 of Table A) has been used in a more in-depth study. In the test to combat bi-35 cuculline-induced convulsions, the ED5Q value is 3 mg / kg. At a dose of 300 mg / kg, the percentage of protection over bicuculline-induced convulsions is 75%.

C? 2081 also has an antagonistic effect with respect to convulsions induced by leptazole and electric shock.

40 Biochemical tests have shown that certain products according to the invention have a GABA mimetic effect. This effect has been investigated in vitro using a method which has been derived

i A

of the method of C. Braestrup and M. Nielsen (Brain Research Bulletin, Vol. 5, Suppl. 2, pages 681-684 (1980)).

A homogenized rat brain product (without small brain), which has been washed to remove the GABA () -aminobutanoic acid present), is used to measure the binding to the receptor using 3H-flunitrazepam in the presence and absence of increasing concentrations of the products to be tested or of a comparative product (in this case GABA).

The nonspecific "binding" is determined in the presence of diazepam.

Incubation is carried out at 0 ° C for 60 minutes with a homogenized product diluted 200 times.

After incubation, the samples are filtered and washed on Whatman GFB flashes. After drying the filter at 60 ° C for 20 minutes, the residual radioactivity is measured using a liquid scintillation counter in a suitable medium.

Under these conditions, the product CF 2818 (Compound No. 20 XVI of Table A) behaves as a GABA mimetic, characterized by an Enhancement concentration 50% EC50 value of 4.7.10 ”3M, similar to the EC50 - value of 8.2.10 ”M from GABA and by an effectiveness identical to that vein GABA.

The compound CP 2818 was also tested in vitro in the assay of the binding of% muscimol to the synaptic membranes of rat brain. This test is specific for GABA ergic receptors and allows to demonstrate an agonistic or antagonistic effect with respect to GABA receptors. These are directly linked to benzo-diazepine receptors.

The preparation of the synaptic membranes as well as the test of the binding of 3 H-muscimol to the synaptic membranes are identical to those described by Enna S.J. and Snyder S.H. published in Brain Research 100, 81-97 (1978).

The value of the specific binding of 3H-muscimol to the membranes 35 is obtained by determining the difference between the binding of 3H-muscimol as such and of this binding in the presence of 10 µGABA.

Different concentrations of CP 2818 have been used to determine the concentration of the product required to prevent 50% of the binding of H-muscimol to membranes 8302 01 6 33 (IC50). the compound CP 2818 has obtained an IC5Q value of 2.5 x 10 5 m. The IC50 value of GABA in this system is 2.10 "7 M.

The antagonistic effect with respect to bicuculline, leptazole and electric shock-induced convulsions as well as the GABA mimetic effect indicate that the compounds of the invention have pharmaceutical properties which make them particularly suitable for the treatment of the various epilepsy and movement disorders, such as Parkinson's disease. In addition, the efficacy of the central nervous system products makes these compounds potentially interesting for the treatment of certain cardiovascular disorders, hypertension and hypotension, for the treatment of mental disorders such as depression, memory and sleep disorders as well as analgesic resources.

Certain products of the invention also have anthelmintic activity.

This activity has been measured in the rat infected with Nippostron gylus Brasiliensis (stage L3).

The compound to be tested is administered by a gullet probe in the form of a gas solution 8 days after the contamination. The rats are killed on the twelfth day and the parasites in the intestine are counted. The results obtained are expressed as an efficiency percentage based on a control group.

In this test, the product CP 2081 (Compound No. 1 of Table A) has an efficacy rate of 91 at a dose of 50 mg / kg.

In humans, the compounds of the invention are administered orally in doses of 500-4000 mg and intravenously in doses of 5-1000 mg.

The products according to the invention can be used in various galenic forms. The examples below are non-limiting and relate to galenic formulations containing an active product designated by the letter A. This active product may be formed by one or more of the following compounds: 4-n-pentylaminobutanamide 5-n-pentylamino pentanamide 6-n-pentylaminohexanamide 4-n-pentylaminobutanoic acid 5- (p-tolylacetylamino) pentanamide 40 6-ni- decylaminohexanamide & TT Λ "" ï ï ï V V J J 34 34 34 34 34 34 34 34 34 6 6 6 6 6 6 6 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 4 4.

Example LXXIV.

Tablets.

5 A 600 mg amidone Sta-Rx 1500 80 mg hydroxypropylmethylcellulose 20 mg aerosil 5 mg magnesium stearate 15 mg.

10 A 100 mg maisamidone 100 mg lactose 80 mg aerosil 5 mg talc 5 mg 15 magnesium stearate 10 mg.

Example LXXV.

Capsules.

A 50 mg lactose 110 mg 20 maisamidone 20 mg gelatin 8 mg calcium stearate 12 mg A 200 mg polyvinylpyrrolidone10 mg 25 maisamidone 100 mg

Cutina HR 10 mg.

Example LXXVI.

l.m. or i.v. injectable preparation.

A 20 mg 30 sodium chloride 40 mg sodium acetate ad pH = 7 distilled water for injectable preparations ad 5 ml.

Example LXXVII.

Im. injectable preparation.

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

Example LXXVIII.

Q "; i y u 5 35

Syrup ». A 5 g tartaric acid 0.5 g nipasept 0.1 g 5 sucrose 70 g flavoring 0.1 g water ad 100 ml »

Example LXXIX.

Solution »10 A 2 g sorbitol 50 g glycerol 10 g peppermint oil 0.1 g propylene glycol 10 g 15 demineralized water ad 100 mg»

Example LXXX.

Suppository.

A 500 mg but ylhyd roxyanisol 10 mg 20 semi-synthetic glycerides ad 3 g.

Example LXXXI »

Rectal gel.

A 100 mg carbomer 15 mg 25 tri'ethanolamine ad pH 5.4 * purified water 5 g.

r \.% -¾ O W S-J "x * C- *

Claims (23)

4 C atoms and / or by one or two halogen atoms such as fluorine, chlorine or bromine atoms, a straight or branched acyl radical with 2-6 C atoms, which is substituted by a phenyl nucleus optionally substituted by one or two or two straight or branched chain alkyl radicals with 1 to 4 C atoms, by one or two straight or branched chain alkoxy radicals with 1 to 4 C atoms and / or by one or two halogen atoms such as fluorine, chlorine or bromine atoms, R 1 represents a hydrogen atom, a straight or branched acyl radical with 2-11 C atoms, a straight or branched acyl radical with 2-6 C atoms, which is substituted by a phenyl core, which is optionally substituted by one or two straight or branched alkyl radicals having 1 -4 C atoms, by one or two straight or branched alkoxy radicals with 1-4 C atoms and / or 25 by one or two halogen atoms, such as fluorine, chlorine or bromine atoms, R2 represents a hydroxyl group, an alkoxy group R3O- wherein R3 represents a straight or branched chain alkyl radical with 1-3 C atoms, an amino group r, and n has the values 3, 4 or 5. 2. Derivative according to claim 1, characterized in that in formula 1 R a straight or branched alkyl radical with 2-12 carbon atoms, a straight or branched alkyl radical with 2-4 carbon atoms, which is substituted by a phenyl or phenoxy nucleus, which may be substituted by one or two straight or branched chain alkyl radicals with 1-4 C atoms, by one or two straight or branched chain alkoxy radicals with 1-4 C atoms and / or by one or two halogen atoms such as fluorine, chlorine -40 or bromine atoms, 83 0 2 9 1 6) a straight or branched-chain acyl radical with 2-6 C atoms, which is substituted by a phenyl nucleus, which is optionally substituted by one or two straight or branched chain alkyl radicals with 1- 4 C atoms, by one or two straight or branched alkoxy radicals with 1-4 C atoms and / or 5 by one or two halogen atoms such as fluorine, chlorine or bromine atoms, represents δ, χ a hydrogen atom, a straight or branched acyl radical with 2-11 C atoms, a straight or branched acyl radical with 2-6 C atoms, substituted by or a phenyl core, which is optionally substituted by one or two straight or branched alkyl radicals with 1-4 C atoms, by one or two straight or branched alkoxy radicals with 1-4 C atoms and / or by one or two halogen atoms, such as fluorine -, chlorine or bromine atoms, R-2 represents a hydroxyl group, an alkoxy group R30-, wherein R3 represents a straight or branched chain alkyl radical with 1-3 C atoms, represents an amino group, n has the values 3, 4 or 5; When R represents a dodecyl radical and R 1 represents a hydrogen atom, R 2 does not represent a hydroxyl group, when n has the value 4, and when R 2 represents a hydroxyl group and R 1 represents a hydrogen atom, R represents no n-butyl or n-octyl radical When n has the value 4 and when R2 represents an ethoxy group and R1 represents a hydrogen atom, R represents no ethyl or n-butyl radical, when R represents an n-butyl radical, Rj. a hydrogen atom and R 2 represent a methoxy or hydroxyl group, n does not have the value 3, 30 when R represents an isopropyl radical, R] represents a hydrogen atom and R 2 represents a hydroxyl radical, n does not have the value 5 · Derivative according to claim 1 or 2, characterized in that in formula 1 R represents an alkyl radical with 2-10 carbon atoms. 4. Derivative according to claim 1 or 2, characterized in that in the formula 1 R represents an alkyl radical with 2-5 C atoms- Derivative according to claim 1 or 2, characterized in that in formula 1 R represents an alkyl radical with 6-12 carbon atoms. Derivative according to claim 1 or 2, characterized in that in the formula 1 R represents a residue with 5-7 C atoms. Derivative according to claim 1 or 2, characterized in that in the λ - r r 'A? Ö - ΐ: - 2 '«formula 1 R an alkyl radical with 2-4 C atoms, which is substituted by a phenyl or phenoxy nucleus, which may themselves be substituted by a methyl, methoxy, chlorine and / or or bromine atom. 8. Derivative according to claim 1 or 2, characterized in that in formula 1 R represents an acyl radical with 2-4 C atoms, which is substituted by a phenyl radical, which itself is substituted by one or two methyl and / or or methoxy residues and / or by one or two chlorine and / or bromine atoms. 9. Derivative according to claims 1-8, characterized in that in formula 1 R 1 represents an acyl radical with 2-5 C atoms. Derivative according to claims 1 to 8, characterized in that in formula 1 R 1 represents an acyl radical with 6-11 C atoms. 11. Derivative according to claims 1 to 8, characterized in that in the formula 1 R 1 an acyl radical with 2 to 4 C atoms is substituted by a phenyl radical which is itself substituted by one or two methyl and / or or represents methoxy radicals and / or by one or two chlorine and / or bromine atoms. 12. Derivative according to claims 1-8, characterized in that in formula 1 R 1 represents a hydrogen atom and R 2 represents an amino radical. Derivative according to claim 1, characterized in that it contains 4-n-pentylaminobutanamide 5-n-pentylaminopentanamide 6-n-pentylaminohexanamide 25 4-n-pentylaminobutanoic acid 5- (p-tolylacetylamino) pentanamide 6-n-decylaminohexanamide 6- [ (2-p-chlorophenoxyethyl) amino] hexanamide 4 - [(N-nrhexyl-N-4-chlorophenylacetyl) amino] butanamide 30. Amine derivative, in particular for the preparation of the derivatives according to claims 1-13, characterized in that it corresponds to the formula 2, wherein R, Ri and n have the meanings mentioned in claims 1-12 and Z has an amide function, a carboxylic acid function, a nitrile function, an ester function (COOR *, wherein R 'corresponds to the symbol R3 defined in claim 1 or 2 or represents an alkyl or phenyl residue, which is optionally substituted in such a way that the ester is , an attack of a nudeophile is activated), an amidine function (group of the formula 3), an acid halogen function (group of the formula 4, in which X is a halogen atom such as a ”OA · '-> v' Ui * i □ * * represents chlorine, bromine or iodine atom), an anhydride function, an imate function (group of formula 5) or the N-carbonylimidazolyl group, where Z may also represent a precursor group of a carboxylic acid, such as the trihalomethyl group ( -CX3, where X is a chlorine- , Bromine or iodine atom), an oxazoline group, a hydroxymethylene group (-CH2OH), a formyl group (-CHD) which may or may not be in protected form, such as a cyclic or di-thioacetal group, an α , β-dihydroxyalkyl group or alkenylene group (-CHOH-CHOH-R4 or -CB-CH-R4, where R4 represents a straight alkyl group with 10 1-20 C atoms), an acetyl group (-CO-CH3), a 1-hydroxy - ethyl group (-CHOH-CH3), an acetonyl group (-CH2-CO-CH3), a 2-hydroxypropyl-1 group (-CH2-CHOH-CH3) or a halogen atom, such as a chlorine, bromine or iodine atom or the group -CH2-Z, which represents the group of the formula 6, wherein Bi and B2 may be the same or different and a nitrile, carboxyl, carbamoyl or alkoxycarbonyl group (-COOR3, wherein R3 is as defined in claim 1 or 2 given meaning property). 15. Process for preparing derivatives according to claims 1 - 13, characterized in that a derivative of the formula 2 is converted into a compound of the formula 1, wherein R, Ri and n have the meanings mentioned in claims 1 - 12 Z represents a group which, by the action of a suitable reagent, can be converted into an amide, carboxyl or alkoxycarbonyl function (-COOR3), such as the amide function, the carboxylic acid function, the nitrile function, the ester function (-C00R *), in which R Corresponding to the symbol R3 defined in claim 1 or 2 or representing an alkyl or phenyl radical substituted in such a way that the ester is activated in respect of a nucleophile attack), the amidine function (group of the formula 3 ), the acid halide function (group of the formula IV, wherein X represents a halogen atom such as a chlorine, bromine or iodine atom), the anhydride function, the imidate function (group of the formula 5) or the N-carbonylimidazole- group, where e can also represent a precursor group of a carboxylic acid, such as the trihalomethyl group (-CX3, wherein X represents a chlorine, bromine or iodine atom), an oxazoline group, a hydroxymethyl-35-boron group (-CH2OH), a formyl group (-CH0) may not be in protected form, such as a cyclic dithioacetal or non-cyclic, an α, β-dihydroxyalkyl or alkenyl group (-CHOH-CHOH-R4 or CH = CH-R4, where R4 is a straight alkyl group with 1- 20 C atoms), an acetyl group (-CO-CH3), a 1-hydroxyethyl group 40 (-CHOH-CH3), an acetonyl group (-CH2-CO-CH3), a 2-hydroxyprop- / * pyl-1- group (-CH2-CHOH-CH3) or a halogen atom such as a chlorine, t 'bromine or iodine atom, or the group -CH2-Z, which represents the group of the formula 6, wherein Βχ and B2 may be the same or different and represent a nitrile, carboxyl, carbamoyl or alkoxycarbonyl function (-COOR3,5 wherein R3 has the meaning defined in claim 1 or 2). 16. Process according to claim 15, characterized in that an amine of the formula 7 or 8 is subjected to a condensation reaction with an alkylation or acylation reagent such as RW, RiW, the compound of the formula 9, RgCOOH, the compound with the formula 15 or an amine of the formula 11 with a compound of the formula 12 or 0HC- (CH 2) n 2, followed if necessary by a reduction of the intermediate amide, imine or iminium function; wherein in these formulas R, R3. and n have the meanings given in claims 1-12, wherein the groups of the formulas 10, 27, Bg-CO, Rg-CH 2 or the group of the formula 17 are obtained after condensation, followed if necessary by a reduction, represent the group R or Ri, where W represents a chlorine, bromine or iodine atom, a 0-tosyl, 0-mesyl, sulfate, acyl or hydroxyl group and Z represents the meaning of the group with the has formula 26, wherein R 2 has the meaning defined in claim 1 or 2. 17. Process for the preparation of derivatives according to claims 1 to 13, characterized in that a lactam of the formula 25, in which R and n have the meanings indicated in claim 1 or 2, under the action of an inorganic acid or under the action of ammonia, - converts an amide, an alcoholate or a hydroxide of an alkali metal into a derivative of the formula 1. Pharmaceutical composition, characterized in that it contains at least one of the derivatives of the formula 1 according to claims 1 to 13 or one of their salts in combination with one or more pharmaceutically suitable diluents or optionally one or more other therapeutic agents. Preparation according to claim 18, characterized in that it is in the form of dragees, pills, encapsulated forms, tablets, granules, capsules, solutions, syrups, emulsions, suspensions or gels, which are additives customary in Galenus pharmaceutical manufacture. diluents. 20. A composition according to claim 18, characterized in that it comprises at least one derivative of the formula 1 in a solution, such as in sterile water or in an oil such as peanut oil or ethyl oleate. o τ; n r · n »1 & © y & i v ·, -c 21. Method for the use of the derivatives of the formula ♦> Ij, characterized in that these are administered orally in doses of 50-4000 mg and parenterally in doses of 5-400 mg. 22. A method for the use of the derivatives of the formula 1 5 in the treatment of the various forms of epilepsy, in the treatment of muscle spasms of a nervous nature, in the treatment of movement disorders such as Parkinson's disease, in the treatment of mental disorders, such as depression, sleep disorders and memory disorders, in the treatment of certain cardiovascular disorders, such as hypertension and hypotension, as well as analgesic and anthelmintic agents. ******** Λ \ 8 * λ λ a ·? 3 \ f v L y «