CA1256899A - Derivatives of w-amino acids, the preparation and utilisation thereof; and the compositions containing these derivatives - Google Patents

Abstract

ABSTRACT

Derivatives of .omega.-amino acids of general formula :

I

also racemic or non-racemic mixtures thereof, optically pure isomers thereof and salts of these compounds formed with pharmaceutically utilisable acids, bases and metals, wherein R represents a linear or branched alkyl radical C2-C12, a linear or branched alkyl radical C2-C4 substituted by a phenyl or phenoxy nucleus which may be itself substituted, a linear or branched acyl radical C2-C6 substituted by a phenyl nucleus which may be itself substituted; R1 represents hydrogen, a linear or branched acyl radical C2-C11, a linear or branched acyl radical C2-C6 substituted by a phenyl nucleus which may be itself substituted; R2 is an amino group, and n is equal to 3, 4 or 5. Such derivatives can be used in the treatment of neurological, psychic or cardiovascular problems, and as anthelminthic and analgesic agents.

Description

~L~S~899 The present invention relates to derivatives of ~-amino acids, the salts of these dreivatives, the processes for their preparation and pharmaceutical compositions containing at least one of these derivatives, and the method of their ultilisation.
The present invention includes the derivatives of (~-amino acids which response to the general formula I

~N (CH2)~~ ~
R 1 \R2 and the salts of these compounds formed with pharmaceutically utilisable metals, acids or bases.
In the general formula I :-R represents :-a linear or branched alkyl radical C2, C3, C4, C5, C6,C7, C8, Cg, C10~ C11~ C12;
a linear or branched alkyl radical C2, C3, C4 substituted by a phenyl or phenoxy nucleus which may be substituted by one or two linear or branched alkyl radical C1, C2, C3, C4, by one or two linear or branched alkoxy radicals C1, C2, C3, C4, or by one or two atoms of halogen such as fluorine, chlorine or bromine;
a linear or branched acyl radical C2, C3, C4, C5, C6 substituted by a phenyl nucleus which may be substituted by one or two linear or branched alkyl radicals C1, C2, C3, C4, by one or two linear or bl~anched alkoxy radicals C1, C2, C3, C4 or by one or two atoms of halogen such a~ fluorine, chlorine or bromine;

~/

~,.

~L~5~8~
R1 represents:-hydrogen;
a linear or branched acyl radical C2, C3, C4, C5, C~, C7, C8, Cg, C10, C11;
a linear or branched acyl radical C2, C3, C4, C5, C6 substituted by a phenyl nucleus which may be substituted by one or two linear or branchea alkyl radicals C1, C2, C3, C4, by one or two linear or branched alkoxy radicals C1, C2, C3, C4 or by one or two atoms of halogen such as fluorine, chlorine or bromine;
R2 represents:-a hydroxyl group;
an alkoxy group R30-, in which R3 is a linear or branched alkyl radical C1, C2 or C3;
an amino group (-NH2);
n pos~esses the values 3, 4 or 5;
According to a preferred form of the invention the latter has for object compounds of formula I in which :-R represents :-a linear or branched alkyl radical C2, C3, C4, C5, C6, C7, C8, Cg, C10, C11~ C12i a linear or branched alkyl radical C2, C3, C4 substituted by a phenyl or phenoxy nucleus which may be substituted by one or two linear or branched alkyl radicals C1, C2, C3, C4, by one or two linear or branched alkoxy radicals C1, C2, C3, C4, or by one or two atoms of halogen such as fluorine, chlorine or bromine;

.~
J~-j8~9 a linear or branched acyl radical C2, C3, C4, C5 C

substituted by a phenyl nucleus which may be substituted by one or two linear or branched alkoxy radicals C1, C2, C3, C4, or by one or two linear or branched alkoxy radicals C1, C2, C3, C4, or by one or two atoms of halogen such as fluorine, chlorine or ~romine;
R1 represents:-hydrogen;
a linear or branched acyl radical C2, C3, C4, C5, C6, C7, C8, Cg, C10, C11;
a linear or branched acyl radical C2, C3, C4, C5, C6 substituted by a phenyl nucleus which imay be substituted by one or two linear or branched alkyl radicals C1, C2, C3, C4, by one or two linear or branched alkoxy radiaals C1, C2, C3, C4 or by one or two atoms of halogen such as ~luorine, ahlorine or bromine;
R2 represents :-a hydroxy group;
an alkoxy group R30-, in which R3 is a linear or branched alkyl radical C1, C2 or C3;
an amino group (-NH2);
n possesses the value 3, 4 or S;
when R represents a dodecyl radical and R1 hydrogen, R2 does not represent a hydroxyl radical, when n has the value 4 and when R2 represents a hydroxyl group and R1 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 R1 hydrogen, R does not represent an ethyl or n-butyl radical, When R represents an n-butyl radical, R1 hydrogen and R2 a methoxy or hydroxyl radical, n does not possess the value 3, when R represents an i-propyl radical, R1 hydrogen and R2 a hydroxyl radical, n does not possess the value 5.
According to another preferred form o~ the invention the latter has for object compounds of formula I in which :-R represents :
a linear or branched alkyl radical C2-C10;
a linear or branched alkyl radical C2-C4 substituted by a phenyl. or phenoxy nucleus possibly substituted by a methyl or methoxy radical or by an atom of chlorine;
R1 represents :-hydrogen a linear or branched acyl radical C2-C11;
a linear or branched acyl radical C2-C6 substituted by a phenyl nucleu6 which may be substituted by a methyl or methoxy radical or by an atom of chlorine;
R2 represents :-a hydroxyl group;
an alkoxy group R30 in whiah R3 is a linear or branched alkyl radical C1-C3;
an amino group;
n possesses the values 3, 4 and 5 --~L~5~
when n has the value 4 and when R2 represents a hydroxyl group and R1 hydrogen, R does nsot r~pxesent an n-butyl or n-octyl radical;
when n has the value 4 and R2 represents an ethoxy group and R1 hydrogen, R does not represent an ethyl or n-butyl radical;
when R repr~sent~ an n-butyl radical, R1 hydrogen and R2 a methoxy or hydroxyl radical, n does not possess the value 3;
when R represents an i-propyl radical, R1 hydrogen and R2 a hydroxyl radical, n does not possess the value 5.
According to another preferred form of the invention the latter has for object derivatives of formula I in which :-R represents :-a linear or branched acyl radical C2-C6 substituted by a phenyl nucleus whlch may be substituted by a methyl or methoxy radical or an atom of chlorine;
R1 represents hydrogen;
R2 represents :-a hydroxyl group;
an alkoxy group R30 in which R3 is a linear or branchedalkyl radical C1-C3;
an amino group;
n possesses the values 3, 4 and 5.
A preferred class of products of formula I is that in which :
R represents a linear or branched alkyl group C2-C10;
R1 represents hydrogen;

~L256~9~3 R2 represents:-a hydroxyl group;
an alkoxy group R30 in which R3 is a linear or branched alkyl radical C1-C3;
an amine group;
n possesses the values 3, 4 and 5;
when n has the value 4 and when R2 represents a hydroxyl group and R1 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 R1 hydrogen, R does not represent an ethyl or n-butyl radical;
when R represents an n-butyl radical, R1 hydrogen and R2 a hydroxyl radical, n does not possess the value 3;
when R represents an i-propyl radical, R1 hydrogen and R2 a methoxy or hydroxyl radical, n does not possess the value 5.
Another preferred class of products of formula I is that in which:-R represents :-a linear or branched alkyl group C2-C10;
a linear or branched acyl group C2-C6 substituted by a phenyl nucleus;
R1 represents hydrogen;
R2 represents :-a hydroxyl group;
an alkoxy group R30 in which R3 is a linear or branched alkyl radical C1-C3;
n possesses the value 3;

~L~5~8~
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 :-R represents :-a linear or branched alkyl radical C2-C10;
a linear or branched acyl radical C2-C6 substituted by a phenyl nucleus;
R1 represents hydrogen;
R2 represents an amino group (-NH2);
and n has the value 3.
~ xamples of compounds according to the invention are:-4-n-pentylamino butanamide.
5-n-pentylami no pentanamide, 6-n-pentylamino hexanamide, 4-n-pentylamino butanoic acid, 5-(p-tolylacetylamino) pentanamide, 6-n-decylamino hexanamide, 6-[(2-p-chlorophenoxy ethyl)amino] hexanamide, 4-[(N-n-hexyl-N-9-chlorophenylacetyl)amino] butanamide.
If the derivatives of formula I are presented in the form of salts of addition with acids, it is possible to transform them, according to usual processes, into free bases or into salts of addition with other acids.
The salts most currently used are salts of addition of non-toxic, pharmaceutically usable acids, formed with appropriate inorganic acids, for example hydrochloric acid, sulphuric acid or phosphoric acid or with appropriate organic acids such as aliphatic, cycloaliphatic, aromatic, araliphatic ~i~5~89~

or heterocyclic carboxylic or sulphonic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, hydrobenzoic, salicyclic, phenylacetic, rnandelic, embonic, methane-sulphonic, ethane-sulphonic, pantothonic, toluene sulphonic, sulphanilic, cyclohexylaminosulphonic, stearic, alginic, B-hydroxy butyric, oxalic, malonic, galactaric, galacturonic aclds.
In the case where R2 represents a hydroxyl group, the derivative according to the invention can exist in the form either of æwitterion, or of non-toxic and pharmaceutically usable salts or metals or salt6 of addition with bases.
If the derivatives according to the invention in which R2 represents a hydroxyl group are obtained in the form of salt, they can be transformed into acid or into other salts according to conventional processes.
These salts can be derived from metals cuch for example as sodium, potassium, lithium, calcium, magnesium, aluminium, iron, or can be salt8 of addition with bases such for example as ammonia, or amines such as ethylamine, isopropyl amine, ethanolamine, diethylamine, diethanolamine, triethylamine, or basic amino acids, natural or not, such as lysine, arginine, ornithine.
The compounds of formula I can possess one or more asymmetric carbon atoms and thus are capable of existing in the form of optical or racemic isomer6 or diastereoisomers; all these forms are part of the present invention.

~;6~
Thus the derivatives according to the invention can be utilised either in the form of mixtures containing several diastereoisomers, whatever are the relative proportions thereof, or in the form of pairs of enantiomers in equal proportions ~racemic mixture) or not, or again in the form of optically pure co~pounds.
The products according to the invention can be utilised in the treatment of neurological, psychic or cardio~ascular troub~es such for example as epilepsy, depression, dyskine6ias such as Parkinson's disease, muscular spasms of nervous origin, hypertension, hypotension, sleeping troubles, memory defects, and as anthelminthic and analgesic agents.
The present invention likewise covers pharmaceuticel compositions containing, as active ingredient, at least one compound of the general formula I or a salt, with an additive and/or excipient utilised in Galenical pharmacy.
These composi.tions are prepared in suoh manner that they can be administered orally, rectally or parenterally. They can be solids, liquids or gels and can be presented, according to the administration route, in the form of powders, tablets, lozenges, coated tablets, capsules, granules, syrups, suspensions, emulsions, solutions, suppositories or gels.
These compositions can likewise include another therapeutic agent having an activity similar to or different from the products of the invention.
The compounds according to the invention are prepared according to processes which form part of the present invention and are defined below. In the cases where the processes give rise to ~he production of new intermediate compounds, these new ,,~,l ,~ ~

~s~
compounds, likewise the processes serving for their preparation, also form part of the present invention.
PrQcess A.
According to this manner of procedure, the product II is converted into a derivative of formula I :
R R C
> ( 2)n ~ \ M~(CH2)n~C ~
Rl Rl R2 II I
R, R1, R2 and n are as defined above and Z represents a group which, by the action of an appropriate reagent, can be transformed into an amide function, carboxylic acid or ester.
Examples of these functions are, among others, the amide function, the carboxylic acid function, the nitrile function, the ester function (-COOR', in which R' represents either R3, specifled above, or an alkyl or phenyl radical substituted in such manner that it activates the ester in relation to the ttack of a nucleophile), the amidine function (-C~NH), the ~ NH~
acid halide function (-C~O, where X represents a halogen such as chlorine, bromine or iodine), the anhydride function, the imidate function (-C~ 3) or the N-carbonylimidazole group. Z
can likewise represent a carboxylic acid precursor group as for example the trihalometh~l grouping (-CX3, in which X represents an atom of chlorine, bromine or iodine), an oxazoline group, a hydroxymethylene group (-CH20H), a formyl group (-CHO) which may or may not be present in a protected form such for example as a dithioacetal, cyclic or not, an ~ , B-dihydroxyalkyl or alkenyl group (-CHOH-CHOH-R4 or -CH=CH-R4 in which R4 .

1~5~39~

represents a linear alkyl radical Cl-C20), an acetyl group (-CO-CH3), a 1-hydroxyethyl group (-CHQ~-CH3), a 2-hydroxypropyl-1 group (-CH2-CHOH-CH3) or an atom of halogen such as chlorine, bromine or iodine.
The group -CH2-Z can equally represen~ the group -CH__B
in which B1 and B2 can he e~ualt or different and represent a function selected from the following series :- nitrile, carboxylic, carbamoyl or alcoxycarbonyl (-COOR3, R3 ha~ing the values given previously).
The passage from the product II to the product I, that is to say the conversion from the group Z or -CH2-Z into a group ~-COR2), can be realised by conventional reactions very well documented in chemistry, as for example:-a) a conversion of a carboxylic acid into amide.
Several processes permit of effecting this chemicaltransformation.
For example carboxylic acid can be placed in the presence of ammonia, the pyrolysis of the salt thus formed leads to the amide, likewise the action of a dehydration agent such as P205.
Another manner of proceeding consists in transforming the carboxylic acid into acid halide then amide by the action of ammonia.
Yet another manner of proceeding consists in placing a carboxylic acid and ammonia into reaction in the presence of a coupling reagent such as is utilised in synthesis of peptides, as for example dicyclohexyl carbodiimide, N-ethyl-N'-3-dimethyl amino propyl carbodiimide, phosphines, phosphites, silicon or titanium tetrachloride.

~ X~6~9t~3 b) Conversion of a nitrile into amide or acid.
The nitriles can be hydrolysed into amide or acid, either in acid medium or in basic medium. If the hydroly6is is carried out in acid condtions, it is possible to use concentrated sulphuric acid, concentrated a~ueous hydrochloric acid, aqueous hydrobromic acid, nitric acid, formic acid in the absence of solvent, acetic acid in the presence of boron trifluoride.
Another manner of converting a nitrile into amide, in acid medium, consi6ts in treating the said nitrile with hydrochloric acid in an alcohol such as ethanol. Thus an intermediate iminoether i 6 formed which is transformed thermally into amide.
If the hydrolysis is effecte under basic conditions, one will use for example potassium hydroxide in t-butanol or an aqueous solution of an alkali or earth-alkali metal hydroxide.
The presence of oxygenated water facilitates the hydrolysis.
The nature of the group formed, an amide or a carboxylic group, depends essentially upon the utilised reaction conditions.
c) Transformation of a nitrile into ester.
This conversion i8 effected by opposing the nitrile to an alcohol in acid medium. Alcohol or any other inert solvent can be utilised as solvent. Thus an intermediate iminoether is formed which is converted into ester by hydrolysis.
d) Conversion of an ester into amide.
The aminolysis of an ester is carried out conventionally by opposing ammonia to the este:r, either in water or in an inert organic solvent.
e) Conversion of an amidine into amide.

't.

6~

This reaction i6 carried out principally by acid hydrolysis in aqueous or alcoholic medium. The acid can be inorganic like hydrochloric or sulphuric acid, or organic such as acetic acid.
f) Conversion of an acid halide, an anhydride or an H-carbonimidazolyl group into a carboxylic acid or alkoxy carbonyl group (-COOR3).
This transformation proceeds easily by opposition of product II to water to form the carboxylic group (hydrolysis reaction) or to an alc~hol R30H, R3 being a linear or branched alkyl radical C1-C3, to form the alkoxycarbonyl groups -C00~3 (alcoholysis reaction).
These reactions take place in the presence o~ an excess of water or alcohol or with a stoichiometric quantity of these 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 base.
g) When the group Z in formula II represents a carboxylic acid precursor such as a trihalomethyl grouping or an oxazoline, the transformation into carboxylic acid is conducted either in water, or in an inert organic solvent in the presence of acid. As acid generally there is used a mineral acid such as the halogenated hydracids, concentrated or dilute sulphuric acid, concentrated or dilute nitric acid, phosphoric acid or an organic acid such as acetic acid.
h) The conversion of the group -CH2-Z, representing the group -CH~" 1 in which Bl and B~ possess the values given above, into a carboxymethyl group is effected by hydrolysis in basic or acid medium under conditions identical with those ~56~9 described above for the hydroly~is of a nitrile, followed by a period of heating in acid medium in order to decarboxylate the intermediate ~-di-acid obtained.
i) The conversion of other precursor groups of the carboxylic acid group into a carboxylic group by oxidation.
This conversion concerns especially the intermediates II
in which Z represents a group such as -CH20H; -CHO; -CHOH-CH3;
-CO-CH3; -CH2-CHOH-CH3; -CH2-CO-CH3, -CH=CH-~4 and -CHOH-CHOH-R4 in which R4 possesses the values defined above It is carried out conventionally by the expedient of a large number of oxidation agents and in accordance with a great diversity of well known processes.
The oxidation proceeds by way of several intermediate products which can be isolated in certain cases and according to the nature of the oxidation agent it is carried out in water or in an organic inert solvent.
Of course the selection of the oxidation agent and of the reaction conditions will take place as a function of the nature of the group Z and in such manner as to maintain intact the other groups present in the molecule II.
j) ~he transformation of an acid into ester and vice versa~
~he esterification of an acid is a very general reaction which can be produced in many ways. Classically, acid and alcohol are placed in reaction in the presence of an acid catalyst.
This reaction is advantageously carried out under anhydrous conditions and one of the reactants is used in great excess.
The solvent can be either one of the reactants or an inert organic solvent.
Another manner of proceeding consists in distilling the 1~

~25~399 water as soon as it is formed, utilising an appropriate apparatus. The reaction conditions are identical with those described, with the exception of the fact that one of the reactants must not be engaged in great excess.
The hydrolysi6 of the ester takes place in conditions of acid or basic catalysis but in this case one of the reactants, in the present case the water, i8 usea in vexy great excess.
k) The conversion of the group Z representing an alkoxycarbonyl group (-COOR'), a carboxylic ~roup, its salt or its anion into an alkoxycarbonyl group (-COOR3).
According to the nature of 2 this conversion can be effected by esterification, as described in the previous paragraph, by transesterification, by heating the derivative II
containing the group -COOR' in the presence of an excess o~
alcohol R30H and an acid or basic catalyst, advantageously continuously eliminating the formed alcohol R'OH by distillation, or by alkylation by means of the reactant WR3, where W represents an easily substitutable group like a halogen such as chlorine, bromine or iodine, an O-mesyl or O-tosyl group, a sulpha~e group (-O-S02-OR3) an acyl oxy group (R5-CO-O) or a hydroxyl group. R3 represents a linear or branched alkyl group C1-C3 and R5 represents a group R3 or phenyl. The alkylation of the carboxylic group, its salt or its anion takes place normally in an inert organic solvent in the presence of a weak inorganic base or preferably of an organic base such as pyridi~e or triethylamine.
1) The conversion of Z, representing an atom of halogen, into a carboxylic acid group.

~1 ~5i6~399 This conversion is carried out classically by transforming the halogenated product into an organometallic derivative, the carbon dioxide treatmçnt of which, followed by hydrolysis of the intermediate form, supplies the carboxylic group. The metal utilised can be lithium, magnesium, zinc or manganese.
In order to avoid secondary reactions in this conversion, the functional group RR1N- present in the molecule II will be adequate protected.
For better understanding of the process the principle ways of access to the derivative II will be described below:-he derivative II can be obtained at the expense of theproducts III or IV by alkylation or acylation according to the following outlines.
RlW R
R~NH~(C~2)n~Z - - ~ / N (CH2)n /~
RW
R1-NH-(CH2)n wherein R, R1, Z, W and n possess the values as defi~ed above, but in the reactant R1W the group R1 does not represent hydrogen. RW and R1W can likewise represent6 a cetene of formula R6~ C=C=0, so that the group 6 ~ CH-C0, obtained after the acylation of the derivatives III or IV, corresponds according to the case to a group R or R1. This alkylation or acylation reaction can be effected in an inert organic solvent such as a chlorinated hydrocarbon, an alcohol or an aliphatic or aromatic hydrocarbide, selected as a function of the nature of the reactant.

~'~56~

The reaction proceeds at a temperature between O C. and the reflux temperature of the ~olvent. The reaction can advantageously be carried out in the presence of organic base such as trimethyl amine, pyridine or N-dimethylaniline or of mineral base such as the hydroxides, the carbonates and the bicarbonates of alkaline or sarth-alkaline metals or finely pulverised lime.
A variant of this process is illustrated below :
R R
\ NH + W-~CH2)n - Z ~ / N-(CH2)n - Z
Rl Rl V VI II
R, R1, W, Z and n posses6 the values defined previously.
The above reaction is similar to the alkylation reaction of the derivatives III or IV described above, and of course the operating conditions for these threa reactions are entirely comparable.
According to another variant of the process, the derivative II can be synthesised by acylation from a primary amine by a carboxyl.ic acid making use of phosgene as coupling agent. The phosgene can be introduced in a solution of the amine and carboxylic acid or it can be opposed to one of the two reactants and the intermediate thus formed is then opposed to the second reactant.
This variation in which the phosgene is set into reaction with the amine IV, followed by the transformation of the intermediate isocyanate, is illustrated by the following diagram:

t 89~3 R1NH-(CH2)n O=C=N-(CH2)n ~Z
IV

g~C~j-(cH2)n Rl wherein R11 represents hydrogen, Z and n possess the values specified previously and the group R8-CO corresponds to the group R as defined previously.
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 derivative III or IV,. as described above, followed by a reduction of the amide obtained as intermediate. Numerous methods are described for effecting such a reduction, but it i6 apparent that the selection of the reaction conditions must include ensuring the preservation of the functionality of the group Z.

2. Another way of access to the derivative II is characterised by the formation of an intermediate iminium salt VIII at first from an amine and a carbonyl compound VII.
The reductions of the iminium salt leads to derivative II.

~L2~6~399 R O R ~ / H

/ NH + H-c-(cH2)n-lz / N=~
Rl R'l (CH2)n-1 VII VII:[

~ reduction \

The condensation between the amine and the carbonyl derivative VII takes place conventionally in an inert organic solvent, preferably not miscible with water. The reaction is advantageously catalysed by a mineral or organic acid.
The reducti.on takes place in an appropriate solvent in conventional manner by means o hydrogen in the presence of a hydrogenation catalyst, by means of an alkali metal hydride, by aluminium and lithium hydride or at least one other reducti on agent, but of course the method of reduction of the iminium salt will be selected so as to keep intact the functionality of the group Z. By selecting the reactants differently it is possible to realise a variant of this process which permits of arriving at the product II passing by way of intermediates carrying the same chemical functions as above .

o u~ ~ o ~ o ~ O o o o S

' ~ P~ O ,~
_ _ c C~l . . . ... . ..... _ . , _ . ..
O ~
_ X I I :r: o o o ~_ I
~) C~: T I I 0=~
I ~ ~ ~ _ ' Z~

:
C~:
. 0~~ ~ 0 ~ C~
I X I I ~: r-l ~: ~1 I
~)~

- - - - -O ~ ~ ~ 'U~ ~D 1~ ~
~ u~> ~ ~n Ln In Ln ~_ Q~
V
cl p~ -- -- - -3L~5~i~39!~3 9~ C=O + R1NH~(CH2)n Rg C= f -(CH2)n~Z

Rl/ Rlo G
IX IV
reduction ~ CH
-(CB2)n-Z

R1, Z and n posse 6S the meanings given previously while the groups Rg and R1o possess values such that the group 9~ CH is equivalent to R.
The condensation of the carbonyle derivative with the amine IV and the reduction of the iminium salt X take place under the conditions described above.
It should be remarked that when R1 represents hydrogen, the above-described condesations lead to an imine of formula :
H Rg R-N=C or C=H-(CH2)n~Z
(CH2)n-1 Rlo XI XII
wherein R, Rg, R1o, Z and n have the values defined above.
The conditions of synthesis and reduction of the imines XI and XII are completely comparable with those of the synthesis and reduction of the iminium salts VIII and X.

, ~ ~

5~89~3

3. Another way of access to the derivatives of formula II
consists in the transformation of a product of formula XIII by the expedient of reactant XIV, according to the following diagram :
R R

Rl N (CH2)n R~ N-(CH2)n-Z
XIII XIV II
R, R1, W and n have the meanings given above, M represents hydrogen or a metal such as lithium, sodium potassium or magnesium and Z has the value~ given above compatible with the reaction envisaged above, such that :
a nitrile group, a trihalomethyl group or a oyclia or non-cyclic dithioacetal group.
The transformation of the product XIII can be realised in accordance with different conventional methods selected as a function of the nature of W and Z. Certain o~ these methods are summarised here by way of example :-a) when Z represents a nitrile or trihalomethyl group, the reaction can be carried out in different solvents such for example as water, a lower alcohol, dimethyl formamide 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.
b) when Z represents a cyclic or non-cyclic dithioacetal group, the reaction occurs under anhydrous, low-temperature conditions, in an inert solvent such as diethyl ether or , ., . ~ , ~56~3~9 tetrahydrofuran. Then the product II is obtained by deprotection of the formyl group by well-known methods such as hydrolysis in acid medium or by the action of mercury salts.

4. Another way of access to derivatives of formula II in hich -CH Z repr~sents the group -CH' consists in the alkylation of a derivative XV by means of the reactant XVI
according to the following diagram :

N-(CH ) -W ~ M-CH -~ N-(CH2~n-l-cH

Rl B2 Rl B2 XV XVI
R, R1, B1, B2, W and n have the values given previously, with the exception of W which, in this case, does not represent a hydroxyl group.
M represents an alkaline metal such as sodium, potassium or lithium.
This conventional reaction generally occurs under inert atmosphere and anhydrous conditions, utilising a solvent such as an alcohol or an aliphatic or aromatic hydrocarbon.
Process B
This process consists in the opening of a lactam XVIII, under the action of a base or an acid. The said lactam XVIII
is conventionally obtained from the lactone XVII according to the diagram :-~'~S6~C39 o o (CH~)n ~ RNH~ (CH2) XVII R
XV:[II

R ~ ~ O
N-(cH2)n-c Rl R2 I(R1 = ~) R, R2, M and n have the value6 defined above. The conversion of the lactone into lactam takes place in an inert oryanic solvent, advantageously at the reflux temperature of the reaction medium. The opening of the lactam can take place under the action of ammonia, an amide, an alcoholote or a hydroxide of an alkali metal, or under the action of a mineral acld such as hydrochloric acid or sulphuric acid. It proceeds in water or in an inert organic solvent such as an ether, an alcohol, an aliphatic hydrocarbon or anomatic hydrocarbon or a chlorinated hydrocarbon.
It is apparent that the methods described for the synthesis of the compound II can apply equally to products in which the group Z already possesses the value of the group C~O
as specified pxeviously and thus can lead directly the products of the invention corresponding to the general formula I.

~5~

Of course for all the processes of synthesis of the compounds of formulas I and II, and for those cited for the transformation of group ~ and CH2-Z into a group -C~ R the reactants and the reaction conditions are selected 80 as to keep intact the functional groups already present in the molecule and not involved in the envisaged reaction.
Thus in order to be able to carry out the synthesis of the compounds I and II it is sometime6 necessary to utilise protective groups in order to preserve the functionality of the groups present in the intitial molecule. The selection of the experimental conditions will condition the selection of the protective groups which, like the processes for their introduction and the methods of deprotection, are clearly de~cribed in literature.
Some detailed examples of preparation of several derivative according to the invention are given below.
These examples are primarily for the purpose of further illustrating the particular characteristics of the processes according to the invention.
Exam~le 1.
Svthesis of 4-n-pentylamino butanamide.
5g. (0.041m.) of 4-chlorobutanamide are dissolved in 19 ml. (0.165m.) of pentanamine and agitated for 48 hours at ambient temperature. By addition of ether (400 ml.) a precipltate forms which is filtered and recrystallised twice in isopropanol.

~5~39~
M (C) : 187 Elementary analysis : C H N
% calculated 51.7 10.1 13.4 % found 52.0 10.2 13.4 Example 2.
~.
a) A mixture of 4.5 g. of 5-chloropentane nitrile (0.040m.), 3.8 g. (0.044 m.) of pentanamine, 3.7 g. of sodium bicarbonate in 60 ml. of absolute ethanol is brought to reflux for 48 hours. The formed sodium chloride is filtered and the filtrate is evaporated to dryness in vacuo to eliminate the excess pentanamine. The residual oil is dissolved in ether and ether/HC1 is added. A white precipitate forms which i6 filtered (5-n-pentylamino-pentanenitrile hydrochloride).
M (C) : 207-209.
b) 2.78 g. (0.013 m.) of 5-n-pentylamino pentanenitrile hydrochloride are suspended in 3.4 ml. of concentrated HC1 and agitated at 5 C. for 6 days. The limpid solsution obtained is poured over 20 ml. of isopropanol, the solid which crystallises is filtered and washed with isopropanol.
M. ~ C) : 216-217.
Elementary analysis : C H N
% calculated 53.9 10.4 12.5 % found 54.2 10.5 12.6 Exam~le 3.
SYnthesis of 6-decylaminohexanamide.
4.5g. of 6-chlorohexanamide (0.030 m.) are heated under reflux in 100 ml. of ethanol containing 5.2 g. of decanamine (0.033 m.) and 2.52 g of NaHC03 (0.033 m.). After 2 days and `~, ~5~899 2 nights the solution is cooled, filtered and evaporated; the solid i6 recrystallised twice in sthyl acetate. The solid obtained is dissolved in ethanol and ether/HC1 is added: the new solid obtained is recrystallised twice in isopropanol.
M. (C.) : 206.
Elementary analysis : C H N
% calculated 62.6 11.5 9.1 % found 63.0 11.7 9.3 Exam~le 4.
Svnthesis of 5-(p ~olyl acetYlaminoL_p~ntanamlde, 2.9 g ~0.017 m.) of p-tolylacetyl chloride and a 601ution of 0.7 g. of NaOH in 4 ml. of water are added drop by drop simultaneously to a solution of 0.7 g. (0.017 m.) of NaOH and 2 g. of 5-aminopantanamide (0.017 m.) in 10 ml. of water cooled to 0C. The Buspension which has formed is agitated for one hour at room temperature. The solid is filtered and recrystallised twice in isopropanol.
M. (C.) : 206 Elementary analysis : C H N
% calculated 67.7 8.1 11.3 % found 67.8 8.1 11.3 ExamPle S.
Svnthesis of 4-Pentylamino butanoic acid 7.75 g. of pentanal (0.090 m.), 7.73 g. of gamma aminobutanoic acid (0.075 m.), 800 mg. of palladium at 10% over carbon, 5 g.
of 3 A molecular seeve~ and 200 ml. of absolute ethanol are introduced into a Parr bottle. The bottle is agitated under an atmosphere of hydrogen for 18 hour~. The su6pension is filtered and the filtrate evaporated to dryness at 20 C. under ~ 1 ,, ~5Ç~399 reduced pxessure. The solid i6 washed with ether, dissolved in the minimum of ethanol and ether i6 added. The crystals obtained are recrystallised once again in the same manner.
M (C.) : 161-lS2 Elementary analysis : C H N
% calculated 62.4 11.1 8.1 % founa 62.1 11.1 8.0 Example 6.
Svnthesi~ of _~(3-~3,4-~lmethoxvnhenyl~ropanoyl laminoL-hexanamide 4.6 g (0.02 M) of 3-~3,4-dimethoxyphenyl)propanoyl chloride and 2.4 g. of NaOH in 20 ml of water are added simultaneously to a solution of 2.6 g. (0.020 M) of 6-aminohexanamide and 0.8 g. of NaOh in 15 ml of water, oooled to 0C. The suspension is agitated for two hours at room temperature. Then the solid is filtered and recrystallised in isopropanol.
M (C) : 137.
Elementary analysis : C H N
% calculated 63.3 8.1 8.7 % found 63.2 8.2 8.6 Example 7 SYnthçsis of 6-n-~entYlaminohexanam~Q
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 is heated under reflux for four days. Then after cooling of the solution the salts are iltered and the solvents are evaporated to dryness. The gL~56~399 solidifying product is crystallised twice in ethyl acetate, dissolved in a min.imum of methanol and ether/HC1 is adaed. The solid forming is filtered and dried.
M (C) : 190.5 Elementary analysis : C H N
% calulated 55.8 10.6 11.8 % found 55.8 10.6 11.8 ExamPle 8 Svnthesis of 4-n-hexylaminobutanamide~
a) A mixture of 18.5 ml of 4-chlorobutanenitrile (0.2m), 29.1 ml of hexanamine (0.22m) and 18.5 g. of sodium bicarbonate (0.22 M) in 500 ml of ethanol is heated under reflux for two days. Then the suspension is cooled, the salts are filtered and the filtrate is evaporated. The residue is shared between water and dichloromethane. The dichloromethane phase is washed with water, dried over K2CO3 and evaporated at room temperature. The excess of hexanamine is evaporated under high vacuum and the residual oil is dissolved in anhydrous ether and ether/HC1 is added. The solid appearing is filtered, dissolved in a minimum of methanol and anhydrous ether is added. The product thus obtained is engaged as such in the following stage.
b) 4.2 g. of 4-hexylaminobutanenitrile (0.02 m) are agitated for four days at 5C in 5 ml. of concentrated HC1.
Then this solution is poured into 50 ml. of chilled acetone.
The white solid which forms is recrystallised in isopropanol.

~S689~3 M (C) : 194 Elementary analysis : C H N
% calculated 53.9 10.4 12.6 % found 54.1 10.4 12.6 Example 9 SYnthesis of 4- _N-n-hexvl-N-4-chlQro~henvlacetYle)amino butanamide 650 mg. of 4-hexylaminobutanamide hydrochloride (0.003m) are dissolved in 9.4 ml. of KOH 1 N at 10 C. To this solution 0.65 ml. of 4-chlorophenyl acetic acid chloride are added drop by drop. An oil appears immediately and solidifie6. After two hours of reaction the oil is extracted with ether, the ethereal phass is washed with water and 1 N hydrochloric acid, it is dried over K2C03 and evaporated. The residual solid is recry6tallised in ethyl acetate.
M (C) : 105-106 Elementary analysis : C H N
% calculated 63.1 8.0 8.2 % found 63.0 7.9 8.1 * calculated for a content of 1.03% H20.
Example 10 Sxnthesis ~f 5 n-dodecvlaminQ~çntanamidç
a) 7~4 g of dodecanamine ~0.04m), 4.23 g. of 5-chloropentanenitrile (0.036 M) and 3.4 g. of sodium bicarbonate (0.04 m) in 100 ml. of ethanol are heated under reflux for two days. Then the cooled solution is filtered and the filtrate evaporated. The residual oil is distilled under 0.25 mm. of Hg. The fraction distilling at 170C. is collected. It is dissolved in ethanol and ether/HC1 is added. The solid 1~56~99 precipitating is filtered and used without supplementary purification in the following stage.
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 agitated at room temperature for two days. The acetic acid is then evaporatea, the solid taken up in ether is filtered and the solid recrystallised twice in isopropanol.
M (C) : 212 Elementary analysis : C H N
% calculated 63.6 11.6 8.7 % found 63.9 11.6 8.8 I
" ~;

~*" ! 3 lX56899 xample ll Synthesis of 4-n.pen-tylaminobutanamide a) A mix-ture of 18.5 ml of 4~chlorobutanenitrile (0~2 m), 1~.1 g of pentanamine (0.22 m) and 18.5 g of sodium bicarbonate (0.22 m) in 500 ml of ethanol is heated under reflux for 2 days.Then the suspension is cooled, the salts are filtered and the filtrate is evaporated. The residue is shared between water and dichloro-methane. The dichloromethane phase is washed with water, drled over K2C03 and evaporated at room temperature. The excess of pentanamine is evaporated under high vacuum and the residual oil is dissolved in anhydrous ether and ether/HCl is added. The solid appearing is filtered, dissolved in a minimum of methanol and anhydrous ether is added until an abundant precipitate is ob-bained which is filtered and engaged as such in the following stage.
b) 3.1 g of 4-pentylaminobutanenitrile (0.02 m) are dissolved in ~0 ml of glacial acetic acid and are saturated with HC1 at room temperature.
~fter agitation for 24 hours, the acetic acid is evaporated and the residual solid is recrystallised in isopropanol.
M(C) : 187.5 Elementary analysis : C X
calculated 51.7 lo.l 1~.4 found 51.8 10.2 1~.4 ~3 , _ 3~ 89~

Example 12 ~ynthesis of 4-n.pentylaminobutanamide.
2.76 g of ~-aminobutanamide hydrochloride (0.02 m), 1.9 g of pentanal (0.022 m), 100 mg of Pd/C at 10~/o and 50 ml of ethanol are introduced into a Pa~r*~ottle. The bottle is agitated for one night under an atmosphere of hydrogen at ambient temperature.
The catalyst is then filtered, the solvent evaporated and the residue solidified in e-ther. The solid obtained is recrystallised three times in isopropanol~.
M(C) : 186.5 ~lemen-tary analysis : C H 1~
V/0 calculated 51.7 10.1 13.4 fo~ld 52.0 10.3 13.5 ~xam~le 13 Synthesis of 4-n. pentylamino'butanamide.

-3.1 g of ~-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 hours, after which there are added 10 ml of E20 and sufficient HCl 1 N to render the solution acid (pH 2~. The aqueous phase is decanted and lyophilised. The residue is extracted with boiling isopxopanol, the solid which crystallises is filtered and recrystallised twice in isopropanol.
M(C) : 186 ~lementaxy analysis ~ C H 1~
~o calculated 51.7 10.1 13.4 % found 51.4 10.0 13.7 *Trade mark

5~ 39~

Example 14 Synthesls of 4-(2-phenylethylamino) butanoic acid.

a) 500 ml of toluene and 15.2 ml of pyrrolidone (0.2 m) are introduced under nltrogen into a 1 litre flask cooled in an ice bath. 9.6 g of sodium hydride (0.4 m) are added in three stages to this solution. After stirring for one hour at 0C, the suspension is allowed to return to room temperature. ~7.15 ml of 2-phenyl-1-bromoethane (0.27 m) are then added and the whole amount is brought to reflux for 12 hours. After adding 100 ml of water, the tolu~ne phase is decanted and washed three times wlth water, dried over K2C03 and evaporated; the residual oil is distilled under 10 mmHg. The colou.rless liquid is collected which distills at 175C and which is identified as N-(2-phenyl-ethyl)pyrrolidone.
b) 17.9 g of N-(2 phenylethyl)pyrrolidone (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 solid residue is crystall ised in methylethyl ketone.
M(C) : 149-150.

~lementary analysis : C H N
~/o calculated 59.1 7.4 5.8 u/o found 59.2 7~5 5.7 Example 15 Synthesis of the ethyl ester of 4-(2-phenylethylamino) butanoic acid 1 g of the hydrochloride of 4-(2~phenylethylamino) butanoic acid (0.004 m) is b,rought to reflux for 1 hour in 10 ml of :

~ S~8~

ethanol/XCl 5N. The solution is then evaporated to dryness and the solid obtained is recrystallised in methylethyl ketone.
M(C) 206-207 Elementary analysis C X N
~/o calculated 61.9 8.2 5.1 ~/o found 61.9 8.2 5.2 Table~I given below a~ssembles the derivatives of the above examples and also other derivatives of the invention prepared in accordance with the above processes. All the compounds assembled in Table I give a correct C.X.N. elementary analysis.

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~2~689~

The products according to the invention were subjected to a series of pharmacological tests the methodology of which is described below.
The LD50s are calculated according to the method of Lichtfield and Wilcoxon (J. Pharmacol. E~p. Ther. 96, 99, 1949) and expressed in mg/kg. The products were administered orally to mice. In general the products of the invention revealed themselves of low toxicity. The effect upon the behaviour is studied utilising a method derived from that of S. Irwin (Gordon Res. Conf. on Me~icinal Chem., ~, 1959). The substances, suspended in a mucilage 1% of gum tragacanth, are administered orally by means of an intragastric probe to groups of five male mice fasting for eighteen hours. The doses tested as a function of the observed activity go from 3,000 to 3 mg/ky.
The behaviour is studied 2, 4, 6 and 24 hours after treatment. The observation is prolonged if symptoms persist at this time. The mortalities were registered in the course of 14 days following the treatment. None of the products tested has induced any abnormal behaviour in the mouse.
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 anti-convulsive activity. The anti-convulsive activity is examined in relation to tonic convulsions induced by bicuculline. The compounds according to the invention were administered orally at the dosage of 10 mg/kg. to 20 mice, three hours before the intravenous injection -of bicuculline, at the dose of 0.7 mg/kg. The number of mice protected again tonic convulsions and death is noted.

_ ~. _ ~5 Ei~

In this test products Nos. 1, S, 8, 10 and 13 were revealed to be particularly active and give a protection percentage equal to or greater than 55%.
CP 2081 (compound No. 1 in Table I) was the subject of a more profound evaluation. In the test of inhibition of convulsions induced by bicuculline, the ED50 is 3 mgtkg. At the dose of 300 mg/kg. the percentage of protection against convulsions induced by bicuculline is 75%.
CP 2081 likewise po6ses6es an effect opposing convulsions induced by leptazols and by electric shocks.
Biochemical tests have demonstrated that certain products of the invention possess a GABA-mimetio effect. This effect was examined in vitro utilising a method derived from that of C. Braestrup and M. Nielsen (Brain Research Bulletin, Vol. 5, suppl. 2, p. 681-684 (1980)).
A homogenate of rat brain (with cerebellum) washed in order to eliminate the GABA ( ~ -aminobuanoic acid) present, is utilised to measure the connection to the receiver (the "binding") by means of 3H-flunitrazepam in the presence of and absence of increasing concentrations of the products to be tested or of a reference product (in the present case GABA).
The non-specific "binding" is determined in the presence of Diazepam.
The incubation takes place for 60 minuts at 0C., on a homogenate diluted 200 times. After incubation the samples are filtered and washed over Whatman GF~ filters. After dessication of the filter at 60 for 20 minutes, the residual radioactivity is measured by means of a liquid scintillator in an appropriate medium.

_ 2~ --~1 ~ . .

~L2S6~9~

Under these circumstances the product CP2818 (compound No. 16 of Table I) behaves like a GABA-mimetic, characterised by an EC50 ("Enhancement concentration 50%) of 4.7-10 M compared with the EC50 of 8.2-10 7M of GABA and by an efficacity identical with that of GABA.
CP 2818 was likewise evaluated i~ Yi~ in the test of the connection of 3H-muscimol to the synaptic membranes of rat brains. This test is ~pecific to the GABA-ergic receivers and permits of showing an effect for or against the GABA receivers.
These are directly connected to the benzodiazepine recei~ers.
The preparation of the synaptic membranes and the test of connection of 3H-muscimol to the synaptic membranes are identical with those published by Enna, S.J. and Snyder S.H. in Brain Research 100, 81-97 (1978).
The value of the specific connection of the 3H-muscimol to the membranes is obtained by forming the difference between the connection of the 3H-muscimol alone and this connection in the presence of 10 ~M of GABA.
; Different concentrations of CP 2818 were utilised to determine the concentration of the product necessary to inhibit 50% of the connection of the 3H-muscimol to the membranes (IC50).
For CP 2818 and IC50 of 2.5 x 10 M was obtained. ~he IC50 f GABA in this system is 2 x 10 7M.
The effect opposing convulsions induced by bicuculline, leptazol and electric shock and the GABA-mimetic effect indicate that the compounds according to the invention possess pharmaceutical properties which render them specially indicated for the treatment of various of epilepsy and dyskinesias such as _ ~ _ ~, ~5~39~
Parklnsons Disease. Moreover the activity o~ the products at the level of the central nervous system renders these compounds potentially of interest for the treatment of certain cardiovascular troubles such as hypertension and hypotension, for the treatment of psychic troubles such as depression, troubles of the memory and troubles of the sleep, also as analgesic agents.
Certain products of-the invention likewise possess an anti-thelmintic activity. This activity is measured in the rat, infested with nippostrongylus brasiliensis (stage L3). The product to be tested is administered by oesophagus probe in the form of mucilage, eight days after infestation. The rats are slaughtered on the twelfth day and the enumeration of the parasites in the intestine i8 effected. The results obtained are expressed in percentage of efficacity in relation to a control group.
In this test the product CP 2081 (compound No. 1 of Table I) has an efficacity percentage of 91 at the dose of 50 mg/kg.
In man the compounds according to the invention will be administered orally at doses which may be 50 mg. to 4,000 mg.; by the intravenous route the doses will be from 5 mg. to 1,000 mg.
The products according to the invention can be utilised in various Galenical forms. The following examples are not limitative and concern Galenical formulations containing active product designated by the letter A. This active product can be formed by one of the following compounds:-~7 ~L~5~99 4-n-pentylaminobutanamide 5-n-pentylaminopentanamide

6-n-pentylaminohexanamide 4-n-pentylaminobutanoic acid 5-(p.tolylacetylamino)pentanamide 6-n-decylaminohexanamide 6- ~(2-p-chlorophenoxyethyl)amino) he~canamide 4- ((N-n-hexyl-N-4-chlorophenylacetyl)amino3 butanamide Tablet~
A 600 mg Sta-RX 1500 starch 80 mg hydroxypropylmethyl cellulose 20 mg Aeosil* 5 mg magnesium stearate 15 mg A 100 mg maize starch 100 mg lactose 80 mg aerosil 5 mg talc 5 mg magnesium stearate 10 mg ~1~
A 50 mg lactose 110 mg maize starch 20 mg gelatin 8 mg calcium stearate 12 mg * Trade Mark SD

iL25689~
A 200 mg polyvinylpyrrollidone 10 mg maize 6 tarch 100 mg cutina HR 10 mg IniQctable I,M~r I,V.
A 20 mg sodium chloride 40 mg sodium acetate to pH = 7 distilled water for injection to 5 ml Iniectable I.H.
A 200 mg benzyl benzoate 1 g oil for injection to 5 ml A 5 g tartaric acid 0.5 g nipasept 0.1 g saccharose 70 g aroma 0.1 g water to 100 ml Solution A 2 g ~orbitol 50 g glycerine 10 g mint essence 0.1 g propylene glycol 10 g ; demineralised water to 100 ~1 ~ 51 ~.256~39~
SuppositorY
A 500 mg butylhydroxyan~sol 10 mg semi-synthetic glycerides to 3 g Rectal ael A 100 mg carbomer 15 mg triethanolamine to pH 5.4 purified water 5 g

Claims (28)

The embodiments of the invention in which an exclusive property or privilege is claimed, are defined as follows:

1. A process for the synthesis of derivatives of .omega.-amino acids of general formula:

also racemic or non-racemic mixtures thereof, optically pure isomers thereof and salts of these compounds formed with pharmaceutically utilisable acids, bases and metals, wherein:-R represents -a linear or branched alkyl radical C2, C3, C4, C5, C6, C7, C8, 9, C10, C11, or C12, a linear or branched alkyl radical C2, C3, C4 substituted by a phenyl or phenoxy nucleus which may be substituted by one or two linear or branched alkyl radicals C1, C2, C3, C4, by one or two linear or branched alkoxy radicals Cl, C2, C3, C4 or by one or two atoms of halogen a linear or branched acyl radical C2, C3, C4, C5, C6 substituted by a phenyl nucleus which may be substituted by one or two linear or branched alkyl radicals C1, C2, C3, C4, by one. or two linear or branched alkoxy radicals C1, C2, C3, C4, or by one or two atoms of halogen, R1 represent.
hydrogen, a linear or branched acyl radical C2, C3, C4, C5, C6, C7, C8, C9, C10, C11.

a linear or branched acyl radical C2, C3, C4, C5, C6, substituted by a phenyl nucleus which may be substituted by one or two linear or branched alkyl radicals C1, C2, C3, C4, by one or two linear or branched alkoxy radicals C1, C2, C3, C4 or by one or two atoms of halogen, R2 represents an amino group;
n possesses the value 3, 4 or 5;
the process comprising:-(a) converting a derivative of formula II

II

into a corresponding compound of formula I, R, R1 and n having the meanings given above, Z representing a group which, by an aminolysis or hydrolysis reaction can be transformed into an amide function, like the carboxylic acid function, the nitrile function, the ester function (-COOR', in which R' represents either R3, being an alkvl C1-C3 group, or an alkyl or phenyl radical substituted in such manner that it activates the ester in relation to the attack of a nucleophile), the amidine function (), the acid halide function (, where X represents a halogen such as chlorine, bromine or iodine), the anhydride function, the imidate function () or the N-carbonylimidazol group, or the grouping -CH2-Z representing the group in which B1 and B2 can be equal to or different from one another and represent a function selected from among the following series : nitrile, carboxylic, carba-moyl or alkoxycarbonyl (-COOR3, R3 having the values given above), which by aminolysis or hydrolysis and sub-sequent decarboxylation by heat is transformed in the group ;
b) subjecting an amine of formuld RNH-CH2)n-Z
or R1NH-(CH2)n-Z to a condensation reaction with an alkyl-ation or acylation reactant such as RW, R1W, , R8COOH, , or an amine of formula with a compound W-(CH2)n-Z or OHC-(CH2)n-1-Z, as appropriately followed by a reduction of the obtained intermediate amide, imine or iminium function; R, R1 and n in these formulae having the meanings given above, the groups , , R8-CO, R8-CH or obtained after the condensation, followed as appropriate by a reduction, representing the group R or R1, W representing an atom of chlorine, bromine or iodine, an O-tosyl, O-mesyl, sulphate, acyloxy or hydroxyl group, and Z having the significance of the group , in which R2 has the values specified previously, or c) converting a lactam of formula XVIII

XVIII

in which R and n possess the significances given above, by aminolysis into a derivative of formula I, under the action of ammonia, or an amide of an alkali metal.

2. A process according to claim 1 wherein R
represents an alkyl radical C2-C10.

3. A process according to claim 1 wherein R
represents an alkyl radical C2-C5.

4. A process according to claim 1 wherein R
represents an alkyl radical C6-C12.

5. A process according to claim 1 wherein R
represents an alkyl radical C5-C7.

6. A process according to claim 1 wherein R
represents an alkyl radical C2-C4 substituted by a phenyl or phenoxy nucleus which may themselves be substituted by a methyl or methoxy radical or of an atom of chlorine or bromine.

7. A process accordlng to claim 1 wherein R
represents an acyl radlcal C2-C4 substituted by a phenyl radical itself substituted by one or two methyl or methoxy radicals or bv one or two atoms of chlorine or bromine.

8. A process according to claim 1 wherein R1 represents an acyl radical C2-C5.

9. A process according to claim 1 wherein R1 represents an acyl radical C6-C11.

10. A process according to claim 1 wherein R1 represents an acyl radical C2-C4 substituted by a phenyl radical itself substituted by one or two methyl or methoxy radicals or by one or two atoms of chlorine or bromine.

11. A process according to claim 1 wherein R1 represents hydrogen.

12. A process according to claim 1, wherein the derivative is selected from the following group of compounds:
4-n-pentylamino butanamide 5-n-pentylamino pentanamide 6-n-pentylamino hexanamide 5-(p-tolylacetylamino) pentanamide 6-n-decylamino hexanamide 6-[2-p-chlorophenoxy-ethyl)amino] hexanamide 4-[(N-n-hexyl-N-4-chlorophenylacetyl)amino] butanamide

13. A process according to claim 1 wherein the derivative is prepared as defined in paragraph (a).

14. A process according to claim 1 wherein the derivative is prepared as defined in paragraph (b).

15. A process according to claim 1 wherein the derivative is prepared as defined in paragraph (c).

16. A derivative of general formula I as defined in claim 1 when prepared by the process of claim 1 or any obvious chemical equivalent thereof.

17. A derivative of ?amino acids of general formula:- also racemic or non-raoamic mixtures thereof, optically pure isomers thereof and salts of these compounds formed with pharmaceutically utilisable acids, bases and metals, wherein:-R represents -a linear or branched alkyl radical C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, or C12, a linear or branched alkyl radical C2, C3, C4 substituted by a phenyl or phenoxy nucleus which may be substituted by one or two linear or branched alkyl radicals C1, C2, C3, C4, by one or two linear or branched alkoxy radicals C1, C2, C3, C4 or by one or two atoms of halogen, a linear or branched acyl radical C2, C3, C4, C5, C6 substituted by a phenyl nucleus which may be substituted by one or two linear or branched alkyl radicals C1, C2, C3, C4, by one or two linear or branched alkoxy radicals C1, C2, C3, C4, or by one or two atoms of halogen, R1 represents -hydrogen a linear or branched acyl radical C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, a linear or branched acyl radical C2, C3, C4, C5, C6, substituted by a phenyl nucleus which may be substituted by one or two linear or branched alkoxy radicals C1, C2, C3, C4 or by one or two atoms of halogen, R2 represents -an amino group; and n posesses the value 3, 4 or 5.

18. A derivative according to claim 17 wherein R represents an alkyl radical C2-C10.

19. A derivative according to claim 17 wherein R represents an alkyl radical C2-C5.

20. A derivative according to claim 17 wherein R represents an alkyl radical C2-C12.

21. A derivative according to claim 17 wherein R represents an alkyl radical C2-C7.

22. A derivative according to claim 17 wherein R represents an alkyl radical C2-C4 substituted by a phenyl or phenoxy nucleus which may themselves be substituted by a methyl or methoxy radical or of an atom of chlorine or bromine.

23. A derivative according to claim 11 wherein R represents an acyl radical C2-C4 substituted byt a phenyl radical itself substituted by one or two methyl or methoxy radicals or by one or two atome of chlorine or bromine

24. A derivative according to claim 17 wherein R1 represents an acyl radical C2-C5.

25. A derivative according to claim 17 wherein R1 represents an acyl radical C6-C11.

26. A derivative according to claim 17 wherein R1 represents an acyl radical C2-C4 substituted by a phenyl radical itself substituted by one or two methyl or methoxy radicals or by one or two atoms of chlorine or bromine.

27. A derivative according to claim 17 wherein R1 represents hydrogen.

28. A derivative according to claim 17 selected from the following group of compounds:
4-n-pentylamino butanamide 5-n-pentylamino pentanamide 6-n-pentylamino hexanamide 5-(p-tolylacetylamino) pentanamide 6-n-decylamino hexanamide 6-[2-p-chlorophenoxy ethyl)amino] hexanamide 4-[(N-n-hexyl-N-4-chlorophenylacetyl)amino] butanamide.