IE55872B1

IE55872B1 - Derivatives of omega-amino acids,the preparation and utilisation thereof,and the compositions containing these derivatives

Info

Publication number: IE55872B1
Application number: IE1933/83A
Authority: IE
Original assignee: Continental Pharma
Priority date: 1982-08-20
Filing date: 1983-08-18
Publication date: 1991-02-14
Also published as: NL8302916A; ES8602608A1; DK373383D0; JPS5962555A; FR2531950A1; OA07525A; ES546625A0; SE8304513L; PT77226A; MA19882A1; CA1256899A; GB2126224B; DE3329628A1; IT8322591A1; NO163770B; NO832965L; FR2531950B1; ES8800658A1; ES525031A0; IT1169767B

Abstract

Compounds of the formula I for use in treating epilepsy, depression, dyskinesias such as Parkinson's disease, muscular spasms of nervous origin, hypertension, hypotension, sleeping troubles, memory defects, and as anthelminthic and analgesic agents wherein R represents:- a linear or branched C2 to C12 alkyl radical a linear or branched C2 to C4 alkyl radical substituted by a phenyl or phenoxy nucleus which may be substituted by one or two linear or branched C1 to C4 alkyl radicals by one or two linear or branched C1 to C4 alkoxy radicals or by one or two halogen atoms a linear or branched C2 to C6 acyl radical substituted by a phenyl nucleus which may be substituted by one or two linear or branched C1 to C4 alkyl radicals by one or two linear or branched C1 to C4 alkoxy radicals or by one or two halogen atoms. R1 represents hydrogen, a linear or branched C2 to C11 acyl radical a linear or branched C2 to C6 acyl radical substituted by a phenyl nucleus which may be substituted by one or two linear or branched C1 to C4 alkyl radicals by one or two linear or branched C1 to C4 alkoxy radicals or by one or two atoms of halogen, such as fluorine, chlorine or bromine, R2 represents:- a hydroxyl group an alkoxy group R3O- in which R3 is a linear or branched C1 to C3 alkyl radical; an amino group; and n is 3, 4 or 5; or a pharmaceutically or veterinarily acceptable salt thereof.

Description

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

The present invention includes the derivatives of iV-amino acids which respond to the. general formula I 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, Cg, C4, C5, C^, C7' Cg, Cg, C10, Cllf C12? a linear or branched alkyl radical Cg, Cg, C^, substituted by a phenyl or phenoxy group which may be substituted by one or two linear or branched alkyl radical C^, Cg, Cg, C4, by one or two linear or branched alkoxy radicals Cp Cj, Cg, C4, or by one or two atoms of halogen such as fluorine, chlorine or bromine; a linear or branched acyl radical C2, C^, C4, (?5, Οθ, substituted by a phenyl group which may be substituted by one or two linear or branched alkyl radicals C^, C?, C^, C4, by one or two linear or branched alkoxy radicals C^, C2, C4 or by one or two atoms of halogen such as fluorine chlorine or bromine? R^ represents:hydrogen; a linear or branched acyl radical C2, C^, C4, C$, C&, C?, C8' C9' C10' Cll? a linear or branched acyl radical c2< C^, c4, substituted by a phenyl group which may be substituted by one or two linear or branched alkyl radicals Cp C^, C^, C4 by one or two linear or branched alkoxy radicals C^, C2, C^, C4 or by one or two atoms of halogen such as fluorine, chlorine or bromine; R2 represents:an amino group (-NHj)? 2o n is 3, 4 or 5; hAccording to a preferred form of the invention the latter has For its object compounds of formula I in which:R represents: a linear or branched alkyl radical C2^l0* a linear or branched alkyl radical C^-C^ substituted by a phenyl or phenoxy group possibly substituted by a methyl or methoxy radical· or by an atom of chlorine; R^ represents:hydrogen a linear or branched acyl radical C2"C^; a linear or branched acyl radical substituted by a phenyl group which may be substituted 15 by a methyl or methoxy radical or by an atom of chlorine; R^ represents:an amino group; n possesses the values 3, 4 and 5 20 According to another preferrred form of the invention the latter has for its object derivatives of formula I in which:R represents:a linear or branched acyl radical 25 substituted by a phenyl group which may be substituted by a methyl or methoxy radical or an atom of chlorine; R^ represents hydrogen; R^ represents : an amino group; n possesses the values 3f 4 and 5.

A preferred class of products of formula I is that in which: R represents a linear or branched alkyl group r -f u2 cl0* . represents hydrogen; ί<2 represents:an amino group; n possesses the values 3, 4 and 5; A last preferred class of products of formula I is that in which: R represents:a linear or branched alkyl radical ^2~^10' a linear or branched acyl radical C^-C^ substituted by a phenyl group; represents hydrogen; represents an amino group (-NH^); and n has the value 3.

Examples of compounds according to the invention are : 4- n-pentylamino butanamide, - n-pentyLamino pentanamide, 6- n-pentylamino hexanamide, - (p-tolylacetylamino) pentanamide, 6-n-decylamino hexanamide, 6- [(2-p-chlorophenoxy ethyl) amino] hexanamide, 4-[(N-n-hexyl-N-4-chlorophenylacetyI) 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 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, salicylic, phenylacetic, mandelic, embonic, methane-sulphonic, ethane-suIphonic, pantothenic, toluene sulphonic, sulphaniLic, cyclohexylaminosulphonic, stearic, alginic, β-hydroxy butyric, oxalic, malonic, galactaric and galacturonic acids.

The compounds of formula 1 can possess one or more asymmetric carbon atoms and thus are capable of existing in the form of optical or racemic isomers or disasteroisomers; ail these forms are part of the present invention.

Thus the derivatives according to the invention can be utiLised either in the form of mixtures containing several diasteroisomers, whatever are the relative proportions thereof, or in the form of pairs of enantiomers in equal properties (racemic mixture) or not, or in the form of optically pure compounds The products according to the invention can be I utilised in the treatment of neurological, psychic or cardiovascular troubles such for example as epilepsy, depression, dyskinesias such as Parkinson’s disease, muscular spasms of nervous origin, hypertension, S hypotension, sleeping troubles, memory defects, and as anthelminthic and analgesic agents.

The invention includes compounds as described when for use in a method of treatment by therapy or surgery practised on the human or animal body.

The invention also includes pharmaceutical or veterinary formulations comprising such a compound formulated for pharmaceutical or veterinary use.

The present invention likewise covers pharmaceutical 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 compositions are prepared in such 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.

In particular, the compounds may be ln solution as eg. sterile water or in an oil such as groundnut oil or ethyl oleate.

The compounds may be utilised in medical treatment by being administered as dosages of 50 mg to 400 mg by the oral route or 5 mg to 400 mg parenterally and unit dosage formulations may be provided for this purposes.

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 the production of new intermediate compounds, these new compounds, likewise the processes serving for their preparation, also form part of the present invention.

Process A.

According to this manner of procedure, the product II is converted into a derivative of formula I: II R, Rp 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 group. Examples of these groups are, among others, the carboxylic group, the nitrile group, the ester group (-COOR*, in which R* represents either R^, which is a C|.j alkyl group, or an alkyl or phenyl radical substituted in such manner that it activates the ester in relation to the attack of a nucLeopniLe), the amidine group (-C^NH J, the acid halide group (-C where X represents a halogen such as chlorine, bromine or iodine), the anhydride group, the imidate group (-CR3)or the N-carbonyliraidazole • ^NH group.

The group -CH7-Z can equally represent the group -CH in which and can be the same or different and represents a group selected from the following series: 20 nitrile, carboxyLic, carbamoyl or alkoxycaroonyl (.-COORj, having the values given previously).

The conversion of the product 11 to the product I, that is to say the conversion of the group Z or -CH^-Z into a group (-COR2), can be realised by conventional reactions very well documented in cnemistry, as for example :a) conversion of a carboxylic acid into amide.

Several processes permit of effecting this chemical transformation.

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 denydration agent such as P^O^.

Anotner manner of proceedings consists in transforming the carboxyLic acid into an acid halide then into an 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 carbodimide, N-ethyl-N*-3-dimethyl amino propyl carbodiimide, phosphines, phosphites, silicon or titanium tetrachloride. b) Conversion of a nitrile into amide The nitriles can be hydrolysed into amides either 10 in acid medium or in basic medium. If the hydrolysis is carried out in acid conditions, it is possible to use concentrated sulphuric acid, concentrated aqueous hydrochloric acid, aqueous hydrobromic acid, nitric acid, formic acid in the absence of solvent, acetic IS acid in the presence of borq^tr if luor ide.

Another manner of convertings nitrile into amide, in acid medium, consists in treating the said nitrile with hydrochloric acid in an alcohol such as ethanol. Thus an intermediate iminoether is formed which is transformed thermally into amide.

If the hydrolysis is effected 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) Conversion of an ester into an amide.

The aminolysis of an ester is carried out conventionally by opposing ammonia to the ester, either in water or in an inert organic solvent. d) Conversion of an amidine into amide.

This reaction is 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.

For better understanding of the process the principle ways of access to the derivative II will be described below: 1. The derivative II can be obtained at the expense of 5 the products III or IV by alkylation or acylation according to the following outlines.

R-NH-(CH2)n-Z III R,-NH- (CH.,) -Z I ζ n N-(CH2)n-Z II IV wherein R, Rp Ζ, W and n possess the values as defined above, but in the reactant R^W the group R^ does not represent hydrogen. RW and R.W can likewise represent a R6 R6 cetene of formula C=C=O, so that the group ^CH-CO, obtained after the acylation of the derivatives III 3r IV, corresponds according to the case to a group R or Rp 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 hydrocarbon, selected as a function of the nature of the reactant.

The reaction 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 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 earth-alkaline metals or finely pulverised lime.

A variant of this process is illustrated bclow:NH + W-{CHj χ n V VI IX R/ w, Z and n possess 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 three 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 carboxylic acid making use of phosgene as coupling agent. The.phosgene can be introduced in a solution of ene 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. 3L 3 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:COCI, R,NH-(CH0) -Z -—A O=C=N-(CHJ -Z i a n f n IV Rq-COOH Rq-C0-N- (CHJ ο ι ί n wherein R^ represents hydrogen, Z and n possess the values specified previously and the group Rg-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 derivatives 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 is 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 The reduction of the iminium salt leads to derivative VII.

II. ί 4 NH + H-C-(CH2)n_1Z R . © H N-C n-rZ VII VIII reduction \X N-(CHO) -Z z n II 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 reduction takes place in an appropriate solvent in conventional manner by means of 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 reduction 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 intermediate carrying the same chemical functions as above. fl £ H+ C-0 + R,NH-(CH,) ι 4 n ΊΟ IX \ I1 ON-(CHJ -Z / © 2 n R1O IV \J/ reduction CH _/ 2 *1 • R., Z and n possess the meanings given previously while the Ro groups Ro and R.- possess values such that the group \ ... iU --CH R1O is equivalent to R.

The condensation of the carbonyl 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 R^ represents hydrogen, the above-described condensations lead to an imine of formula: h R-N=C \ or C=N-(CHJ -Z ζ n Wn-r2 XI XII wherein R, Rg, R^, 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.

J16 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.

N-(CH-) -Z 2 n XIII XIV II R, R. W and n have the meanings given above, M represents 1t hydrogen or a metal such as lithium, sodium potassium or magnesium and Z is a nitrile group.

The transformation of the product XIII can be realised 10 in accordance with different conventional methods selected as a function of the nature of W and Z. Certain of these methods are summarised here by way of example:when Z represents a nitrile group, the reaction can be carried out in different solvents such for example as water, a lower alcohol, dimethyl formam-ide 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. 4. Another way of access to derivatives of formula II in B which -CH~Z represents the group -CH Z consists in the 2 B2 alkylation of a derivative XV by means of the reactant XVI according to the following diagram:N-(CH2)n„1"W + M-CH^ B.

R^N-(CH2)n^-CH R1 B.

XV XVI R, R , Β. B , W and n have the values given previously, with i 1t i the exception of W which, in this case, does not represent a hydroxyl group.

M represents an alkaline metal such as sodium, potassium 10 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. The said lactam XVIII is conventionally obtained from the lactone XVII 8 according to the diagram; XVII RNH,Jb> / NHCH2)-C RXR1 ί I(R1=H) R, R2, M and n have the values defined above. The conversion of the lactone into lactam takes place in an inert organic solvent, advantageously at the reflux temperature of the reaction medium. The opening of the lactam can take place under the action of ammonia or an amide of an alkali metal. It proceeds in water or in an inert organic solvent such as an ether, an alcohol, an aliphatic hydrocarbon or aromatic 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 -±=2value of the group Cr^Z^R^ as specified previously and thus can lead directly co che produces of che invention corresponding to che general formula 1.

Of course for all the processes of synthesis of the compounds of formulas I and II the reactants and reaction conditions are selected-so as to keep intact the functional groups aLready present in tne molecule and not involved in the envisaged reaction.

Thus in order to be able to carry out the synthesis of the compounds 1 and 11 it Is sometimes necessary to utilise protective groups in order to preserve the functionality of the groups present in the initial molecule. The selection of the experimental conditions will contain the selection of the protective groups which, like the processes for their introduction and the methods of deprotection, are clearly described in literature.

Some detailed examples of preparation of several 10 derivatives 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.

SC Example 1.

Synthesis of 4-n-pentylamino butanamide 5g. (0.041 m.) of 4-chlorobutanamide are dissolved in ml. (0.165 m.) of pentanamine and agitated for 48 hours at ambient temperature. By addition of ether (400 ml.) a precipitate forms which is filtered and recrystallised twice in isopropanol.

M (°C) : 187 Elementary analysis: C H N % calculated 51.7 10.1 13.4 % found 52.0 10.2 13.4 Example 2.

Synthesis of S-n-pentylaminopentanamide, a) A mixture of 4.5 g. of 5-chloropentane nitrile (0.040 m.), 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/HCl is added. A white precipitate forms which is filtered (,5-n-pentviamino-pentanenitrile hydrochloride) .

M l°C) : 207-209. b) 2.78 g. (0.013 m.) of 5**n~pentylamino pentanenitrile hydrochloride are suspended in 3,4 ml. of concentrated HCl and agitated at 5°C, for 6 days. The limpid solution 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 H % calculated 53.9 10.4 12.5 10 % found 54.2 10.5 12.6 Example 3.

Synthesis of 6-decylaminohexanamide. 4.5g. of 6-chlorohexanamlde (0.03o m.) are heated under reflux in 100 ml. of ethanol containing 5.2 g. of decanamine (0.033 m.) and 2.52 g. of NaHCOg ¢0.033 m.) .

After 2 days and 2 nights the solution is cooled, filtered and evaporated; the solid is recrystallised twice in ethyl acetate. The solid obtained is dissolved in ethanol and ether/HCl Is added; the. new solid obtained ls recrystallised twice in isopropanol.

M. (°C.) : 206 Elementary analysis ; C H N % calculated 62.6 11.5 9.1 25 § found 63.0 11.7 9.3 ZZ Example 4.

Synthesis of 5-(p,tolyl acetylamino) pentanamide 2.9 g. (0.017 m.) of p-tolylacetyl chloride and a solution of 0.7 g. of NaOH in 4 ml. of water are added 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 0°C. The suspension 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 Η N % calculated 67.7 8,1 11.3 % found 67.8 8.1 11.3 Example 5.

Synthesis of 6-(3- (3,4-dlmethoxyphenyl) propanoylamino)hexanamide 4.6 g. (0.02 m.) of 3-(3,4-dimethoxyphenyl)propanoyl 5 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-amino hexanamide and 0.8 g. of NaOH in 15 ml. of water, cooled to 0°C. The suspension is agitated for two hours at room temperature. Then the solid is filtered and recrystallised 10 in isopropanol.

M (°C.) : 137 Elementary analysis C Η N % calculated 63.3 8.1 8.7 % found 63.2 8.2 8.6 Example 6.

Synthesis of 6-n-pentylaminohexanamide A mixture of 5 g. of 6-chlorohexamide (0.033 m,), 4.25 ml. of pentanamine (0.037 m.) and 2.8 g. of sodium bicarbonate (0.034 n.) in 100 ml. of ethanol is heated under the reflux for four days. Then after* cooling of the solution the salts 2d are filtered and the solvents are evaporated to dryness. The solidifying product is crystallised twice in ethyl acetate, dissolved in a minimum of methanol and ether/HCl is added. The solid forming is filtered and dried.

M (°C.) : 190.5 Elementary analysis : C Η N % calculated 55.8 10.6 11.8 % found 55.8 10.6 11.8 Example 7.

Synthesis of 4-n-hexylaminobutanamide a) A mixture of 18.5 ml. of 4-chlorobutanenitrile (0.2 m.), 29.1 ml. of hexanamine (0-22 m.) 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 I^CO^ 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/HCl is added. Ths 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-hexylamlnobutanenitrlie (0,02 m.) are agitated for four days at 5°C in 5 ml. of concentrated HCl. Then this solution is poured into 50 ml. of chilled acetone. The white solid which forms is recrystallised 5 in isopropanol. M (°C.) : 194 Elementary analysis: C H N % calculated 53.9 10.4 12.6 10 % found 54.1 10.4 12.6 Example 8, Synthesis of 4-2~(N-n-hexyl-N-4-c_hlorophenylacetyl) amino7 butanamide 650 mg. of 4-hexylaminobutanamide hydrochloride (0.003 m.) are dissolved in 9.4 ml. of KOH 1 N at 10°C. To this solution 0.65 ml. of 4-chlorophenyl acetic acid cnloride are added drop by drop. An oil appears immediately and solidifies. After two hours of reaction the oil is extracted with ether, the ethereal phase is washed with water and 1 N 20 hydrochloric acid, it is dried over K2COg an<^ evaporated.

The residual solid is recrystallised in ethyl acetate.

M (°C.) : 105-106 Elementary analysis; C H N 25 % calculated * 63.1 8.0 8.2 % found 63,0 7.9 8.1 n calculated for a content of 1.03% HgO.

Example Synthesis of S-n-dodecylaminopentanamide a) 7.4 g. of dodecanamine CO.04 mJ, 4.23 g. of 5-chloropentanenitrile (0.036 mJ and 3.4 g. of sodium bicarbonate (0.04m.) 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 0.25mm of Hg. The fraction distilling at 170°C. is collected. It is dissolved in ethanol and ether/HCl is added. The solid precipitating is filtered and used without supplementary purification in the following stage. b) 2 g. of 5-dodecylaminopentanenitrile hydrochloride (0.007 mJ 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 evaporated, the solid taken up in ether is filtered and the solid recrystallised twice in isopropanol.

M (°C.) : 212 Elementary analysis: C % calculated 63-6 ΐ fovnd 63.C H 11.6 Ί 1 < +. - ♦ 0 N 8.7 δ. 3 Example 1Q.

Synthesis of 4-n.pentylaminobutanamide a) A mixture of 18.5 ml. of 4-ehlorobutanenitrile (0.2 mJ , 19.1 g. of pentanamine (0.22 mJ and 18.5 g of sodium bicarbonate (0.22 mJ 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 dlchloromethane. The • dlchloromethane phase is washed with water, dried over K2C^3 an<^ evaP°rated 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, dissolving in a minimum of methanol and anhydrous ether is added until an abundant 10 precipitate is obtained which is filtered and engaged as such in the following stage. b) 3.1 g. of 4-pentylaminobutanenitrile (0.02 m.) are dissolved in 30 ml. of glacial acetic acid and are saturated with HCI at room temperature.

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

M (°C.) : 187.5 Elementary analysis; calculated % found C 51.7 H .1 N 13.4 51.8 .2 13.4 Example 31.

Synthesis of 4-n. pentylaminobutanamide 2.76 g. of 4-aminobutanamide hydrochloride (0.02m.), 1.9 g. of pentanal (0.022 m.), 100 mg. of Pd/C at 1O% and 50 ml. of ethanol are introduced into a Parr bottle. 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 ether. The solid obtained is recrystallised three times in isopropanol.

M (°C.) : 186.5 Elementary analysis: C Η N % calculated 51.7 10.1 13.4 % found 52.0 10.3 13.5 Example 12.

Synthesis of 4-n. pentylaminobutanamide 3.1 g. of N-pentylpyrrolidone (0.02 m.) arc introduced into a 200 ml. flask containing 3.9 g. of sodium amide (0.1 m. Ϊ suspended in 50 ml. of toluene. The suspension is brought to reflux for 3 hours, after which there are added 10 ml. Η2θ 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 isopropanol, the solid which crystallises is filtered and recrystalllsed twice in isopropanol. Μ (°C.) : 186 Elementary analysis: C % calculated 51.7 % found 51.4 Η N .1 13.4 .0 13.7 Table I given below assembles 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.H.N. elementary analysis.

TABLE I -π- (c«2)n - c * , d n X CP Code Ko R R. 2081 1nC5Hll 0 H 2455 2 -θ-0Η2σ- H 2624 3 -®-(ch2)2- H 2651 4'n08H].7" H 2652 5 nCc-H-,.5 i-i- H 2633 6nC6H13" H 2657 7 -^o)-ch2ch2- H 2659 8nC5Hll" H Rg n B^p (°C)/mb Recrystallisation Solvent KHg 3 187-188 Isopropanol (1) NHg 3 164-166 Isopropanol kh2 3 188-189 Isopropanol (1) kh2 3 195-196 •Isopropanol (1) nh2 4 216-217 Isopropanol (1) NHg 3 193-194 Isopropanol (1) nh2 4 214-215 EtOH (1) nh2 5 190-191 MeOH-Ether TABLE I r - x - (ch5)_ - c η κ CP Code No. RR1 *2 n U(°C)n B.P.(°C)/mb Recrystallisation Solvent 2673 9nC6H13 o <§H:i2-c- nh2 3 76-78 Benzene-pentane 2679 10 ci-<^-o( ch2)2- H nh2 5 193 Isopropanol (1) 2581 11 ch52)4- H nh2 5 196 Isopropanol (1) 2685 12 <§Mch2)4- · H o MII2 3 179-180 Iaopropanol (1) 2711 13 nCgKi3- y—\ ft C12-C- NH2 3 105-106 u AcOEt ·- 2684 14 -(ch2)4- hh2 3 88-89 AcOEt 2728 15 @-(ch2)2- H nh2 5 . 195 EtOH (1) I TABLE I " n < R2 CP Code Ho. R 2982 17 η o C. Hft * 4 3 2983 18 n.CgH19- 2964 19 <®-O-(OH2 3002 20n’C10H21" 3003 21n' ^7H15** 3027 22 ©>-ch2-ch CH 5028 23 n.CJ^-CH4 9 , c2« 3045 24η·θ11Η23" R1 *2 H(°C)0 B.Be ( C)/mb Recrystailisation Solvent H hh2 5 184 EtOH (1) H mr2 5 205 MeOH-Ether (1) H hh2 5 169 EtOH (1) H nh2 5 206 EtOH (1) H nh2 5 201 Isopropanol (1) H nh2 5 170°/2,10*3 - H bh2 5 180°/8b10**^ - H hh2 4 212 AcOH (1) TABLE .I » - (0H2)n - 0 CP Code Ko. R 0 5063 25 -@>CHrc- Cl 0 3064 26Br"\2/CK2"^· 3065 27 0Η3-°-<ρ}-0-(0Η2)2. 0 3073 ' 20 /o/CH-C C2H5 °CH?2 5 θ CH.j0-<0}-( CH2)2-C- 3074 29 3075 30n-c12H25" B^PC(oq)/dI> Recrystailisation Solvent 1IH2 5 142 IsopropanolKH2 5 149 Isopropanol kh2 4 · 204 MeOH (1) . hh2 5 109.6 Isopropanol nh2 5 137 Isopropanol NH 4 212 Isopropanol (1) >ΤΑΒΙΕ ϊ iCP Code Ko. R *1 3076 31 0 cH5~/oycH2-c H 3077 32 n. 0 φ-CH-C- 3078 33 CH^-CKg- °2H5 R 3087 34 n.C H,,~ 5 11CH3-(c^-CH 3088 35n°C5Hll" Br-(o}-CH2 3089 1 36 CH^O CH50-^o)-CH2-CH2- H 3112 37n-C5Hll- 0 Ώ-CgHlg-C- l2 Ώ u(°c)_ B.P.(°C)/mb Recrystallisatioa Solvent MH2 4 206 Xsopropanol nh2 4 250/3.IO5 - KKg 4 166 Xsopropanol KHg 4 270/3.105 - HH2 4 75 AcOEt kh2 4 192 EtOH-Ether (1) NHg 4 24Ο/1Ο5 - TABLE I r TABLE I H - (CH2)n - C CP Code Ho. ft 3148 47 I _ 0 ch3o-®- The LD^qS are calculated according to the method of 5 Lichtfield and Wilcoxon (J. Pharmacol. Exp. Ther. 9_6, 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 Medicinal Chem., 133, 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/kg.

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 2Q 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-con25 vulsive activity is examined in relation to tonic convulsions induced by bicuculline. The compounds according <80 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 against tonic convulsions and death is noted.

In this test products Nos. 1, 5, 8, IO 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 LI)^0 is 3 mg/kg.

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

CP 2081 likewise possesses an effect opposing convulsions induced by leptazole and by electric shocks.

Biochemical tests have demonstrated that certain products of the invention possess a GABA-mimetic 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 (without cerebellum) washed in order to eliminate the GA5A ( -γ* -aminobutanoie acid) present, is utilised to measure rhe connection to the receiver (the binding) by means of ^Ηχ-flunitrazepam in the presence 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 minutes at 0°C., on a homogenate diluted 200 times. After incubation the samples are filtered and washed over Whatman GFB 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.

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 forms of epilepsy and dyskinesias such as Parkinsons Disease. Moreover the activity of 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 anthelmintic 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 is effected.

The results obtained are expressed in percentage of efficacy In relation to a control group.

In this test the product CP 2081 (compound No. 1 of Table I) has an efficacy 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 from 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 Λ.

This active product can be formed by one of the following compounds:4- n-pentylaminobutanamide - n-pcntyJ aminopentanamido 6- n-pcntylaminohexanamide - (p.tolylacetylamino)pentanamide 6-n-decylaminohexanamide 6- Z(2-p-chiorophenoxyetr.vl)amine/ hex an ami ie 4-/"(N-n-hexy 1-N-4-chloropheny lacetyl) amino/ butanamide.

Composition Examples 1. Tablets A Sta-Rx 1500 starch hydroxypropyImethyl cellulose aerosil magnesium stearate 600 mg 80 mg 20 mg 5 mg 15 mg 2. A 100 mg maize starch 100 mg IO lactose 80 mg aerosil 5 mg talc 5 mg magnesium stearate 10 mg 3. Gelatin-coated pills 15 A 50 mg lactose 110 mg maize starch 20 mg gelatin 8 mg calcium stearate 12 mg 20 4. Λ 200 mg polyvinylpyrrolidone 10 mg maize starch 100 mg cutina HH mg 4 . Injectable I.M. or I.V.

A 20 mg sodium chloride 40 mg sodium acetate to pH = 7 distilled water for injection to 5 ml 6- Injectable I.M. A 200 mg benzyl benzoate 1 g oil for injection to 5 ml 10 7. Syrup A 5 g tartaric acid 0.5 g nipasept 0.1 g saccharose 70 g 15 aroma 0.1 g water to 100 ml 8. Solution A 2 g sorbi tc3 50 g 20 glycerine 10 g mint essence 0.1 g propylene glycol 10 g demineralised water to 100 ml 9. Suppository A 500 mg butylhydroxyanisol 10 mg semi-synthetic glycerides to 3 g . Rectal gel A 100 mg carbomer 15 mg triethanolamine to pH 5.4 purified water 5 g

Claims

CLAIMS:

1. A derivative of an ω-amino acid which derivative is of general formula :- (CH 2’n o 5 wherein : R represents a linear or branched C 2 , Cj, ¢^, C$, C 6 , C 7 , Cg, Cg, C 10 , C n or C 12 alkyl radical 10 a linear or branched C 2> Cj, or alkyl radical substituted by a phenyl or phenoxy group which may be substituted by one or two linear or branched Cj, C^, Cj, or C^ alkyl radicals by one or two linear or branched Cj, C 2 , Cj, or alkoxy 15 radicals or by one or two halogen atoms a linear or branched C 2 , Cj, C 4 , or C^ acyl radical substituted by a phenyl group which may be substituted by one or two linear or branched Cj, C 2 , Cj, or C^ alkyl radicals by one or two 20 linear-or branched Cj, C 7 , Cj, or C^ alkoxy radicals or by one or two halogen atoms, Rj represents a hydrogen, a linear or branched C^, C^, C^, C 5’ C 6’ C 7’ C 8’ C 9* C 10’ ° Γ C U aCyl radical 5 <9 a linear or branched , C^, C^, C^, or acyl radical substituted by a phenyl group which may be substituted by one or two linear or branched 10 Cj, C 2 , C-j or C 4 alkyl radicals by one or two linear or branched Cj, C 2 , Cj or alkoxy radicals or by one or two atoms of halogen, such as fluorine, chlorine or bromine, 15 R 2 represents :- an amino group; and n is 3, 4 or 5; or a pharmaceutically or veterinarily acceptable salt thereof. ZO 2. A derivative as claimed in Claim 1 wherein R represents ία linear or branched C 2 -Cjq alkyl radical; a linear or branched C 2 C 4 alkyl radical substituted by a phenyl or phenoxy group optionally substituted by a methyl or methoxy radical or by an atom of chlorine; c 25 « Rj represents :- hydrogen a linear or branched C 2 -Cjj acyl radical; a linear or branched C 2' C 6 ac Y 1 radical substituted by a phenyl group which may be substituted by a methyl or methoxy radical or by an atom of chlorine; represents:an amino group; and n is J, 4 or 5. 3. A derivative as claimed in Claim 1 wherein R represents : a linear or branched acyl radical substituted by a phenyl group which may be substituted by a methyl or methoxy radical or an atom of chlorine; Rj represents a hydrogen; R 2 represents :an amino group; and n is 3, 4 or 5. 4. A derivative as claimed in Claim 1 wherein R represents a linear or branched alkyl ^’^ΙΟ 8 rou P> R^ represents hydrogen; represents :an amino group; and n is 3, 4 or 5. 5. A derivative as claimed in Claim 1 wherein R represents : a linear or branched C2~Cio al ^yl radical; a linear or branched C^-C^ acyl radical 4 20 substituted by a phenyl group; Rl represents hydrogen; R 2 represents an amino group (-NH^); and n has the value 3. 6. A derivative as claimed in Claim 1 or Claim 2 wherein in Formula I, R represents a C^-C^q alkyl radical. 7. A derivative as claimed in Claim 1 or Claim 2 wherein in Formula I, R represents a C^-C^ alkyl radica1. 8. A derivative as claimed in Claim 1 or Claim

2. Wherein in Formula I, R represents a alkyl radical. 9. A derivative as claimed in Claim 1 or Claim 2 wherein, in Formula I, R is a C^-C^ a lkyl radical. 10. A derivative as claimed in Claim 1 or Claim I wherein, in Formula 1, R represents a alkyl radical substituted by,a phenyl or phenoxy group which may themselves be substituted by a methyl or methoxy radical or by an atom of chlorine or bromine. 11. A derivative as claimed in Claim 1 SC wherein, in Formula I, R represents a acyl radical substituted by a phenyl grouo itself substituted by one or two methyl or methoxy radicals or by one or two atoms of chlorine or bromine.

3. 5 12. A derivative as claimed in any one of Claims 1, 2 or 6 to 11 wherein in Formula I, Rj represents a Cj-C^ acyl radical. 13. A derivative as claimed in any one of ClAims 1, 2 or 6 to 11 wherein, in Formula I, Rj

4. 10 represents a C^-Cjj acyl radical.

5. 14. A derivative as claimed in any one of Claims 1, 2 or 6 to 11 wherein, in Formula 1, Rj represents a C 2 C 4 ac y^ radical substituted by a phenyl grouo itself substituted by one or tvo methyl

6. 15 or methoxy radicals or by one or two atoms of chlorine or bromine. 15. A derivative as claimed in any one of Claims 1, 2 or ό to 11 wnerein, m Formula I, R, A represents hydrogen.

7. 16. 4-n-pentylamino butanamide.

8. 17. 5-n-pentylamino pentanamide.

9. 18. 6-n-pentylamino hexanamide.

10. 19. 5-(p-tolylacGtylamino) pemanamide.

11. 20. 6-n-dccylamino hexanamide.

12. 21.6-[(2-p-chlorophenoxy ethyl) amino] hexanamide. 5

13. 22.4-((N-n-hexyl-N-4-chlorophenylacetyl)amino] butanamide.

14. 23. A derivative as claimed in Claim 1 as herein before named in any one of Examples 1 to 1? or according to the formula given in any entry in Table I. 10

15. 24. A derivative as claimed in Claim 1 substantially as hereinbefore described in any one of Examples 1 to 12 or any entry in Table I.

16. 25. A process of the synthesis of a derivative as claimed in any one of Claims 1 to 24 comprising 15 converting a derivative of Formula ΙΪ - (CH 2 ) n into a corresponding compound of Formula I, R, R^ and n having the meanings defined in Claim 1, Z representing a group which, by the action of an appropriate reactant, can be transformed into an amide group.

17. 26. A process as claimed in Claim 25 wherein Z is a carboxylic acid group, a nitrile group, an ester group (-COOR', in which R' is a linear or branched C^-Cj alkyl group or an alkyl or phenyl radical substituted in such manner that it activates the ester in relation to the attack of a nucleophile), an amidine group ( .NH NHg ), an acid halide group (C f wherein X represents halogen), an anhydride group, an OR. imidate group (-C^ ), a N-carbonylimidazole group, NH or a chlorine, bromine or iodine atom, or wherein the grouping Ok-Z represents a group CH in which 1 is a carbamoyl group and a carboxyl or alkoxycarbonyl group.

18. 27. A process as claimed in Claim 25, wherein an amine of formula RNH-(CH 2 ) n Z or R^NII- (CII 2 ) n -2 is subjected to a condensation reaction with an alkylation or acylation reactant RW , :=0, RgCOOH, or 9 ^C=O, or R l< wherein an amine of Formuli condensation reaction wir/i reaction with a compound W-(CHg) -Z or OHOfCHgJfl^-Z, as appropri -2, as appropriate followed by a reduction of the obtained intermediate amide, imine or iminium function; R, and n in these formulae having the meanings defined in claim 1, the grouos R c *^CH-CO, °>CH-CH_, R fl -CO, R -CH p -x* * 2o 8 X. *7 R ? or CH obtained after the condensation, followed R 10 as appropriately by a reduction, representing the group R or Rj, W representing an atom of chlorine, bromine or iodine, an O-tosyl, O-mesyl, sulphate, acyloxy or LO hydroxyl group, and Z being the group C is as defined in Claim 1. , in which

19. 28. A process for the synthesis of a derivative as claimed in any one of Claims 1 to 24, wherein a lactam of Formula XVIII R XVIII 15 in which R and n are as defined in Claim 1 is converted into a derivative of Formula I, by the action of ammonia or an amide of an alkali metal.

20. 29. A process as claimed in any one of Claims 25 to 28 substantially as hereinbefore described in any one of Examples 1 to 12. J

21. 30. A derivative as claimed in Claim 1 produced by a process as claimed in any one of Claims 25 to 28. I

22. 31. A derivative as claimed in any one of Claims 1 to 24 or Claim 30 which contains one or more assymetric carbon atoms, in the form of a racemic or non-racemic mixture of optical isomers.

23. 32. A derivative as claimed in any one of Claims 1 to 24 or Claim 30 which contains one or more assymetric carbon atoms, in the form of an optically pure isomer.

24. 33. A derivative as claimed in any one of Claims 1 to 24, or 30 to 32 for use in the treatment of neurological, psychic or cardiovascular deficiencies or diseases or as an anaesthetic or anthelmintic agent.

25. 34. A pharmaceutical or veterinary formulation comprising a derivative as claimed in any one of Claims 1 to 24, or 30 to 32 formulated for pharmaceutical or veterinary use.

26. 35. A pharmaceutical or veterinary composition comprising a derivative as claimed in any one of Claims 1 to 24, 30 to 32 and a carrier, diluent or excipient therefor.

27. 36. A composition as claimed in Claim 35 in the ί 5 form of a lozenge, tablet, gelatine coated pill, pill, granule, capsule, solution, syrup, emulsion, suspension or gel.

28. 37. A composition as claimed in Claim 35 comprising a derivative as claimed in any one of Claims 10 1 to 24, 30 to 32 in solution in sterile water or in an oil.

29. 38. A composition as claimed in Claim 35 in unit dosage form wherein each unit dose provide from 50 mg to 4000 mg in forms for oral administration and from 15 5 mg to 400 mg in forms for parenteral administration.

30. 39. A composition as claimed in Claim 35, substantially as hereinbefore described in any one