WO1990011292A2 - Controlled-action anesthetic compounds and pharmaceutical compositions containing same - Google Patents

Abstract

The present invention concerns the application of compounds having formula (I), wherein B is such that R-NH-B is an aminobenzoic acid-derived anesthetic: wherein R represents H or an alkyl C1-C5 radical, preferably linear, possibly functionalized in position 2 to 5; wherein AAn is an oligopeptide group consisting of 1 to 10 alpha amino acids, preferably 2 to 6, i.e. in which n is a whole number from 1 to 10 and AA represents natural amino acids or synthetic alpha amino acids in the form of D or or D, L, whereby said alpha amino acids in the form of D or L or D,L, whereby said alpha amino acids may be different, bearing in mind that when R-NH-B represents benzocaine, the first C-terminal acid is L phenylalanine when n = 1 and L, D or D,L pehnylalanine when n is greater than 1 and their pharmaceutically acceptable salts, to the preparation of pharmaceutical compositions useful as anesthetics. The invention also concerns compounds for anesthetic use and a process for increasing the potency of anesthetics having an aromatic amine group.

Description

ANESTHETIC COMPOUNDS WITH CONTROLLED DURATION OF ACTION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.

The present invention relates to anesthetic compounds and pharmaceutical compositions containing them.

 The present invention more particularly relates to local anesthetics, surface anesthetics or conduction anesthetics.

 Local anesthetics are used when general anesthesia is not necessary or is particularly dangerous. Their use is frequent in ophthalmology, laryngology, dentistry, obstetrics, as well as for minor surgical operations.

 Finally, local anesthetics can be applied to relieve itching or pain in the skin and mucous membranes.

 There are two types of local anesthetics, surface anesthetics which cause anesthesia by contact with the skin or mucosa, for example in the form of ointment or drops and conduction anesthetics which cause anesthesia by injection, in particular by injection. parenteral.

 The first disadvantage of local anesthetics, in particular benzocaine, is that they undergo a rapid metabolism, which limits the pharmacological effect in intensity and duration.

 The second drawback of these anesthetics is that the anesthetic effect persists for a long time with a reduced intensity, therefore insufficient to operate but sufficient to hinder the patient in the case of an ambulatory intervention.

 In order to avoid these drawbacks, in addition to numerous chemical derivatives, a large number of combinations have been proposed, for example local anesthetics and vasoconstrictors, but none of these solutions can be considered to be completely satisfactory.

 This is why one of the aims of the present invention is to provide local anesthetics whose duration of action is adapted to different durations of intervention.

Another object of the present invention is to provide new anesthetics whose activity, greater than that of benzocaine, presents a "plateau" of activity and then decreases very quickly. These goals and others which will appear by the

 following are achieved by the application of the compounds of formula I: (I)

where B is such that R-NH-B is an anesthetic derived from aminobenzoic acids;

where R is H or a C ₁ -C ₅ alkyl radical, preferably linear, optionally functionalized in position 2 to 5;

where [AA] _n is an oligopeptide group of 1 to 10 alpha amino acids, preferably 2 to 6, that is to say in which n is an integer from 1 to 10 and AA represents natural amino acids or synthetic alpha amino acids in form D or L or D, L, the alpha amino acids can be different, with the precision that when R-NH-B is benzocaine, the first C-terminal acid is L phenylalanine when n = 1 and L, D or D, L phenylalanine when n is greater than 1 and their pharmaceutically acceptable salts,

in the preparation of pharmaceutical compositions useful as anesthetics.

By pharmaceutically acceptable salts, it is necessary to include all the salts used in the field for the applications considered. As an indication, the salts may be those of mineral acids such as sulfuric, hydrochloric or boric acids, those of alkyl sulfonic acids such as methylsulfonic acid, those of carboxylic acids, aliphatic with short chain such as formic acid and isobutyric acid, or aromatic acid such as benzoic acid or phenylpropionic acid. Mention may also be made of the salts of carbonic acid and those of the acids themselves having pharmacological properties such as chlorotheophyllinic acid.

The symbols used for alpha amino acids are those commonly used in this area. It has been surprisingly found that among the oligopeptide derivatives of benzocaine and of compounds with a structure close to that of benzocaine according to the invention, those in which the C-terminal alpha amino acid is phenylalanine, preferably L phenylalanine , had particularly advantageous properties, in particular as conduction anesthetics, and that these properties can be modulated using the N-terminal alpha amino acids. To do this, the alpha amino acids coming after phenylalanine are advantageously hydrophilic. Among the amino acids considered to be hydrophilic, mention may be made of glycine, alanine, serine, lysine and glutamic acid.

However, the preferred alpha amino acids are alanine and glycine. The number of amino acids located on the peptide chain makes it possible to modulate the anesthetic activity. The expression "derivative of amino-benzoic acids" suggests the possibility of substitution of an oxygen of the carboxyl function by a sulfur.

 More particularly preferred are the compounds and their pharmaceutically acceptable salts corresponding to formula la:

wherein :

 - R, AA and n have the same meaning as in formula (I).

 Advantageously,

 1) n is an integer from 1 to 6 inclusive,

 2) the alpha amino acids are different in D, L or D, L form, preferably in L form. They can be synthesized either by biological or chemical routes,

3) R is H or a C ₁ -C ₅ alkyl radical; the compounds in which R = H are preferred; - X ₁ and X _{2 which are} similar or different are H or known substituents for local anesthetics derived from aminobenzoic acids, in particular the C ₁ -C ₄ alkyl, halogen, hydroxy or C ₁ -C ₆ alkoxy radicals;

- R ₁ is H or the radical corresponding to an alcohol, this alcohol derivative possibly leading to an ester of benzoic acid, in particular the radicals R ₁ for which the R-NH-B compounds corresponding to the are of formula :

et possèdent une activité anesthesique locale. Par exemple, R ₁ peut être C ₁-C₅ alcoyle linéaire ou ramifié. Cet alcoyle peut porter des groupements fonctionnels en position 2 à 5, tels que des groupements hydroxy, C ₁-C₅ alcoxy, amino ; ce dernier étant en général mono ou disubstitué par des groupements C ₁-C₅ alcoyles et/ou alcoyl-amino. Dans le cas de disubstitution, les substituants peuvent former avec le groupement aminé un hétérocycle azoté en C ₅ ou C ₆.

and have local anesthetic activity. For example, R ₁ can be C ₁ -C ₅ linear or branched alkyl. This alkyl may carry functional groups in positions 2 to 5, such as hydroxy, C ₁ -C ₅ alkoxy, amino groups; the latter being generally mono or disubstituted by C ₁ -C ₅ alkyl and / or alkylamino groups. In the case of disubstitution, the substituents can form with the amino group a nitrogen heterocycle C ₅ or C ₆ .

 Derivatives of p-aminobenzoic acid are preferred; these are, for example, compounds:

dans lesquels X₁ = X₂ = H et les AA sont des amino-acides hydrophiles, notamment la glycine et l'alanine.

in which X ₁ = X ₂ = H and AA are hydrophilic amino acids, in particular glycine and alanine.

 Thus, the benzocaine derivatives of formula Ib 'are particularly targeted:

dans laquelle A' représente :

in which A 'represents:

 . H

 . an oligopeptide group [AA] where r is an integer from 1 to 9 and where [AA] represents either a natural amino acid or a synthetic alpha amino acid in D or L form, the amino acids can be different when r is different from 1, and their pharmaceutically acceptable salts,

in which more particularly [AA] represents a natural amino acid. In particular and preferably A 'represents:

. _{2 p} where p is an integer such that 0≤ p≤ 4

(L-alanine)

(L-serine)

. (L-lysine)

Some of these compounds have been the subject of more complete study, in particular the compounds:

dans lesquels n est compris entre 2 et 6.

in which n is between 2 and 6.

 As an indication, there may be mentioned as an anesthetic of formula R-NH-B having an aminobenzoic group the following anesthetics:

 - derivatives of meta-aminobenzoic acid such as betoxycaine, metabutethamine, metabutoxycaine, orthocaine, piridocaine, proxymetacaine;

 para-aminobenzoic acid derivatives such as ambucaine, amoxecaine, butacaine, buthetamine, butoform, chioroprocaine, cornecaine, dimethocaine, hydroxyprocaine, hydroxytetracaine, isobutylcaine, largacaine (derivative of p-amino-thaine, thiobin naepaine, oxybuprocaine, paridocaine, procaine, propoxycaine, risocaine, tetracaine, tutocaine.

 The invention also relates to pharmaceutical compositions useful in particular as local anesthetics, comprising at least one compound of formula I, la, Ib, Ib 'or lc.

 These compositions may also contain the vectors and potentiating agents common in the matter, in particular vasoconstrictors.

 Another subject of the present invention is the application of the compounds according to the invention to the preparation of anesthetic conduction compositions, the latter being injectable.

 Some authors have synthesized benzocaine derivatives by acylation of the aromatic amino function by means of amino acids. Thus, were synthesized by Wincenty Kwapiszewski and Jan Kolwas, Acta Polon, Pharm. XXXIV, nr. 2, 1977, pages 167 to 170, XXXIV, nr. 3, 1977, pages 257 to

260 and XXXIV, nr. 4, 1977, pages 377 to 3S2 of the benzoains substituted by glycine and its derivatives methylated on nitrogen, DL-alanine, DL-phenyl-alanine, DL-valine, DL-leucine, the gamma-methyl ester of glutamic acid as local anesthetics possible.

 Furthermore, M.Zaoral in the Czechoslovak Collection, Chem. Common. /Flight. 36 (1971) indicated that the glycine-substituted benzocaine itself substituted by isoleucine gave a compound which possessed an activity close to that of novocaine.

 More recently, studies have been carried out on a benzocaine substituted on its nitrogen by glycine, dimethyl-glycine or N, N-dimethylbeta-alanine (cf. Pharmacological and Metabolic Studies on

Amino Acid Benzocaine Derivatives, by Z. Slojkowska, K. Misterek, H. Kiimecka, J. Pachecka, Pol. 3. Pharmacol. Pharm. 1981, 33, 99-106). These compounds were considered as prodrugs (chemical compounds releasing the active principle under the influence of the ases of the organism) having an activity lower than that of novocaine with a disappearance of the anesthetic activity hardly slower than that of the latter.

 To the knowledge of the applicants, the derivatives of the other synthesized alpha amino acids specified above have not been the subject of pharmacological study, it should be noted that the results of the pharmacological analyzes mentioned above were not very encouraging, in particular with a view to obtaining conduction anesthetics with a relatively long duration of action with a "plateau" effect. It should be noted as we will see in the experimental part that these poor results have been confirmed by the present studies carried out on benzocaine substituted by a single alpha amino acid, when the latter is glycine, serine or alanine . The pharmacological effect is even zero when the amino acid is lysine or glutamic acid.

 It should be noted that benzocaine is particularly well potentiated by the oligopeptide chains according to the invention.

Thus, the present invention makes it possible to potentiate the activity of conduction anesthetics derived from amino-benzoic acids, in particular benzocaine, by grafting on the amino function an oligopeptide of 1 to 10 alpha amino acids, the first of these alpha amino acids being, in the case of benzocaine, phenylalanine, preferably L phenylalanine and its form L when phenylalanine is the only amino acid grafted.

The compounds according to the present invention of formula: (I, la, Ib, Ib 'or le)

where B is such that this formula meets formulas I, la, Ib, Ib 'or le and where

[AA] _n is [AA] _{m +} [AA] _nm ,

where R is H or a C ₁ -C ₅ alkyl radical, preferably linear, optionally functionalized in position 2 to 5;

where [AA] _n is an oligopeptide group of 1 to 10 alpha amino acids, preferably 2 to 6, that is to say in which n is an integer of 1 to

10 and [AA] represents the natural amino acids or the synthetic alpha amino acids in form D or L or D, L, the alpha amino acids being able to be different, with the condition that when n = 1 and R-NH- B benzocaine, the amino acid is L phenylalanine,

can be synthesized by a process in which a compound of formula is reacted:

(II)

where R, B, [AA] and n have the same meaning as above, and where m is an integer between 1 and n, the possible reactive functions of the compound of formula II being protected,

with an oligopeptide chain of formula [AA] _m (III) in which the carboxylic group of the C-terminal amino acid is activated (that is to say susceptible to react with the amino function of the N-terminal amino acid of the compound of formula II) and in which the amino function of the N-terminal amino acid, as well as any reactive functions are protected and in which once the reaction finished, the protected functions are unprotected.

 According to one of the implementations of the method according to the invention, nm is equal to 1, and the compound of formula II is produced by reacting a derivative of the C-terminal amino acid activated on the carboxylic group and whose amino function and the possible reactive functions have been protected, with a compound of formula H (R) NB where the possible reactive functions of B will have been protected, in which the protected functions are released once the condensation is complete and in which one grafts step by step the other alpha amino acids constituting the oligopeptide chain to obtain the compound of formula II.

 According to another implementation of the present invention, the value of m for the compound of formula II is equal to n, the compound of formula III having been synthesized step by step according to the so-called C → N or N → C technique.

 The synthesis techniques according to the present invention are detailed below:

 The compounds according to the present invention start from anesthetics having an aromatic amine function, which aromatic amine can be substituted once by an alkyl radical with low carbon number (1 to 5) optionally functionalized. This substitution can only be a monosubstitution so as to leave an H on the nitrogen of the aromatic amine, nitrogen on which the substitution of hydrogen takes place by the oligopeptide group. During the implementation of the invention, the property of these anilines to react was used as the amino function of an alpha amino acid.

It should be noted that for steric reasons, it is preferable for the simplicity of the synthesis, whether R is H, methyl or ethyl, preferably hydrogen. In what follows, benzocaine serves as a model for the other anesthetics targeted by the invention. The synthesis of the new compounds according to the present invention is therefore carried out as the synthesis of a simple peptide chain. The compounds according to the present invention were produced by the so-called step-by-step synthesis techniques, that is to say by grafting the first alpha amino acid onto the anesthetic compound then by grafting the subsequent alpha amino acids one by one. .

 It is the step-by-step synthesis technique called C → N starting from the C-terminal alpha amino acid residue.

The diagram below clearly shows the synthesis routes that can be used and used according to the present invention. In this case, the amino acid C can be replaced by the anesthetic compound R-NH-B whose possible reactive functions have been protected.

avec : Y et Y' = groupements N-protecteurs (identiques ou différents).

with: Y and Y '= N-protective groups (identical or different).

 E = protective group for the carboxyl of the C-terminal amino acid

L ₁ , L ₂ , L ₃ = protective groups of functional side chains (identical or different).

Z = carboxyl activator group As protective groups, Y or Y ′, the ter-butyloxycarbonyl group called BOC can be chosen. The advantage of using the BOC is that it considerably reduces the risks of racemization during the activation and coupling processes.

 To protect the amino function, the ter-butyl di-carbonate is reacted:

 which in the presence of water / organic solvent mixtures and a base leads to the formation of an alpha amino acid protected by the BOC group:

at

 with: R '= H or C-protective group,

R ₄ = side chain of the amino acid, possibly protected.

Despite the advantages of the BOC group, other groups known to protect the amino function of alpha amino acids can be used.

 As regards the carbonyl activating groups, they can be chosen from dicyclohexylcarbodiimide derivatives according to a technique used by KWAPISZEWSKI et al. (already cited). The reaction implemented can be symbolized by the following reaction:

 BOC- amino acid DCC O-acylisoured

(intermediary activated) then:

BOC-amino acid -Benzocaine DCU with: R ₄ = side chain of the amino acid, possibly protected.

 This technique is suitable both for fixing an alpha amino acid on the nitrogen of an aniline group and for the synthesis of oligopeptides themselves.

 It is also possible to choose, as group Z activating the carboxyl group, alcohol esters forming a particularly stable oxygenated anion. Mention may be made, for example, of the esters derived from pentafluorophenol and the esters derived from N-hydroxysuccinimide.

 The use of activated esters has the advantage of giving as a coupling by-product compounds which are more easily separated from the desired product.

However, these activated esters are not always sufficiently activated to allow the reaction with all the anesthetics derived from amino-benzoic acids, and in particular with benzocaine. Another way to activate the carboxyl group is to form mixed anhydrides. The reaction for the formation of peptide bonds is then as follows:

 Peptide mixed anhydride with: Y = N-protective group,

R ₄ = side chain of the activated amino acid,

 R '= radical of the activating compound,

 R "= structure of the amino component, except for its end

-NH ₂ .

 This technique has been used in the past but has the disadvantage of having two electrophilic centers capable of giving, by attack of an amino reagent, two acylation products. The preferred mixed anhydrides are the anhydrides formed from chloroformates and more particularly hindered chloroformates such as, for example, isobutyl chloroformate. The preferred reagent for grafting the first link onto the anesthetic compound is the use of the mixed anhydride formed by the amino acid which it is desired to graft with isopropenyl chloroformate (IPCF). This compound can be prepared according to the method described in French patent 2,421,866.

Such mixed anhydrides were used by Mr. JAOUADI during his State thesis defended at the University of Montpellier USTL, 1984. Once the first link has been attached to the anesthetic compound, the side chain can be lengthened according to the preceding diagram which is detailed below, taking benzocaine as an example of an anesthetic compound.

 From the BOC-aminoacyl-benzocaine derivative, the synthesis supposes the elongation of the peptide chain by:

deprotection of the α -NH _{2 end} of BOC-amino-acylbenzocaine,

 . a succession of coupling steps and of N α -protection,

. a final deprotection of α -NH ₂ and, optionally, functional side chains, in one or more stages.

 Aspects relating to deprotection methods will be discussed later.

 The lengthening of the peptide chain was carried out according to the same activation and coupling method as that described for the synthesis of BOC-aminoacyl-benzocaΪne:

 "Higher" BOC-peptide-Benzocaine with: m = number of identical or different amino acids, m varying from

 1 to 9,

R ₄ = side chain of amino acids, possibly protected. NOT

L ₁ , L ₂ , L ₃ represent possible protective groups of the side chains R ₅ , R ₂ , R ₃

-CH₂-CH₃ La protection des fonctions des alpha amino-acides, telles que les groupements amines supplémentaires dans la lysine, ou le groupement hydroxyle de la serine est réaiisé selon la technique classique en la matière. -And

-CH ₂ -CH ₃ The protection of the functions of alpha amino acids, such as the additional amine groups in lysine, or the hydroxyl group of serine is carried out according to the conventional technique in this field.

 The following nonlimiting examples, all implemented from natural alpha amino acids, therefore in L form when the C in alpha is asymmetric, will enable those skilled in the art to better understand the oligopeptide synthesis of the compounds according to l invention, their reaction intermediate and the compounds synthesized for comparison as well as the advantage of the present invention.

 The abbreviations of the alpha amino acids used are those commonly used in the matter, namely:

Gly (glycine), Ala (alanine), Val (valine), Leu (leucine), lleu (isoleucine), Phe (phenylalanine), Ser (serine), Thr (threonine), Lys (lysine), Lys-OH (δ -hydroxylysine), Arg (arginine), Asp (aspartic acid), Asp-NH ₂

(asparagine), Glu (glutamic acid), Glu-NH ₂ (glutamine), CySH (cysteine), CyS-SCy (cystine), Met (methionine), Tyr (tyrosine), Thy (thyroxine), Pro (proline), Hypro (hydroxyproline), Try (tryptophan), His (histidine).

EXAMPLE 1 Synthesis of the Oligopeptides

Synthesis of BOC-ala-Benzocaine (reaction intermediate for compound cited for comparison).

21.12 mmol of protected amino acid (BOC-ala-COOH) are dissolved in 100 ml of anhydrous THF (dried over sodium wires). After the addition of 23.0 mmol of N-methylmorpholine, the medium is cooled to 0 ° C. 21.1 mmol of IPCF are then added dropwise. Instantly a precipitate of N-methyl-morpholinium hydrochloride appears. The formation of the anhydride is verified by IR spectroscopy: 1830 cm (F), 1755 cm ^{- 1} (f). After 15 minutes between 0 and + 5 ° C, 20.0 mmol of benzocaine, in the presence of 21.1 mmol of triethylamine, dissolved in 100 ml of THF, are added to the mixture. Let the temperature rise to ambient

(about 20 ° C).

 The reaction is followed by:

-IR: gradual disappearance of the band at 1830 cm ^{- 1} , -CCM: ethyl acetate / hexane solvent 1/1 by volume.

After 3 hours at room temperature, the reaction medium is filtered and then concentrated. The mixture is redissolved in ethyl acetate, then performs a series of extracts, successively with water saturated with NaHCO ₃ , with distilled water, with 0.1 N HCl, and with distilled water until the pH is close to neutral. The organic phase is dried over MgSO ₄ , and the desired product obtained, in the pure state, by precipitation in diethyl ether and drying under a partial vacuum of 133 Pascal, or approximately

1 mm of mercury (room temperature).

Yield = 70%

Product identification :

(1) MS: 337 (MH) ⁺ , 281 (HOOC-NH-ala-benzocaine + H ⁺ , i.e.

MH ⁺ - (CH ₃ ) ₃ C + H ⁺ )

 (2) Elementary analysis (%) C H N O theo. 60.71 7.14 8.33 23.81 exp. 58.85 6.95 8.40 23.80.

Synthesis of BOC-gly-benzocaine (reaction intermediate for compound cited for comparison)

 In the same way, BOC-gly-benzocaine was prepared, the infrared spectrum data of which are as follows:

IR (KBr): 3360 cm ^{- 1} (m), 1720 cm ^{- 1} (F), 1680 cm ^{- 1} (F), 1600 cm ^{- 1} (F),

1540 cm (F and wide), 1289 cm ^{- 1} (F and wide).

Synthesis of BOC-L phe-benzocaine (reaction intermediate for compound according to the invention).

 In the same way, BOC-L phe-benzocaine was also obtained.

¹ H NMR (200 MHZ, chloroform-d):

δ (ppm): 1.40 (12H, CH ₃ benzo. and BOC), 3.15 (2H, H _ββ , phe),

4.35 (2H, CH ₂ benzo.), 5.20 (1H, H _α phe),

 7.25 (5H, ∅ phe), 7.50 and 7.90 (2H and 2H, ∅ benzo.), 8.30 (1H, NH benzo.)

IR (KBr): 3360 cm ^{- 1} (m), 1710 cm ^{- 1} (F), 1690 cm ^{- 1} (m), 1670 cm ^{- 1} (F),

1520 cm ^{- 1} (F and wide), 1275 cm ^{- 1} (F and wide).

Elementary analysis: (%) CHNO theo. 66.99 6.79 6.79 19.41 exp. 67.09 6.81 7.02 18.91 The synthesis of di-BOC-lys-benzocaine, BOC-glu (OBzl) -benzocaine and BOC-ser (OBzl) -benzocaine (Bzl meaning benzyl) was thus also carried out. These compounds are reaction intermediates for the compound cited for comparison.

 N deprotection is carried out with cold hydrochloric acid

(temperature below 20 ° C) in anhydrous dioxane.

 The deprotection of the acid and alcohol functions is carried out by catalytic hydrogenation on palladium.

The lengthening of the oligopeptide chain is carried out in the same way as the synthesis of BOC-ala-benzocaine.

 The following compounds were prepared according to the same synthesis techniques:

HCl, NH ₂ gly-benzocaine (compound cited for comparison), HCl, NH ₂ alabenzocaine (compound cited for comparison), HCl, NH ₂ phe-benzocaine (compound according to the invention), HCl, NH ₂ lys-benzocaine (compound cited for comparison), HCl, NH ₂ glu-benzocaine (compound cited for comparison), HCl, NH ₂ ser-benzocaine (compound cited for comparison), HCl, NH ₂ gly-gly-benzocaine (compound cited for comparison), HCl, NH-gly-phe-benzocaine (compound according to the invention), HCl, NH ₄ ala-phe-benzocaine (compound according to the invention), HCl, NH ₂ phe-phe-benzocaine (compound according to the invention),

HCl, NH ₂ lys-phe-benzocaine (compound according to the invention), HCl, NH ₂ glu-phe-benzocaine (compound according to the invention), HCl, NH ₂ ser-phe-benzocaine (compound according to the invention) , HCl, NH ₂ (gly), - benzocaine (compound mentioned for comparison), HCl, NH ₂ (gly) ₂ -phe-benzocaine (compound according to the invention), HCl, NH ₂ (gly) ₄ -benzocaine ( compound cited for comparison), HCl, NH ₂ (gly) ₃ - phebenzocaine (compound according to the invention), HCl, NH ₂ (ser) ₄ -benzocaine (compound cited for comparison), HCl, NH ₂ (gly) ₄ -phosphocaine (compound according to the invention).

EXAMPLE 2 Test of the Anesthetic Conduction Activity

The solutions intended to be administered to rabbits or guinea pigs are prepared extemporaneously. The suspensions (in physiological saline or the DMF / physiological saline mixture 1/9 by volume are previously prepared in the laboratory, the average diameter of the particles being close to 20 μm. These suspensions are chemically stable, over a minimum period of one month .

 The anesthetic conduction activity of the composition tested was measured by the disappearance of the contraction reflex of the skin muscle when the skin is pricked from the back of the animal.

 The tests were carried out on batches of ten albino guinea pigs of the Hartley strain, weighing approximately 300 g.

 The benzocaine derivatives were administered, either in solution in physiological saline, or in the form of a suspension for the derivatives which are sparingly soluble in water, and were prepared as indicated.

 At time t = 0, the test substance is injected by subcutaneous injection, at the level of the lumbar region. The volume injected is 0.25 ml. Thirty minutes after the injection, then again every 30 minutes and until the effect disappears, the local anesthetic activity is checked by pricking with a needle the point where the injection was carried out: we thus control the presence or absence of the skin reflex. The puncture of the point symmetrical to that of the injection with respect to the spine makes it possible to verify the existence of the reflex for a point not anesthetized.

 The test is considered positive when the bite does not cause a reflex.

 For each time, the sum of the positive tests collected from the 10 guinea pigs is carried out, and an average score is determined.

The local anesthetic activity of the different products is compared by drawing the curve connecting the logarithm of the average rating obtained at the time elapsed since the injection.

- Figure 1 shows the anesthetic conduction activity of benzocaine and its HCl derivatives, NH ₂ X-benzocaine with X = gly, ala, phe, ser in 1% solution in physiological saline.

We note here the completely exceptional and surprising aspect of the compound for which X = phe which is the only one in the series to have an activity significantly greater than that of benzocaine. Note that all the solutions are at 1% by weight and that when the grafted alpha amino acids have a high molecular weight, the actual amount of benzocaine injected is much lower; in the case of phenylalanine, this represents only 47% of the active ingredient equivalent.

 - Figure 2 shows the influence of the concentration of the compound

HCl, NH ₂ -phe-benzocaine on the anesthetic conduction activity, in comparison with benzocaine.

 It should be noted that in the case where a benzocaine substituted with ia phenylalanine is used at the same molar amount as benzocaine, that is to say phenylalanine-benzocaine at 2.1%, a plateau effect is obtained. 5 hours, which is quite exceptional.

- Figure 3 shows the anesthetic conduction activity of HCl derivatives, NH ₂ (gly) p-phe benzocaine at a concentration of 1% in physiological saline. Note the extremely prolonged plateau effects of the compounds for which p = 1, greater than 6 hours, the relatively short plateau effects of the compounds for which p - 2 or p = 4 with a very rapid decrease from the end of the effect tray.

 - Figure 4 shows the anesthetic conduction activity of the same compounds but for which the concentration instead of being 1% corresponds to an equi-molar concentration to that of benzocaine 1%.

All the compounds tested have a plateau effect, while the compounds for which p = 3 or p = 4 exhibit a rapid decrease at the end of the plateau effect. The compounds for which p = 2, p = 1 have a particularly long duration of action since no change is detected after more than 6 hours.

- Figures 5 and 6 show the anesthetic conduction activity of benzocaine and its derivatives of the HCl series, NH ₂ X-phe benzocaine with X = gly, ala, phe, lys or ser. All the compounds have an activity greater than that of benzocaine. Those with the longest duration of activity are very clearly those where X represents glycine or alanine. Figure 5 corresponds to a concentration of 1% by weight in physiological saline, while Figure 6 corresponds to a concentration equimolar to that of benzocaine 1%. - Figure 7 shows the anesthetic conduction activity of benzocaine and its derivatives of the HCl series, NH ₂ (gly) _p -benzocaine as a function of time and of the number p of glycine units at equimolar concentrations at 1% benzocaine.

 Thus, it has been shown that the activity of benzocaine could be modified by grafting an oligopeptide chain on the nitrogen of the aniline group. The choice of the amino acid sequence is decisive on the anesthetic conduction action, its intensity, its duration and the speed of its absorption after the maximum effect. The choice of L phenylalanine as C-terminal alpha amino acid allows a very significant increase in intensity and duration of activity vis-à-vis the starting anesthetic. The subsequent addition of alpha amino acid C terminal modulates the plateau effect, its duration and the speed of the fall from anesthesia at the end of the plateau.

More specifically, the family of anesthetics derived from benzocaine and symbolized by the formula NH ₂ (gly) _p -benzocaine, has the following characteristics, when these compounds are injected at a molar concentration equivalent to 1% of benzocaine:

 - the derivatives for which p = 0, 1 or 2 injected in suspension in the physiological saline, allow long-term anesthesia (5 or 6 hours).

 - the derivatives for which p is equal to 3 or 4 administered in solution both have a substantially identical pharmacological action, constant for 3 hours at around 100% of activity (100% of the animals tested being anesthetized ). After this period the anesthetic activity drops suddenly by 50% (half of the animals tested are no longer anesthetized) in 30 minutes and disappears completely in 1 hour - 1 hour and a half.

 Compounds of the above type in which glycine has been replaced by alanine give similar results. The lysine / phenylalanine and serine / phenylalanine sequences also have their specificity.

Claims

1. Application of the compounds of formula I:

where B is such that R-NH-B is an anesthetic derived from aminobenzoic acids; where R is H or a C ₁ -C ₅ alkyl radical, preferably linear, optionally functionalized in position 2 to 5; where [AA] _n is an oligopeptide group of 1 to 10 alpha amino acids, preferably 2 to 6, that is to say in which n is an integer from 1 to 10 and AA represents natural amino acids or synthetic alpha amino acids in D or L or D or L form, alpha amino acids can be different, with the precision that when R-NH-B is benzocaine, the first C-terminal acid is L phenylalanine when n = 1 and L, D or D, L phenylalanine when n is greater than 1 and their pharmaceutically acceptable salts, in the preparation of pharmaceutical compositions useful as anesthetics. 2. Application according to claim 1, characterized in that said compounds correspond to formula la:

in which R, AA and n have the same meaning as in claim 1, the first C-terminal acid being of preferably an alpha amino acid chosen from alpha lipophilic amino acids, preferably phenylalanine; X ₁ and X _{2 which are} similar or different are H or C ₁ -C ₄ alkyl, halogen, C ₁ -C ₆ hydroxy radicals; R ₁ is H or the radical corresponding to an alcohol, this alcohol derivative possibly leading to an ester of benzoic acid, in particular R ₁ can be C 1-C5 linear or branched alkyl, said alkyl possibly carrying one or more functional groups in positions 2 to 5. 3. Application according to claim 2, characterized in that when R ₁ is an alkyl group carrying functional groups, said functional groups are chosen from the group consisting of hydroxy, C ₁ -C ₅ alkoxy, amino groups, said group amino can be mono or disubstituted by C ₁ -C ₅ alkyl groups, the substituents being able to form with the amine group a nitrogen heterocycle C ₅ or C ₆ . 4. Application according to claims 2 and 3 taken separately, characterized in that the said compounds have the following formula:

in which A 'represents:  . H . an oligopeptide group [AA] _r where r is an integer from 1 to 9 and where [AA] represents either a natural amino acid or a synthetic alpha amino acid in D or L form, the amino acids possibly be different when r is different from 1. 5. Application according to claim 4, characterized in that A 'represents: O ) _p where p is an integer such as 0≤ p≤4, L-alanine), (L-serine), or (L-lysine)

6. Application according to one of claims 1 to 5 characterized in that said compositions are injectable anesthetic conduction compositions. 7. Formula compounds

in which A 'represents:  . H . an oligopeptide group [AA] _r where r is an integer from 1 to 9 and where [AA] represents either a natural amino acid or a synthetic alpha amino acid in D or L form, the amino acids possibly be different when r is different from 1, and their pharmaceutically acceptable salts. 8. Compounds according to claim 7, characterized in that A 'represents: p where p is an integer such that 0≤ p≤ 4 L-alanine) (L-serine) (L-lysine)

9. Method for potentiating anesthetics having an aromatic amino group, characterized in that an oligopeptide of 1 to 10 alpha amino acids is grafted onto said aromatic amine, the first of these alpha amino acids being, when the aromatic amine is benzocaine, phenylalanine, preferably L phenylalanine, and its L form when phenylalanine is the only grafted alpha amino acid.