FR2711137A1 - Allylamino esters, their process of preparation and their application in therapeutics - Google Patents

Abstract

Allylamino esters of formula (I): in which: R1 is H or lower alkyl, R2 is lower alkyl, lower cycloalkyl or phenylcycloalkyl, pyridyl or alternatively phenyl, lower phenylalkyl, lower diphenylalkyl or lower phenylalkenyl, in which the phenyl ring is optionally mono-, di- or trisubstituted by chlorine atoms, lower alkyl or lower alkoxy radicals or alternatively trifluoromethyl, acetamido or acetyloxy radicals, their racemic forms, their (S) enantiomers and their addition salts. Antiallergy medicaments.

Description

-1-

  Allylaminoesters, their preparation process and their application in theraneutics.

Summary

  The present invention relates to esters derived from 2-allylamino-2- (3,4dichlorobenzyl) -n-propanol, their preparation process and their applications particularly in therapy. Technological background of the invention British Patent No. 1,434,826 describes esters and carbamates of amino alcohols of general formula:

R1 R4

  R2 (CH2) x- - (CH2) y -CH2-O -COR7 R (CH2) z I

NOT

  / \ GB n. 1,434,826 R5 R6 in which R1, R2 and R3 are hydrogen, alkyl, hydroxyalkyl, trifluoromethyl or halogen, R4 is hydrogen, alkyl, cycloalkyl or aryl, R5 and R6 are hydrogen, alkyl, arylalkyl or together form a heterocyclic structure, and x, y, and z are zero or one, R7 being alkyl, arylalkyl, aryl, arylalkenyl, diarylalkyl, arylcycloalkylalkyl, heteroaryl,

amino or amino substituted.

  These compounds are announced as inhibitors of spasms and gastrointestinal peristalsis, some of them have analgesic properties, and this by being remarkably inactive on the

central nervous system.

  In patent application FR n 92 05518 not yet published, the applicant describes an invention which relates to new aminoesters of formula Cl

CI / CH2 \ / CH2-O-CO- R3

/C\NN_._R

  CH3 I R1 -2 - in which: R1 is H or lower alkyl, R2 is lower alkyl, phenylalkyl, cycloalkylalkyl; or R1 and R2 together form, with the nitrogen atom to which they are linked, a saturated heterocycle of five to seven members which can include a second heteroatom like oxygen not juxtaposed with nitrogen, R3 is lower alkyl, cycloalkyl or lower phenylcycloalkyl, pyridyl or phenyl, lower phenylalkyl, lower diphenylalkyl, optionally hydroxylated, lower phenylalkenyl, optionally mono, di or trisubstituted by chlorine atoms, lower alkyl radicals, lower alkoxy or radicals

  trifluoromethyl, acetamido or acetyloxy.

  These compounds show analgesic properties associated with activity on the system

  central nervous system (CNS), while having no effects on the gastrointestinal tract.

Detailed summary of the invention

  The present invention relates to new esters derived from 2allylamino-2- (3,4-

  dichlorobenzyl) -n-propanol, their preparation process and their therapeutic application,

  especially for their anti-allergic properties.

  The allylaminoesters of the invention correspond to formula (I): CI

CI CH12 CHO2CH - OCO - R2

c CH CH / cX

(2I) R1 --CH2

  in which: R1 is H or lower alkyl, R2 is lower alkyl, cycloalkyl or lower phenylcycloalkyl, pyridyl or even phenyl, lower phenylalkyl, lower diphenylalkyl, phenylalkenyl lower, in which the phenyl ring is optionally mono, di or trisubstituted by atoms of chlorine, alkyl radicals

  lower, lower alkoxy or trifluoromethyl, acetamido or acetyloxy radicals.

  Among all of the compounds, the preferred products are those in which R1 is methyl and R2 is methyl, phenyl or pyridyl, and, moreover, the invention preferably targets

  enantiomers of the compounds (I) of absolute configuration (S), established according to the rule of Cahn-

  Ingold-Prelog. The addition salts of the esters (I) with the acids are also included in the invention. More precisely with regard to the compounds, by lower radicals is meant linear or branched radicals comprising from 1 to 5 carbon atoms. Alkoxy radicals are more

particularly methoxy.

  As regards the acids, in particular those which are therapeutically acceptable, which are used in the preparation of the addition salts, mention may be made, by way of examples, of mineral or organic acids, such as acetic, benzenesulfonic, camphorsulfonic and citric acids. , ethane sulfonic, fumaric, hydrobromic, hydrochloric, lactic, maleic, malic, methanesulfonic, nitric, pamoic, phosphoric, salicylic, stearic, succinic,

sulfuric and tartaric.

  The invention also relates to a process for the preparation of aminoesters (I) from allylamino alcohols of formula (II) CI CI CH 2 \ *; k / CH2OH CH

CII) CH3

(11) R 1 --CH2

  in which R1 is H or lower alkyl, which consists in engaging them in alcoholysis reactions according to the scheme:

CI CI

Cl C

  CI \ H2 \ * / CH2OH \ -H2 \ * CH2- O-CO-R2

CC/

CH3 N CH \

3 P / C-

  C II) Ra R CH2 + R3_COR2 I) R1 CH2 on substrates R3-CO-R2 (III) in which - R3 represents a halogen atom X which is preferably chlorine or bromine, acyl halide R2-CO-X (IV) being used according to a procedure A, - R3 represents a labile radical -OR4 in which R4 is lower alkyl comprising from 1 to 4 carbon atoms which is preferably methyl or ethyl, the ester of formula R2-CO-OR4 (V) being used according to a procedure B, For the implementation of the process, the racemic allylamino alcohols (II) can be prepared as described in Examples 7 and 13 (R1 = H, R1 = CH3 ) of patent EP 237 366. The corresponding enantiomers of configuration (S) being prepared according to a method adapted from that described in this same patent or according to that of French application No. 92 05519 not yet published. This last preparation consists either of splitting their racemic correspondents or, preferably, by reaction of (S) - (-) - 2-amino-2- (3,4-dichlorobenzyl) -npropanol prepared in Example 1C of the EP patent 237,366, with an allyl halide in an inert solvent to obtain the allylamino alcohol (S) (I) in which R1 is hydrogen; then, by reductive methylation with formaldehyde and formic acid according to the Eschweiler-Clarke method, to obtain

  allylaminoalcohol (S) (II) in which R1 is CH3.

  As previously presented, procedure A which consists in obtaining the allylaminoesters (I) by alcoholysis of the acyl halides (IV) under the action of the allylamino alcohols (II) is carried out according to various techniques fully described (Sonntag, Chem. Rev . 52, 237-416 (1953) pages

312 to 324).

  The halides (IV) involved are commercially available or are prepared by the reaction of halides of mineral acids such as thionyl chloride, pentachloride or

  phosphorus pentabromide on corresponding R2-COOH acids.

  The actual alcoholysis reaction consists in reacting the compounds (II) and (IV) in an aprotic anhydrous solvent such as benzene, toluene, diethyl ether, tetrahydrofuran, dioxane, acetone, acetonitrile, pyridine, dimethylformamide, methylene chloride

  or chloroform which is the preferred solvent.

  Optionally, an acid acceptor is added to the reaction medium. This agent can be mineral or organic. Sodium or potassium carbonates,

  corresponding bicarbonates, or alternatively triethylamine or pyridine.

  An alternative method consists in previously preparing "in situ" the metal alcoholates of the allylamino alcohols (II), which are then subjected to the reaction with the compounds (IV). The metal alcoholates are prepared by the action of alkali metals such as sodium or its hydride or its amide, or also by reaction with sodium ethylate or potassium tert-butoxide in the presence of an inert compatible solvent. For example, the metallation reaction consists in reacting 1 mole of allylaminoalcohol (II) dissolved in 5 to 20 parts of dimethylformamide with 0.9 to 1.1 mole of sodium hydride, the reaction for forming l alcoholate being generally complete between 1 to 3 hours and at a temperature

between 0 and 30 C.

  The N-allylaminoesters (I) are obtained by reacting one mole of (II) or its alcoholate in solution in 5 to 20 parts of suitable solvent with 0.6 to 1.8 mole of acyl halide ( IV). However, the preferred ratios for one mole of (II) or its alcoholate are 8 to 15 parts of solvent and 0.8 to 1.3 mole of halide (IV). The reaction is then continued at

  a temperature between 10 and 110 C for a period between 1 and 24 hours.

  Preferably, the reaction, carried out between 20 and 60 C for 3 to 7 hours, allows

  to obtain the ester (I) with satisfactory yields.

  The compounds (I) are isolated from the reaction medium and purified by conventional methods

  such as extractions, crystallizations, column chromatographies.

  According to procedure B, the alcoholysis of the esters (V) previously defined by the allylamino alcohols (II) leads to the products of the invention (I) by transesterification according to the reaction:

(II) + R2CO-OR4 (V) -, (I) + R4OH.

  which is carried out in solution in anhydrous aprotic solvents in the presence of catalysts of acidic or basic nature. The elimination during the reaction of the alcohol R4OH formed is favorable, which is achieved by adding alcohol-sequestering agents to the medium such as molecular sieves of suitable porosity or by eliminating the alcohol as the as it is formed by distillation. The latter method is preferred and leads, on the one hand, to the use of esters (V) in which R4 is an alkyl radical comprising from 1 to 3 carbon atoms to obtain low-boiling R4OH alcohols such as methyl and ethyl alcohols , propyl or isopropyl and on the other hand to use as reaction solvents benzene, toluene or xylenes which form with the abovementioned alcohols

  azeotropes of low boiling point.

  The acidic or basic catalysts can be mineral and / or organic in nature. Basic catalysts are however preferred, such as alkali metals or not and their derivatives such as for example potassium tert-butoxide, aluminum triisopropylate, magnesium methylate, sodium, sodium hydride, ethylate and sodium methylate, these

  the latter alcoholates being particularly preferred.

  Practically the reaction consists in dissolving one mole of allylaminoalcohol (II) in 10 to 50

  parts by weight of the appropriate solvent, then add to the solution from 1.1 to 2.0 moles of ester (V).

  After adding 0.025 to 0.05 mole of catalyst, the mixture is heated to a temperature sufficient to distill off the alcohol formed or its azeotrope with the solvent. This temperature can be between 50 and 130 C and be maintained between 1 to 6 hours to obtain a satisfactory result. A particularly preferred technique consists in adding the catalyst in fractions or even continuously during the reaction, and, also in the case of azeotropic distillation, adding during the reaction of the solvent to compensate for the

loss caused by distillation.

  The preferred conditions consist in dissolving 1 mole of alcohol (I), 1.25 to 1.75 mole of ester (V) in which R4 is methyl in 25 to 35 parts by weight of toluene relative to the amount of ( II) engaged. The solution is heated to 65-75 ° C., 0.025 to 0.05 mole of sodium methylate is added and the toluene-methanol -6- azeotrope is slowly distilled for 1 to 2 hours. 0.0125 to 0.025 mol of sodium methylate are added again and distilled for minutes to 1 hour and this last operation is repeated once again. The products of the

  reaction are then isolated and purified according to the techniques mentioned above.

  The invention is illustrated in a nonlimiting manner by the following examples which make use of the procedures A and B previously described. The purity, the identity and the physico-chemical characteristics of the products of the invention are determined, as follows: - the purity is verified by chromatography on thin layers of silica gel. The Rf

  observed in the elution solvent used is reported in the examples.

  - the identity of the products obtained with the proposed structures is verified by their proton nuclear magnetic resonance spectrum at 60 or 90 MHz, the products being dissolved in deuterochloroform with tetramethylsilane as internal reference and, when studied under their salified form, by displacing beforehand, in situ, the base of its salt. The nature of the signals, their chemical shifts in ppm as well as the number of protons they

represent are noted.

  - for the products obtained in crystalline form, the crystallization solvent is indicated, as well as the value of the melting point, not corrected, determined by the capillary tube method.

  EXAMPLE 1: (R.S) -1-acetvloxv-2- [(N-allvl) -methvlaminol-

  2-methyl-3- (3.4-dichlorophenyl) -n-propyl. (R, = R2 = CH3). Procedure A.

  In a 200 ml reactor protected from humidity, 6.0 g (20.8mmol) of (R, S) -2 - [(N-allyl) -

  methylamino] -2- (3,4-dichloro-benzyl) -n-propanol are dissolved in 75 ml of anhydrous chloroform. With stirring in about 15 minutes and at 20 ° C, 2.0 g (25.3 mmol) of chloride

acetyl are introduced.

  The solution is heated for 5 h at reflux. After distillation under vacuum and on a water bath, the residue is dissolved in cold in 75 ml of 2N hydrochloric acid solution. The solution is extracted at

  three successive times with 25ml of ether.

  The ethereal phases are discarded; the acid phase is basified to pH 12 to 5 C with a concentrated solution of sodium hydroxide (d = 1.33), then extracted three times with 25ml

ether.

  The combined ethereal phases are washed by extraction with a saturated chloride solution.

  sodium and then dried over SO4Na2.

  After evaporation of the ether, the oily product obtained is purified by chromatography on

  column (Kieselgel (R) 60, reference 9385, Merck).

  Elution with a methylene chloride-acetone mixture 95-5 (v / v) makes it possible to obtain the product.

t - 7 -

  purified as a viscous oil.

  Weight = 5.3 g Yield = 77.1% Molar equivalent = 329.5 (theory 330, 2) TLC: Rf = 0.40-0.50 (methylene chloride-acetone 9/1 v / v) 1H-NMR 1.00 (s, 3H); 2.10 (s, 3H); 2.32 (s, 3H); 2.78 (d, 2H) 3.2 (d, 2H); 4.00 (s, 2H), 00-5.30 (m, 2H); 5.60-6.00 (m, 1H); 7.00-7.40 (m, 3H). Chlorhvdrate In 60 ml of anhydrous methylene chloride, 5.1 g (15.4 mmol) of the preceding product are dissolved. At a temperature below 10 ° C., 12 ml of 4N hydrochloric ether solution are added. The solution is stirred for 2 h at room temperature, then the solvents evaporated in vacuo and on a water bath. The residue taken up in 75 ml of methylene chloride is treated again

  identically with 10 ml of 4N hydrochloric ether solution.

  The crude amorphous residue is purified in 80 ml of petroleum ether. The product is filtered, dried under

empty at 40'C.

  Weight = 5.0g F = 94 C Efficiency = 98%

  EXAMPLE 2: (S) - 1-acetvloxv-2- [(N-allyl) -methylaminol-

  2-methvl-3- (3.4-dichlorophenyl) -n-propyl. (R1 = R2 = CH3). Procedure A.

  The product is prepared according to the procedure of the previous example from (S) -2 - [(N-

  allyl) -methylamino] -2- (3,4-dichlorobenzyl) -n-propanol [Ca] D20 = + 13 (c = 1, HC1 N) and acetyl chloride. The ester is obtained with a yield of 44% after chromatographic purification. Molar equivalent = 328.3 (theory 330.2) TLC: Rf = 0.40-0.50 (methylene chloride-acetone 9/1 v / v)

  1H-NMR signals and displacements identical to those of the compound of Example 1.

  EXAMPLE 3 (R.S) -1-Benzoyloxy-2 - [(N-allyl) -methylaminol-

  2-methvl-3- (3.4-dichlorophenvl) -n-propvle. (R1 = CH3, R2 = C6H5).

Procedure A.

  Preparation according to Example 1 from (R, S) -2 - [(N-allyl) methylamino] -2- (dichloro-3,4-

  benzyl) -n-propanol and benzoyl chloride. Yield after purification = 45%.

  Molar equivalent = 390.5 (theory 392.4) TLC: Rf = 0.60-0.65 (methylene chloride-acetone 9/1 v / v) 1H-NMR 1.10 (s, 3H); 2.40 (s, 3H); 2.80 (s, 2H); 3.30 (d, 2H) 4.30 (s, 2H); 5.00-5.30

  (m, 2H); 5.60-6.00 (m, 1H); 7.00-8.10 (m, 8H).

  Hydrochloride Yield = 86% F = 84'C (ethanol)

t - 8 -

  EXAMPLE 4: (R.S) -1-acetyloxy-2-allylamino-2-methyl-3- (3.4dichlorophenvl) -n-

  propyl. (R1 = H; R2 = CH3). Operating mode A "alternative".

  In a 250 ml reactor protected from humidity and under a nitrogen atmosphere, 14.0 g (51 mmol) of (R, S) -2-allylamino-2- (3,4-dichlorobenzyl) -npropanol are added in portions in 20 minutes in 1.25 g (51 mmol) of sodium hydride suspended in 45 ml of anhydrous dimethylformamide. The addition is slightly exothermic. The greenish suspension obtained is stirred for one hour at -25 ° C., then 3.3 ml (46 mmol) of acetyl chloride are added at 20 ° C. and in approximately 15 minutes.

  pure. During the addition a beige precipitate is formed.

  The mixture is stirred for one hour at room temperature and then precipitated in 500 ml of ice water. The aqueous suspension is brought to pH 1 by addition of concentrated hydrochloric acid, then

  extracted three successive times with 125ml of ether.

  The ethereal phases are discarded. The acidic aqueous phase is basified in the cold to pH 12 by addition of concentrated sodium hydroxide solution (d = 1.33), then extracted at three

taken up in 100 ml of ether.

  The combined ethereal phases are washed by extraction with a saturated sodium chloride solution and then dried over SO4Na2. After evaporation of the ether, the residue weighing 10.2 g is purified by column chromatography (Kieselgel 60, reference 9385, Merck). Elution with a methylene chloride-acetone mixture 95-5 (v / v) makes it possible to obtain the purified product.

in the form of a viscous oil.

  Weight = 4.3 g Yield = 26.7% Molar equivalent = 312.4 (theory 316, 2) TLC: Rf = 0.60-0.65 (methylene chloride-acetone 9/1 v / v) 1H-NMR 1.00 (s, 3H); 1.50 (s, large, 1H exchangeable with D20); 2.10 (s, 3H); 2.70 (s, 2H);

  3.25 (d, 2H); 3.90 (s, 2H) 5.00-5.40 (m, 2H); 5.70-6.20 (m, 1H); 6.90-7.40 (m, 3H).

  Hydrochloride Yield = 78% F = 165 C (ethyl acetate)

  EXAMPLE 5: (R.S) -1-benzoyloxv-2-allvlamino-2-methvl-3- (3.4dichlorophénvyl) -n-

  propyl. (R1 = H, R2 = C6H5). Procedure B. 280 ml of anhydrous toluene, 9, Og (32.8 mmol) of 2-allylamino-2- (3,4-dichlorobenzyl) -n-propanol and 6 are successively introduced into a reactor protected from humidity. , 7g (49.2mmol) of

methyl benzoate.

  The mixture is stirred and after dissolution of the reagents brought to 65-70 ° C. Drop by drop, 1.6 ml of 4.1 M methanolic sodium methoxide solution are added. For one hour, the

nW - -9-

  The reaction mixture is gradually heated so as to ensure slow distillation. The mixture is cooled to 60 ° C., 0.54 ml of sodium methylate solution is added and

  the distillation operation started again.

  A third and final addition of 0.54 ml of methylate solution is carried out followed by a period of slow distillation lasting 30 minutes. After cooling to 200C, the mixture is extracted three times with an acid solution

2N hydrochloric acid (100-75-75 ml).

  The combined acid phases are made alkaline at 10 C to pH 12 by addition of solution

  concentrated sodium hydroxide (d = 1.33), then extracted three times with 75 ml of ether.

  The combined ethereal phases are washed by extraction with a saturated sodium chloride solution and then dried over SO4Na2. After evaporation of the ether, the crude product (86.5 g) is purified by column chromatography (Kieselgel (R) 60 - reference 9385 - Merck). Elution with the methylene chloride-acetone mixture 90-10 (v / v) makes it possible to obtain the pure product under

oil form.

  Weight = 10.0 g Yield = 80.6% Molar equivalent = 382.9 (theory 378.31) TLC: Rf = 0.35-0.45 (methylene chloride-acetone 9/1 v / v) 1HRMN 1 , 10 (s, 3H); 1.40 (s, 1H exchangeable D20); 2.80 (s, 2H); 3.30 (d, 2H); 4.20

  (s, 2H); 5.00-5.35 (m, 2H); 5.70-6.15 (m, 1H); 6.90-8.10 (m, 8H).

  Hemimaleate 9.2 g (24.6 mmol) of the ester obtained above and 2.9 g (24.6 mmol) of maleic acid in 90 ml of ethanol are refluxed for 5 minutes. The solution is left at room temperature and then cooled for one hour to 0-5 ° C. The crystalline compound is filtered and then dried under vacuum at 50 ° C. Weight = 9.8g (80.5%) F = 149'C

  EXAMPLE 6 (R.S) -1- (3-pyridyl) carbonyloxy-2-allvlamino-2-

  methyl-3- (3.4-dichlorophenyl) -n-propyl. (R1 = H, R2 = 3-pyridyl).

Procedure B.

  The compound is prepared according to the procedure of Example 5 above from (R, S) -

  2-allylamino-2- (3,4-dichlorophenyl) -n-propanol and methyl nicotinate.

  Viscous oil Yield = 50.5% Molar equivalent = 382.9 (theory 379.3) TLC: Rf = 0.20-0.30 (methylene chloride-acetone 75/25 v / v) 1H-NMR 1.00 (s, 3H); 1.20-1.30 (m, 1H exchangeable D20); 2.65 (s, 2H); 3.30 (d, 2H) 4.15 (s, 2H); 5.00-5.30 (m, 2H); 5.70-6.20 (m, 1H); 6.90-7.60 (m, 3H); 8.15-8.35

  (m, 1H); 8.75-8.90 (m, 1H); 9.20-9.30 (m, 1H).

- 10- Hydrochloride

  Yield = 82.8% F = 121 ° C (ethanol / ether).

  Toxicity and pharmacological tests.

  In animals, the acute toxicity of the products appears to be low. Their pharmacological study highlights their antihistamine activity as well at the bronchial level as at the vascular level, the compounds being administered by oral or intravenous route, which authorizes their use for the treatment of various allergic reactions and more particularly of those

caused by histamine.

  The acute toxicity of the compounds has been studied orally in male mice. For this, the

  products were administered in aqueous solution at a rate of 2 ml per 100 g of body weight.

  The animals were observed for three hours after administration and then

  daily for 14 days, after which they were sacrificed and autopsied.

  The LDs50 (lethal doses causing the death of 50% of the animals) were calculated according to the method of Reed J.L. and Muench H. (Am. J. Hyg. 1939, 27, p.493) and are not lower

  at 1000 mg / kg for the products of the invention.

  The antihistamic properties of allylaminoesters (I) have been demonstrated by their ability to protect the guinea pig from this allergen-induced bronchospasm, as well as their ability to inhibit in the rat the increased capillary permeability induced at the injection site.

  intra-dermal with a histamine solution.

  - Inhibition of histamine-induced bronchospasm The study is carried out in guinea pigs by the bronchoconstriction test performed according to the method of H. Konzett and R. Rossler (Arch. Exp. Path. Pharmak. - Naunym Schmiedeberg -195 , 71-74,

  1940), the products of the invention being studied after intravenous administration.

  The preparation of the animals engaged in the test consists in anesthetizing male guinea pigs weighing 350 to 400 g by intraperitoneal injection (ip) of a sterile and isotonic solution containing% (w / v) ethyl carbamate at 6.0 ml / kg, then pair the animals with a tracheal cannula to allow measurement of pulmonary pressure, a cannula in the right jugular vein for intravenous (iv) solution administration and also a cannula

  in the left carotid artery for qualitative observation of blood pressure.

  The animals are then connected to a pump (Harvard, ref. 50-1718) in order to maintain artificial ventilation at a frequency of 60 breaths per minute; intratracheal pressure is recorded by a set comprising a transducer, an amplifier and a recorder

  (Gould, respective refs: PLOEZ, 13-4615-50 and 8188-G4400-06).

  Thus fitted, the animals are left to rest for 10 minutes before the start of

the actual experiment.

  it - The treatment of animals consists of a series of administrations of an isotonic solution of histamine dihydrochloride at a rate of 100 gmol / kg, before and after treatment with an isotonic solution of test product, which is carried out according to the following chronology: t = 20 minutes - histamine (100zmol / kg) t = - 10 minutes - id. control t = 0 - injection of the test product t = + 10 minutes - histamine (100 fLmol / kg)

t = + 20 minutes - id.

t = + 30 minutes - id.

t = + 40 minutes - id.

t = + 50 minutes - id.

t = + 60 minutes - id.

  The results of the tests are presented in Table 1, the activity of the products being expressed by the percentage of variation in amplitude of bronchoconstriction calculated relative to that caused by the "control" administration of histamine which precedes the administration of the product. for testing. The% variation is calculated according to the formula: Bc (tx) - Bo (tx)% variation = 100- (X 100) Bc (to) - Bo (to) in which: Bc (tx) represents the amplitude in mm from bronchoconstriction at time x, Bo (tx) the amplitude in mm of basal respiration at time x, Bc (to) and Bo (to) the corresponding amplitudes in mm during the "control" administration of

  the histamine which precedes that of the product under test.

  The results are expressed in% of variation at the time considered and for a given concentration of the test product. Under these conditions, a positive percentage corresponds to a potentiating effect of bronchoconstriction, and, conversely, a negative percentage to the effect

inhibitor sought.

  Statistical analyzes of the results were performed by Student's t test. A value of p

  <0.05 is considered significant.

- 12 -

  Compound Dose iv% variation -mg b./kg -jÀmol / kg 1 min 11 min 21 min 31 min 41 min 51 min 61 min Ex. 1 -1, 37mg -6.6 (ns) -83.1 -92, 5 -94.0 - 87.3 -90.2 -86.3 -4.15 / mol Ex. 3 -1.37mg +0.5 (ns) -93.8 -95.0 -91.7 - 92.7 -85.9 -84.6 -3.40 / mol Ex. 4 -1.37mg -15.7 (ns) -33.0 (ns) -53.6 -59.8 (ns) - 57.1 -58.7 -59.6 -4.33 / xmol Ex.5 -1.37mg -14.6 (ns) -50.2 -66.4 -67.0 (ns) -54.0 (ns) -56.6 -56.3 -3.62itmol Ex. 6 -1, 37mg +12.5 (ns) -29.1 (ns) -59.7 (ns) -68.3 (ns) -66.9 -65.9 -63.8 -3.62 / mol (ns): result not statistically significant Table 1: Inhibition of histamine-induced bronchospasm in guinea pigs -13- -Inhibition of increased capillary permeability The study consists in determining in rats the protective effect of the compounds of the invention administered orally on the increase in capillary permeability caused by

  intra-dermal injection of a histamine solution into the dorsal region of the animal.

  The test is carried out on male Sprague Dawley rats weighing 180 to 200 grams which, on the day of the test, are randomized at the rate of 6 animals per cage then shorn over their entire dorsal region. The test consists, 45 minutes before the injection of histamine (t = -45), in administering the product by the oral test in aqueous solution and at the rate of lml of solution for 10Og of weight

  body, then 30 minutes after this administration (t = -15) to be injected intra-

  venous solution of Bleu Evans at a rate of 0.5 ml per 100 g of animal body weight.

  A histamine solution (1001 g / ml) is then injected intradermally at the rate of 0.1 ml.

  by injection and in four separate areas in the back of each animal.

  The animals are sacrificed fifteen minutes after these injections, the dorsal skin is then removed and there are observed on the inner face of blue papules of oval shape. Their large diameter L and their small diameter 1 are measured and the area of each papule is determined using the formula: Area (mm2) = L x 1 x X / 4 The average area of the papules is calculated for each batch d 'animal. The statistical analysis is carried out using the Student's t test and a percentage of reduction compared to the control batch is determined for each of the treated batches. The ED50 (effective dose of compound which decreases the size of papules by% compared to that of the control batch) is then calculated. The results of

  these tests are presented in Table 2.

  Compound DE5e mg / kg - oral Example 1 20.2 mg / kg Example 4 19.8 mg / kg Example 5 28.4 mg / kg Example 6 27.4 mg / kg table 2: Inhibition of the increase in capillary permeability caused

by histamine in rats.

  - 14- The results of these tests are conclusive of the inhibitory activity against the effects caused by histamine in the bronchoconstriction test in guinea pigs and that of the increase in

  capillary permeability in rats.

  Also, in the form of suitable pharmaceutical compositions, the compounds of the invention, by their activity, are useful for human or veterinary therapy aimed at treating asthmatic states and in particular at inhibiting bronchoconstriction or

  bronchospasm from allergic asthma or those resulting from acute or chronic bronchitis.

  Also the antihistamine activity of the compounds justifies their application to the symptomatologies caused by the release of histamine such as for example in allergies of the nasal and connective mucous membranes, allergic rhinitis, certain forms of edema, dermatoses,

pruritus or eczema.

  The low toxicity of the products allows, to obtain the expected effects, daily dosages of up to 1000 mg orally. Usually, however, they are 50 to 500 mg per day, orally, which can be divided if necessary into

several takes.

  The products of the invention or their pharmaceutically acceptable salts are administered in the form of compositions suitable and compatible with the routes suitable for the nature and

  the importance of the condition to be treated.

  These compositions are, for example, tablets, dragees, capsules, powders, suppositories, gels, suspensions or even injectable, drinkable or even sprayable solutions. They are prepared by methods common to a person skilled in the art and comprise from 1 to% by weight of active principle consisting of one or more compounds of formula (I) or their salts and 99 to 50% by weight of vehicle. pharmaceutical suitable and compatible with

  active ingredients and the physical form of the intended composition.

  By way of nonlimiting examples, the preparation of tablets and isotonic solutes

  injectable with the compounds of the invention is presented.

  Tablets - Formula Active substance according to Example 1 5 to 75 mg Polyvinylpyrrolidone 2 mg Carboxymethyl starch 8 mg Magnesium stearate 3 mg Lactose 60 to 76 mg Monocrystalline cellulose 122 to 76 mg

- 15 -

for a 200 mg tablet.

- Manufacturing.

  Dissolve polyvinylpyrrolidone at 0.1 to 1.0% by weight in water, a low alcohol

  molecular weight such as ethanol or a hydroalcoholic mixture.

  Furthermore, thoroughly mix the active substance, lactose, half the amount of cellulose and carboxymethyl starch and moisten this mixture with the solution obtained previously. Granulate the dough, dry the granules to calibrate them on a sieve. Add the rest of the

  components, mix thoroughly then compress at a rate of 200 mg per unit.

  Isotonic solution - Formula Active substance of Example 1 10 mg Sodium chloride 9 mg Distilled water in sufficient quantity for 1.0 ml The solution is divided into ampoules which can be sterilized after sealing by the usual thermal means. However, preferably, the solute is sterilized by filtration, divided into

  ampoules which are then sealed, these operations being carried out in a sterile atmosphere.

A cs - 16-

Claims (2)

  1) Allylaminoesters of formula (I): CI cI Iy H C I C CH2 / CH 2 -O - CO-R2 C CH C (I) R1 CH2   in which: R1 is H or lower alkyl, R2 is lower alkyl, cycloalkyl or lower phenylcycloalkyl, pyridyl or even phenyl, lower phenylalkyl, lower diphenylalkyl, phenylalkenyl lower, in which the phenyl ring is optionally mono, di or trisubstituted by atoms of chlorine, lower alkyl, lower alkoxy or alternatively trifluoromethyl, acetamido or acetyloxy radicals, and their addition salts, 2) Allylaminoesters according to Claim 1, characterized in that R1 is methyl, 3) Allylaminoesters according to Claim 1 or 2 characterized in that R2 is methyl, phenyl or pyridyl, 4) Allylaminoesters according to claim 1, 2 or 3 characterized in that their   absolute configuration is established in form (S), according to the CahnIngold-Prelog rule.   ) Process for the preparation of the allylaminoesters (I) according to claim 1, characterized in that it consists in engaging in alcoholysis reactions of the allylaminoalcohols of formula (II) CI CH C3 ({II) R1 -CH2 - 17 -   in which R1 is H or lower alkyl, on substrates R3-CO-R2 (III) in which - R3 represents a halogen atom X which is preferably chlorine or bromine, the substrate being an acyl halide R2 -CO-X (IV), - R3 represents a labile radical -OR4 in which R4 is lower alkyl comprising from 1 to 4 carbon atoms which is preferably methyl or ethyl, the substrate being an ester of formula R2-CO-OR4 (V),   6) Process according to claim 5, characterized in that it consists in reacting the compounds obtained by the said process with acids to obtain their addition salts, 7) Antiallergic medicament characterized in that it comprises, as active ingredient   an allylaminoester (I) according to one of claims 1 to 4.