FR2760454A1 - (R) N- (1-CYCLOPROPYLMETHYL-PYRROLIDINE-2YLMETHYL) -BENZAMIDE AND ITS UTILITY AS ANTIDIARRHEIC - Google Patents

Abstract

(R)N-(1-cyclopropylmethylpyrrolidin-2-ylmethyl)benzamide of formula (I); its (R,S) racemic mixture and their addition salts with pharmaceutically acceptable acids; their use as antidiarrhoeals in mammals.

Description

(R) N- (1-cyclopropylmethyl-pyrrolidin-2-ylmethyl) -benzamide and its usefulness

  The invention relates to (R) N- (1-cyclopropylmethyl-pyrrolidin-2-ylmethyl) -benzamide and the racemic (R, S) corresponding thereto, their salts, and their usefulness as medicaments.

antidiarrheals in humans.

  BACKGROUND OF THE INVENTION Secretory disorders of the gastrointestinal tract, together with motor disorders, are responsible for the majority of chronic or acute diarrhea which, in 1990, was estimated to be the second leading cause of global mortality, particularly among infants.

  countries under development.

  Chronic diarrhea is defined by its persistent duration usually beyond two weeks. Their known mechanisms and the diagnostic strategy to be followed in these cases has been documented by M. CERF - Gastroenterol. Clin. Biol, 1992, 16, T 12-T 21. and more

  recently by M.J.G.FARTHING - Eur. J. of Gastroenterol. & Hepatol. 1996, 8: 157-167.

  Acute diarrhea, which is largely infectious, was also

  documented by M.CERF and M.HAGIAGE: Acute diarrhea of infectious origin. -

  Technical Editions - Encycl. Med. Chir. (Paris-France), Gastroenterology, 9061 A ', 1992, 20p., And H.L.DuPONT - Review article: infectious diarrhoea - Aliment. Pharmacol. Ther. 1994; 8: p.3-13. Among other causes is the important role of toxinogenesis during bacterial infection, and in particular the expression of pathogenicity by the synthesis of cytotoxins and enterotoxins, thermolabile or thermostable, which are responsible for secretory diarrhea to hydroelectrolytic component whose representative pathophysiological model is that of cholera. Other infectious agents are known to cause such diarrhea as strains of Salmonella, Escherichia coli

  (E. coli) and Clostridium difficile (C.difficile).

  These latter agents, and more particularly C. difficile, are responsible for chronic and abundant secretory diarrhea, often of nosocomial origin, in subjects undergoing intensive antibiotic therapy such as HIV + patients. In the latter, especially debilitating diarrhea, are often associated with malabsorption, and contribute to

  quickly establish a state of alarming malnutrition.

  For the treatment of secretory diarrhea, rehydration of patients is advised and is sometimes necessary. The usual symptomatic treatments use adsorbent compounds (smectite), modulators of the intestinal flora and, very largely, so-called "retarders", which are morphinomimetic antidiarrheals: loperamide (INN) and diphenoxylate (INN). ), recognized inhibitors of the motility of the tract and, therefore, controversial utility if not recommended for certain diseases, among other reasons by the delay they bring to the natural evacuation of pathogenic germs. More recently, it has been proposed to treat these diarrheas with acetiphan (DCI), an antisecretory inhibitory enkephalinase synthesis dipeptide, which maintains the effect of enkephalins, endogenous antisecretory neuropeptides of the intestinal wall, which are normally rapidly hydrolysed. "in vivo" by enkephalinases which makes their effect

fleeting.

  Recently, for cases refractory to conventional therapies, peptides inhibiting the motility and gastrointestinal secretion related to somatostatin (M.CAMILLERI - Digestion 1996; 57 (suppl 1): 90-92 & MJGFARTHING - Digestion 1996; 57 (suppl 1): 107-113). Substituted synthetic compounds of this endogenous mediator are octreotide (INN) and valtreotide (INN), both octapeptides proposed with some success for the treatment of secretory diarrhea of AIDS. These expensive compounds are active only by parenterally repeated administration which leads to prohibitive treatment costs which are increased by their method of administration with difficulty.

  feasible in an extra-hospital environment.

  Moreover, certain compounds defined as sigma receptor-specific ligands have shown antisecretory properties suggesting their usefulness in the treatment of diarrhea. So,

  WO 95/15948 published June 15, 1995 claims 2-arylalkenyl derivatives.

  azacycloalkane ligands at sigma receptors, their method of preparation and their therapeutic application. The compounds, their isomers and their addition salts are proposed for the preparation of antipsychotic drugs and useful in gastroenterology. In particular, it is mentioned that the compounds of the application are active on secretory diarrhea induced in mice by lipopolysaccharide (LPS) of salmonella, which suggests that they are

  utility in the treatment of secretory diarrhea of various etiologies.

  The presentation of treatments and further research for new secretory diarrhea therapies is indicative of an imperfectly fulfilled need for

  concerns the proposed drugs.

  In the field of structures related to the compounds of the invention, the state of the art reveals two families of compounds which differ essentially in the number

  and / or the nature of the substituents of their "benzamide" sequences.

  As regards the unsubstituted compounds, the publication of patent JP 53025560 (Chem Abstracts, 89, 109068, 1978) describes, without mention of pharmacological activity, the

  preparation of the racemic 2- (aminomethyl) -1-ethylpyrrolidine by saponification of N- (1-

  Intermediate Ethylpyrrolidin-2-ylmethyl) -benzamide of Formula H N C2H5 In a conformational analysis of dopaminergic benzamides, I. Petterson et al. (J. Med Chem 1992, 35, 2355-2363) show in the publication, by way of general formula and without exemplifying it, (S) N- (1-methylpyrrolidin-2-ylmethyl) -benzamide of formula Moreover, with regard to the compounds of which the benzamide sequence is substituted, FR 5,916 M claims heterocyclic benzamide-containing medicaments including sulpiride (DCI) of the formula

SO2NH2

H Ha N N OCH3

C2H5

  which was developed and made available for the treatment of psychoses.

  The adverse effects, particularly neurological, of this product have caused considerable research efforts to control them. Among others, the resolution of racemic sulpiride in its R (+) and S (-) enantiomers, the latter named levosulpiride (DCI), being recognized as a selective dopamine D2 receptor inhibitor in the central nervous system and the gastrointestinal tract whose motility it increases while its antipode R (+) is without effect (E. Zuccato et al - Pharmacological Research, Vol.26, No. 2, 1992, pp. 179-185; Guslandi - Curr Therap Researc, Vol 53, No. 5, May 1993,

p. 484-501).

  More particularly, considering the related substituted benzamides which comprise the N- (1-cyclopropylmethylpyrrolidinyl-2-ylmethyl) sequence: FR 2 294 698 discloses 2-methoxybenzamide derivatives useful for the treatment of nervous and psychosomatic affections and of formula R2 (CH2) n N

(CHN OCH3

  O R.1 in which more particularly - n represents an integer equal to 1,

  - R, represents a cycloalkyl alkyl (CH2) m = CH-A-

  wherein m is at least 2 and A is linear alkylene of 1 to 4 carbon atoms. * The certificate of addition FR 2 327 771 refers to the enantiomers corresponding to the compounds

of the main patent FR 2 294 698.

  A second addition certificate FR 2 394 529 relates to compounds, in their racemic form and to enantiomers, which can be used in the treatment of affections of the field of the central nervous system and of formula R.sub.2 N

N OCH3

  In which more particularly: R 'is cycloalkylalkyl of formula (CH2) m = CH-A-om represents the number 2, 3, 4 or and A is an alkylene radical of 1 to 4 carbon atoms * Patent FR 2 418 226 relates to methoxy-2-alkylthio-5-benzamides, racemic or enantiomers, active in the field of the central nervous system and of formula R

CN> \ N - 0CH3

(CH2) n

  in which more particularly n is equal to 1, 2, 3 or 4.

  * Application for a certificate of addition FR 2 447 910 relates to 2-methoxy-5-alkylthiobenzamides, racemic or enantiomers, which are related to the compounds of main patent FR 2 418 226 and of formula

S

N OCH3

  (CH2) m, (CH2) n in which more particularly: m is 2, 3 or 4, is not equal to 1,2,3 or 4

  also the invention specifically targets the (S) (-) enantiomer of N [(cyclopropylmethyl)

  2-pyrrolidinyl-2-methyl-2-methoxy-5-methylthio benzamide compound for which m = n =

I and R = methyl.

  * The application FR 2,447,911 published on 29/08/90 relates to benzamides, racemic or enantiomers, active on the central nervous system and CF3 formula

H

* NOT

N OCH3

^ (CH2) m (CH2) n

  in which more particularly m = n = 1.

  The application EP 207 913 relates to catechols racemic benzamides or optical isomers of formula

No. A2

3

  in which more particularly R3 is a cycloalkyl group, compounds useful for the treatment of emesis, anxiety states, psychosomatic diseases such as schizophrenia and depression, alcoholism-related diseases, confusion states and sleep disorders in the elderly. The applicant indicates that, for the enantiomers, the compounds of (S) configuration are preferred when R 3 is alkyl or alkenyl and those

  of configuration (R) when R3 is phenyl or substituted phenyl.

  Patent FR 2 593 504 relates to derivatives of dihydrobenzofuran and chromane carboxamides, racemic or enantiomers, of neuroleptic activity and of the formula -7-YZN (CH 2) n (CH 2) m 2 O + in which more particularly Z is a group N X-. R3

  wherein R3 is cycloalkylalkyl.

  The application FR 2 678 266 relates to derivatives of 2-hydroxy-4-amino-ethylsulfonyl benzamides, racemic and optical isomers, useful as anxiolytics and of formula

S02C2H5

X HNH2

  Embedded image in which m = n = 1; R is cyclopropymethyl, the carbon of the ring

  substituted pyrrolidine in position 2.

  As just presented, the state of the art close to the product of the invention essentially teaches that the N- (pyrrolidinylmethyl) -benzamides substituted at the 1-position of the pyrrolidine radical by lower alkyl or cycloalkylalkyl groups and comprising on the radical benzamide a

  ortho oxygen radical of the carboxamide function are drugs.

  This oxygen radical is found to be essential to an activity on the central nervous system, an activity which, for the enantiomers, is preferential of the (S) configuration when the 1-substituent of pyrrolidine is alkyl or cycloalkyl-lower alkyl, and is preferred for the (R) configuration when this substituent comprises an aromatic such as phenyl

or substituted phenyl.

  The present invention differs radically from this state of the art in proposing as a medicament useful in the treatment of secretory diarrhea a new benzamide, which is not substituted in the ortho position by an oxygen atom, and for which, contrary to what is taught, the activity is preferred for the configuration enantiomer (R) although

  the substituent radical at the 1-position of the pyrrolidine is cyclopropylmethyl.

-summary of the invention

  The object of the invention is as new compounds (R) N- (1cyclopropylmethyl)

  pyrrolidin-2-ylmethyl) -benzamide of formula (I), N the corresponding racemic compound (R, S) (I '), their addition salts with acids

  pharmaceutically acceptable, process for their preparation.

  It also relates, as medicaments, to (R) N- (I cyclopropylmethylpyrrolidine-

  2-ylmethyl) -benzamide of formula (I), the corresponding racemic compound (R, S) (I '), and their addition salts and their use in the preparation of pharmaceutical compositions for the treatment of secretory diarrhea in the man. It also comprises the drug compositions comprising as active principle the (R) N- (1-cyclopropylmethyl-pyrrolidin-2-ylmethyl) -benzamide of formula (I), the corresponding racemic compound (RS) (I '), and their addition salts in quantity

therapeutically effective.

  - detailed description of the invention

  In the first place the invention aims as new products on (R) N- (l-

  cyclopropylmethyl-pyrrolidin-2-ylmethyl) -benzamide of formula (I), the corresponding racemic compound (R, S) (I '), and their addition salts with pharmaceutically acid -9 -

acceptable.

  As a pharmaceutical active ingredient and according to the standards in force in this industry, the eutomer (R) is preferably optically pure, that is to say that the product is practically free of its antipode (S) and is at least with an optical purity of 95% and preferably equal to or greater than 98% in a (R) -steromer and determined by the means

appropriate analytics.

  By racemic is conventionally meant the compound comprising equal parts enantiomers (R) and (S). However, the compounds comprising a mixture in which the eutomer (R) is in an amount greater than 50% are considered an integral part of

the invention.

  By pharmaceutically acceptable addition salts are meant those, inorganic or organic, including their possible isomers, demonstrated to be atoxic at the current therapeutic doses of which, for example, a list is presented in J. Pharm. Sci., 1977, vol. 66, p. 1-19. As non-limiting examples, acetic acid, benzenesulphonic acid, camphorsulfonic acid, citric acid, ethanesulphonic acid, hydrobromic acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, mucic acid, nitric acid, pamoyl acid, phosphoric acid

  salicylic, stearic, succinic, sulfuric, tartaric and hydrochloric acid which is preferred.

  In another aspect, the invention relates to a process for preparing (R) N- (1)

  cyclopropylmethyl-pyrrolidin-2-ylmethyl) -benzamide of formula (I) and its racemic (R, S) (I ') which consists of performing an N-substitution of the pyrrolidine radical of the eutomer (R) or the racemate ( R, S) of Npyrrolidin-2-ylmethyl-benzamide (II), either by alkylation with a halomethylcyclopropane, preferably bromomethylcyclopropane, or by reductive alkylation with cyclopropanecarboxaldehyde in the presence of a reducing agent, or else to carry out an acylation by the chloride, an anhydride or a cyclopropanecarboxylic acid ester and then reducing the cyclopropanecarboxamide intermediate by an appropriate reducing agent or - to carry out the benzoylation of the eutomer (R) or the racemic (RS) of the 2- aminomethyl-1-cyclopropylmethyl pyrrolidine (III) by reaction with benzoic acid or a derivative thereof such as a halide, such as preferably chloride or an anhydride

  optionally mixed or a lower alkyl ester such as methyl or ethyl.

  However, the preferred methods used consist in carrying out the N-substitution of the

- 10 -

  pyrrolidine radical of the eutomer (R) or racemic (R, S) of Npyrrolidin-2-ylmethyl-

  benzamide (II) by alkylation with bromomethylcyclopropane and, particularly preferably, benzoylation of the (R) or racemic (R, S) eutomer of 2-aminomethyl-1-cyclopropylmethyl pyrrolidine (III) with benzoyl as described in Scheme 1.

N H N, N H

  (It I) Ol (II) ++ Br Cl (1) The N-substitution reaction of intermediates (II) by alkylation with bromomethylcyclopropane consists in treating the reactants in equimolecular ratio at a temperature of 20 ° C. at room temperature. reflux of the reaction solvent which is selected from acetone, low molecular weight alcohols, dimethylformamide (DMF), dimethylsulfoxide (DSMO) or acetonitrile which is preferred, optionally in the presence of a mineral base, such as a carbonate alkaline, or organic like triethylamine. The benzoylation of an intermediate (III) consists in reacting it with 1.0 to 1.25 moles of benzoyl chloride at a temperature of between 20 ° C. and the reflux temperature of the reaction solvent which is chosen from diethyl ether, tetrahydrofuran (TiF), dichloromethane, chloroform, toluene and, preferably, in the presence of a base

  organic like triethylamine in an equimolecular amount with benzoyl chloride.

  Intermediates (II) and (III) of Scheme 1 are accessible by synthetic routes 11 - documented in the literature in particular by an adaptation of the method described in J. Med. Chem. 1982, 25, p. 1286-92 with regard to (II) and patents FR 2 294 698, FR

  2,394,529 and FR 2,395,261 for the (RS) and (R) forms of (III).

  Specifically, the process used for the preparation of (II) adapted from the literature is described in Scheme 2 and consists of: - preparing (R) 1-trityl-pyrrolidine-2-carboxamide (VI) from L- prolinamide, then, to reduce the trityl derivative by LAH to obtain (R) (1-tritylpyrrolidin-2-ylmethyl) -amine (V), then,

  benzoylating the amine with benzoyl chloride to obtain (R) N (1-trityl)

  pyrrolidin-2-ylmethyl) -benzamide (IV), and then hydrolyzing the trityl-proctoring group with hydrochloric acid to obtain

  (R) N-pyrrolidin-2-ylmethylbenzamide (II).

N5 - CONH2 N- CONH2 NS CH2NH2

I I t H Trp - Trp

(VI) (V)

N CH2NH2 N CH2NHCO-

  Trp> Trp (V) (IV) (II) and for the preparation of intermediate (III) as shown in Scheme 3 and prepared for the preparation of the configuration of the invention (I) ): - to prepare (R) cyclopropyl- (2-hydroxymethylpyrrolidin-1-yl) -methanone (IX) by acylation of R - (-) - 2- (hydroxymethyl) -pyrrolidine with cyclopropane acid chloride carboxylic, then,

  to reduce the intermediate by LAH to obtain (R) (1cyclopropylmethyl-pyrrolidine

2-yl) -methanol (VIII), then

  reacting intermediate (VIII) with thionyl chloride to obtain (R) 2-

  chloromethyl-1-cyclopropylmethyl-pyrrolidine (VII), then

- 12 -

  - to react the intermediate (VII) with ammonia to obtain the (R) (1-)

  Cyclopropylmethyl-pyrrolidin-2-ylmethyl) -amine (III)

N 1 CH 2 OH N CH 2 OH CH 2 OH

Ho

N'CH2OH N CH2C I

  <(v7 1 1) (IX) (III) As set forth in this specification, the compounds (I), (I '), and the enantiomeric mixtures included in the invention in which the eutomer (I) is in proportion greater than 50%, and their salts have remarkable pharmacological properties, indicative of their usefulness, in the form of medicaments, in the treatment of diarrhea, especially secretory diarrhea in man. The Applicant, continuing his research in the field of sigma affinity compounds has considered, by declining the compounds of his application WO 95/15948 to replace the alkylene sequence -CH = CH- of the chain of these molecules with a carboxamide group. NH-CO-, the results of this modification being evaluated, for the compounds obtained, "in vitro" by their affinity to sigma receptors and, "in vivo" by their inhibitory activity in a model of secretory diarrhea caused by salmonella lipopolysaccharide (LPS)

  which is considered representative of toxigenic secretory diarrhea in this study.

  From the outset, the first products synthesized and tested, namely the configuration (R) eutomer (I) and its distomeric antipode (S), showed surprising results. Thus, whereas in the "in vitro" test practiced, the two compounds show only a weak affinity to the sigma receptors, it turns out to be "in vivo" that the configuration (R) eutomer (I) possesses, from

  stereoselective way, a very powerful antidiarrheal activity.

- 13 -

  Thus, the eutomer (I) is at least three times more active than its antipode configuration (S) orally in mice, on the model of secretory diarrhea caused by salmonella lipopolysaccharide (LPS), model in which the antipode (S)

  has a maximum inhibitory effect limited, whatever the dose, to about 30%.

  In mice, orally, in the models of toxigenic secretory diarrhea caused by salmonella lipopolysaccharide (LPS), the thermostable toxin of coli and toxins A and B of C. difficile, when compared to compounds reported or potentially capable of treating secretory diarrhea, the eutomer (I) object of the invention is found, without affecting the transit: - from about 12 to more than 250 times more active than loperamide, and - on diarrhea caused by LPS, more than 1000 times more active than acetorphan, also compound (I) shows remarkable inhibitory activity secretion

  intestinal tract induced in rats by cholera toxin.

  These studies, developed in the experimental part, are conclusive of the particularly interesting anti-diarrheal activity of (R) N- (1cyclopropylmethyl-pyrrolidin-2-ylmethyl) -benzamide (I), of its racemic correspondent (R, S) (I '). ), their salts and their utility in the preparation of pharmaceutical forms administrable by the appropriate routes to the pathology and the state of the patient. Thus the drugs can be administered by

  parenteral, transdermal or transmucosal route in conventionally known forms.

  However, pharmaceutical forms adapted to ambulatory treatments are preferred

  and especially those intended for oral administration.

  The pharmaceutical compositions according to the invention which contain a therapeutically effective amount of eutomer (I), racemic (I ') or a salt thereof, are suitable for the treatment of diarrhea which may be commonplace, such as that of infants. or traveler, and that they are acute or persistent and of various etiologies in which the secretory component may as well result from a decrease in absorption.

  than intestinal hypersecretion.

  Thus, the compositions according to the invention are indicated for the treatment of diarrhea whose origin is inflammatory (Crohn's disease, post-radiotherapy enteritis),

  obstructions due to lymphoid hyperplasia or anti-cancer chemotherapy.

  These compositions are also suitable for the symptomatic treatment of hypersecretory diarrhea, such as those following neuroendocrine tumoral affections.

- 14 -

  (Zolliger-Ellison syndrome, VIPome, somatostatinome, carcinoid syndrome), HIV, viral, bacterial infections, or congenital or cathartic drug dysfunction, and in hypersecretion of syndromes

inflammatory bowel.

  The good tolerance to the product shown in the preliminary tests authorizes for a two to three week treatment a daily dosage of 5 to 250 mg and,

  exceptionally, for short-term attack treatments up to 500 mg.

  However, the majority of the treated diarrheal conditions are improved by daily dosages of 10 to 100 mg, the product being administered orally divided in two to

0 four taken in 24 hours.

  The product is administered in various pharmaceutical forms containing unitarily from 2.5 to 50 mg of the eutomer (I) or is racemic (I ') or a salt thereof, in particular the hydrochloride, the latter being able to present in crystallized or amorphous form or be prepared extemporaneously during the manufacture of pharmaceutical forms, which may be, for non-limiting examples, tablets, dragees,

  capsules, capsules, powders, solutions, suspensions, gels.

  For so-called "solid" forms the compound (I) or a congener, salified or not, may represent from 1 to 90% by weight of the total of the finished form, the pharmaceutically acceptable excipients representing from 99 to 10%. For liquid forms or considered as such, the active ingredient may represent from 0.1 to 10% by weight of the

  finished form for a liquid phase of 99.9 to 90% by weight.

  - Experimental part Examples 1: Chemical syntheses Example 1L.A comparison product

  (S) N- (1-Cyclopropylmethyl-pyrrolidin-2-ylmethyl) -benzamide.

  a) Preparation of (Si N-pyrrolidin-2-ylmethyl-benzamide (II:

  stage I: (S) (1-trityl-pyrrolidine-2-carboxamide (VI).

  In a 250 ml protected humidity reactor, 2.00 g (17.5 mmol) of L-prolamine and 2.7 ml (1.95 g, 19.3 g) are dissolved in 75.0 ml of anhydrous dichloromethane. mmol) of triethylamine. At a temperature below 10 ° C., 5.40 g of chloride are added

  triphenylmethane then stirred at 20 C the mixture for 16 hours.

- 15 -

  The solution is extracted twice with 100 ml of water and then dehydrated. The solvent is removed by distillation under vacuum and on a water bath. the amorphous white residue (6.10 g) is recrystallized under reflux in 30 ml of ethyl acetate. After cooling, the precipitate is

filtered and dried.

  Weight = 4.70 g Yield = 75% TLC: Rf 0.80 (CH2Cl2-MeOH / NH4OH 10% 95-5 v / v)

  Step 2: (S) (1-Trityl-pyrrolidin-2-ylmethyl) -amine (V).

  In a reactor protected from moisture, and under a nitrogen atmosphere, 1.00 g (26.4 mmol) of LAH is introduced into 20.0 ml of anhydrous TI-IF. The suspension is cooled to around

  10 C and then 4.70 g (13.2 mmol) of the amide (VI) in solution in 25.0 ml of THF are added.

  The mixture which becomes red is refluxed 1 hour and then cooled by an ice bath.

  2.5 ml of water at 5 ° C. are then added dropwise, followed by 2.5 ml of 10% NaOH solution and then 7.5 ml of water. The mixture is stirred for two hours at 20-25 C and the insoluble is filtered. The solvent is distilled off to obtain the crude compound (V) in the form

of a yellow oil.

  Weight = 4.5 g Yield = 100% TLC: Rf 0.45 (CH2Cl2-MeOH / NH4OH 10% 95-5 v / v)

  Step 3: (S) (1-Trityl-pyrrolidin-2-ylmethyl) -benzamide (IV).

  In a reactor protected from moisture, is dissolved in 4.70 g (13.7 mmol) of the intermediate amine (V) in 60 ml of anhydrous dichloromethane, is added to the solution 2.10 ml or 1.53 g (15.1 mmol) of triethylamine. The mixture is cooled by an ice-water bath

  and 1.8 ml, ie 2.12 g (15.1 mmol) of benzoyl chloride at t <10 ° C., is added.

  The mixture is stirred at 20-25 ° C. for one hour and then extracted successively with 100 ml of 10% aqueous ammonia, 100 ml of water, 100 ml of 10% HCl, 100 ml of water and 100 ml of water.

  saturated solution of sodium bicarbonate and finally 100 ml of water. After dehydration the organic phase is concentrated. We get a

  yellow meringue residue. Weight = 5.00 g Yield = 82% TLC Rf 0.65 (CH2Cl2- acetone 95-5 v / v)

  Step 4: (S) N-pyrrolidin-2-ylmethyl) benzamide (II).

  In a reactor is added, without exceeding 15-20 C, 80 ml of 0.6 N hydrochloric ethanol to 5.0 g of intermediate (IV). The mixture is stirred for 1 hour at 20-25 C and then concentrated in vacuo and on a water bath. the residue is taken up in ether and water. The acidic aqueous phase is alkalinized and then extracted with ether. After removal of the ether, the pure crude product is obtained

- 16 -

in the form of yellow oil.

  Weight = 1.50 g Yield = 66% TLC: Rf 0.20 (CH2Cl2-MeOH / NHIOH 10% 95-5 v / v) b) Preparation of (S) N- (1-cyclopropylmethyl) pyrrolidin-2-ylmethylbenzamide ( comparison product - antipode of (I))

  In a reactor protected from moisture, 1.50 g (7.3 mmol) of intermediate (S) N-

  -pyrrolidin-2-ylmethyl-benzamide (II) in 20.0 ml of acetonitrile and then 0.75 ml or 1.0 g (7.3 mmol) of bromomethylcyclopropane is added. The solution is refluxed for 5 hours and the solvent is then distilled off under vacuum. The residue is dissolved in 100 ml

  0 dichloromethane and extracted with 100 ml of a 2N NaOH solution and then with 100 ml of water.

  After drying, the dichloromethane is removed by distillation in vacuo. 1.55 g of orange residual oil is obtained which is purified by rapid chromatography on a silica column. Elution with a 10% dichloromethane / methanol ammonia mixture allows

  to obtain 1.40 g of purified product which are recrystallized in 70 ml of hexane.

  Weight = 0.9 g Yield = 47.7% F = 86 C TLC: Rf 0.65 (CH2Cl2-MeOH / NH4OH 10% 90-10 v / v) Elemental analysis according to C16 H22 N2 0 IR (KBr): 3300, 2750, 1640, 1540, 1310, 1290, 1180, 1140, 1020, 920, 830, 700, 680, 540 cm -1 H NMR (CDCl 3 TMS): δ (ppm) 0.05 - 0.30 (m, 2H); 0.40-0.55 (m, 1H); 1.60 - 1.85 (m, 3H); 1.85 - 2.00 (m, 1H); 2.00 - 2.15 (m, 1H); 2.20 2.40 (m, 1H); 3.25 - 3.45 (m, 2H); 3.65 - 3.80 (m, 1H); 6.90 - 7.10 (m, 1H); 7.40 - 7.60 (m, 3H); 7.75 - 7.90 (d, 2H) [OC] D2 = -110 (CH2Cl2, c = 1) Example 1.B - product (I) of the invention (R) N- (1cyclopropylmethyl-pyrrolidine-2 -ylmethyl) -benzamide (I) a) Preparation of (R) (1-cyclopropylmethyl-pyrrolidin-2-ylmethyl) -amine (II):

  Step 1: (R) cyclopropyl- (2-hydroxymethyl-pyrrolidin-1-yl) -methanone (IX).

  In a reactor protected from moisture, 50.0 g (494 mmol) of (R) (-) - 2

  (hydroxymethyl) -pyrrolidine in 500 ml of dehydrated dichloromethane, then 116.5 ml or 85.0 g (840 mmol) of triethylamine are added. The solution is cooled with an ice-water bath and 45.0 ml, ie 51.7 g (494 mmol) of cyclopropanecarboxylic acid chloride, is added over 1 hour at t <10 ° C. The mixture is stirred for one hour at t <C and then extracted with 250 ml of 10% ammonia, then 250 ml of water, then 4 times 120 ml of N HCl solution. The organic phase is dried, the solvent removed. by distillation - 17-

  to obtain the crude product in the state of purity.

  Weight = 60.47 g Yield = 72.4% TLC: Rf 0.80 (CH2Cl2-MeOH / NH4OH 10% 90-10 v / v) - Step 2: (R) (1-Cyclopropylmethyl-pyrrolidin-2-yl ) -methanol (VIII) In diethyl ether, according to the procedure described in Step 2 of Example 1A and from 59.0 g (350 mmol) of methanone (IX) and 33.1 g (873 g). mmol) from LAH, one

  38.8 g of crude product (VIII) are obtained in the state of purity.

  Yield = 71.4% TLC: Rf 0.55 (CH 2 Cl 2 -MeOH / 10% NH 4 OH 90-10 v / v) - Step 3: (R) 2-Chloromethyl-1-cyclopropylmethyl-pyrrolidine hydrochloride (VII) With the reactor protected from moisture, 38.0 g (245 mmol) of intermediate (VIII) were dissolved in 200.0 ml of dehydrated chloroform. The solution is cooled to t <0 ° C. with a bath of acetone / dry ice mixture and a solution of 22.2 ml, ie 36.4 g (305 mmol) of thionyl chloride in 65 ml of dehydrated chloroform, is added dropwise.

exceed 5 C.

  The solution is stirred for 30 minutes at 20-25 then heated and maintained at reflux for 40 minutes.

  The mixture is concentrated under vacuum. The residue is dissolved in 200 ml of chloroform.

  The addition of 350 ml of ether causes the precipitation of the hydrochloride which is filtered and dried. Weight = 48.45 g Yield = 94.9% TLC drawn from 0.0 to 1.0 (CH2Cl2-MeOH / 10% NH4OH 90-10 v / v) - Stage 4 (R) (1cyclopropylmethyl-pyrrolidin-2 In a 1-liter autoclave, 645 ml of ethanol and 70 ml of water were pre-cooled to -25.degree. C. and 48.0 g of liquid ammonia was then added. The autoclave is hermetically closed and stirred for 48 hours at 20-25 C. After opening, the solution is concentrated by

  distillation under vacuum, the residue taken up in 500 ml of ethanol and the insoluble filtered.

  The filtrate is evaporated, taken up in 500 ml of dichloromethane, and after dehydration evaporated under vacuum. The residual brown oil (51.7 g) is purified by rapid chromatography

on a silica column.

  Elution with a gradient of dichloromethane gradually enriched in methanol

  ammonia at 10% makes it possible to obtain the pure product in the form of a yellow oil.

  Weight = 28.9 g Yield = 80% TLC: Rf 0.35 (CH 2 Cl 2 -MeOH / NH 4 OH 10% 90-10 v / v) [c] ID - 39 (MeOH, c = 2)

- 18 -

  b) Example of the invention: (R) N- (1-Cyclopropylmethyl-pyrrolidin-2-ylmethyl) -benzamide (eutomer (I1)

  In a reactor protected from moisture, 27.0 g (175 mmol) of (R) (1-

  cyclopropylmethyl-pyrrolidin-2-ylmethyl) amine intermediate (III) in 500 ml of anhydrous dichloromethane and then added 26.85 ml or 19.5 g (192.5 mmol) of triethylamine. The solution is cooled with an ice-water bath and a solution of 22.4 ml, ie 27.1 g of benzoyl chloride (192.5 mmol) in 150 ml of dichloromethane, is added at t <10 ° C. The solution is stirred for 1 h 30 at 20-25 C and then extracted by successive fractions of 350 ml

  10% ammonia, water, 10% HCl, then water.

  The hydrochloric phase and the last aqueous phase are combined alkalinized with NaOH and extracted with ether. The combined ether phases are dehydrated and the ether removed by

  distillation. The residue (31.0 g) is purified by flash chromatography on a silica column.

  Elution with dichloromethane gradually enriched with methanol makes it possible to obtain 14.0

  purified product which are recrystallized from 400 ml boiling hexane.

  After cooling, the crystalline insoluble material is filtered and dried.

  Weight = 10, SgRdt = 24% F = 87 C TLC: Rf 0.70 (CH 2 Cl 2 -MeOH / NH 4 OH 10% 90-10 v / v) IR (KBr): 3300, 2750, 1640, 1540, 1310, 1290, 1180, 1140, 1020, 920, 830, 700, 680, 540 cm -1. 1H-NMR (CDCl 3 TMS): δ (ppm) 0.05-0.30 (m, 2H); 0.40 - 0.55 (m, 1H); 1.60 - 1.85 (m, 3H); 1.85 - 2.00 (m, 1H); 2.00 2.15 (m, 1H); 2.20 - 2.40 (m, 1H); 3.25 - 3.45 (m, 2H); 3.65 - 3.80 (m, 1H); 6.90 - 7.10 (m, 1H); 7.40 - 7.60 (m, 3H); 7.75 - 7.90 (d, 2H) [c] D20 = + 115 (CH2Cl2, c = 0.5) Example 2: Toxicity study In the animal the toxicity study was carried out in the mouse by oral route. Any

  mortality is observed up to the highest dose studied ie 300 mg / kg.

  There are no toxic symptoms at doses below 100 mg / kg. From this dose are observed symptoms such as respiratory depression, tremors, convulsions, prostration or lethargy which are reversible within a period of time

24 hours after treatment.

- 19 -

  EXAMPLE 3 Pharmacological Studies "In Vitro" i) - Affinity to Sigma Receptors The study of the capacity of interaction with the sigma receptors of the eutomère object of the invention of its antipode was carried out by determining their fixation. or binding, on membrane preparation of rat brain, previously loaded with the labeled ligand specific for sigma receptors, in this case (+) [3H] -SKF 10,047. The technique used is that described by Largent, B. L. et al. in J. Pharmacol. Exp. Ther., 1986, vol. 238, p. 739- 748 The results, expressed in IC5, of the test product, which is the concentration for displacing the tritiated ligand of 50% of its binding sites, are 784 nM for the eutomer (I) and 365 nM for its distomeric antipode, values which for both

  in absolute values correspond only to poor affinities.

  ii) - dopamine receptor affinity The D1, D2, D3 dopaminergic receptor affinity study is carried out on rat striatum membranes according to Trampus M. et al., Eur. J. Pharmacol., 194, 17, 1991, for D1 receptors, [3H] -SCH 23390 (0.3ng) being used as a ligand and SCH 23390 (10 AM) being used to determine affinity non-specific, - on rat striatum membranes according to Terai M. et al., Eur. J. Pharmacol., 173, 177, 1989, for D2 receptors, [3H YM091512 (0.1nM) being used as ligand and (+) butaclamol (10M) to determine nonspecific affinity, and, for D3 receptors, on recombinant human D2 receptors expressed in CHO cells, [3H] -spiperone (0.2 gM) being used as ligand and (+) butaclamol being used to determine non-specific affinity according to Mac Kenzie RG

  et al., Eur. J. Pharmacol., 266, 79, 1994.

  In these tests the eutomer (I) of the invention shows no affinity, the IC5odans

  each test being greater than 10000 nM.

  Example 4: "In vivo" pharmacological studies 4-1) - Inhibition of experimental toxigenic diarrhea - Protocols a) Salmonella lipolysaccharide (LPS) induced diarrhea: the test is performed on

  the mouse according to a procedure inspired by M.J.CANCIO et al. Gastroenterology Nov.

- 20 -

  1992, 103 (5), 1437-43, which in the rat induced endotoxin

  transport of water and electrolytes in the colon.

  procedure: male mice dBA2 (Iffa-credo, Oncins, France) weighing between 20 and 25 g are placed in individual cages. After adaptation of the animals to their environment, the test product is administered orally in solution or in aqueous suspension, then an hour later (in the test) an injection of lipopolysaccharides (LPS) is applied to the tail vein. Salmonella enteriditis (Sigma product - ref L6761) at 15 mg / kg. We then place a pre-weighed filter paper under

  each cage and determines the weight of feces eliminated by the animals in two hours (tl20).

  The effect of the test product is determined and is expressed as a percentage of inhibition of the weight of faeces at the dose in relation to the weight of the faeces of a batch of control animals that have received under the same conditions as LPS. These results make it possible to calculate the DE5, of the compounds which is the effective dose making it possible to inhibit 50% of the weight of the faeces.

  caused by the administration of the diarrheal agent.

  b) - diarrhea induced by E. coli heat-stable toxin: fed male NMRI mice (30-35 g) were weighed and placed in individual cages previously lined with white paper allowing visualization of the feces emitted. The feces are recovered immediately emitted and grouped by periods of 30 min, for 120 min. The faeces thus grouped are weighed before (fresh weight) and after (dry weight) drying at 120 ° C. for 24 hours. The amount of water present in the faeces is calculated as the difference (fresh weight

- dry weight).

  The thermostable toxin of Escherichia coli (Sigma, E5763) is administered orally at zero time at a dose of 600 U / mouse. The animals of the control batch receive, at time zero, an oral administration of physiological saline. The administration of products to

  the test is performed orally one hour before administration of the toxins.

  The results are expressed as the amount of faecal water accumulated at 120 min. and make it possible to calculate the ED50 of the compounds which is the effective dose making it possible to inhibit

  % water weight feces under the action of the product under test.

* c) - diarrhea induced by toxin A and B of Clostridium difficile: the experimental protocol, the calculation and the expression of the results are identical to those described previously. Clostridium difficile toxins A and B are administered orally

  at time zero at the dose of 6 ng / mouse.

- 21 -

  Results i) - stereospecificity of the inhibitory effect of (I) in diarrhea induced by salmonella LPS. In this test the activity of the eutomer (I) of configuration (R) is compared with that of its antipode (S), the compounds being respectively described in Examples 1-B and 1-A. dose mg / kg inhibitory activity% route p.o (I) ex. 1-B (R) pdt ex. 1-a (S)

0.01 9.4%

0.03 50% (DE50) -

0.10 35.5%

1.00 33.9%

  ii) - Comparative Inhibitory Activity of Eutomer (I) with Loperamide (INN) and Acetorphan

  (INN) in mice, p.o administration, ED50 mg / kg or% inhibition at the dose considered.

  diarrhea. tox. eutomer (I) loperamide acetorphan LPS salmon. 0.030 0.37 34 E.Coli 0.015 3.92 N.T C.difficile 95% at 0.05mg 4.27NT N.T not tested 4-2) - Inhibition of intestinal secretion induced by cholera toxin: technique known as

"enteropoolin."

  Female Wistar rats (160-180 g) are fasted on solid food 24 hours before the test.

  At time zero, the animals receive, orally, 0.1 mg / kg of cholera toxin (Sigma, C3012). Three hours after the animals are sacrificed by cervical dislocation. After

  median laparotomy, the intestine is ligated at the level of the pylorus and the ileo-

  cecal. It is then removed (from the duodenum to the caecum), weighed full and empty.

  The administration of the test products is carried out orally one hour before

- 22 -

  the administration of cholera toxin. The results are expressed in weight of intestinal contents and make it possible to calculate the ED50 of the compounds which is the effective dose allowing

  to inhibit by 50% the weight of the intestinal contents under the action of the product under test.

  In this study the eutomer (I) shows an ED50 of 0.017 mg / kg.

  EXAMPLE 5 Pharmaceutical Forms As an illustration, the formulation and the preparation of the eutomer (I) of the invention in the form of capsules and tablets containing 25 mg of active ingredient per unit are presented. I - Unit formulation of capsules and preparation: Hydrochloride of the eutomer (I) 25.0 mg lactose 74.3 mg colloidal silica 0.2 mg magnesium stearate 0.5 mg total: 100 mg The powders are intimately mixed then divided by 100 mg per unit in

capsules of appropriate size.

  Unit dosage of tablets and preparation: eutomer (I) 25.0 mg 20. lactose 87.0 mg hydroxypropyl methylcellulose (HPMC) 3.6 mg crosslinked carboxymethylcellulose (CMC) 3.6 mg colloidal silica 0.24 mg stearate magnesium 0.6 mg total: 120 mg The active substance is mixed with lactose and then granulated with HPMC in solution. The grains are dried and screened on an opening grid of 1 mm. CMC and silica are mixed and then added to the granules. It is then intimately mixed with the stearate of

  magnesium then compresses at a rate of 120 mg per scored tablet.

- 23 -

Claims (4)

claims   1) (R) N- (1-cyclopropylmethyl-pyrrolidin-2-ylmethyl) -benzamide of formula (I), N% '- NH 7 '0   its racemic mixture (R, S) (I ') and their addition salts with pharmaceutically acceptable acids,   2) Process for preparing (R) N- (1-cyclopropylmethyl-pyrrolidin-2-ylmethyl)   benzamide of formula (I) which consists of: either N-substituting the pyrrolidine radical of (R) N-pyrrolidin-2-ylmethyl-benzamide (II) by alkylation with bromomethylcyclopropane, or benzoylating (R) 2- aminomethyl-1-cyclopropylmethyl pyrrolidine (III) with benzoyl chloride,   3) As a drug, (R) N- (1-cyclopropylmethyl-pyrrolidin-2-ylmethyl) -   benzamide of formula (I), its racemic mixture (R, S) (I ') and their addition salts with pharmaceutically acceptable acids,   4) Therapeutic composition containing as an active ingredient, the (R) N- (1)   cyclopropylmethyl-pyrrolidin-2-ylmethyl) -benzamide of formula (I), its racemic mixture (R, S) (I ') and their addition salts with pharmaceutically acceptable acids.) Use of (R) N- (1cyclopropylmethyl) pyrrolidin-2-ylmethyl) -benzamide of formula (I), its racemic mixture (R, S) (I ') and their addition salts with pharmaceutically acceptable acids, for the preparation of antidiarrheal drugs,