MXPA99006192A - (-)e-2-(3,4-dichlorocinnamyl)-1-cyclopropylmethyl-piperidine and its antidiarrhoeal use - Google Patents

Abstract

(-)E-2-(3,4-dichlorocinnamyl) -1-cyclopropylmethyl-piperidine of formula (I) and its addition salts with pharmaceutically acceptable acids;their use as antidiarrhoeals in mammals;pharmaceutical compositions intended for treatment of diarrhoeas.

Description

(-) E - 2 - (3,4 - DIC OROCINAMIL) - 1 - CICLOPROPYLMETHYPIPERIDINE AND ITS ANT DIARRHETIC USE Field of the Invention The invention relates to (-) E - 2 - (3,4 - dichlorocinamyl) - 1 - cyclopropylmethyl piperidine, its salts and its use as antidiarrheal drugs in man.

Prior art The secretory abnormalities of the gastrointestinal tract are responsible, with motor disorders, for the majority of chronic or acute diarrhea which, in 1990, was calculated as the second cause of global mortality, especially in infant populations of developing countries.

Chronic diarrheas are defined by their usually persistent duration of more ttwo weeks. Its known mecsms and the diagnostic strategy to adopt in view of these cases has been determined by M. Cerf - Gastroenterol. Clin. Biol., 1992, 16, T12 -T21 and more recently by M.J.G. Farthing - Eur. J. of Gastroenterol. & Hepatol. 1996, 8: 157 - 167. Acute diarrhea, of which a large majority is of infectious origin, has been documented in a similar way by M. Cerf. and M. Haiage: Acute diarrhea of infectious origin. - Editions Techniques - Encycl. Med. Chir. (Paris - France), gastroenterology, 9061 A10, 1992, page 20; and H.L. DuPont - Review article: infectious diarrhea - Aliment. Pharmacol. Ther. 1994; 8: pages 3 - 13. Among other causes, the important role of toxinogenesis during bacterial infection is discussed, and, especially, the expression of pathogenic capacity through the synthesis of thermolabile or thermostable cytotoxins and enterotoxins, which are responsible of secretory diarrhea with a hydroelectrolytic component, and whose representative physiopathological model is cholera.

Other infectious agents are known to cause diarrhea of this type, such as the Salmonella, Escherichia coli (E. Coli) and Clostridium difficile (C. difficile) chains.

The latter agents, and more particularly C. diffícile, are responsible for chronic and abundant secretory diarrheas, often of nosocomial origin, in subjects subjected to intensive antibiotic therapy such as HIV positive patients. In the latter, disabling diarrhea particularly is often associated with malabsorption and contributes to the rapid development of an alarming state of malnutrition.

For the treatment of secretory diarrhea, rehydration of patients is recommended and often essential. Some compounds have been shown to be active (phenothiazine, clonidine, bismuth salts) but their sensible use due to their side effects has led to their generalization being abandoned. The usual symptomatic treatments require absorbent compounds (Fuller's earth), modulators of intestinal flora and, very broadly, compounds called retardants, which are morphine-like antidiarrheals: loperamide (INN) and diphenoxylate (INN), known inhibitors of tract motility Gl and, in fact, of controversial utility if not inadvisable for certain diseases, among other reasons for the delay that contribute to the natural evacuation of pathogenic bacteria.

More recently, it has been proposed to treat these diarrheas with acetorfan (INN), a synthetic inhibitor of enkephalinase dipeptide with antisecretory effect, which maintains the effect of enkephalins, endogenous antisecretory neuropeptides of the intestinal wall, which are hydrolyzed normally and rapidly in vivo by the enkephalinases that make their passenger effect.

As regards the therapy of diarrhea in patients infected with HIV, it is often necessary to take serious methods, which can only be carried out in an environment with the internal patient, such as rehydration and renutrition through enteric or parenteral routes, which are combined with the symptomatic antidiarrheal treatment and antibiotic therapy directed against the possible pathogenic agent. The usual antidiarrheal agents only have, more often, a relative and episodic efficacy. Recently, for these diarrheas and, more generally, cases resistant to conventional therapies, the peptides that inhibit the mobility and gastrointestinal secretion related to somatostatin have been proposed (M. Cmilleri - Digestion 1996; 57 (suppl 1): 90-92 and MJ.G. Farthing - Digestion 1996; 57 (suppl 1): 107-113). The synthetic substitute compounds for this endogenous mediator are actreotide (INN) and valtreotide (INN), both octapeptides proposed with some success for the treatment of secretory diarrhea of AIDS. Although their duration of action is considerably longer than that of somatostatin, these expensive compounds are only active through repeated parenteral administration which leads to prohibitive treatment costs and, due to their mode of administration, makes it virtually impossible in a environment with the patient without hospitalization. In addition, its lack of specificity, which has been pointed out, may involve side effects that dramatically aggravate the state of malnutrition of patients (disorders of the regulation of hydrocarbon metabolism and increase in statorrea).

In addition, certain compounds defined as specific ligands for sigma receptors have demonstrated antisecretory properties suggesting their use in the treatment of diarrhea. Thus, (+) - M-cyclopropylmethyl-N-methyldiphenyl.1,4-ethyl-1-buten-3-yl-1-amine, or igmesin (INN) and its hydrochloride are presented together with other compounds in the European Patent 0 362 001. The compounds of this patent are defined in vitro as specific ligands for sigma receptors and demonstrated in vivo, in rats, to be inhibitors of amnestic phenomena caused by scopolamine, and cysteamine inhibitors, the latter activity is related to their ability to increase alkaline duodenal secretion in anesthetized animals. In the broad sense, the compounds of this patent are indicated as being useful for the treatment of peristalsis, mobility, gastroesophageal and gastroduodenal reflux phenomena as well as for gastric or gastroduodenal ulceration.

Subsequent to these studies, sigma receptors, whose location was known in the central nervous system and the immune system, have been demonstrated by F. Román et al., In the guinea pig gastrointestinal tract (Life Sciences 1988, 42, 2217-2222) and then of man (Gastroenterology 1991, 100, A662).

In relation to these locations, several experiments, among others those of J.L. Junien et al., (TSTeuropharmacology, volume 30, number 10, October 1991, pages 1119-1124) have demonstrated the inhibitory action of igmesin in tension-induced colonic hypermobility via the hormone that releases corticotropin (CRH or CRF) in man. In addition, P. Riviere et al., (Gastroenterol, Clin Biol. 1991, 15 (2B), A70) show in vitro that igmesin modifies transmembrane ion transport through portions of the mouse jejunum. This effect, antagonized by haloperidol, involves the participation of sigma receptors. VJ. Carlisi, et al., (Faseb J. 1992, 6 (4), Al 287) studied the effect of in vivo igmesin in mice, in a model of inflammatory diarrhea caused by PGE2: at a dose of 30 mg / kg, igmesin , coadministered by the ip route with PGE2, delayed in about 15 minutes the calving of diarrhea, an inhibitory effect antagonized by haloperidol and which, proven by the oral route, turned out to be zero at a dose of 60 mg / kg. More recently, G.Shi, et al., (UEGW 1996 - Paris - abstract number 0786) demonstrated the effect of igmesin at a dose of 200 mg p.o. in men on intestinal hypersecretion induced by PGE2.

On the other hand, the application WO 95/15948 presents derivatives of 2-arylalzezazazacycloalkanes as ligands for sigma receptors, a process for their preparation and their application in therapeutic uses. The compounds, their isomers and their addition salts are proposed for the preparation of antipsychotic drugs and are useful in gastroenterology. The experimental section describes in Example 2E racemic E-2 - (3,4-dichlorocinamyl) -1-cyclopropylmethylpiperidine and its hydrochloride and furthermore mentions without specific experimental results that the compounds of the application are active on secretory diarrhea induced in mice by lipopolysaccharide of Salmonella (LPS), which suggests its use in the treatment of secretory diarrhea of aetiologies. Overcoming the difficulties and uncertainties of the prior art as set forth, the present invention proposes for the purposes of the symptomatological treatment of secretory diarrheas the use, in appropriate drug forms, of an optically active compound, which is a ligand for sigma receptors, and whose spectrum of antidiarrheal properties is particularly remarkable and is formally distinguished from the prior art.

Summary of the Invention The object of the invention as a novel compound is optically pure (-) E-2 - (3,4-dichlorocinnamyl) -1-cyclopropylmethyl-piperidine (I) of the formula (-) chiral (I) its addition salts with pharmaceutically acceptable acids and a process for its preparation.

It also refers, in the manner of medicaments, to (-) E-2 - (3,4-dichlorocinnamyl) -1-cyclopropylmethyl-piperidine (I) and its addition salts as well as to its use in the preparation of pharmaceutical compositions that are intended for the treatment of diarrhea. It also comprises medicinal compositions comprising, as an active principle (-) E-2 - (3,4-dichlorocinnam) -1-cyclopropylmethyl-piperidine (I) or its addition salts in a therapeutically efficient amount.

Detailed Description of the Invention First of all, the invention is directed to optically pure (-) E-2 - (3,4-dichlorocinamyl) -1-cyclopropylmethyl-piperidine (I) and its addition salts with pharmaceutically acceptable acids.

By optically pure it is understood that the product is practically pure from its optical antipode and is at least of an optical purity of 95% and, preferably, equal to or greater than 98% in levorotatory eutomer, determined by appropriate analytical means.

It is understood that pharmaceutically acceptable addition salts mean those inorganic or organic salts and their possible isomers, which have been shown to be non-toxic at the therapeutically customary doses of which, for example, a list is presented in J. Pharm. Sci., 1977, Volume 66, pages 1 to 19. The non-limiting examples are acetic, benzenesulfonic, camphorsulfonic, citric, ethanesulfonic, hydrobromic, lactic, maleic, malic, methanesulfonic, mucic, nitric, pam, phosphoric, salicylic, stearic, succinic, sulfuric or tartaric and hydrochloric acid, which is the favorite. In another aspect, the invention relates to a process for the preparation of optically pure (-) E - 2 - (3,4 - dichlorocinamyl) - 1 - cyclopropylmethyl - piperidine (I) which consists of either resolving the corresponding racemic compound described in Example 2E of the application WO 95/15948 or by carrying out the chemical synthesis initiating from (+) E-2 - (3,4-dichlorocinnam) piperidine (III), thereby obtained, in accordance with WO 95/15948, by resolution of the corresponding racemic compound described in the 2E preparation of the same patent application.

The resolution of the racemic compound corresponding to the product of the invention consists in using an optically active acid to obtain, with the racemate, diaesteroisomeric addition salts which are separated by crystallization, and from which the two resolved enantiomers are generated by appropriate treatment. The acids currently used for the preparation of said salts are, as non-limiting examples, the enantiomers of α-phenylglycine, α-phenylalanine, malic, mandelic and tartaric acid of campanic acid or as an alternative to α-methoxy-α-trifluoromethylacetic acid. An alternative method of resolution in the direct resolution of the racemic compound by high performance liquid chromatography in a column containing, for example, as stationary phase a cellulose polymer bevelled with carbamate groups such as the CHIRACEL OD (Daicel) phase and carrying An elution is carried out with hexane containing a small amount of triethylamine.

However, the preferred process is an adaptation of the methodology described in the application WO 95/15948 and consists in carrying out the resolution of (+ / -) E-2 - (3,4-dichlorocinnam) piperidine via the eutomeric salt diaesteroisomeric with N-acetyl-L-phenylalanine, which, purified and treated, leads to (+) E-2 - (3,4-dichlorocinnamyl) piperidine (III), and then to acetylate (JS) with cyclopropanecarboxylic acid to obtain ( *) E - 2 - (3,4 - dichlorocinnamyl) - 1 - cyclopropanecarbonylpiperidine (II), and then, reduce (TI) with a metal or organometallic hydride to obtain (-) E - 2 - (3,4 - dichlorocinamyl) - 1-Cyclopropylmethyl-piperidine (I) of optically appropriate purity and, optionally, make a pharmaceutically acceptable salt: . { 4. / - J Rácenselo Resolution I • *. N-aceJ-L-feijílalanÍHa < +) chiral (XXX) I 4"cycloprop cadwul chloride CJ 3 In the resolution step, the recovery and purification of the antipode (-) of the intermediate compound (III) allows, according to the same process, that the stromer of the compound of the invention be prepared, namely (+) E-2 - ( 3,4-dichlorocinnam) -1-cyclopropylmethyl-piperidine synthesized as a comparison product.

The compound which is the subject of the invention and its salts have remarkable pharmacological properties, indicative of their usefulness in the form of drugs for the treatment of secretory diarrhea in man. Although in vitro its affinity for sigma receptors is not stereospecific but of intensity comparable to that of its antipode, completely unexpectedly, (-) E - 2 - (3,4 - dichlorocinnam) - 1 -cyclopropylmethyl - Piperidine eutomer (I) shows in vivo, in several representative models of toxigenic secretory diarrhea, a very strong and stereoselective antidiarrheal activity.

Thus, the levorotatory eutomer appears from 4 to more than 50 times more active, by the oral route in mice, than its original racemate in the models of secretory diarrhea caused by lipopolysaccharide Salmonella (LPS), the thermostable toxin of E. coli and the toxincas A and B of C. difficile, dina act in transit. Similarly, the eutomer turns out to be about 50 times more active than the racemate by the oral route, in rats, in the inhibition of the intestinal secretion caused by the cholera toxin.

In mice, by the oral route in models of toxigenic secretory diarrhea that have hardly been presented, compared to published compounds or those potentially capable of treating secretory diarrhea, the eutomer that is the subject of the invention turns out to be: from 66 to more 4000 times more active than loperamide; from 75 to 1400 times more active than igmesina; and, in diarrhea caused by LPS, more than 6000 times more active than acetorfan.

Finally, in comparison with the enantiomers described in the application WO 95/15948 and which are similarly active in vivo in diarrhea caused by LPS, the study as a function of the dose, shows, by comparison products (-) E - 2-cinnamyl-1-cyclopropylmethylpyrrolidine (Example 1.3 of WO 95/15948) and (-) E-2-cinnamyl-1-cyclopropylmethyl-piperidine (Example 2A.3), a progressive effect which, after a maximum, significantly decreases , whereas, in a different way, the eutomer shows a progressive effect followed by a stage in which this activity is maintained, which is demonstrative of a safety of medical use and therapeutic help, contrary to the comparison products for which the active concentration zone, or therapeutic window, is narrow and leads to a dose that is difficult to manage and thus to a risky inefficiency.

These studies, expanded in the section, demonstrate the particularly interesting antidiarrheal activity of (-) E - 2 - (3,4 - dichlorocinnamyl) - 1 - cyclopropylmethylpiperidine (I) and its salts and its usefulness in the preparation of pharmaceutical forms which can be administered to mammals including humans by routes appropriate to the pathology and condition of the subject. Thus, the drugs can be administered by the parenteral, transdermal or transmucosal route in conventionally known ways. However, pharmaceutical forms adapted for non-internal treatments are preferred and especially those that are intended for oral route administration.

The pharmaceutical compositions according to the invention containing a therapeutically effective amount of the compound (I) or one of its salts, are suitable for the treatment of diarrheas which may be common, such as those of infants or travelers, and which may be acute. and / or persistent and variant aetiology in which the secretory component may equally result from a decrease in absorption of intestinal hypersecretion.

Thus, the compositions of the compound (I) are indicated for the treatment of diarrheas of inflammatory origin (Crohn's disease, whole after radiotherapies) or obstructions by lymphatic hyperplasia or alternatively of anti-cancer chemotherapy.

Similarly, these compositions are suitable for the symptomatic treatment of hypersecretory diarrheas such as those following neuroendocrine tumor conditions (Zollinger-Ellison syndrome, VLPoma, somatostatin, carcinoid syndrome) or viral, including VLH, or bacterial infections, or even of congenital dysfunctions or those caused by cathartic drugs and during hypersecretions of intestinal inflammatory syndromes.

The good tolerance to the product demonstrated in the preliminary tests justifies, for treatments of two to three weeks, a daily dose of 5 to 50 mg and, in exceptional cases, for aggressive treatments of short duration of up to 100 mg. However, most diarrheic conditions treated are improved by daily doses of 10 to 30 mg, the product is administered by the oral route, divided into two to four administrations per 24 hours.

The product is administered in several pharmaceutical forms, containing per unit from 1.25 to 25 mg of the compound (I) or one of its salts, especially its hydrochloride; these forms may be, as non-limiting examples, tablets, coated tablets, capsules, pills, powders, solutions, suspensions or gels.

For the so-called solid forms, the compound (I) or its salt can represent from 1 to 90% by weight of the finished form, the pharmaceutically acceptable excipients represent from 99 to 10%. For liquid forms or those considered as such, the active ingredient can represent from 0.1 to 10% by weight of the finished form, the liquid phase represents from 99.9 to 90% by weight.

Experimental Section Example 1: (-) E - 2 - (3,4 - dichlorocinnamyl) - 1 - cyclopropylmethylpiperidine (I) and its hydrochloride Step a): (+) E - 2 - (3,4 - dichlorocinamyl) piperidine (III) The compound is prepared by the resolution of (+ / -) E-2 - (3,4-dichlorocinnam) piperidine via the diastereomeric salt eutomeric obtained from N-acetyl-L-phenylalanine. In a 500 ml round bottom flask equipped with an agitator and a condenser in the reflux position, 23.00 g (85.1 mmol) of the racemic compound (preparation E2 of WO 95/15948) and 8.82 g (42.6 mmol) of N - acetyl-L-phenylalanine are introduced into 325 ml of acetone.

The mixture was heated to reflux with stirring, and a solution was obtained which was progressively cooled and then kept at 20 ° C for 16 hours with stirring. The eutomeric salt was filtered (dry weight: 15.50 g - mp 134 - 141 ° C), the filtrate was made alkaline and extracted with dichloromethane, and the residual oil of the concentration (13.60 g, 50.2 mmol) was salified in in the same manner as before in 200 ml of acetone with 6.25 g (30.1 mmol) of N-acetyl-D-phenylalanine. The distomeric salt is removed and the filtrate is treated by making alkaline to obtain 7.15 g (26.5 mmol) of residual product which is salified in 150 ml of acetone with 3.57 g (17.2 mmol) of N-acetyl-L-phenylalanine. A second supply of eutomeric salt 6.00 g, melting point 150 - 152 ° C was thus obtained after filtration.

The combined eutomeric salts (21.50 g) were recrystallized for purification in 60 ml of boiling water; 4.30 g of the product are recrystallized at 20 ° C (melting point 151 - 152 ° C).

The insoluble matter is recrystallized from 60 ml of boiling water; 10.9 g of product (melting point 153 - 154 ° C) recrystallized at 20 ° C. The salt is suspended in water, made alkaline with a sodium hydroxide solution and extracted with dichloromethane. The solvent is removed by distillation under vacuum and in a water bath. 6.10 g of product are obtained in the form of a pale yellow oil. Production = 53% - [a] 20D = + 9 - 60 ° (c = 0.5, dichloromethane) - TLC and NMR of conformity (identical to the racemic product).

Step b): In a 250 ml reactor equipped with a stirrer and protected against moisture, 6.00 g (22.2 mmol) of (+) E - 2 - (3,4 - dichlorocinnam) piperidine (III) obtained in the previous step they are introduced under a nitrogen atmosphere in 100 ml of dry dichloromethane over molecular moieties. 3.40 ml or 2.47 g (24.4 mmol) of triethylamine were added to the pale yellow oil and, after cooling to 10 ° C, 2.20 ml or 2.55 g (24.4 mmol) of cyclopropanecarbonyl chloride were added in 10 minutes. The mixture was kept under stirring for 30 minutes at 20-25 ° C and then successively extracted with 100 ml of 10% ammonia, 100 ml of 10% hydrochloric acid, 100 ml of saturated sodium bicarbonate solution and finally 100 ml of water. After drying over sodium sulfate, the dichloromethane is removed by distillation under vacuum and over a water bath. The residual product is obtained in the pure state as a yellow oil. Weight: 7.50 g - production = 100% - [a] 20D + 22.60 ° (c = 0.5, dichloromethane) -TLC (CEbC MeOH 10% ammoniacal 90/10 v / v): Rf = 0.90 - 1.00.

Step c): (-) E-2 - (3,4-dichlorocinnamyl) -1-cyclopropylmethyl-piperidine (I) Under a nitrogen atmosphere, protected against humidity and without exceeding 0 ° C, on the one hand a suspension of 2.65 g (69.5 mmol) of lithium aluminum hydride (LAH) was prepared in 40 ml of dry THF, and on the other hand a solution of 2.99 g (22.4 mmol) of aluminum chloride in 40 ml of dry diethyl ether. After 30 minutes of contact for preparation, the LAH / LHT suspension was introduced in 10 minutes at 0 ° C in an ethereal solution of A1C13, then a solution of 7.40 g (21.9 mmol) of the amide (II) obtained in the step in 30 ml of dry THF was introduced at this temperature and in 10 minutes.

After 30 minutes at 0 ° C, the mixture is brought to reflux for 10 minutes and then rapidly cooled to 0 ° C. 4.6 ml of 15% NaOH solution (v / v) and then 4.6 ml of water were then added in drops with caution, after 30 minutes of contact, the mixture was filtered on a buchner provided with an infusorial earth bed. The filtrate was concentrated in vacuo and in a water bath to obtain (-) E-2 - (3,4-dichlorocinnamyl) -1-cyclopropylmethyl-piperidine (I) in the form of a yellow oil, its purity was verified by TLC Weight: 3.2 g, production: 84.6% - [a] 20D = - 67.2 (MeOH, c = 8.0) - TLC (CH2Cl2 / 10% ammonia MeOH 90/10 v / v): Rf = 0.65 - 0.80. 1 H-NMR (CDI3-TMS): d (ppm) 0.00 - 0.20 (m, 2H); 0.40-0.70 (m, 2H); 0.70 -1.10 (m, 1H); 1.10-1.80 (m, 6H); 2.10 - 2.80 (m, 6H); 2.90 - 3.20 (m, 1H); 6.20-6.40 (m, 2H); 7.10-7.50 (m, 3H). - optical purity > 98%, determined by HPLC column 4.6 x 150 Chiracel ODH5 μm (Daicel), elution with hexane containing 0.1% triethylamine, t ° = 30 ° C.

Hydrochloride: The base was dissolved in 60 ml of dichloromethane, 7.0 ml of 5.5 N-hydrochloric ether were added, and then the solvents were removed by distillation. The solid residue was crystallized by dissolving in a mixture of isopropanol diethyl ether. The insoluble white matter was filtered and dried in vacuo at constant weight. Weight: 5.40 g - production = 68%. melting point ^ 182 - 183 ° C - [a] 20D = - 19.20 ° (c = 0.5; CH2C12) - Analysis (C18H24C13N):% C, H, Cl, N in accordance; - IR (KBr): 3400, 2900, 2500, 1450, 1130, 1020, 990, 820, 800 cm "1.

According to this process, starting from the isomeric salt removed in the resolution in step a), the recovery and purification produce the antipode (-) corresponding to the intermediary compound (III) to be recovered, of which the stromer of the compound of the invention is prepared, namely (+) E 2 - (3,4-dichlorocinnamyl) -1-cyclopropylmethylpiperidine, synthesized as a comparison product.

Example 2: Toxicity study In animals, the toxicity study was carried out in mice by the oral route. No mortality was noted even at the strongest dose studied, namely 300 mg / kg. No toxic symptoms were evident at doses lower than 100 mg / kg. Starting from this dose, symptoms were observed such as respiratory depression, tremors, seizures, a stage of prostration or lethargic that were reversible in a period of time of 24 hours after treatment.

Example 3: In vivo pharmacological study: affinity for sigma receptors The study of the interaction capacity with the sigma receptors of the eutomer that is the object of the invention, of this antipode and of its racemic compound, was carried out by means of the determination of its links to a rat brain membrane preparation, previously loaded with a labeled ligand specific for sigma receptors, in this case, (+) [3H] - SKF 10,047. The technique used (described by Lrgent, B.L., et al., J.

Pharmacol. Exp. Ther., 1986, volume 238, pages 739-748) consists of the incubation, in solutions of varying concentrations of the test product, the membrane preparation previously loaded with (+) [3H] - SKF 10,047. After filtration, the radioactivity of the solution, which is representative of the displacement of the ligand by the product of the test, is measured. The results were expressed as IC 50 of the test product, which is the concentration that allows the tritiated ligand to travel from 50% of its binding sites in the membrane preparation.

Results: The values obtained are presented in Table 1: Table 1: In vitro study - affinity Example 4: Pharmacological studies In vivo 4 - 1) - Inhibition of experimental toxogenic diarrhea Methods a) Salmonella lipopolysaccharide-induced diarrhea LPS): The test was carried out in mice according to a working procedure, instigated by M.J. Cancio, et al., Gastroenterology, November 1992, 103 (5), 1437-43, which in the rat induces, by an endotoxin, alterations in the transport of water and electrolytes at the level of the colon.

- Working procedure: male dBA2 mice (Iffa - credo, Les Oncines, France) with weights between 20 and 25 g are placed in individual cages. After adaptation of the animals to their environment, the test product was administered orally in solution or in aqueous suspension and then after one hour (t0 of the test) an injection of lipopolysaccharide (LPS) of Salmonella enteriditis ( Sigma ref L6761) is carried out in the vein of the tail in a proportion of 15 mg / kg. A pre-weighted filter paper is then placed under each cage and the weight of the feces removed by the animals in two hours (t12o) is determined. The effect of the test product is determined and expressed as a percentage of stool weight inhibition at a dose considered with respect to the weight of the faeces of a group of control animals that only received LPS under the same conditions. These results allow the EDso of the compounds to be calculated, which is the effective dose to allow 50% of the weight of the feces caused by the administration of the diarrheal agent to be inhibited. b) thermostable toxin-induced diarrhea of E. coli NMRI-fed male mice (30-35 g) were weighed and placed in individual cages previously covered with white paper that allows to see the fecal material poured. Stools are recovered as soon as they are discharged and put together, for periods of 30 minutes, for 120 minutes. The feces thus collected are weighed before (fresh weight) and then) dry weight) to dry 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 by the oral route at time zero at a dose of 600 U / mouse. The animals of the control group receive, at time zero, an oral administration of saline. The administration of the test products is carried out by the oral route 1 hour before the administration of the toxins. The results are expressed as the amount of fecal water kneaded in 120 minutes, and allow the ED50 of the compounds to be calculated, which is the effective dose that allows 50% of the water in the feces to be inhibited under the action of test product. c) - diarrhea induced by toxins A and B of C. difficile: The experimental protocol, the calculation and the expression of the results are identical to those described above. Toxins A and B of C. difficile are administered by the oral route at a zero time at a dose of 6 ng / mouse.

Results: i) The comparative inhibitory activity of the levorotatory eutomer (J) with the original racemate (+ / -) in mice, p.o. administration. Table 2: Inhibitory Activity *: non-reverse inhibitory effect by naloxone ii) Comparative inhibitory activity of the levorotatory eutomer (I) with loperamia (INN) > igmesin (INN) and acetorfan (INN) in mice, p.o. administration Table 3: Inhibitory activity: ED50 (mg / kg) iii) Salmonella-induced diarrhea LPS: comparative inhibitory activity of the levorotatory eutomer (I) with (-) E-2-cinnamyl-1-cyclopropylmethylpyrrolidine (Example 1.3 of WO 95/15948) and (-) E-2-cinnamyl-1-cyclopropylmethyl-piperidine (Example 2A.3) in mice, p.o. administration. Table 4: Inhibition of diarrhea (%) These results demonstrate the therapeutic advantage provided by the compound of the invention, since it demonstrates a significant effect at a dose of 0.003 mg / kg (46.1%), an effect that continues up to a dose of 0.1 mg / kg and more. In contrast, the comparison compounds only show valuable activity within narrow dose limits: from 0.003 to 0.03 mg / kg (63.8 to 46.7%) for the compound of Example 1.3; - from 0.00003 to 0.001 mg / kg (45 to 36.8%) for the compound of Example 2A.3; the activity decreases considerably at higher doses for these compounds. 4 - . 4 - 2 - Inhibition of intestinal secretion induced by cholera toxin: technique called enteroaccumulation.

Female Wistar rats (160-180 g) were fasted on solid foods 24 hours before the test. At time zero, the animals receive, by the oral route, 0.1 mg / kg of cholera toxin (Sigma, C3012). Three hours later, the animals are sacrificed by cervical dislocation. After median laparotomy, the bowel is ligated to the pylorus level and the ileocaecal junction. It is then removed (from the duodenum to the caecumo) and filled and then empty. the administration of the test products is carried out by the oral route one hour before the administration of the cholera toxin. The results are expressed by the weight of the intestinal contents and allow the ED50 of the compounds to be calculated, which is the effective dose that allows the inhibition of the weight of the intestinal contents by 50% under the action of the test product.

Results Table 5: Inhibition of intestinal secretion induced by cholera toxin: EDsn (mg / kg) Example 5: Pharmaceutical Forms By way of illustration, the formulation and preparation of the hydrochloride of the levorotatory eutomer (I) of the invention in the form of capsules and tablets containing 40 mg of the active ingredient per unit is presented. - . 5 - . 5 - 1 - capsule unit formulation and preparation: • Eutomer hydrochloride (I) 40.0 mg Lactose 59.3 mg Colloidal silica 0.2 mg Magnesium stearate 0.5 mg Total 100 mg The powders are intimately mixed and then distributed in a proportion of 100 mg per unit in capsules of approximate size. - 2 tablet unit formulation and preparation: Eutomer hydrochloride (I) 40.0 mg Lactose 72.0 mg Hydroxypropylmethylcellulose (HPMC) 3.6 mg Carboxymethylcellulose (CMC) 3.6 mg Colloidal silica 0.24 mg Magnesium stearate 0.6 mg Total 120 mg The active ingredient is mixed with lactose and then granulated with HPLC in solution. The beans are dried and filtered on a 1 mm mesh filter. The CMC and the silica are mixed and then added to the granules. The mixture is then intimately mixed with the magnesium stearate and then compressed in a proportion of 120 mg per finished tablet.

Claims (7)

1. REGVTNDICATIONS: 1. (-) E - 2 - (3,4 - diclorocinamil) - 1 - cyclopropylmethyl - piperidine (I) (-) chiral (I) its addition salts with pharmaceutically acceptable acids.
2. 2. The chiral (-) hydrochloride (I) its addition salts with pharmaceutically acceptable acids and a process for its preparation. 0).
3. 3. Process for the preparation of (-) chiral (I) its addition salts with pharmaceutically acceptable acids and a process for its preparation. (I) consisting of; carry out the resolution of (+ / -) E - 2 - (3,4 - dichlorocinnamyl) piperidine via the diastereoisomeric eutomeric salt with N - acetyl - L - phenylalanine, which leads to (+) E - 2 - (3, 4-dichlorocinnamyl) piperidine (III), and then; in acetylating (UJ) with cyclopropanecarboxylic acid to obtain (+) E-2 - (3,4-dichlorocinnamyl) -1-cyclopropanecarbonylpiperidine (II), and then; reducing the compound (II) with a metal or organometallic hydride to obtain (-) E-2 - (3,4-dichlorocinnamyl) -1-cyclopropylmethyl-piperidine (I) and optionally making the addition salt with a pharmaceutically acceptable acid.
4. 4. As a medicament, (-) E-2 - (3,4-dichlorocinnamyl) -1-cyclopropylmethyl-piperidine (I) and its addition salts with pharmaceutically acceptable acids.
5. 5. Therapeutic composition in the form of active ingredient (-) E-2- (3,4-dichlorocinnamyl) -1-cyclopropylmethyl-piperidine (I) and its addition salts with pharmaceutically acceptable acids.
6. 6. Use of (-) E-2 - (3,4-dichlorocinnamyl) -1-cyclopropylmethyl-piperidine (I) or one of its pharmaceutically acceptable salts for the preparation of antidiarrheal drugs.
7. 7. As novel industrial products, (+) E-2 - (3,4-dichlorocinnam) piperidine (UJ) and (+) E-2 - (3,4-dichlorocinnamyl) -1-cyclopropanecarbonylpiperidine (II) as prepared in the Claim EXTRACT OF THE INVENTION (-) E-2 - (3,4-Dichlorocinnamyl) -1-cyclopropylmethyl-piperidine of Formula I and its addition salts with pharmaceutically acceptable acids, its use as antidiarrheals in mammals, pharmaceutical compositions intended for treatment of diarrhea.