MXPA00000451A - (+)-norcisapride useful for 5-ht3 and 5-ht4 mediated disorders - Google Patents

Abstract

The present invention concerns (+)-norcisapride of formula (I) and compounds (V), and its pharmaceutically acceptable acid additions salts, a process for preparing said compound, and its use for the manufacture of a medicament for treating gastro-intestinal disorders while avoiding central nervous system effects. Also provided are method of treating gastro-intestinal disorders. Compounds of formula (V) wherein the piperidine ring has the absolute configuration (3S, 4R) and PG is methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl or phenylmethyl.

Description

(+) - NORCISAPRIDE USEFUL FOR MEDICAL DISORDERS BY 5-HTg AND The present invention relates to (+) - norcisapride, and its pharmaceutically acceptable acid addition salts, to a process for preparing said compound, and its use for the manufacture of a medicament for treating gastrointestinal disorders while at the same time time they avoid effects of the central nervous system. Cisapride is a widely used gastrokinetic drug known commercially as "Prepulsid ™". It is normally used primarily to treat gastroesophageal reflux disease. This disease is characterized as the reverse flow of stomach contents into the esophagus. Delayed gastric emptying, insufficient cleansing of the esophagus due to impaired peristalsis and the corrosive nature of the reflux material that can damage the esophageal mucosa are other factors in the pathogenesis of the disease. Due to its activity as a prokinetic agent, cisapride 20 may also be useful to treat dyspepsia, gastroparesis, constipation, post-surgical colic, and intestinal pseudo-obstruction. Cisapride is metabolized mainly by means of the cytochrome P 450 3A4 enzyme. As a result of extensive metabolization, ^^^^^^^^^^^^^^ '^^^^^^^^^^^^^^ ^ cisapride metabolised represents not less than 10% of urinary and fecal recovery from oral administration. The main metabolite, found in plasma, feces and urine, described by Meuldermans W. et al, in Drug Metab. Dispos 16 (3): 410-419, 1988, is called "norcisapride" and is a racemic mixture of two enantiomers. The racemic norcisapride is also described in EP-A-0,076,530, published on April 13, 1983, as the compound 211 having gastrointestinal stimulation properties. The (+) - norcisapride is one of the optical stereoisomers. The full chemical name is (+) - 4-am¡no-5-chloro-N- (3-methoxy-4-piper¡din¡l) -2-methoxybenzamide, from now on referred to as "(+) - norcisapride. " The term "(+) - norcisapride" and particularly the term "(+) - norcisapride optically pure" encompasses the (+) - stereoisomer which is substantially free of its (-) - stereoisomer. WO 96/40133 explains the use of (-) - norcisapride to treat disorders of the digestive tract, in particular to treat gastroesophageal reflux disease while at the same time substantially reducing the adverse effects associated with the administration of racemic cisapride. Said document still mentions that optically pure (-) - norcisapride would be an effective anti-vomiting agent, useful as an additional therapy in the treatment of cancer to relieve the nausea and vomiting induced by chemotherapy or radiotherapy. It has now been discovered that (+) - norcisapride, in particular the "optically pure (+) - norcisapride", also referred to as "(+) - norcisapride substantially free of its (-) - stereoisomer", has both the antagonistic properties of 5-HT3 as the agonistic properties of 5-HT4 and also substantially lacks effects on the central nervous system. The present invention relates to (+) - norcisapride and in particular to (+) - norcisapride substantially free from its (-) - stereoisomer, its pharmaceutically acceptable acid addition salts, and its use to treat disorders mediated by 5-HT3 and / or 5-HT4 while at the same time avoiding the effects on the central nervous system. It can be represented by (+) - norcisapride by the following chemical structure: In the above representation of the chemical structure of (+) - norcisapride, the bonds linking the NH-CO and the OCH groups piperidine ring are represented in bold to indicate that these two groups are in a cis configuration. The term "(+) - norcisapride" and particularly the term "(+) - norcisapride optically pure" encompasses the (+) - stereoisomer which is substantially free of its (-) stereoisomer. In particular, the term ^^^^^^^^^^ jí ^ p ^^^^^ s "substantially free of the (-) - stereoisomer" refers to a stereochemical mixture of norcisapride containing at least 90% by weight of the (+) - norcisapride and 10% by weight or less of (-) - norcisapride. In a more preferred embodiment the term "substantially free of (-) - stereoisomer" means that the stereochemistry mixture of norcisapride contains at least 98% by weight of (+) - norcisapride, and 2% or less of (-) - norcisapride. In a more preferred embodiment, the term "substantially free of the (-) stereoisomer" as used herein refers to the composition containing more than 99% by weight of (+) - norcisapride. These percentages are based on the total amount of norcisapride in the stereochemical mixture. Compounds that are able to rotate the plane of polarized light are said to be optically active. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule around its chiral center (s). The prefixes d and / or (+) and (-) are used to designate the sign of rotation of the polarized light in the plane by means of the compound, meaning (-) and / that the compound is levorotatory. A compound with a prefix (+) or ci is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that one is the mirror image of the other. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of these stereoisomers is often called a racemic mixture. The amount of rotation is not a constant for a ^^^^^^ S ^^^^^ & ^ M ^^ i enantiomer given, depends on the length of the container for the sample, the temperature, the solvent and the concentration (for the solutions) and the wavelength of the light. Therefore, the specific rotation [a] is defined as having a parameter that is independent of the length of the vessel and the concentration of the solution. The specific rotation a [a] = you where a is the observed rotation, I is the length of the container in decimeters and c is the concentration in grams per milliliter. The specific rotation is usually given along with the temperature and the wavelength, in this way 20 [a] D, where 20 is the temperature in degrees Celsius and D means that the rotation was measured with sodium light D, that is to say that it has a wavelength of 589 nm. X-ray analysis of the salt of L-tartaric acid of (+) - norcisapride, ie (+) - (3S, 4R) -cis-4-amino-5-chloro-2-methoxy-N- (3 -methoxy-4-piperidinyl) benzamide [R- (R *, R *)] - 2,3-d-hydroxybutanediotate monohydrate, reveals the absolute configuration of (+) - norcisapride as (3S.4R). Therefore, (+) - norcisapride has the following absolute stereochemistry: ^^ = | ^^ j ^^^ j ^ (3S, 4R) -cis-4-amino-5-chloro-2-methoxy-N- (3-methoxy-4-piperidinyl) benzamide. The pharmaceutically acceptable acid addition salts as mentioned hereinabove, comprise the therapeutically active, non-toxic acid addition salt forms which the (+) - norcisapride base is capable of forming. The base (+) - norcisapride can be converted into its pharmaceutically acceptable acid addition salts by treating the (+) - norcisapride base with a suitable acid. Suitable acids include, for example, inorganic acids such as, for example, hydrohalic acids, for example hydrochloric or hydrobromic acid; sulfuric, nitric, phosphoric and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (ie butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p- toluenesulfonic, cyclic, salicylic, p-amonosalicylic, pamoic and similar acids. Conversely, said acid addition salt forms can be converted by treatment with a suitable base to the free base (+) - norcisapride form. The term "addition salt" as used herein also encompasses solvates that (+) - norcisapride as well as their salts, are capable of forming. These solvates are, for example, hydrates, alcoholates and the like. When used herein, the term (+) - norcisapride also includes its pharmaceutically acceptable acid addition salts and its solvate forms. The base (+) - norcisapride can be prepared as detailed in scheme 1.

SCHEME I The amino and methoxy substituents on the piperidine ring in the intermediates of the formula cis- (ll) and the cis- (IV) reaction product have the cis- configuration, that is, the methoxy and the amino group are in the same side of the median plane determined by the piperidine ring and is a racemic mixture of 2 enantiomers. To indicate this configuration, the links joining these functional groups are represented in bold, as in formula I. In accordance with the reaction of scheme 1, an intermediate of the formula cis- (ll), where PG is a suitable protecting group such as, for - ^ rliiil ^ ii - • * »j *? A? T? Mm. ^^ - > For example, methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl, phenylmethyl and the like, is reacted with a carboxylic acid of the formula (III), or reactive functional derivative thereof, in an amide-forming reaction, thus producing intermediates of the formula cis- (IV). The intermediates cis- (II) and (III) are reacted in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or cis- (ll) is reacted with a reactive derivative of the carboxylic acid (III), for example an acid chloride or mixed anhydride. The reaction can be carried out in a solvent inert to the reaction such as, for example, dichloromethane or chloroform, and optionally in the presence of a suitable base such as, for example, sodium carbonate, potassium carbonate or triethylamine. Agitation can promote the speed of the reaction. The reaction may conveniently be carried out at a temperature within a range between room temperature and the reflux temperature of the reaction mixture. Subsequently, the intermediates of the formula cis- (IV) are separated into their enantiomers and each isolated enantiomer of the cis- (IV) intermediate becomes its corresponding enantiomer of norcisapride by removing the protecting group PG; depending on the nature of the PG group, by solvolysis in acidic or basic medium or by catalytic hydrogenation, for example by treatment with an inorganic base such as, for example, potassium hydroxide in an aqueous medium. Alternatively, the protecting group PG of the intermediates of the formula cis- (IV) can be removed, thus giving the racemic mixture of norcisapride, which subsequently separates into its ^^^^? ^? ^ MM ij & M & amp; enantiomers. Intermediates of the formula cis- (IV) as prepared in scheme 1 are a mixture of enantiomers that can be separated from one another following the resolution procedures known in the art. The mixture of the enantiomeric forms of the intermediates of the formula cis- (IV) can be separated by means of the conversion to the corresponding diastereomeric salt forms by means of the reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by means of selective or fractional crystallization and the enantiomers are liberated therefrom by means of the alkali. An alternative way of separating the enantiomeric forms of the intermediates of the cis- (IV) formula includes liquid chromatography using a suitable chiral stationary phase. Suitable chiral stationary phases are, for example, polysaccharides, in particular cellulose or amylose derivatives. The chiral stationary phases based on commercially available polysaccharides are ChiralCel ™ CA; OA, OB, OC; OD; OF; OG, OJ and OK, and ChiralpakTM AD, AS, OP (+) and OT (+). Suitable eluents or mobile phases to be used in combination with said chiral stationary polysaccharide phase are hexane and the like, modified with an alcohol such as, for example, ethanol, isopropanol and the like. The enantiomerically pure forms of the intermediates of the formula cis- (IV) may also be derived from the corresponding enantiomerically pure forms of the appropriate starting materials, if the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by means of the stereospecific methods of the preparation. These methods will advantageously use the enantiomerically pure starting materials. The present invention also provides novel intermediates of formula (V). Said intermediates of the formula (V) are intermediates of the formula cis- (IV) in which the piperidine ring has the absolute configuration (3S.4R) and PG is a suitable protecting group such as, for example, methyloxycarbonyl, ethyloxycarbonyl, tert. -butyloxycarbonyl, phenylmethyl and the like.

The starting materials and some of the intermediates are known compounds and are commercially available or can be prepared in accordance with conventional reaction procedures generally known in the art. For example, an intermediate of the formula cis- (ll), ie cis-ethyl 4-amino-3-methoxy-1-piperidinecarboxylate, is described in EP-0,076,530 as intermediary 54, and an intermediate of the formula cis- ( IV), ie cis-ethyl 4- (4-amino-5-chloro-2-methoxybenzoylamino) -3-methoxy-1-piperidinecarboxylate is described in EP-0,076,530 as the compound 168. Furthermore, the intermediate (III) , ie 4-amino-5-chloro-2-methoxybenzoic acid, is commercially available. In view of its 5-HT3-antagonist activity, (+) - norcisapride is useful for the treatment of disorders associated with over-stimulation of 5-HT3 receptor activity. The disorders mediated with 5-HT3 are, for example, vomiting, for example, vomiting induced by a cytotoxic drug and radiation (Drugs 42 (4), 551-568 (1991)), irritable bowel syndrome, especially bowel syndrome. irritable with predominant diarrhea, and related disorders. Accordingly, the present invention provides a method for treating warm-blooded animals suffering from disorders or conditions associated with over-stimulation of 5-HT 3 receptor activity or in general 5-HT 3 mediated diseases such as, for example, vomiting, for example, vomiting induced by a cytotoxic drug and radiation, irritable bowel syndrome, especially irritable bowel syndrome with predominant diarrhea, and associated disorders. This method comprises administering a therapeutically effective amount of (+) - norcisapride, or a pharmaceutically acceptable acid addition salt thereof, to said warm-blooded animals. Or alternatively, (+) - norcisapride, and its pharmaceutically acceptable acid addition salts, are useful for the manufacture of a medicament for treating disorders or conditions associated with over-stimulation of 5-HT3 receptor activity or in general with diseases mediated by 5-HT3, for example, vomiting, vomiting induced by a cytotoxic drug and radiation, irritable bowel syndrome and irritable bowel syndrome with diarrhea predominant. In particular, (+) - norcisapride is an effective anti-vomiting agent, useful as adjunctive therapy for the treatment of cancer to relieve nausea and vomiting induced by chemotherapy and radiotherapy. (+) - norcisapride also has 5-HT4 agonist properties and therefore the invention provides a method for treating warm-blooded animals, including humans, that suffer from conditions associated with over-stimulation of receptor activity 5-HT4. More generally, a method is provided for treating disorders or conditions mediated by 5-HT. These conditions are, for example, complicated or worsened gastric emptying or more general conditions related to the gastrointestinal transit worsened or impaired. As a result, a treatment method is provided to relieve warm-blooded animals from the suffering of conditions such as, for example, gastroesophageal reflux (including the curative and maintenance treatment of esophagitis), dyspepsia, and gastroparesis. Said method comprises the administration of a therapeutically effective amount of (+) - norcisapride, or a pharmaceutically acceptable acid addition salt thereof, to said warm-blooded animals. Gastroparesis may arise from an abnormality in the stomach or from a complication of diseases such as diabetes, progressive systemic sclerosis, anorexia nervosa, after a vagotomy or partial gasterectomy, and myotonic dystrophy. Dyspepsia is a difficulty of ^^^^^^^^^^^^^^^^^^^^^ the function of digestion, which may arise as a symptom of a primary gastrointestinal dysfunction, especially a gastrointestinal dysfunction related to increased muscle tone or as a complication due to other disorders such as appendicitis, bladder disorders or poor nutrition. The (+) - narcisapride can thus be used both to eliminate the real cause of the condition or to relieve patients of the symptoms of these conditions. Symptoms of dyspepsia may also arise due to the taking of chemicals, for example, selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, paroxetine, fluvoxamine, sertraline and the like. Other symptoms that can be treated include post-operative constipation, which is an obstruction or a kinetic difficulty due to an interruption in muscle tone after surgery; upper gastrointestinal discomfort symptoms of X-rays or negative endoscopy; in infants: regurgitation or chronic and excessive vomiting; intestinal pseudo-obstruction, associated with dysfunction of mobility resulting in insufficient propellant peristalsis and in stasis of gastric and intestinal contents; constipation, which may result from conditions such as lack of bowel muscle tone or intestinal spasticity; in particular restoration of the propellant mobility of the colon as a long-term treatment of chronic constipation. Therefore, the use of (+) - norcisapride is provided for the manufacture of a medicament for the treatment of disorders or conditions that include under stimulation of the activity of the 5-HT4 receptor. The use of (+) - norcisapride is also provided for the manufacture of a medicament for the treatment of 5-HT-mediated disorders such as, for example, gastroesophageal reflux, dyspepsia or gastroparesis. Both prophylactic and therapeutic treatment are contemplated. In one aspect, the use of (+) - norcisapride is also provided for the manufacture of a medicament for treating disorders associated with feeding such as, for example, anorexia. Therefore, a method is provided for treating disorders related to feeding such as, for example, anorexia, in warm-blooded animals comprising administering to said warm-blooded animal a therapeutically effective amount of (+) - norcisapride. Accordingly, the present invention also provides a method for treating gastrointestinal disorders in a warm-blooded animal that are simultaneously associated with a sub-stimulation of 5-HT4 receptor activity and an over-stimulation of 5-HT3 receptor activity that comprises administering to said hot-blooded animal a therapeutically effective amount of (+) - norcisapride. Hence, the use of (+) - norcisapride for the manufacture of a medicament for the treatment of gastrointestinal disorders associated simultaneously with a sub-stimulation of 5-HT4 receptor activity and an overstimulation of receptor activity 5- HT3. In addition, (+) - norcisapride has a synergistic effect with the osmotic agents to obtain an intestinal wash, for example, a form of induced diarrhea. Therefore, the present invention also relates to the use of (+) - norcisapride for the manufacture of a medicament that will improve intestinal cleansing by means of a laxative, in particular an osmotic agent. Accordingly, a method for a treatment by which an effective amount of (+) - norcisapride in combination with a laxative is administered is claimed. Furthermore, a method is provided for accelerating and / or reinforcing the action of laxatives, especially osmotic agents. The patients included in this treatment are people whose bowel needs to be cleaned before diagnostic or surgical procedures. Another group of patients are those who must avoid the effort to defecate, these patients include people suffering from hernia or cardiovascular disease. In addition, the combination of the present invention can be indicated both before and after surgery, to maintain soft stools in patients with hemorrhoids and other anorectal disorders. Osmotic agents are often used in cathartic doses before the radiological examination of the gastrointestinal tract, the kidneys and other abdominal or retroperitoneal structures and before the selective bowel surgery. Therefore, the combination of (+) - norcisapride with a laxative may also be useful for these applications. Furthermore, the combination of (+) - norcisapride with a laxative may also be useful for the treatment of overdose or poisoning ^^^^^^^^^^^^^^^^ a ^ & * ^^^^^^^^^^^ ^^^^^ & ^ drug by removing agents from the intestine. Said combination can also be used in additional combination with certain anthelmintics. Laxatives are drugs that promote defecation. The precise mechanisms of action of many laxatives remain unknown because of complex factors that affect colonic function, significant variations in the transport of water and electrolytes among experimental species and preparations, and certain research costs in this area. Three general mechanisms of laxative action can be described. (1) By their hydrophilic or osmotic properties, laxatives may cause retention of fluid in colonic contents, thereby increasing the volume and softness and facilitate the intestinal transit. (2) Laxatives can act, both directly and indirectly, on the colonic mucosa to decrease the net absorption of water and NaCl. (3) Laxatives can increase intestinal mobility, causing a decreased absorption of salt and water secondary to a decreased transit time. Most recognize three main classes of laxatives, for example, 1) dietary fiber and volume-forming laxatives, 2) saline and osmotic laxatives and 3) stimulant laxatives (see Goodman and Gilman, Seventh Edition, pages 994 to 1, 003). . Saline and osmotic laxatives are the primary class of laxatives included in this invention. Saline and osmotic laxatives include several magnesium salts; sulfate, phosphate and salts of sodium and potassium tartrate; the disaccharide lactulose; glycerin and sorbitol. They absorb poor and ß «| í ^^ and > ^^^ ¿M ^^ g ^ ¡d ^ slowly and act by their osmotic properties in the luminal fluid. Two examples of these osmotic agents that are commercially available for intestinal cleansing are KleanPrepR and GoLytely®. The KleanPrepR solution consists of polyethylene glycol 3350 (59 g / l), sodium sulfate (5,685 g / l), sodium hydrogen carbonate (1,685 g / l), sodium chloride (1,465 g / l), potassium chloride (0.7425 g / l), aspartate (0.0494 g / l) and vanilla (0.3291) g i). Moreover, (+) - norcisapride, and its pharmaceutically acceptable salts, are substantially deprived of the effects of the central nervous system, in particular the absence of the antagonistic activity of dopamine and the antagonistic activity of central serotonin. It has also been discovered that (+) - norcisapride is metabolized by a different route to that responsible for the metabolism of cisapride. The latter apparently is metabolized mainly by the cytochrome p450 system. Certain therapeutic agents that inhibit the main metabolic pathway of cisapride may give rise to undesirably high plasma levels of cisapride that could be responsible for the side effects. The co-medication of such therapeutic agents with cisapride may be dissuasive, which will not be the case with (+) - norcisapride. The present invention also relates to oral dosage forms containing the salt forms (L) -tartrate or (D) -tartrate of (+) - norcisapride. Said salt forms advantageously present, a dissolution profile that is less dependent on pH. The absorption and bioavailability of drugs that have a pH-dependent solubility profile, when taken orally, can be affected by the presence of food in the gastrointestinal tract (Gl), particularly in the stomach. The gastric residence time of a drug is usually significantly greater in the presence of food than in the fasting state, ie the presence of food will prolong the stay of the drug in the relatively acid medium of the stomach. If the bioavailability of a drug is affected beyond a certain point due to the presence of gastrointestinal food, it is said that the drug shows an "effect by food" or shows a drug-food interaction. In order to achieve adequate bioavailability, such frequent drugs have to be administered under specific feeding conditions, for example before the consumption of a food, as is the case with cisapride. Oral dosage forms containing said tartrate salts have the advantage that the bioavailability of (+) - norcisapride is independent of the consumption of a food. Therefore such dosage forms are attractive because patients do not always have the necessary discipline to take their medication at the optimal time point resulting in variable and sometimes inadequate effectiveness. This in particular is the case in pediatric applications. Such dosage forms show the additional advantage of "pro-drug" administration, i.e. symptom-driven administration.Also, because of their pH independence, said oral dosage forms can be co-administered with altering agents.

»¿. ^ Tf? A & ^ fe2 ^ &l- the pH of the stomach, for example agents that increase the pH of the stomach. Examples of such co-medication agents are antacids, such as aluminum-containing antacids, for example AI (OH) 3, calcium-containing antacids, for example CaCO3 or antacids containing magnesium, for example Mg (OH) 2; H2 antagonists, for example cimetidine, ranitidine, famotidine, nizatidine, roxatidine and the like; or proton pump inhibitors, for example omeprazole, lansoprazole, rabeprazole, pantoprazole and the like. Therefore, dosage forms, preferably solid dosage forms for oral administration containing (+) - norcisapride tartrate and any of these antacids, are provided as a combined preparation for separate or sequential simultaneous use. In a further aspect, therefore, the present invention relates to pharmaceutical formulations, in particular solid dosage forms, preferably for oral administration, suitable for rapid dissolution containing as an active ingredient L- or D-tartrate of ( +) - norcisapride and an appropriate vehicle. The term "suitable for rapid dissolution" refers to the fact that the active ingredient can be dissolved from the dosage form by more than 60% within 1 hour in a pH range between 1 and 7. The dissolution can be measured from conform to the standard methods described in the European Pharmacopoeia or as indicated in the < 711 > of the USP in a USP-2 dissolution apparatus (described in the Pharmacopeia E.U.A. XXII pages 1578-1579). In order to achieve rapid dissolution the excipients should be selected such that the tablets disintegrate sufficiently rapidly, in particular in less than about 30 minutes, or less than about 20 minutes and more particularly in less than about 15 minutes, of preference less than about 3 or 1.5 minutes. In a still further aspect, the invention relates to a method for treating patients suffering from gastrointestinal disorders, without drug-food interaction, comprising the administration of (D) - or (L) -tartrate of (+) - norcisapride and for the treatment of gastrointestinal disorders in patients taking medications that increase the pH of the stomach; or the use for the manufacture of a dosage form without drug-food interaction for the treatment of said disorders. The formulations of the present invention may optionally include an anti-flatulent, such as simethicone, alpha-D-galactosidase and the like. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in the form of base or acid addition salt, as the active ingredient is combined in an intimate mixture with a pharmaceutically acceptable carrier, which vehicle can have a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are convenient in the unit dosage form suitable, preferably, for oral, rectal or parenteral injection. For example, to prepare the compositions in the oral dosage form, they can be used -? -fe- »S, - any of the usual pharmaceutical media such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as, for example, suspensions, syrups, elixirs and solutions; or solid carriers such as, for example, starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously used. For parenteral compositions, the vehicle will usually comprise sterile water, at least in large part, although other ingredients may be included, for example, to aid solubility. Injectable solutions can be prepared, for example, in which the vehicle comprises a saline solution, glucose solution or a mixture of saline solution and glucose solution. Injectable suspensions may also be prepared in which the vehicle comprises a saline solution, glucose solution or a mixture of a saline solution and a glucose solution. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suitable suspending agents and the like may be used. In compositions suitable for percutaneous administration, the carrier optionally comprises a penetration promoting agent and / or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, whose additives do not cause a significant deleterious effect on . «If the skin. Said additives can facilitate the administration on the skin and / or can be administered in various ways for example as a transdermal patch, as a product to be applied in a specific place or as an ointment. The acid addition salts of (I) due to their increased solubility in water on the corresponding base form, are obviously more suitable in the preparation of the aqueous compositions. It is essentially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form to facilitate administration and uniformity of dosage. The unit dosage form As used in the specification and claims herein refer to the physically discrete units as unit doses, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of these dosage unit forms are tablets (including fluted or coated tablets), capsules, pills, powder packets, disks, injectable solutions or suspensions teaspoons of tea, spoonfuls and the like, and their segregated manifolds. For oral administration, the pharmaceutical compositions can take the form of solid dosage forms, by For example, tablets (both swallowable and chewable forms), capsules or gelcaps, prepared by conventional means pharmaceutically acceptable excipients such as binding agents, fillers or diluents, lubricants, disintegrants, wetting agents (eg , Mh, ¿3BiÉ ^^ 3 ^, -CTg > 'al - ia' B 'example sodium lauryl sulfate) and other excipients such as coloring agents and pigments. The tablets can be coated by methods known in the art. The binding agents can be acacia, alginic acid, carboxymethylcellulose (sodium), cellulose (microcrystalline), dextrin, ethylcellulose, gelatin, glucose (liquid), guar gum, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, polyvinylpyrrolidone (povidone), or starch (pregelatinized), hydroxypropylmethylcelluloses, especially low viscosity hydroxypropylmethylcelluloses. Examples of fillers or diluents are anhydrous or spray-dried lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (e.g., microcrystalline cellulose; Avicel ™), hydrated or anhydrous calcium dibasic phosphate, and other materials known in the art. the technique or mixtures thereof. For example, a mixture of lactose and microcrystalline cellulose can be used. Lactose is used as a pure diluent, while microcrystalline cellulose is a filler having the property of providing tablets with an appropriate hardness and this has disintegrating properties due to the cellulose fibers swell in contact with water. A preferred form of lactose is DC monohydrate lactose, in particular spray-dried lactose monohydrate (Pharmatose DCL 11 ™). Filling materials or diluents may be - ~ H <> * * & amp; amp; present in a range of 50% to 95%, or 65% to 90%, or from 66% (w / w) to approximately 86%, in particular approximately 75% (all w / w) based on the total weight of the tablet or tablet core. The mixture can be commercially obtained at 75% under the trade name 5 MICROCELA® which is preferably present in an amount ranging from 80% (w / w) to 95% (w / w) based on the total weight of the mixture. the tablet or tablet core in case of film-coated tablets. Examples of lubricants are magnesium stearate, talc, silica, stearic acid, sodium stearyl fumarate, magnesium lauryl sulfate, oils hydrogenated vegetables and other materials known in the art. Lubricants are generally present in an amount ranging from 0.2% (w / w) to 7.0% (w / w) based on the total weight of the tablet or tablet core in the case of film-coated tablets. Interestingly, lubricants are present in amounts varying from 0.5% (w / w) to approximately 3.0% (w / w). Preferably, the lubricants are present in amounts ranging from 0.9% (w / w) to approximately 1.25% (w / w). The disintegrating agents comprise starch, for example corn starch, pregelatinized starch, sodium starch glycolate (Explotab®), cross-linked povidone, cross-linked sodium carboxymethyl cellulose, clays, microcrystalline cellulose (Avicel®), alginates, gums, sodium caramellose, also known as croscarmellose sodium and other disintegrants known in the art. The disintegrant may be present in a amount from 2% (w / w) to 15% (w / w) or from 3% (w / w) to approximately 10% (w / w). As used herein, the percentages are weight by weight (w / w) and represent the ratio (in percent) of the ingredient or excipient based on the total weight of the tablet (or in the case of tablets) coated core tablets). Commonly, the tablet mixture is either dry granulated or wet granulated before tabletting. In some cases, particularly when using (D) - or (L) -tartrates it is possible to prepare tablets using direct compression techniques, which can give a better dissolution profile. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions or these may be presented as a dry product to be reconstituted with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means, optionally with pharmaceutically acceptable additives such as suspending agents for example sorbitol syrup, methylcellulose, hydroxypropyl methylcellulose or hydrogenated edible oils); emulsifying agents (for example lecithin or acacia); non-aqueous vehicles (for example almond oils, oily esters or ethyl alcohol); and preservatives (for example methyl- or propyl p-hydroxybenzoates or sorbic acid). The pharmaceutically acceptable sweeteners comprise of preference for at least one intense sweetener such as saccharin, sodium or calcium saccharin, aspartame, acesulfame potassium, sodium cyclamate, alitame, a sweetener of dihydrochalcone, monelin, stevioside or sucralose (4,1,, 6'-trichloro-4, r.6, -trideoxygalactosucrose), preferably saccharin, sodium or calcium saccharin and optionally a volumetric sweetener such as sorbitol, mamitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey. Intense sweeteners are conveniently used at low concentrations. For example in the case of sodium saccharin, the concentration can vary from 0.04% to 0.1% (w / v) based on the total volume of the final formulation, and preferably is about 0.06% in the case of dose formulations low and approximately 0.08% in the case of high dosage formulations. The volumetric sweetener can be used effectively in larger amounts ranging from 10% to about 35%, preferably from 10% to 15% (w / v). Optionally, flavors may be incorporated into the composition, for example to mask the bitter taste. Flavors that can mask the bitter taste ingredients in low dose formulations are preferably fruit flavors such as cherry, raspberry, currant or strawberry flavor. A combination of two flavors can yield very good results. Stronger flavors may be needed in high dose formulations such as caramel flavor, chocolate, fresh mint flavor, fantasy flavor and similar pharmaceutically acceptable strong flavorings. Each flavor can be present in the final composition in a concentration ranging from 0.05% to 1% (w / v). The combinations of said strong flavorings can be used advantageously. Preferably a flavor is used that does not undergo any change or loss of taste and color under the acidic conditions of the formulation. The compounds of the invention can also be formulated as depot preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or in ion exchange resins, or as slightly soluble derivatives, for example as a slightly soluble salt. The compounds of the invention can be formulated for parenteral administration by injection, conveniently intravenous, intramuscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion. Formulations for injection may be presented in unit dosage forms for example in ampules or in multiple dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as isotonicifying, suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with an appropriate vehicle, for example sterile, pyrogen-free water before use. The compounds of the invention can also be formulated into rectal compositions such as suppositories or retention enemas, for example containing conventional suppository bases such as cocoa butter and other glycerides. The compounds of the invention can be used for intranasal administration, for example, as a liquid spray, as a powder or in the form of drops. It is generally contemplated that a therapeutically effective amount would be between about 0.001 mg / kg to about 2 mg / kg of body weight, preferably between about 0.02 mg / kg to about 0.5 mg / kg of body weight. Appropriate solid oral dosage forms when in a unit dosage form contain the equivalent of about 0.1 mg to 100 mg of the active ingredient, more particularly they are about 1 mg to about 50 mg to about 20 mg. mg. A method for treatment may also include administering the active ingredient over a regimen of several intakes per day, eg 2-4 intakes per day. The following examples are provided for the purpose of illustration and not of limitation. ^^^^^^^ gaa ^? ^ j ^^^ M & ^ jg ^ ljgj ^^ EXPERIMENTAL PART Hereinafter "ACN" means acetonitrile, "CH3OH" means methanol and "DI PE" means diisopropyl ether. Of some of the compounds of the present invention, the absolute stereochemical configuration was not determined experimentally. In these cases, the stereochemically isomeric form that was first isolated was designated "B" and the second was designated "A", without another reference to the current absolute stereochemical configuration. Measurements of optical rotation (RO), or specific rotation [a] 20o were performed with a Perkin Elmer model 241. The rotation [a] was measured at a temperature of 20 ° C, using the sodium D line (wavelength of 589 nm) and a cuvette with a path length of 100 mm. The compound was dissolved in methanol at a concentration of 1% w / v. Chiralpak Ad (amylose 3,5-dimethylphenyl carbamate) is a chiral stationary phase column material purchased from Daicel Chemical Industries, LTD, in Japan.

A.- SYNTHESIS OF (+) - NORCISAPRIDE EXAMPLE A.1 Cis-ethyl 4- (4-amino-5-chloro-2-methoxybenzoylamino) -3-methoxy-1-piperidine carboxylate (0.12 moles, 46 g) (exemplified in EP-0,076,303 as compound No. 168) is separated in its enantiomers by means of chiral column chromatography in a Chiralpak AD (2 kg, internal diameter of the column (ID): 110 mm, eluent: n-hexane / ethanol 70/30, injection 5 g / liter, speed flow: 400 ml / minute, detection: UV at 254 nm). Two desired fraction groups were collected and their solvent was evaporated. The residue of the first eluent enantiomer was dissolved in methanol, filtered over dicalite, and the solvent was evaporated. The residue was suspended in DIPE, then cooled to 0 ° C, and the resulting precipitate was filtered and dried (vacuum, 40 ° C), giving 18 g (-) - cis -ethyl 4- (4-amino- 5-chloro-2-methoxybenzoylamino) -3-methoxy-1-piperidinecarboxylate (enantiomerol; OR (-); Mp 164 ° C); [α] 20 D = -55.88 ° (c = 1% w / v in CH 3 OH) (interm. Said intermediary 1 had an optical purity better than 99%. The residue of the second eluent enantiomer was dissolved in methanol, filtered over dicalite, and the solvent was evaporated. The residue was suspended in DIPE; it was then cooled to 0 ° C, and the resulting precipitate was filtered and dried (Vacuum at 40 ° C), giving 17.6 g (+) - cis -ethyl 4- (4-amino-5-chloro-2-methoxybenzoylamino) 3-methoxy-1-piperidinecarboxylate (enantiomer 2; OR (+); Mp: 164 ° C); [α] 20 D = + 55.10 ° (c = 1% w / v in CH 3 OH) (interm, 2), which have an optical purity greater than 98%.

EXAMPLE A.2 A mixture of intermediate (2) (0.042 moles, 16 g) and potassium hydroxide (23 g) in 2-propanol (230 ml) was stirred and refluxed for 6 hours. hours. The reaction mixture was cooled and the solvent was evaporated. Water was added. The solvent was evaporated. The residue was suspended in water, then filtered and the solid was dissolved in dichloromethane. The organic solution was washed with water, dried, filtered and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered and dried (evacuated) to give fraction 1 (57%, mp .: 188 ° C). This fraction was recrystallized with ACN. The precipitate was filtered and dried to give fraction 2 (5.3 g). All crystallization filtrates were collected and the solvent evaporated. The residues, as well as fraction 2, were purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / (CH 3 OH / NH 3) 90/10). The pure fractions were collected and the solvent was evaporated. The solid residues were dried, yielding 5.6 g of (+) cis-4-amino-5-chloro-2-methoxy -? / - (3-methoxy-4-piperinyl) benzamide (i.e., (+) - norcisapride); [a] 20 D = + 5.60 ° (c = 1% w / v in CH 3 OH) (compound 1).

EXAMPLE A.3 A mixture of intermediate (1) (0.044 moles, 17 g) and potassium hydroxide (24 g) in 2-propanol (250 ml) was stirred and refluxed for 6 hours. The reaction mixture was cooled and the solvent was evaporated. Water was added. The solvent was evaporated. The residue was stirred in water, then filtered and the solid was crystallized from ACN. The precipitate was filtered and dissolved in DCM. The organic solution was washed with water, dried, filtered and the solvent was evaporated. The residue was crystallized with ACN. The precipitate was filtered and dried, yielding 7 g (54%) of (-) - cis-4-amino-5-chloro-2-methoxy-? / - (3-methoxy-4-piperidinyl) benzamide (ie, (-) - norcisapride); [α] D20 = -6.09 ° (c = 50.90 mg in 5 ml in CH 3 OH) (compound 2).

EXAMPLE A.4 To a stirred solution of (+) - cis-4-amino-5-chloro-2-methoxy-V- (3-methoxy-4-piperidinyl) benzamide (compound 1) in a mixture of water and methanol was added a solution of acid [R (R *, R *)] -2,3-dihydroxybutanedioic acid 10 (L-tartaric acid) in a mixture of water and methanol and the product was allowed to crystallize. It was filtered and dried, giving [R (R *, R *)] - 2,3-dihydroxybutanedioate (+) - (3S, 4R) -cis-4-amino-5-chloro-2-methoxy-monohydrate. N- (3-methoxy-4-piperidinyl) benzamide. The X-ray diffraction measurements were run on a four-circle Siemens P4 diffractometer. 15 B.- PHARMACOLOGICAL EXAMPLES EXAMPLE B.1 Intestinal lavage induced with MgSO4 Beagle dogs (of both sexes with varied body weight, 16 hours fasting) were orally pre-treated with (+) - norcisapride or solvent and one hour later they were given an oral administration of magnesium sulfate (MgSO4.7H2O, 64 g / l, 0.26M, 200 ml). The onset of induced intestinal lavage ^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ a period of 4 hours after administration. Liquid stools within 4 hours did not occur in the control animals treated with distilled water (2.5% false positives, n = 200) and were considered to reflect a significant acceleration of intestinal lavage induced with MgSO4. Doses within the range of active doses were given to five animals each, were tested in separate experimental sessions including the control animals treated with solvent. The absolute or no reaction criterion was used, based on the distribution of results obtained in a large number of animals treated with solvent, to calculate the ED5o (effective dose) and 95% confidence limits in accordance with the iterative method of Finney (Finney, 1962). As illustrated in Table B.1, a small increase in the dose from 0.032 mg / kg to 0.15 mg / kg was sufficient to obtain diarrhea within the first hour after taking magnesium sulfate.

TABLE B.1 EDgo values (95% confidence limit mg / kq, p.o.) of (+) - norcisapride to promote intestinal lavage induced with magnesium sulfate in dogs in the first hour after p.o. EDsn are listed to obtain liquid stools within 1 to 4 hours after taking magnesium sulfate.

EXAMPLE B.2 Apomorphine test. triptine. norepinephrine (ATN) in rats The absence of the central dopamine antagonistic activity and the serotonin antagonistic activity of the subject compounds is evidenced by the experimental data obtained in the combined test of apomorphine (APO), tryptamine (TRY) and norepinephrine (ÑOR) in rats Said combined test of apomorphine, tryptamine and norepinephrine was described in Arch. Int. Pharmacodyn, 227, 238-253 (1977) and provides an empirical evaluation of the relative specificity with which drugs can affect both CNS and peripherally the particular neurotransmitter systems. In this test, the rats were observed in the effects or responses indicating peripheral or central activity. Antagonism of central depamine was evaluated by stimulating rats, pretreated subcutaneously with different doses of the test compound, such as apomorphine which is a dopamine agonist. Then, antagonism of serotonin stimulated to the same rats, pretreated subcutaneously with different doses of the test compound, was evaluated with tryptamine which is an agonist at the 5HT2 serotonin receptors. In this test, both central and peripheral serotonin antagonism can be classified. Serotonin antagonists that act centrally are potential anti-psychotic drugs, particularly when they simultaneously show antagonism to dopamine in the first part of this test. Finally, the alpha-adrene antagonist activity of the test compounds was evaluated by stimulating the same rats, pre-treated subcutaneously with different doses of the test compound, with norepinephrine which is an alpha-adrenergic agonist. The experimental data are summarized in Table B.2 and expressed as ED50 mg / kg body weight values, which are defined as the dose at which each of the test compounds protect 50% of the animals tested in the relevant response evoked by the stimulating substances mentioned above. The APO column lists the results of the stimulation with apomorphine, indicating the antagonistic activity of the central dopamine. The TRY seizure column and the TRY hyperemia column, list the results of the stimulation with tryptamine, indicating the central and peripheral antagonist activity, respectively. The ÑOR column lists the results of norepinephrine stimulation, indicating the alpha-adrenergic agonist activity. The favorable pharmacological properties of (+) - norcisapride are based on the absence of central dopamine antagonist activity (APO column) and central serotonin (column TRY seizures).

TABLE B.2 EXAMPLE B.3 Antagonism of 5-hydroxyquinuramide on guinea pig ileum It was shown that 5-HT3 receptors play an important role in vomiting. As 5-OH-K (5-hydroxyquinuramine) is a specific agonist at the 5-HT3 receptor, this test evaluates the potential antagonistic effects of 5-HT3. A. "% Guinea pigs of both sexes were slaughtered by decapitation, with a body weight of ± 450 g. Segments were cleaned, intact, nonterminal ileus strips (the distal 10 cm were discarded), 4.5 cm in length were suspended vertically with a pre-load of 0.75 g in a water bath. 100 m for the isotonic record; [(Transducer control unit of Displacement; Janssen Scientific Instrument Division), HP7 DGDT-1000 (Hewlett-Packard CY)]. The organ bath was filled with a Tyrode solution (37.5 ° C), gasified with a mixture of 95% O2 and 5% CO2. After a stabilization period of 20 minutes, methacholine (3.10"6 M, 30 seconds of contact time) was added to the bath fluid to evaluate the maximum potential contraction, then the fluid in the bath was changed. 5-OH-K serotonin (30 seconds contact time) was added (final concentration 3.10"6 M) at intervals of 10 minutes, changing the bath fluid 30 seconds after each addition. After reaching the reproducible contractile effects, a single dose of the test compound was added to the bath fluid followed by the addition of 5-OH-K, 5 minutes later. After determining the concentration-response log curve of the test compound, the IC50 values that reduce the effect induced by 5-OH-K by 50% were calculated by linear regression analysis. Compound 1, for example, (+) - norcisapride has an IC50 of 93 nM; and compound 2, for example, (-) - norcisapride has an IC50 of 450 nM.

EXAMPLE B.4 Coaxial stimulation of guinea pig ileus Dunkin-Hartley guinea pigs of both sexes (weighing between 600-900 g) were sacrificed by decapitation. The ileum was removed and cleaned with a warm, oxygenated solution of Krebs-Henseleit. Parts of ileus (15 cm) were slid over the glass pipette. The longitudinal muscle layer with the mionteric plexus was removed by means of a cotton thread moistened with a Krebs solution. The strips with the length of 8 cm were folded and these strips (4 cm) were mounted between two platinum electrodes (8 cm long, 0.5 cm apart). The strips were suspended with a pre-loading of 1.5 g of 100 ml of a solution of Krebs-Henseleit (37.5 ° C), were gasified with a mixture of 95% O2 and 5% CO2. The preparations were excited with simple rectangular stimuli [1 ms; 0.1 Hz; sub-maximal response (current leads to 80% maximum response), from a programmable stimulator (Janssen Scientic instruments Division)]. The contractions were measured somatically (Statham UC2, Janssen Scientific Instruments amplifier, Kipp BD-9 boom recorder). During the 30 minute stabilization period, the strips were stretched repeatedly to obtain a stable tension of 1.5 g. Before starting the electrical stimulation, a cumulative concentration response curve of acetylcholine was given (3.10"9, 10" 8 and 3.10"8 and 10" 7 M). The bath fluid was replaced with a new Krebs solution and the strips were allowed to stabilize for another 30 minutes. Subsequently, the strips (power stimulator) were electrically stimulated at a frequency% of 0.1 Hz for 1 ms. The voltage was increased in steps of 2 V (maximum 15 V) until the development of the maximum force was observed. The spasm response was decreased (by voltage reduction) to approximately 80% of the maximum operating voltage. Carefully adjusting the voltage it was possible to obtain a submaximal acute spasm response that did not vary for at least 2 hours When the acute spasm responses were stable for at least 15 minutes, the test compound was added to the bath fluid for 30 minutes . If the test compound caused less than 50% inhibition, cisapride 3.10"7 M was added to the bath fluid to discover that the test compound would antagonize the stimulatory effect of cisapride If the test compound caused more than 50% inhibition, 10" 7 M naloxone was added to discover if the inhibition mediated by opioid receptors. After the addition of either cisapride or naloxone, supramaximal stimulation was again given. Then, the electrical stimulation was discontinued and a second cumulative-response curve was given with acetylcholine. These two acetylcholine cumulative-response curves were given in order to distinguish the effects by means of a decreased release of acetylcone, from a direct anticholinergic effect or to distinguish the effects by means of the increased release of acetylcholine from the sensitization of acetylcholine. the muscarinic receptors. The EC50 (that is, the concentration that stimulates the response to electrical stimulation by 50%) of linear regression when Compound 1, that is, the (+) - norcisapride has an EC50 of 0.6 μM; and compound 2, that is, (-) - nocisapride has an EC50 of 5 μM.

EXAMPLE B.5 Coaxial stimulation of guinea pig colon Guinea pigs of both sexes were slaughtered by decapitation (body weight ± 450 g). The ascenders were removed from the colon and rinsed, then segments of approximately 3 cm long were prepared. These strips were suspended in an organ bath (100 ml) and connected with an isotonic transducer under a preload of 2 g: Displacement Transducer Control (Janssen Scientific Instrument Division); HP 7DGDT 1000 (Hewlett-Packard)]. The organ bath was filled with a Dejalon solution (37.5 ° C), gassed with a mixture of 95% O2 and 5% C02. After a stabilization period of 20 minutes, 3.10"6 M methacholine was added to the bath fluid to evaluate the maximum potential effect of the strip (contact time of 30 seconds), then the bath fluid. This was repeated at 10 minute intervals until a reproducible response was obtained after adding methacholine. Then, the test compound was added for 10 minutes. Then, without changing the bath fluid, cisapride 3.10"7 M was added to evaluate a possible effect of 5HT.

L ^^^^^^^^^^^^^^ contraction, caused by cisapride obtained a stable maximal level, methacholine was added 3.10"6 M to evaluate a potential anticholinergic effect bath fluid until a maximal contraction. the EC50 (ie concentration that stimulates the effect of maximum tone 50%) from 5 compound, was calculated using linear regression analysis compound 1, i.e. (+) -. norcisapride has an EC50 of 1.9 .mu.M and compound 2, ie (-) - norcisapride has an EC or 11 μM.

C- EXAMPLES OF PHARMACEUTICAL COMPOSITION 10 C.1.- Tablets covered with film The active ingredient, the lactose and the unmodified starch are mixed in a fluid bed process and the powder obtained in this way is sprayed with a solution of HPMC in water. The granules homogeneously moistened thus obtained were dried, sieved together with microcrystalline cellulose, sodium melosa croscara, colloidal anhydrous silica and magnesium stearate. The sieved powder is mixed and compacted into tablets. The coating suspension is prepared by first dissolving HPMC and propylene glycol in water by adding this solution to a mixture homogenized water, talc, titanium dioxide and the dye. The coating solution is sprayed onto the tablets in a coating apparatus at increased temperature. ^^^^^^^^^^^^^^^^^ & ß ^^^^^^^^^^^^^^^^^^^^^^ Core of the peta Tablet film coating (* 1) Mesh 200 is an indication of the type of lactose monohydrate that was used. (* 2) HPMC means hydroxypropylmethylcellulose, the number "2910" refers to the type of hydroxypropylmethylcellulose that was used. The first two digits "29" represent the approximate percentage of methoxyl groups and the third and fourth digits "10" represent the approximate percentage of hydroxypropyl groups. The viscosity "15 mPa.s" of a 2% aqueous solution measured at 20 ° C is also indicated. This is an indication of the molecular weight of the HPMC that is used.

C.2.- Uncoated tablet 10 The ingredients were mixed in a planetary mixer and compacted in a tablet press. fifteen twenty l gká & amp! a! 3mt £. -Yes

Claims (5)

1. NOVELTY OF THE INVENTION CLAIMS 5 1.- A process for preparing a base of (+) - norcisapride of the formula characterized in that a) the enantiomers of cis-ethyl (4-amino-5-chloro-2-methoxy-benzoylamino) -3-methoxy-1-piperidine carboxylate are separated by means of liquid chromatography on a chiral stationary phase, and b) the fraction having a specific rotation [a] 20D in methanol which is dextrorotatory is isolated, and c) said fraction is solvolved to (+) - norcisapride.
2. 2. A process according to claim 1, further characterized in that the chiral stationary phase is a cellulose or amylose polysaccharide.
3. 3. A process according to claim 2, further characterized in that the eluent is a mixture of hexane and an alcohol.
4. 4. A method according to claim 1, ^^^^^? ^^^^^^^^^^^^^^^^^ ^^^^^^^^ ¿^^ further it characterized in that the solvolysis comprises hydrolysis in a basic aqueous medium.
5. 5. The (+) - norcisapride obtainable by means of a method of any of claims 1 to 4. 5 - A compound according to claim 5 which contains at least 90% by weight of the ( +) - stereoisomer and 10% by weight or less of the (-) - stereoisomer. 7. A compound according to claim 5 which contains more than 99% by weight of the (+) - stereoisomer. 8. The (+) - norcisapride according to claim 5 substantially free of its (-) - stereoisomer. 9.- The (+) - norcisapride that has a specific rotation [a] 20D in methanol that is dextro rotatory. 10. The (+) - norcisapride having a specific optical rotation 15 [a] 20o of approximately + 5.60 ° (c = 1% w / v in methanol). 11.- The norsisapride that has the absolute configuration of (3S, 4R) (3S, 4R) -cis-4-amino-5-chloro-2-methoxy-N- (3-methoxy-4-piperidinyl) benzamide. ^^^^^^^^^ x ^^^^^^^^^^^^^^^^^^^^^^^^^^ M ^^^^^ 12. - A pharmaceutically acceptable acid addition salt of a compound according to any of claims 5 to 11. 13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound as described in any of claims 5 to 12. 14. a process for preparing a pharmaceutical composition according to claim 13, further characterized in that a therapeutically effective amount of a compound as defined in any of claims 5 to 12 is intimately mixed with a pharmaceutically acceptable vehicle. 15. The use of a compound as defined in any of claims 5 to 12 for the manufacture of a medicament for the treatment of gastrointestinal disorders associated with overstimulation of the activity of the 5-HT3 receptor. 16. The use of a compound as defined in any of claims 5 to 12 for the manufacture of a medicament for the treatment of gastrointestinal disorders associated with low stimulation of 5-HT4 receptor activity. 17. The use of a compound as defined in any of claims 5 to 12 for the manufacture of a medicament for the treatment of gastrointestinal disorders associated simultaneously with the low stimulation of the 5-HT4 receptor activity and the overstimulation of the 5-HT3 receptor activity. 18. The use according to any of claims 15 to 17 while avoiding the effects of the central nervous system. 19. The use according to any of claims 15 to 17 with reduced risk of cardiovascular side effects. 20. The use according to any of claims 15 to 17 in patients susceptible to the interaction of 10 cardiovascular drugs. 21. The use of a compound as defined in any of claims 5 to 12 for the manufacture of a medicament for the treatment of disorders mediated by 5-HT3 and avoiding effects on the central nervous system. 22. Use according to claim 21, wherein the disorder is irritable bowel syndrome or irritable bowel syndrome with predominant diarrhea. 23. The use according to claim 21, wherein the disorder is vomiting by cytotoxic drug or radiation induced vomiting. 24. The use of a compound as defined in any of claims 5 to 12 for the manufacture of a medicament for treating disorders in the diet. 25. The use according to claim 24, wherein the ^^^^^^^^^ & ^^^^^^^^^^^^ Smí ^ í ^^ í ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^ Eating disorder is anorexia. 26. The use of a compound as defined in any of claims 5 to 12 for the manufacture of a suitable medicament for accelerating intestinal cleansing with a laxative. 27. Use according to claim 26, wherein the laxative is an osmotic agent. 28. A use according to claim 26, wherein the laxative is a solution of polyethylene glycol (PEG) -electrolyte. 29. The use of a compound as defined in any of claims 5 to 12 for the manufacture of a medicament for the treatment of disorders mediated by 5-HT and avoiding effects on the central nervous system. 30. The use according to claim 29, wherein the disorder is the gastrointestinal transit hindered or obstructed. 15. The use according to claim 29, wherein the disorder is gastric emptying hindered or obstructed. 32. The use according to claim 29, wherein the disorder is gastroesophageal reflux. 33. A use according to claim 29, wherein the disorder is dyspepsia or gastroparesis. m ^^^? ¿^^^^ ^^^ ¿^ ^ ^ ^ ^ ^ 34. - The compounds of the formula (V), wherein the piperidine ring has the absolute configuration (3S, 4R) and PG is methyloxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl or phenylmethyl.