UA63954C2 - (+/-) norcisapride, a process for the preparation thereof, intermediate compounds, composition based thereon for use in the manufacture of medicaments for treating gastro-intestinal 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. , (I) , (V)

Description

Description of the invention

The present invention relates to (i)-norcisapride and its pharmaceutically acceptable acid addition salts, 2 methods of obtaining the specified compound, and its use for the production of a medicament for the treatment of gastrointestinal disorders, while avoiding effects on the central nervous system.

Cisapride is a widely used gastrokinetic agent and is commercially known as Prepulsid

SRheriividtm"), now it is used mainly for the treatment of gastroesophageal reflux syndrome.

This disease is described as the reflux of stomach contents into the esophagus. Other factors in the pathogenesis of disease 0 are delayed gastric emptying, insufficient esophageal cleansing due to impaired peristalsis, and the corrosive nature of the reflux material, which can damage the esophageal mucosa.

Due to its activity as a prokinetic agent, cisapride can also be used in the treatment of dyspepsia, gastroparesis, constipation, postoperative intestinal obstruction and intestinal pseudo-obstruction.

Cisapride is metabolized mainly by the enzyme cytochrome P 450 ЗА4. As a result of significant metabolism 79, unchanged cisapride is less than 1095 of the product isolated from urea and feces after oral administration. The main metabolite found in plasma, urea and feces was described as Mepsidegtapez MU. oh oh in

Disgust Meillard. Oizrovz. 16(3): 410-419, 1988, was named "norcisapride" and is a racemic mixture of two enantiomers.

Racemic norcisapride is also described in EP-A-0,076,530, published April 13, 1983, as compound 211, 70 which has gastrointestinal stimulant properties. (-3-Norcizapride is one of the optical stereoisomers. The full chemical name is -(9-4-amino-5-chloro-N-(33-methoxy-4-piperidinyl)-2-methoxybenzamide, hereinafter referred to as "( γ-norcisapride". The term "(k)-norcisapride" and especially the term "optically pure (α)-norcisapride" covers (t)-norcisapride, which is essentially free of its (-)-stereoisomer. p. 29 MO 96/ 40133 describes the use of (-)-norcisapride for the treatment of gastrointestinal disorders, in particular for the treatment of gastroesophageal reflux disease, while significantly reducing the adverse effects associated with the administration of racemic cisapride. This document further states that optically pure (- U-norcisapride would be an effective antiemetic agent useful as an adjunctive course in cancer treatment to alleviate nausea and vomiting induced by chemo- or radiotherapeutic agents.

It has now been found that (w)-norcisapride, in particular "optically pure (w)-norcisapride", also called "w)-norcisapride, which is essentially free of its (-)-stereoisomer", has as 5-HT3-antagonist and 5-HT4-agonist properties, and, in addition, essentially devoid of influence on the central nervous system. b

The present invention relates to ()-norcisapride and, in particular, (i)-norcisapride, which is essentially free of its co (-)-stereoisomer, its pharmaceutically acceptable acid addition salts, and their use for the treatment

From v-HT3 and/or 5-HT./-mediated disorders, while avoiding effects on the central nervous system. ish (4)-Norcizapride can be represented by the following chemical structural formula:

Osn, () «

M shi s n-M what MN,

And" Fr

Osn, SI (e)) (e-cis o In the chemical structural formula of (k)-norcisapride presented above, bonds connecting МН-СО- and

Te) OSN-groups with a piperidine ring, marked with bold lines as a sign that these two groups are in the CcCys-configuration. ini The term "(R-norcisapride" and, in particular, the term "optically pure (r)-norcisapride" covers the stereoisomer which

Ta' is essentially free of its (-)-stereoisomer. In particular, the term "substantially free of (-)stereoisomer" refers to a stereochemical mixture of norcisapride that contains at least 909 omas. (k)-norcisapride and 109omas. or less (-)-nsorcisapride. In a preferred embodiment, the term "substantially free of (-)stereoisomer" refers to a stereochemical mixture of norcisapride that contains at least 989 omas. (i)-norcisapride and 29omas. or less (-)-norcisapride. According to an even better embodiment, the term "substantially free of (-)stereoisomer" as used herein means that the composition contains more than 9995 wt. co (i)-norcisapride. These ratios are determined in terms of the total amount of norcisapride in the stereochemical mixture. Compounds capable of rotating the plane of polarized light are called optically active. When defining an optically active compound, the prefixes О and И or К and З are used to indicate the absolute configuration of the molecule with respect to its chiral center(s). The prefixes 4 and И or (ж) and (-) are used to indicate the sign of rotation of the plane of polarized light by the compound, and (-) and И indicate that the compound is left-handed. The compound with the prefix (у) or и is dextrorotatory. For any particular chemical structural formula, these compounds, called stereoisomers, are identical except that they are mirror images of each other. A particular stereoisomer may also be called an enantiomer, and a mixture of such stereoisomers is often called a racemic mixture.

The amount of rotation A is not constant for a given enantiomer, but depends on the length of the vessel with the sample, temperature, solvent and concentration (for solutions), and the wavelength of light. Thus, the specific rotation (vi) is determined in such a way that the obtained parameter is independent of the length of the vessel and the concentration of the solution. The specific rotation (p. , where o denotes the observed rotation, | denotes the length of the vessel

ST in decimeters, and c - concentration in grams per milliliter. Specific rotation is usually indicated together with temperature and wavelength, that is, and ; where 20 denotes the temperature in degrees Celsius and O denotes that the rotation was measured with light from the O sodium spectral line, which has a wavelength of 589 nm.

X-ray analysis of ()-norcisapride Y-tartaric acid salt, i.e. (1)-(35.4K)-cis-4-amino-5-chloro-2-methoxy-M-(3-methoxy-4-piperidinyl)benzamide|Kk -(K",Ky)1-2,3-dihydroxybutanedi oate monohydrate determined the absolute configuration of (h)-norcisapride as (35,4K). Hence, (h-)-norcisapride has the following absolute stereochemical formula:

Osn, " n-M m-s MN, o

Osn, a (3554K)-cis-4-amino-5-chloro-2-methoxy-M-(3-methoxy-4-piperidinyl)benzamide

The pharmaceutically acceptable acid addition salts mentioned above are considered to include the therapeutically active pentaxic forms of the acid addition salts that the parent form of (i)-norcisapride was able to form. The main form of (y)-norcisapride can be converted to its (o) pharmaceutically acceptable acid addition salts by treating the main form of (w)-norcisapride with the appropriate acid. Suitable acids include, for example, inorganic acids, such as hydrohalic acids, for example, hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like - 2r Acids, or organic acids, such as, for example, acetic, propionic, oxyacetic, lactic, pyruvic acid .

On the contrary, the specified forms of acid addition salts can be converted by treatment with the corresponding /-:C9 with a base to form the free base of ()-norcisapride. with

The term addition salt in the sense that was used above also includes solvates that (i)-norcisapride, as well as its salts, are capable of forming. Such solvates are, for example, hydrates, alcoholates, etc.

As used herein and hereinafter, the term (i)-norcisapride shall also include its pharmaceutically acceptable acid addition salts and solvate forms thereof. -in

The main form of ()-norcisapride can be obtained as shown in Scheme 1.

Fu osn, and Osn, pis-() TSI cis-() (95) so -- (ku norcisapride GO)

Amino- and methoxy-substituents of the piperidine ring in the intermediate compounds of the formula cis-(II) and the product of reaction 1 cis-(IM) have a cis-configuration, that is, the methoxy- and amino-group are on the same side of the average

T» of the plane defined by the piperidine ring and is a racemic mixture of 2 enantiomers. To indicate this configuration, the bonds that join these functional groups are marked with bold lines, as in the formula |.

According to the reaction depicted in Scheme I, an intermediate compound of the formula cis-(II) in which RO represents a corresponding protecting group, such as, for example, methyloxycarbonyl, ethyloxycarbonyl, tert-butoxycarbonyl, phenylmethyl, etc., is introduced into the reaction formation of an amide with a carboxylic acid of the formula (II) or its reactive (Ф) functional derivative, thereby obtaining intermediate compounds of the formula cis-(IM). Reaction of intermediate compounds

Ge of formulas cis-(I) and (IP) is carried out in the presence of a dehydrating agent, such as dicyclohexylcarbodiimide, or cis-() is introduced into a reaction with a reactive derivative of a carboxylic acid (II), for example, an acid chloride or a mixed anhydride. The reaction can be carried out in a reaction-inert solvent, 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 may increase the reaction rate. The reaction can conveniently be carried out at a temperature in the range from room temperature to the reflux temperature of the reaction mixture. After that, the intermediate compounds of the formula cis-(IM) are separated into their enantiomers and each isolated enantiomer of the intermediate compound cis-(IM) is converted to its corresponding b5 enantiomer of cisapride by removing the protecting group PO, depending on the nature of the PO group, by acid or basic solvolysis or by catalytic hydrogenation, for example, by treatment with an inorganic base such as potassium hydroxide in an aqueous medium. According to another variant, the protective group PO of intermediate compounds of the formula cis-(IM) can be removed, thereby obtaining a racemic mixture of norcisapride, which

Subsequently, it is separated into its enantiomers.

The intermediate compounds of the formula cis-(IM), obtained as shown in Scheme I, are a mixture of enantiomers that can be separated from each other by separation methods known to those skilled in the art. A mixture of enantiomeric forms of intermediate compounds of the formula cis-(IM) can be resolved by conversion into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. These diastereomeric salt forms are subsequently separated, for example, by means of selective or fractional crystallization, and enantiomers are released from them by treatment with alkalis. An alternative method of separation of enantiomeric forms of intermediate compounds of the formula cis-(IM) involves the use of liquid chromatography using a suitable chiral stationary phase.

Suitable chiral stationary phases are, for example, polysaccharides, in particular cellulose or amylose derivatives. Commercially available chiral stationary phases based on polysaccharides are SpigaIractm CA, 75 OA, OB, OS, OO, ONR, Ob, 0) and OK and SpigaIractm AC, A5, ОР(x) and OT(k). Suitable eluents or mobile phases for use with said polysaccharide chiral stationary phases are hexane, etc., modified with an alcohol such as ethanol, isopropanol, etc.

Enantiomerically pure forms of intermediate compounds of the formula cis-(M) can also be obtained from the corresponding enantiomerically pure forms of the corresponding starting materials, provided that the reaction occurs stereospecifically. If a specific stereoisomer is needed, then it is better to synthesize the specified compound by stereospecific methods of preparation. These methods make better use of enantiomerically pure starting materials.

The present invention also provides novel intermediates of formula (M). Said intermediates of the formula (M) are intermediates of the formula cis-(IM) in which the piperidine ring is in the absolute configuration (35.4K), aPOo c denotes a suitable protecting group, such as methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl, phenylmethyl and others i) osn, I z n M

RO-M Mm-E MN, yuyu o (22) - osn, a so (Se)

The starting materials and some of the intermediates are known compounds and are commercially available or can be prepared by conventional reaction techniques known to those skilled in the art. For example, the intermediate compound of formula cis-(II), that is, 4-amino-3-methoxy-i-piperidinecarboxylate, is described in EP-0,076,530 as intermediate compound 54, and the intermediate compound of formula cis-(IM), that is, "cis-ethyl- 4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-methoxy-1-piperidinecarboxylate, described in EP-0,076,530 U c as compound 168. In addition, intermediate compound I, i.e. 4-amino-5-chloro -2-methoxybenzoic acid is commercially available. available "" Taking into account its 5-HT z-antagonistic activity, (i)-norcisapride is used for the treatment of disorders associated with excessive stimulation of the activity of 5-HT z-receptors. 5-HT3-mediated breakdowns include, for example, emesis, such as emesis induced by cytotoxic drugs and

Ge") by radiation (Ogydz 42(4), 551-568 (1991)), irritable bowel syndrome, especially diarrhea-predominant irritable bowel syndrome, and related disorders. Accordingly, the present invention provides a method of treating warm-blooded animals suffering from disorders or conditions associated with excess

Ge) by stimulating the activity of the 5-HT z-receptor or in general on 5-HT3-mediated diseases, such as vomiting, 5p for example, vomiting induced by cytotoxic drugs and radiation, irritable bowel syndrome, especially diarrhea-predominant irritable bowel syndrome , and relatives

And" disorders. This method includes the introduction of a therapeutically effective amount of (i-)-norcisapride, or its pharmaceutically acceptable acid addition salt, to said warm-blooded animals.

Or, in another embodiment, (i-)-norcisapride and its pharmaceutically acceptable acid addition salts are suitable for the manufacture of a medicament for the treatment of disorders or conditions associated with excessive stimulation of 5-HT z-receptor activity, or 5-HT3- mediated diseases, i.e. iF) emesis, emesis induced by cytotoxic drugs and radiation, irritable bowel syndrome and diarrhea-predominant irritable bowel syndrome.

In particular, (i)-norcisapride is an effective antiemetic agent useful for use in the treatment of bo aku as an adjunctive course of treatment for the relief of nausea and vomiting induced by chemo- or radiotherapeutic agents. (I-Norcizapride also has 5-HT agonistic properties, and thus the invention offers a method of treating warm-blooded animals, including humans, suffering from conditions associated with insufficient stimulation of 5-HT receptors. In a more general sense, it is proposed method of treating 5-HT/-mediated disorders or conditions such as delayed or impaired gastric emptying or more general conditions related to delayed or impaired gastrointestinal transit.

Thus, a method of treatment is provided for the relief of warm-blooded animals suffering from conditions such as, for example, gastroesophageal reflux (including the treatment or maintenance of esophagitis), dyspepsia, and gastroparesis. The specified method includes the introduction of a therapeutically effective amount of (i)-norcisapride or its pharmaceutically acceptable acid addition salt to the specified warm-blooded animal.

Gastroparesis can be caused by an abnormality of the stomach or a complication of diseases such as diabetes, progressive systemic sclerosis, anorexia nervosa, after vagotomy or partial gastrectomy, and miotic dystrophy. Dyspepsia is an indigestion that may occur as a symptom of primary gastrointestinal dysfunction, especially gastrointestinal dysfunction associated with increased 7/0 muscle tone, or as a complication of other disorders such as appendicitis, gallbladder disorders or lack of nutrition. Thus, (i4)-norcisapride can be used either to treat the actual cause of the condition or to alleviate the symptoms of the condition in patients. Symptoms of dyspepsia can also occur due to the introduction of chemical substances, for example, inhibitors of selective reuptake of serotonin (55KI), such as fluoxetine, paroxetine fluvoxamine, sertraline, etc. Other treatable symptoms /5 include postoperative ileus, which is an obstruction or kinetic disturbance of bowel function due to impaired muscle tone after surgery; symptoms of unsettling discomfort in the upper part of the digestive tract after X-ray or endoscopy; in children: chronic or excessive belching or vomiting; intestinal pseudo-obstruction associated with motor dysfunctions leading to insufficient propulsive peristalsis and stasis of stomach and intestinal contents; constipation, which can be caused by conditions such as insufficient intestinal muscle tone or intestinal elasticity; and especially restoration of propulsive colonic motility as a result of long-term treatment of chronic constipation.

It follows that the use of (t)-norcisapride for the manufacture of a medicament for the treatment of disorders or conditions involving insufficient stimulation of 5-HT )D receptor activity is provided. It is also proposed to use (i)-norcisapride in the manufacture of a medicament for the treatment of 5-HT )-mediated disorders of the brain, such as, for example, gastroesophageal reflux, dyspepsia, or gastroparesis. Both prophylactic and therapeutic treatment are provided. and)

In one aspect, the use of (i)-norcisapride in the manufacture of a medicament for the treatment of eating disorders such as, for example, anorexia is provided. It follows that a method of treating eating disorders, such as, for example, anorexia, in warm-blooded animals is provided, which comprises administering to said warm-blooded animal a therapeutically effective amount of (i)-norcisapride.

Thus, the present invention also offers a method of treating gastrointestinal disorders in warm-blooded animals, which are simultaneously associated with insufficient stimulation of 5-HT/-receptor activity and excess Ge! stimulation of 5-HT3 receptor activity, which includes the administration of a therapeutically effective amount of (i)-norcisapride to the specified warm-blooded animal. Hence, the use of (i)-norcisapride in the production of me) c5 medicine for the treatment of gastrointestinal disorders, simultaneously associated with insufficient stimulation of 5-HT /-receptor activity and excessive stimulation of 5-HT c-receptor activity.

In addition, (i)-norcisapride exhibits a synergistic effect with osmotic agents to induce intestinal lavage, i.e., an induced form of diarrhea. Hence, the present invention also relates to the use of (i-norcisapride) in the production of a medicament that improves intestinal lavage with a laxative, "

In particular, an osmotic agent. As a result, a method of treatment is claimed, in which an effective amount of ()-norcisapride is administered in combination with a laxative. In addition, a method of accelerating and/or enhancing the action of laxative agents, especially osmotic agents, is proposed. ;" This course of treatment is prescribed for patients whose digestive tract needs to be cleansed before diagnostic or surgical procedures. Another group of patients are those who need to prevent straining during defecation; these are patients suffering from hernia or cardiovascular disease. In addition, the combination for

Ge" of this invention can be indicated both before and after surgery to maintain soft stools in patients with hemorrhoids and other anorectal disorders. o Osmotic agents in doses that cause a laxative effect are often used before radiological studies of the gastrointestinal tract, kidneys, or other structures of the abdominal cavity or retroperitoneal space before elective surgery of the digestive tract. Thus, a combination of (i)-norcisapride and a laxative agent may also be useful for this application. In addition, the combination of (i)-norcisapride and a laxative agent may also be useful in the treatment of overdose and poisoning by eliminating the agents from the intestine. This combination can also be used in further combination with additional certain anthelmintics.

Laxatives are medicines that promote defecation. The exact mechanisms of action of many laxatives remain unclear due to complex factors affecting colon function,

F) significant variations in the transport of water and electrolytes observed for different species of experimental animals and drugs, and a certain high cost of research in this field. Three general mechanisms of action of laxatives can be described. (1) Due to their hydrophilic or osmotic properties, laxatives can cause water to be retained in the contents of the colon, thereby maintaining its volume and softness and facilitating passage. (2) Laxatives can act, either directly or indirectly, on the colonic mucosa to decrease the overall absorption of water and Mass. (3) Laxatives may increase intestinal motor function, causing decreased absorption of salt and water due to decreased transit time. Three main classes of laxatives are usually distinguished, namely 1) dietary fiber and bulking laxatives, 65 2) saline and osmotic laxatives, and 3) stimulant laxatives (see boodtap apa siitap, zemepii eayiop, pp. 994-1003).

The present invention is directed primarily to the class of laxatives to which saline and osmotic laxatives belong. Saline and osmotic laxatives include various magnesium salts, sodium and potassium sulfate, phosphate, and tartaric salts, lactulose disaccharide, glycerin, and sorbitol. They are bad and slow

They are absorbed and act due to their osmotic properties in the luminal fluid. Two examples of such osmotic agents that are commercially available for colon cleansing are KiegapRgerfd and Soy ugeiuF. Solution

KieapRgert! consists of polyethylene glycol 3350 (5Og/l), sodium sulfate (5.685g/l), sodium bicarbonate (1.685g/l), sodium chloride (1.465g/l), potassium chloride (0.7425g/l), aspartate (0 .0494g/l) and vanilla (0.3291g/l).

In addition, (i)-norcisapride and its pharmaceutically acceptable salts are essentially devoid of influence on the central /о0 Nervous system, in particular, they do not show central dopamine-antagonistic and central serotonin-antagonistic activity.

()-norcisapride was found to be metabolized by a pathway different from that responsible for the metabolism of cisapride. The latter is probably metabolized mainly through the cytochrome p4or system.

Some therapeutic agents that inhibit the main metabolic pathway of cisapride may cause undesired 7/5 High levels of cisapride in the blood which may cause side effects. Combined drug therapy using such therapeutic agents in combination with cisapride can be disappointing, but this is not the case with (k)-norcisapride.

The present invention also relates to dosage forms for oral administration, which include (I)-tartrate or (O)-tartrate salt forms of (I)-norcisapride. Said salt forms favorably exhibit a dissolution profile that is less dependent on pH. Absorption and bioavailability of orally administered drugs with a pH-dependent solubility profile may be affected by the presence of food in the gastrointestinal (GI) tract, particularly the stomach. The residence time of the drug in the stomach in the presence of food will usually be much longer than in the fasting state, that is, the presence of food will prolong the stay of the drug in the relatively acidic environment of the stomach. If the bioavailability of a medicinal product is influenced to a greater extent due to the presence of food in the gastrointestinal tract, it is said that the medicinal product exhibits a "food effect" or exhibits a medicinal-food interaction. In order to ensure adequate bioavailability, (8) such drugs often have to be administered under special nutritional conditions, such as before food, as in the case of cisapride. Dosage forms for oral administration, including the specified tartrate salts, have the advantage that the bioavailability of (i)-norcisapride is independent of food intake. Therefore, such "gzo" dosage forms are attractive, since patients do not always have the necessary discipline to take their medications at the optimal time, which leads to variable and sometimes inadequate effectiveness. In particular, this is the case with pediatric use. Such dosage forms show the additional advantage of "rho hepaia" administration, i.e. administration based on symptoms. In addition, due to their independence from pH, these dosage forms for oral administration can be administered in combination with agents that alter the pH of the stomach , for example, agents that increase the pH of the stomach. Examples of such combined drug therapy are antacids, such as aluminum-containing antacids, for example, Akon), calcium-containing antacids, for example,

Saso»z, or magnesium-containing antacids, for example, Moa(OH)»z; N»o-antagonists, for example, cimetidine, ranitidine, famotidine, nizatidine, roxatidine and the like; or proton pump inhibitors, such as omeprazole, lansoprazole, rabeprazole, pantoprazole, and the like. Thus, dosage forms, preferably solid dosage forms for oral administration, comprising (g)-norcisapride tartrate and any of these antacids are provided as combined medicaments for simultaneous, separate or sequential administration.

Therefore, according to another aspect, the present invention relates to pharmaceutical compositions, in particular, solid dosage forms, preferably for oral administration, suitable for rapid dissolution, which include as an active ingredient (i)-norcisapride-i! - or -U-tartrate and a suitable carrier. The term "quickly soluble" refers to the fact that the active ingredient can dissolve from the dosage form by more than 6095 within 1

Ge" hours in the pH range from 1 to 7. Dissolution can be measured by the usual methods described in

European Pharmacopoeia, or as described in the "711" test of the US Pharmacopoeia (US), in the apparatus for determining the dissolution of Sh5R-2 (described in the US Pharmacopoeia XXII, pp. 1578-1579). To ensure rapid dissolution, the excipients should be selected so that the tablets disintegrate quickly enough, in particular less than about 30 minutes, or less than 20 minutes, and especially less than about 15 minutes, preferably less than about 3 or 1.5 minutes. In yet another aspect, the invention relates to a method of treating patients suffering from gastrointestinal disorders without a drug-food interaction comprising the administration of (t)-norcisapride-(O)- or -(I)-tartrate, and treatment of gastrointestinal disorders in patients taking drugs that increase the pH of the stomach; or use in the production of a dosage form that does not DETECT drug-food interactions for the treatment of the specified disorders.

The compositions of the present invention may optionally include a carminative such as simethicone,

F) alpha-O-galactosidase and the like. In order to obtain pharmaceutical compositions according to the present invention, an effective amount of a specific compound in the form of a base or addition salt of an acid, as an active ingredient, is combined with thorough mixing with a pharmaceutically acceptable carrier, which can take various forms depending on the form of the drug that is desired for administration. These pharmaceutical compositions are preferably in the form of single dosage forms, suitable, preferably, for oral or rectal administration, or by parenteral injection.

For example, in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions, any conventional pharmaceutical medium may be used in the preparation of the oral dosage form composition, such as, for example, water, glycols, oils, alcohols, etc., or in the case of powders, pills, capsules and tablets, solid carriers such as starches, sugars,

kaolin, lubricants, binders, disintegrating agents, etc. Due to the ease of administration, tablets and capsules are the best dosage form for oral administration, and in this case, of course, solid pharmaceutical carriers are used. For parenteral compositions, the vehicle will usually include sterile water, at least for the most part, although other ingredients may be included, for example to aid dissolution. For example, injectable solutions may be prepared in which the carrier includes saline, glucose, or a mixture of saline and glucose. Suspensions for injection can also be prepared, for which appropriate liquid carriers, suspending agents, etc. can be used. In compositions suitable for transdermal administration, the carrier optionally includes a 7/0 penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable impurities of any nature in small amounts, which impurities do not have a significant deleterious effect on the skin

Said impurities may facilitate dermal delivery and/or may be useful in the preparation of the desired composition. These compositions can be introduced in different ways, for example, as a transdermal patch, as a local application, as a liquid ointment. Acid addition salts (I) due to their increased solubility in water 7/5 Compared to the corresponding basic form are obviously more suitable for the production of aqueous compositions.

It is especially appropriate to prepare the above-mentioned pharmaceutical compositions in the form of dosage forms for ease of administration and uniformity of doses. Dosage forms, as used herein in the description and claims, refer to physically discrete units suitable for use as single doses, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in combination with the appropriate pharmaceutical carrier . Examples of such dosage forms are tablets (including tablets with a coating or shell), capsules, pills, powders in bags, pressed wafers, solutions or suspensions for injections, liquid compositions dosed per teaspoon or tablespoon and divided into multiple doses of the package.

For oral administration, the pharmaceutical compositions may take the form of solid dosage forms, such as tablets (both swallow-only and chewable forms), capsules or gel capsules prepared by conventional means with pharmaceutically acceptable excipients such as and) gelling agents, fillers or diluents, lubricating agents, disintegrating agents, wetting agents (eg, sodium lauryl sulfate), and other excipients such as coloring agents and pigments.

Tablets may be coated by methods known to those skilled in the art. Binding agents can be gum arabic, alginic acid, carboxymethyl cellulose (sodium), cellulose (microcrystalline), dextrin, ethyl cellulose, gelatin, glucose (liquid), guar gum, o oxypropyl cellulose, oxypropyl methyl cellulose, methyl cellulose, polyethylene oxide, polyvinylpyrrolidone Ge! (povidone), or starch (pre-gelatinized), oxypropyl methyl cellulose, especially low-viscosity oxypropyl methyl cellulose. at

Examples of excipients or diluents are spray-dried or anhydrous lactose, sucrose, so dextrose, mannitol, sorbitol, starch, cellulose (e.g., microcrystalline cellulose; Amise!m), hydrated or anhydrous secondary calcium acid phosphate, and others known to those skilled in the art, or their mixtures. 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 that has the property of giving the tablets the appropriate "hardness" and has disintegrating properties because the cellulose fibers swell on contact with water. c A preferred form of lactose is lactose monohydrate OS, particularly spray-dried lactose monohydrate (Rpaptayuze OSI 11tm), The fillers or diluents can be from about 5095 to 9595, or "» from about 6595 to 9095, or from about 6695 (w/w .) to 8695, in particular, about 7590 (all w/w values) of the total weight of the tablet or tablet core. 7595 mixture is commercially available under the 435 trade name MISKOSEG ASF, preferably used in an amount of about 8095 (w/w) to 9595 (w/w) of

Ge") of the total weight of the tablet or of the tablet core in the case of film-coated tablets.

Examples of lubricants are magnesium stearate, talc, silicon oxide, stearic acid,

Mn sodium stearyl fumarate, magnesium lauryl sulfate, hydrogenated vegetable oil and others known to specialists. Lubricants (Ce) are generally used in an amount of about 0.295) (w/w) to 7.095 (w/w) of the total weight of the tablet or tablet core in the case of film-coated tablets. Interesting are the cases where lubricants are used in amounts from approximately 0.595 (wt/wt) to 3.095 (wt/wt).

Preferably, the lubricants are used in an amount of about 0.995 (w/w) to 1.2595 (w/w).

Leavening agents include starches such as corn starch, pregelatinized starch, sodium starch glycolate (EchrioyarF), cross-linked povidone, cross-linked carboxymethyl cellulose sodium salt, clays, microcrystalline cellulose (Amycetm), alginates, resins, carmellose sodium, also called sodium salt croscarmellose, and others known to specialists. The disintegrating agent may be present in an amount of from about 295 (w/w) to 1595 (w/w) or from about 395 (w/w) to 1090 (w/w).

In this specification, percentages are defined as a weight ratio (w/w) and express the proportion (in percent) of an ingredient or excipient relative to the total weight of the tablet (or tablet core in the case of coated tablets).

Of course, tablet compositions are granulated in a dry or wet state before pressing. In some cases, particularly when using (0)- or (I)-tartrates, it may be possible to produce tablets using a direct compression technique, which may provide a better dissolution profile. 6E Liquid preparations for oral administration may be in the form of, for example, solutions, syrups or suspensions, or they may be prepared as a dry product for reconstitution with water or other suitable vehicles before use. Such liquid preparations may be prepared by conventional methods, optionally with pharmaceutically acceptable additives such as suspending agents (eg, sorbitol syrup, methylcellulose, oxypropylmethylcellulose, or hydrogenated edible fats); emulsifying agents (for example, lecithin or gum arabic); non-aqueous carriers (for example, almond oil, esters of fatty compounds or ethyl alcohol); and preservatives (for example, methyl- or propyl-p-oxybenzoates or sorbic acid).

Pharmaceutically acceptable sweeteners preferably include at least one strong sweetener such as saccharin, sodium or calcium salts of saccharin, aspartame, acesulfame potassium, cyclamate sodium, alitham, dihydrochalcone sweetener, monelin, stevioside, or sucralose (4,16'-trichloro-4, 7/0. 7bi-trideoxygalaitosucrose), preferably saccharin, sodium or calcium salts of saccharin, and optionally a background sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, glucose syrup hydrogenated, xylitol, caramel or honey .

Strong sweeteners are usually used in low concentrations. For example, in the case of the sodium salt of saccharin, the concentration may vary from 0.0495 to 0.195 (w/v) in terms of the total volume of the finished composition, and is preferably about 0.0695 in low dose compositions and about 0 ,08905 in compositions with a high dose. The background sweetener can be effectively used in a greater amount, which is from about 1095 to 3595, preferably from about 1095 to 1595 (w/v).

Optionally, flavoring agents can be added to the composition, for example, to hide the bitter taste.

Flavoring agents that mask bitter-tasting ingredients in low-dose formulations are preferably fruity flavoring agents such as cherry, raspberry, blackcurrant, or strawberry flavoring agents. A combination of two flavoring agents can give very good results. In higher dosage formulations, stronger flavoring agents may be required, such as Chocolate Caramel Flavoring (Sagate! Sposoia(e), Cold Mint Flavoring (Mipi Sooi), Fantasy Flavoring (Rapiazoo), and similar pharmaceutically acceptable strong flavoring agents. Each flavoring agent may be included in the finished composition at a concentration of 0.0595 to 1905 s (w/v). Combinations of these strong flavoring agents are effective. It is preferable to use a flavoring agent that does not undergo any change or loss of flavor and color under acidic conditions in the composition. i)

The compounds of the present invention can also be made in the form of delayed absorption compositions. Such long-acting compositions can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. So, for example, compositions of compounds with suitable polymeric or hydrophobic materials (for example, in the form of an emulsion in a suitable oil) or ion-exchange resins, or sparingly soluble derivatives, for example, a sparingly soluble salt, can be made. what)

Compositions of the compounds of the invention can be prepared for parenteral administration by injection, Ge! convenient for intravenous, intramuscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion. Compositions for injection can be made in a dosage form, for example, in ampoules, or in multi-dose containers with an added preservative. Compositions may be in such forms as suspensions, solutions or emulsions in oily or aqueous carriers and may contain pharmacological additives such as isotonic, suspending agents, stabilizers and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution by dilution with a suitable vehicle, such as sterile pyrogen-free water, prior to use. "

The compounds of the invention can also be prepared in the form of compositions for rectal administration, such as suppositories or retention enemas, for example, those containing conventional suppository bases such as cocoa butter or other glycerides. ;" For intranasal administration, the compounds according to the invention can be used, for example, in the form of liquid sprays, powder or in the form of drops.

In general, a therapeutically effective amount is expected to be about 0.001mg/kg to 2mg/kg

He" of body weight, preferably from about 0.02 mg/kg to 0.02 mg/kg of body weight. Suitable solid dosage forms for oral administration in metered dosage forms will include an equivalent of from about 0.1mg to 100mg of the active ingredient, in particular from about 1 to BOmg, up to 20mg. The method of treatment may also include co-administration of the active ingredient in a regimen with several doses per day, for example, 2-4 doses per day.

Non-limiting examples are provided below for illustrative purposes. o Experimental part i» Hereinafter, "ACN" (АСМ) will mean acetonitrile, SNZON will mean methanol and "DIPE" (ОИРЕ) will mean diisopropyl ether.

For some compounds according to the present invention, the absolute stereochemical configuration was not experimentally determined. In these cases, the stereochemically isomeric form that was isolated first was designated as "B" and the second as "A", without further reference to the absolute stereochemical configuration.

Ф) Measurements of optical rotation (00) (OK) or specific rotation were also carried out with the Regkip EITeg model 241 device. Rotation (9) was measured at 20"C using the sodium O line (wavelength 589 nm) and a cuvette with a path length of 100 mm The compound was dissolved in methanol at a concentration of 19w/v SpigaIrak 60 do (amylose-3,5-dimethylphenylcarbamate), which was used as a chiral stationary phase of the column material, was purchased from Ogaise!Spetisai!Ipdisigiez, Ka. (Japan).

A. Synthesis of (n-)-norcisapride

Example A. 1

Cis-ethyl-4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-methoxy-1-piperidine-carboxylate (0.12 mol, 46 g) bo (described in the examples of EP-0076303 as compound Mo168) was separated to their enantiomers using chiral chromatography on a SVigagrak AYU column (2kg; column inner diameter (ID): 110mm, eluent: n-hexane/ethanol 70/30; Bbg/l injection, flow rate 40Oml/min., detection: UV at 254nm). Two required groups of fractions were collected and their solvent was evaporated. The remaining enantiomer, which eluted first, was dissolved in methanol, filtered on dicalite, and the solvent was evaporated. The residue was suspended in DIPE, then cooled to 0"C and the resulting precipitate was separated on a filter and dried (vacuum, 40"C), obtaining 18g of (-)-cis-ethyl-4-(4-amino-5-chloro-2- methoxybenzoylamino)-3-methoxy-1-piperidine-carboxylate (enantiomer 1; 00 (-); m.p.: 1647); and -55.887 (c-190 mass/rev, in SNZON) (intermediate compound 1). The specified intermediate compound 1 had an optical purity above 9995. The remaining enantiomer, which eluted second, was dissolved in methanol, filtered on dicalite, and the solvent was evaporated. The residue was suspended in DIPE, then cooled to 0"C, and the resulting precipitate was separated on a filter and dried (vacuum, 407C), obtaining 17.6 g of (y)-cis-ethyl-4-(4-amino-5-chloro-2- methoxybenzoylamino)-3-methoxy-1-piperidinecarboxylate (enantiomer 2; 00 (v; m.p.: 1647); still - 55.10" (c-190w/v, in SNZON) (intermediate compound 2), which had optical purity above 75 98905.

Example A.2

A mixture of intermediate compound (2) (0.042mol, 16bg) and potassium hydroxide (23g) in 2-propanol (230ml) was stirred and refluxed for b 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 recrystallized from ACN. The precipitate was separated on a filter and dried (vacuum), obtaining fraction 1 (57905; m.p.: 1887°C). This fraction was recrystallized from ACN. The precipitate was separated on a filter and dried, obtaining fraction 2 (5.3 g). All crystallization the filtrates were collected and the solvent was evaporated. The residue, as well as fraction 2, was purified by column chromatography on silica gel (eluent: СНоСИЖ(СНЗОНН/МНУ) 90/10). The pure fractions were collected and the solvent was evaporated. The solid residues were dried to give 5 ,bg (h)-cis-4-amino-5-chloro-2-methoxy-N-(33-methoxy-4-piperidinyl)benzamide (i.e. ()-norcisapride); and -5.607 (c-190 mass/vol, in SNZON) (compound 1).

Example A.Z "

A mixture of intermediate compound (1) (0.044 mol, 17 g) and potassium hydroxide (24 g) in 2-propanol (250 ml) was stirred and refluxed for b 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 recrystallized from ACN. The precipitate was separated on a filter and dissolved in dichloromethane.

The organic solution was washed with water, dried, filtered and the solvent was evaporated. The remaining CO was recrystallized from ACN. The precipitate was separated on a filter and dried, obtaining 7 g (54905) of co (-U-cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide (i.e. (-)-norcisapride ); another -6.097 (c-50.90 mg in 5 ml of SNZON) (compound 2).

Example A.4 "

A solution (K(B", 27) 1-2,3-dihydroxybutanedic acid (I-tartaric acid) in a mixture of water and 3 c methanol, and the product was allowed to crystallize. It was separated on a filter and dried, obtaining "" (13-(35.4K)-cis-4 -amino-5-chloro-2-methoxy-M-(3-methoxy-4-piperidinyl)-benzamide-IR(A"KD")I|-2,3-dihydroxybutanedi" oate monohydrate. X-ray diffraction measurements were carried out on a four-window diffractometer Zietepz P4.

V. Pharmacological examples

Example B.1. MoZO-induced intestinal lavage

Me. Hound (beagle) dogs (both sexes and different body weights, did not receive food for 16 hours) 2) were pre-injected with (i)-norcisapride or a solvent, and after 1 hour orally administered magnesium sulfate (М95О,)-7Н2О, bag/ l, 0.26M; 200 ml). The onset of MaoZ0,-induced intestinal lavage was evaluated within 4 hours and after the introduction of the substance. Liquid stools were almost never observed over a 4-hour period in control 20 animals receiving distilled water (2.596 false positives; p-200) and were thought to reflect a significant acceleration of Mo5O-induced intestinal lavage. Doses in the range of doses of the active substance "i" were administered to five animals each, and testing was carried out in separate experimental sessions, which included control animals that received the solvent. All-or-none criteria based on the distribution of results obtained for a large number of solvent-treated animals were used to 255 calculate EDwo (Eco) values (effective dose) and 95965 probability limits according to the iterative method.

GF) Feeney (Rippeau, 1962).

As shown in Table B.1, a small dose increase from 0.032 mg/kg to 0.15 mg/kg was sufficient to induce diarrhea 1 hour after administration of magnesium sulfate. in magnesium sulfate-induced intestinal lavage in dogs 1 hour after oral administration.

The possibility of obtaining liquid stools within 1-4 hours after the introduction of magnesium sulfate is indicated. vv

Onset of diarrhea within 3 hours 0.049

Example B.2: Test for apomorphine, tryptamine, norepinephrine (ATN, ATM) in rats 9 The absence of central dopamine-antagonistic and serotonin-antagonistic activity of the studied compounds was evidenced by the experimental data obtained in the combined test for apomorphine (APO,

APO), tryptamine (TRI, TKU) and iorepinephrine (NOR, MOC) in rats. The specified combined test for apomorphine, tryptamine and norepinephrine is described in Agsp. Yippee Rpaptasodup., 227, 238-253 (1977), and makes it possible to empirically assess the relative efficiency with which drugs can affect individual neurotransmitter systems both centrally (CNS) and peripherally. In this test, rats were observed for effects or responses indicating peripheral and central activity. Central dopamine antagonism is assessed by administering apomorphine, a dopamine agonist, to rats that have previously received subcutaneously various doses of the test compound. Next, serotonin antagonism is assessed by administering tryptamine, which is an agonist of 5HT»-serotonin receptors, to the same rats that previously received subcutaneously different doses of the test compound. This test can assess both central and peripheral serotonin antagonism. Centrally acting serotonin antagonists are potential antipsychotic drugs, especially if they show concomitant dopamine antagonism in the first part of this test.

Finally, the o-adrenergic antagonistic activity of the test compounds is evaluated by administering to the same rats that previously received subcutaneously different doses of the test compound, norepinephrine, which is an o-adrenergic agonist.

The experimental data are summarized in Table B.2 and are presented as ED 5o values in mg/kg of body weight, which were determined as the dose at which each of the test compounds protects 5095 test animals from the expected reaction caused by the above-mentioned provocative tests. The APO column shows the results for the apomorphine Ha sample, which indicate central dopamine antagonist activity. In the columns "THREE convulsions" and "THREE hyperemia" are given the results for the tryptamine test, which indicate central and peripheral i9) serotonin-antagonistic activity, respectively. The NOR column shows the results for the norepinephrine test, which indicate o-adrenergic agonistic activity. Favorable pharmacological properties of (-)-norcisapride consist in the absence of central dopamine (APO column) and central serotonin "Z" (TRY convulsions column) antagonistic activity. yu

F

77 o

That

Example B.3: Antagonism with respect to 5-oxykynuramine in the guinea pig ileum

It has been shown that 5-HT3 receptors play a significant role in vomiting. Since 5-OH-K (5-oxykynuramine) is a "specific agonist of the 5-HT3 receptor, this test evaluates the potential 5-HT3 antagonistic effect." shsh c Guinea pigs of both sexes with a body weight of 5450 g were killed by decapitation. Strips 4.5 cm long were cleaned from and non-terminal (distal 1Osm were discarded) entire segments of the ileum and vertically suspended with a preload of 0.75 g in a cuvette for isotonic registration; (displacement converter control unit; dapzzep Zsiepiyis Ipvigitepi Oimiviop), НР7 ЮОС0OT-1000 (Nemiek-RaskKaga Sh)). The cuvette for organs was filled with Thugode's solution (37.5"С), saturated with a mixture of 9595 Оо and 595 СО". After a period of stabilization (Ge) lasting 20 minutes, acetylcholine (te(paspoyipe) (30109M, contact time 30 seconds) was added to the liquid in the cuvette ) to assess the potential maximal contraction, after which the fluid in the cuvette was renewed. After that, the serotonin agonist 5-OH-K (contact time 30 seconds, final concentration (se) 30105M) was added at 10-minute intervals, and the fluid in the cuvette was renewed through 30 seconds after each addition. After reaching reproducible sl 50 contraction results, a single dose of the test compound was added to the liquid in the cuvette, and after 5 minutes B-JOHN-K was added. After determining the logarithmic concentration-response curve for the test compound

By the method of linear regression analysis, IC 50 values corresponding to 5095 reduction of 5-OH-K-induced effect were calculated.

Compound 1, i.e. (k)-norcisapride, has an ISbo mass equal to U9ZNM, and compound 2, i.e. (-)-norcisapride, has |Svo equal to 45ОНM. o Example B.4: Coaxial stimulation of the guinea pig ileum

YuOipKip-Napieu guinea pigs of both sexes (weighing between 600-900g) were killed by decapitation. The ileum was removed and washed with warmed and oxygenated Krebs-Hanselteit solution. Fragments of the ileum (15 cm) were placed on a glass pipette. The longitudinal muscle layer with the plexuses of the intestinal muscular membrane was removed with the help of a cotton thread moistened with Krebs solution. Strips 8 cm long were folded and these strips (4 cm) were fixed between two platinum electrodes (8 cm long, at a distance of 00.5 cm from each other). The strips were suspended with a preliminary load of 1.5 g in 100 ml of Krebs-Hayiselya solution (37.57), saturated with a gas mixture of 9595 OO" and 596 CO". Preparations were excited by a single ms rectangular pulse; 01Hz; submaximal response (current that causes 8095 of the maximal response), from a programmable 65 stimulator (dapzzep Zsiepiyis Ipvigitepiv Oimiviop)y. Contractions were measured isometrically (Ziaiiiat ShS2, amplifier apzzep Zsiepiyis Ipvigitepih, pen recorder Kirr VO-9). During the 30-minute stabilization period, the strips were repeatedly stretched to achieve a steady tension of 1.5 g. Before the start of electrical stimulation, a cumulative concentration curve of response to acetylcholine (30109, 108, 320108 and 10-7M) was made. The liquid in the cuvette was replaced with fresh Krebs solution and the strips were allowed to stabilize for another 30 minutes. After that, the strips were subjected to electrical stimulation (electrostimulator) with a frequency of 0.1 Hz for 1 ms. The tension was increased in increments of 28 (maximum 158) until the maximum force produced was observed. The convulsive contraction response was reduced (by lowering the tension) to approximately 8095 of the value observed at maximum tension. By fine-tuning the voltage, it was possible to obtain a submaximal convulsive contraction response that did not change for at least 2 hours. After the twitch response remained stable for at least 15 minutes, the test compound was added to the fluid in the cuvette for 30 minutes. If the test compound caused less than 50595 inhibition, cisapride 3010-7M was added to the fluid in the cuvette to determine whether the test compound could antagonize the stimulatory effect of cisapride.

If the test compound produced more than 5095 inhibition, 10-7M naloxone was added to determine whether the inhibition was mediated by opiate receptors. After adding cisapride or naloxone, supramaximal stimulation was performed again. After that, the electrical stimulation was stopped and a second cumulative concentration-response curve was made for acetylcholine. These two cumulative concentration-response curves for acetylcholine were done in order to distinguish the effect of reduced acetylcholine release from a direct anticholinergic effect, or to distinguish the effects of increased acetylcholine release from sensitization of muscarinic receptors. The EC 50 value (ie, the concentration that stimulates the response to electrical stimulation by 5095) of the compound was calculated by the method of linear regression analysis, if the test compound caused stimulation.

Compound 1, i.e. (n-)N-norcisapride, had an EC0 equal to 0.bµM, and compound 2, i.e. (-)-norcisapride, had an EC0 equal to 5mµM. with

Example B.5: Coaxial stimulation of the colon of guinea pigs o

Guinea pigs of both sexes (body weight 4450 g) were killed by decapitation. The ascending colon was removed and washed, after which segments of approximately 3 cm in length were prepared. These strips were suspended in an organ cuvette (100 ml) and connected to an isotonic transducer with a preload of 2 g; (displacement converter control unit; dapvzep 5siepiyis Ipvigitepi Oimiviop), НР7 ЮОС0OT-1000 (Nemen-RaskKkaga)). The cuvette "for organs" was filled with Dejalon's solution (37.5°С), saturated with a gas mixture of 9590 О 2 ю and 595 СО". After a stabilization period lasting 20 minutes, acetylcholine (tei(paspopyipe)) was added to the liquid in the cuvette. 3010M in order to assess the potential maximum response of the strip (contact time 30 seconds); me) after which the liquid in the cuvette was renewed. These operations were repeated at 10-minute intervals until a reproducible response was obtained after the addition of acetylcholine. After that, for 10 minutes was added to the test

From the compound. Then, without renewing the liquid, cisapride 3210-7M was added to evaluate the possible effect on 5HT./. When the cisapride-induced contraction reached a stable maximal level, acetylcholine C30109M was added to the fluid in the cuvette to evaluate the potential anticholinergic effect before the maximal contraction was reached. The EC 50 value of the compound (ie, the concentration that stimulated the maximum tonal effect on du 50905) was calculated by linear regression analysis. with

Compound 1, i.e. (i)-norcisapride, had an ECo equal to 1.9 µM, and compound 2, i.e. (-)-norcisapride, c had an ECo equal to 11 µM. :z» S. Examples of pharmaceutical compositions

P. 1 Film-coated tablet

The active ingredient, lactose and unmodified starch were mixed in a fluidized bed unit and the powder thus obtained was sprayed with a solution of HPMS (oxypropyl methyl cellulose) in water.

The uniformly wetted granules obtained in this way were dried, sieved together with microcrystalline (95) cellulose, croscarmellose sodium salt, colloidal anhydrous silicon oxide and Ma stearate. The sifted sugar powder was mixed and pressed into tablets. The coating suspension was prepared by dissolving first

NRMS and propylene glycol in water and adding this solution to a homogenized mixture of water, talc, titanium dioxide 1 50 and dye. The coating suspension was sprayed onto tablets in a coating apparatus at

GT" elevated temperature.

Tablet core: ingredient amount 95 (w/w) from the tablet core

HF) ()-norcisapride-(I)-tartrate 13.2Zmg 7.3595 (w/w) lactose monohydrate 200mesh (75μm) (1)" 107.7Zmg 59.8595 (w/w) o unmodified corn starch 36.00 mg 20.0095 (w/w)

НРМС 2910 15mPapse(2) ZbOmg about 2.0095 (w/w) bo microcrystalline cellulose 12.6Omg 7.0095 (w/w) croscarmellose sodium salt 5AOmg 3.0095 (w/w) colloidal anhydrous silicon oxide O ,Ba4mg 0.3095 (wt/wt.) magnesium stearate O.9Omg 0.5095 (wt/wt.) total weight of the tablet core: 180.00mg b5

Film coating of tablets: amount of 95 (wt/wt.) of coating ingredient

NRMSO2910 15mPais 4.00mg 55.9595 (w/w)

Propylene glycol 1.00 mg 13.9995 (w/w)

Titanium dioxide (E171) 1.20O0mg 16.7895 (w/w)

Talc O,8Omg 11,1995 (w/w)

Yellow iron oxide) (U172/С177492) 015 mg 2.1095 (wt/wt.)

Total weight of coating: 7.15 mg

C) 200 mesh (75μm) is an indication of the type of lactose monohydrate used.

C2) HPMS stands for oxypropyl methyl cellulose, the number "72910" refers to the type of oxypropyl methyl cellulose used. The first two digits, "29", indicate the approximate percentage of methoxyl groups, and the third and fourth digits, "10", indicate the approximate percentage of oxypropyl groups.

The viscosity (15 mPag) of the 295th aqueous solution, measured at 2076, is also indicated.

This value is an indicator of the molecular weight of the HPMS used.

C.2 Tablets without a shell

The ingredients were mixed in a planetary mixer and pressed in a tablet press. ingredient quantity 95 (wt/wt.) from the core of the tablet 720 Tablet C.2.1 (k)-norcisapride 10.387mg 58 lactose monohydrate 200mesh (7B5μm) 110.39Zmg 61.3 unmodified corn starch Zbmg 20.0s microcrystalline cellulose 18mg 10, 0 povidone KOO Z,bmg 2.0 o magnesium stearate 0.9mg 0.5 colloidal anhydrous silicon oxide O,B4mMg 0.3 polysorbate 20 0.18mg 0.1 "I

Total weight of the tablet: 180.00 mg

Io)

Tablet C.2.2b (x)-norcisapride-(I)-tartrate 13.23mg 7.35

MISCOSEGASO 157.23mg 87.35 o croscarmellose sodium salt 7.2Mg 4.00 I«o) colloidal anhydrous silicon oxide O.B4mMg 0.3 Ma stearate 1.vmg 1.00 « s 70

Claims (15)

The formula of the invention n-:z» 1. The method of obtaining the main form of (i)-norcisapride of the formula and OS, F m sh- o n-Mm 0, t. k sh v osi, sh "z" (cis) which differs in that o a) separate enantiomers cis-ethyl-4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-methoxy-1- piperidine carboxylate by means of liquid chromatography on a chiral stationary phase, and p) isolate a fraction that is dextrorotatory according to the specific rotation index even in methanol, and c) carry out solvolysis of the specified fraction to (i)-norcisapride. 2. The method according to claim 1, in which the chiral stationary phase is cellulose or amylose polysaccharide. 3. The method according to claim 2, in which the eluent is a mixture of hexane and alcohol. 4. The method according to claim 1, in which the solvolysis includes hydrolysis in a primarily aqueous medium. 65 5. (u-Norcizapride, obtained by the method according to any of claims 1-4. b. The compound according to claim 5, which contains at least 90 95 wt. (i)-stereoisomer and 10 95 wt. or less (-)-stereoisomer. 7. The compound according to claim 5, which contains more than 99 95 wt. (k)-stereoisomer. 8. (y-Norcizapride according to claim 5, which essentially does not contain its (-)-stereoisomer. 9. (4)-Norcizapride, which is dextrorotatory according to the specific rotation index io in methanol. 10. (5-Norcizapride, which has a specific IR optical rotation equal to approximately 5.607 (s - 1 90 wt./vol. in methanol). 11. (5-Norcizapride, which has the absolute configuration (35,4) 70 OSN, M p-M m-e MH, Г8) I osn, C (3554K)-cis-4-amino-5-chloro-2- methoxy-N-(3-methoxy-4-piperidinyl)benzamide. 12. Pharmaceutically acceptable acid addition salt of the compound according to any one of claims 5-11. 13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound according to any one of claims 5-12. 14. The method of preparing a pharmaceutical composition according to claim 13, in which a therapeutically effective amount of the compound according to any one of claims 5-12 is thoroughly mixed with a pharmaceutically acceptable carrier. . with 15. Compounds of the formula (M): Osn, (M) about her РО-М М-с МН, « zo Ii 6) yuyu Я osn, с Ф in which the piperidine ring has an absolute configuration (35,K), and РО means methyloxycarbonyl, co-ethyloxycarbonyl, tert-butyloxycarbonyl or phenylmethyl. (Se) Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2004, M 2, 15.02.2004. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. "shi s;" (22) (95) se) s 50 s» F) ime) 60 b5