HK1079451B - Use of compounds that are effective as selective opiate receptor modulators - Google Patents

Description

Use of compounds that are potent selective opioid receptor modulators

The present invention relates to the use of compounds that are potent opioid receptor modulators for the preparation of a medicament for the diagnosis, prevention and/or treatment of disorders selected from eating disorders and digestive disorders, in particular psychogenic eating disorders; the medicine is effective in modulating gastrointestinal tonicity; also relates to pharmaceutical compositions comprising one or more of said modulator compounds and one or more potent appetite suppressant compounds.

In civilized society, working and living conditions are increasingly associated with various stresses that in many cases cause stress-related disorders. A major group of disorders believed to be induced or influenced, at least to a part, by modern living conditions and the stresses associated therewith is the group consisting of eating disorders and digestive disorders, especially psychogenic eating and digestive disorders. Typically, such disorders are treated with psychotherapy and/or pharmaceutical preparations which act on the central nervous system. Treatment with such pharmaceutical preparations may cause serious side effects, such as habituation and addiction.

It is therefore an object of the present invention to provide pharmaceutically active compounds which can be used for the successful treatment of eating disorders and digestive disorders, in particular psychogenic eating disorders and psychogenic digestive disorders. These pharmaceutically active compounds should be superior to the prior art, in particular showing little or no negative effects on the central nervous system of the treated patient.

Surprisingly, it has been found that potent selective opioid receptor modulator compounds, in particular potent peripherally selective opioid receptor modulator compounds, can be successfully used in the treatment of eating disorders and digestive disorders. More surprisingly, it has been found that these compounds are very effective in modulating the Gastrointestinal (GI) tract tone of the treated patient, especially after GI-surgery. Even more surprisingly, it has been found that modulation of the GI tract tone in a patient can be advantageously dose-dependently controlled, i.e., the desired relaxation or activation of the GI tract can be achieved independently of the dose of each compound administered to the patient.

The subject of the present invention is therefore the use of a potent selective opioid receptor modulator, preferably a selective opioid receptor agonist compound, in the preparation of a medicament for the diagnosis and/or treatment of disorders selected from eating disorders and digestive disorders. Preferably, the receptor modulator is peripherally selective for the receptor. Particularly preferably, the opioid receptor is a kappa-opioid receptor.

A preferred aspect of the present invention thus relates to the use of a potent peripherally selective opioid receptor modulator compound in the manufacture of a medicament for the diagnosis and/or treatment of a disorder selected from eating disorders and digestive disorders. A more preferred aspect of the invention relates to the use as described above, further characterised in that the compound is a potent peripherally selective opioid agonist. A still more preferred aspect of the invention relates to the use as described above, further characterised in that the compound is a potent peripherally selective kappa-opioid agonist.

The compounds used in the present invention preferably exhibit one or more of the following advantageous properties:

the compounds used in the present invention effectively modulate the tonicity of the GI tract; in particular they are capable of inducing relaxation or activation of GI tone; generally, modulation of GI tract tone is dose-dependent;

the compounds used in the present invention are effective in modulating satiety and/or postprandial symptoms, that is, sensations such as bloating in the amount of bloating and sensations of bloating, nausea and/or pain following food intake;

the effect on satiety and/or postprandial symptoms is preferably dose-dependent; in general, lower doses cause a reduction in symptoms, while higher doses can increase symptoms;

the compounds used in the present invention effectively modulate the fasting volume and/or compliance of the GI tract, in particular the colon; for example, lower to medium dose administration can significantly increase fasting volume compared to no administration;

in general, no relevant effects on functional parameters of the GI tract are observed, such as GI transit time, gastric emptying, intestinal and colonic emptying; this effect is preferably not or very rarely dose-dependent; thus, administration of modulatory compounds does not affect the natural function of the GI tract and therefore shows only a minimal tendency to induce undesirable side effects;

preferably, at higher doses, the compounds according to the invention increase the severity of the symptoms of bloating and therefore can correct the absence signals in obese patients, that is to say patients have signals of gastric fullness at lower intake volumes and thus less eating.

The dose dependence of the effect on the GI tract of administration of a compound for use in the present invention can be readily determined according to or analogously to methods known in the art, e.g. as described herein. According to the invention, the low dose is in many cases in the range from about 0.001 to about 0.5mg/kg per day, preferably from about 0.01 to about 1.0mg/kg per day, in particular from about 0.1 to about 2.0mg/kg per day, for example about 0.3mg/kg per day, about 0.75mg/kg per day or about 1.0mg/kg per day, while the high dose is generally above about 2.0mg/kg per day, preferably in the range from about 2.25 to about 5mg/kg, in particular from about 2.5mg/kg to about 10mg/kg per day, for example about 3mg/kg per day, about 5mg/kg per day or about 8mg/kg per day.

The invention further relates to the use of compounds which are potent selective opioid receptor modulators, especially peripherally selective opioid receptor modulators, in the preparation of a medicament which is effective in modulating gastrointestinal tone.

The invention further relates to the use of a potent selective opioid receptor modulator, especially a peripherally selective opioid receptor modulator compound, in the preparation of a medicament for the diagnosis and/or treatment of a disorder selected from eating disorders and digestive disorders, especially psychogenic eating disorders and digestive disorders.

Eating disorders and digestive disorders according to the present invention include, but are not limited to, the regulation of pathological appetite imbalances, loss of appetite or reduction of appetite, for example induced by pregnancy, cancer, infectious diseases, like influenza or HIV, as a postoperative side effect as a consequence of catabolism, cachexia, anorexia (especially anorexia nervosa), appetite disorders, weight disorders, obesity, bulimia, obesity, gastroparesis (especially neurogenic gastroparesis, diabetic gastroparesis, myogenic gastroparesis or drug-induced gastroparesis), gastrolaxity, gastroparesis or enteroparesis (especially after GI surgery) and gastrointestinal stenosis (especially pyloric stenosis).

A preferred embodiment of the present invention therefore relates to the use of potent selective opioid receptor modulator, especially peripherally selective opioid receptor modulator compounds, in the manufacture of a medicament for the treatment of disorders selected from the group consisting of modulation of pathological appetite imbalances, anorexia, obesity, bulimia, obesity, gastroparesis, and gastrointestinal stenosis, especially anorexia nervosa, bulimia, obesity, diabetic gastroparesis, and pyloric stenosis.

Compounds that are potent selective opioid receptor modulators, particularly peripherally selective opioid receptor modulators, or more specifically compounds that exhibit selective activity at opioid receptors, particularly peripheral opioid receptors, are known to the skilled artisan and are widely described in the literature. These modulators are generally classified as opioid agonists and opioid antagonists. Over the years, different subtypes of opioid receptors have been discovered and studied in detail, with kappa-and mu-opioid receptors being the most prominent.

Suitable for use in the present invention are potent selective opioid modulator compounds, preferably peripherally selective opioid modulators, more preferably peripherally selective opioid agonists, even more preferably peripherally selective kappa-or mu-opioid receptor agonists, and especially peripherally selective kappa-opioid agonists. These compounds are hereinafter referred to as "compounds used in the present invention" or "modulating compounds".

A variety of such modulating compounds are known in the art, for example, as cited in: DE-A1-3935371; DE 4034785, DE-A-4215231; EP-A-0569802; EP 0752246; sengupta et al, Pain 79(1990) 175-; LaurentDiop et al, European Journal of Pharmacology, 271(1994) 65-71; gottschlich et al, Chirality 6: 685-689 (1994); gottschlich et al, Drugs Exptl. Clin. Res. XXI (5), 171-; barber et al, br.j.pharmacol, (1994), 113, 1317-; and j.n.junien, p.riviere, aliment.pharmacol.ther 1995, 9: 117-126; and the documents cited in the above publications, are incorporated into the disclosure of the present invention by reference.

Modulating compounds disclosed in the above references are included herein by reference. The use of these modulatory compounds according to the invention in the preparation of medicaments is therefore the subject matter claimed in the present invention.

Further compounds for use in the present invention can be readily determined by the skilled artisan, e.g., by means of art-known and established methods, or analogously to such established methods, e.g., by means of receptor binding assays, high throughput screening, in vitro test systems, in vivo test systems, animal models, and the like.

The following cites examples of methods that can be used to identify compounds for use in the invention: krimer, E.C. et al, Fed.Proc.1982(5), 41 (7): 2319-22; spetea et al, Life Sciences 69(2001), 1775-1782; and Lathi et al, European journal Pharmacology 1985, 109: 281 and 284; and the documents cited in the above publications, are incorporated into the disclosure of the present invention by reference.

In general, compounds are considered to be suitable selective opioid receptor modulators for use in the present invention if they show an affinity for one or more opioid receptors, preferably for μ -and κ -opioid receptors, more preferably for μ -or κ -opioid receptors, especially for κ -opioid receptors, according to the IC₅₀The range of the value is measured in 100. mu. mol or less, preferably 10. mu. mol or less, more preferably 3. mu. mol or less, still more preferably 1. mu. mol or less, and most preferably in the nanomolar range. Particularly preferred for use in the present invention are opioid receptor modulators as defined above/below which are peripherally selective opioid receptor modulators. In many cases, IC at the lower end of a given range₅₀The value is advantageous and in some cases highly desirable is IC₅₀The value is as small as possible, but in general an IC₅₀Values lying between the upper and lower limits given above, above 0.0001. mu. mol, 0.001. mu. mol, 0.01. mu. mol or even above 0.1. mu. mol, are sufficient to reflect the desired pharmaceutical activity.

The meaning of the peripherally selective activity of a compound, preferably a pharmaceutically active compound or a medicament containing such a compound, is known in the art and can be readily determined according to known methods.

A peripherally selective compound according to the invention preferably denotes a compound which, when administered to a patient, shows selectivity for the peripheral nervous system when acting on the body, preferably the nervous system, of said patient. The peripherally selective compound preferably thus shows little, or even more preferably no, detectable effect on the central nervous system of a patient after administration to said patient.

Preferred compounds for use in the present invention are compounds of formula I

Wherein

R¹Is Ar, cycloalkyl having 3 to 7C atoms or cycloalkylalkyl having 4 to 8C atoms,

R²is a group of compounds represented by the general formula (I) Ar,

R¹and R²Together also are

R³Is H, OH, OA or A,

R⁴is A or phenyl, which may optionally be Hal, OH, OA, CF₃、NO₂、NH₂、NHA、NHCOA、NHSO₂A or NA₂Mono-or di-substitution of the amino group,

R⁵is OH, CH₂OH，

R⁶And R⁷Each independently of the others being H, Hal, OH, OA, CF₃、NH₂、NHA、NA₂、NHCOA、NHCONH₂、NO₂Or a methylenedioxy group, or a salt thereof,

a is an alkyl group having 1 to 7C atoms,

ar is a mono-or bicyclic aromatic group which may optionally contain N, O or S atom and may be substituted by A, Hal, OH, OA, CF₃、NH₂、NHA、NA₂NHCOA and/or NHCONH₂Mono-, di-or tri-substituted,

d is CH₂、O、S、NH、NA、-CH₂-CH₂-、-CH＝CH-、-CH₂NH-、-CH₂-NA-or a bond,

hal is F, Cl, Br or I,

and/or salts and/or pharmaceutically acceptable derivatives thereof,

in particular the compounds of formula I are such that,

wherein

Ar is a phenyl group, and Ar is a phenyl group,

R³is a compound of formula (I) wherein the compound is H,

a is a methyl group, and A is a methyl group,

and/or salts and/or pharmaceutical derivatives thereof,

they are pharmaceutically active compounds and are very particularly suitable as peripherally selective opioid receptor modulators for use in the present invention. A particularly preferred compound of formula I is N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide (EMD 61753) and/or a salt and/or a pharmaceutical derivative thereof, preferably a pharmaceutically acceptable salt, especially the hydrochloride salt. This compound is known as Asimadoline.

Other modulating compounds preferred for use in the present invention are selected from the group consisting of Alvimopan (see, e.g., am. J. Surg.2001 Nov; 182(5A Supl): 27S-38S), loperamide (see, e.g., J Pharmacol Exp Ther Ther 1999 Apr; 289 (1): 494) 502), spirodoline (see, e.g., pol. J. Pharmacol.1994 Jan-Apr; 46 (1-2): 37-41), Fedtozin (see, e.g., Expert Opin Investig drugs Drugs.2001 Jan; 10 (1): 97-110), pentazocine (see, e.g., Biol Pharm Bull Nov; 20 (11): 1193-8), ICI204448 (see, e.g., Br J Pharmacol. 1992; 106 (4): 783-9), U-50488H (see, e.g., Mar. 2002. 1723-1721): 01015 (7) L-01013) (see, 7 (7) 01013) and 10 (see, 7-32) (see, e.g., Mar. 20 (7) 14, ADL10-0116 (see, for example, Pain 2002 Mar; 96 (1-2): 13-22) and ADL 1-0398 (from Adolor Corp., USA).

In a preferred embodiment of the invention, the modulating compound is selected from the group consisting of Alvimopan, loperamide, fedotozine and Asimadoline.

In another preferred embodiment of the invention, the modulatory compound is selected from the group consisting of ICI204448, U-50488H, ADL 10-0101, ADL10-0116 and ADL 1-0398.

In a more preferred embodiment of the invention, the modulating compound is selected from the group consisting of Alvimopan, loperamide, Asimadoline. ADL10-0116, and ADL 1-0398.

Particularly preferred for use in the present invention is Asimadoline or a salt or solvate thereof.

According to the present invention, the term "medicament for the diagnosis of disorders" encompasses both medicaments which are directly used for diagnostic purposes as well as medicaments which enable or facilitate the application of the diagnostic method, for example by influencing the sensitivity, in particular the sensitivity to pressure and/or pain, and/or the tonicity of the gastrointestinal tract. In many cases, influencing or modulating the gastrointestinal tonicity causes relaxation or activation of the gastrointestinal tonicity, preferably causes temporary relaxation or activation of the gastrointestinal tonicity. Modulation of gastrointestinal tone facilitates the most widespread use of diagnostic procedures for the GI tract, such as endoscopy (particularly proctoscopy), endoscopic biopsy, endosonography, and endoscopic X-ray. In many cases, affecting gastrointestinal tone may also be beneficial in performing GI tract surgery, especially if endoscopy is used.

Thus, the use of selective opioid receptor modulator compounds (as described above) in the manufacture of a medicament for the maintenance therapy of GI tract injuries, wounds or surgical injuries, such as after anal fissure, recto-anal surgery, in particular after hemorrhoidectomy, is the subject of the present invention.

The compounds used in the present invention are furthermore advantageous in that they do not cross the blood-brain barrier or only to a minor and irrelevant extent. This minimizes the risk of unwanted side effects.

Furthermore, the compounds for use in the present invention do not or only to a minor and irrelevant extent act on the central nervous system of the patient to whom they are administered.

Since the compounds used in the present invention are effective in increasing postprandial symptoms, especially when administered at higher doses, they can be used as appetite suppressants.

Since the compounds for use in the present invention preferably do not act on the central nervous system, it may be very advantageous to combine them with conventional appetite suppressants, preferably appetite suppressants, especially sympathomimetics, effective by affecting the central nervous system, for the treatment of disorders involving excessive food intake or intake, especially obesity or obesity. Combination therapy comprising administration of a compound for use in the present invention and a conventional appetite suppressant can be achieved by administration of two or more separate pharmaceutical preparations, each containing only one type of active ingredient, i.e. a modulatory compound that affects the peripheral nervous system or a conventional appetite suppressant that affects the central nervous system. On the other hand, the combination therapy can be achieved by administering a pharmaceutical composition containing two classes of active ingredients, i.e. one or more modulatory compounds affecting the peripheral nervous system and one or more conventional appetite suppressants, and if desired one or more further ingredients selected from the group consisting of additional active ingredients, excipients and auxiliaries.

Thus, another aspect of the present invention relates to the use of potent selective opioid receptor modulators, especially potent peripherally selective opioid receptor modulator compounds, in the manufacture of a medicament for administration in combination with one or more potent appetite suppressants, preferably appetite suppressants affecting the central nervous system.

Preferred conventional appetite suppressants are selected from the group consisting of phenylpropanolamine, norephedrine (Cathin), sibutramine, amfepramone, ephedrine and norpseudoephedrine or their salts, especially phenylpropanolamine hydrochloride, norephedrine hydrochloride, sibutramine hydrochloride, amfepramone hydrochloride, ephedrine hydrochloride and norpseudoephedrine hydrochloride. The above-listed conventional appetite suppressants are commonly referred to as sympathomimetics.

A preferred embodiment of this aspect of the invention relates to the use of one or more compounds selected from the group consisting of Alvimopan, loperamide, Asimadoline, fedotozine, pentazocine, ICI204448, U-50488 3510-0101, ADL10-0116 and ADL 1-0398, especially Asimadoline, in the preparation of a medicament for use in combination with an appetite suppressant, preferably selected from the group consisting of phenylpropanolamine, norpseudoephedrine, sibutramine, bupropion, ephedrine and methamphetamine.

Another aspect of the invention relates to pharmaceutical compositions comprising one or more potent selective opioid receptor modulator, especially potent peripherally selective opioid receptor modulator compounds, and one or more potent appetite suppressant, preferably one or more conventional appetite suppressant, especially one or more sympathomimetic compounds. Preferred are pharmaceutical compositions as described above, wherein the selective opioid receptor modulator is selected from the group consisting of Alvimopan, loperamide, Asimadoline, fedotozine, pentazocine, ICI204448, U-50488H, ADL 10-0101, ADL10-0116, and ADL 1-0398, and/or the conventional appetite suppressant is selected from the group consisting of phenylpropanolamine, norephedrine, sibutramine, bupropion, ephedrine, and norpseudoephedrine, or salts thereof. Especially preferred are pharmaceutical compositions as described above, wherein the selective opioid receptor modulator is selected from the group consisting of Alvimopan, loperamide, Asimadoline, fedotozine, ADL10-0116, and ADL 1-0398, especially Asimadoline, and/or the conventional appetite suppressant is selected from the group consisting of phenylpropanolamine, norephedrine, sibutramine, amfepramone, ephedrine, and norpseudoephedrine, or salts thereof.

A particular and preferred aspect of the present invention relates to a pharmaceutical composition comprising Asimadoline and at least one appetite suppressant, preferably a conventional appetite suppressant, especially preferably at least one sympathomimetic.

Another aspect of the invention relates to the use of a pharmaceutical composition as described above for the treatment of a disease selected from the group consisting of modulation of pathological appetite imbalances, cachexia, anorexia, appetite disorders, weight disorders, obesity, bulimia, obesity, gastroparesis, gastric atony, gastroparalysis and gastrointestinal stenosis. In this respect, the disease is preferably selected from the group consisting of regulated obesity or obesity with pathological appetite imbalance.

Thus, the invention also relates to the use of a compound which is a potent selective opioid receptor modulator, said receptor modulator being a receptor agonist, said receptor modulator being peripherally selective for the receptor, and/or said opioid receptor being a kappa-opioid receptor, in the manufacture of a medicament. In a preferred embodiment, the compound is selected from the group consisting of Alvimopan, loperamide, Asimadoline, fedotozine, pentazocine, U62066E, ICI204448, U-50488H, ADL 10-0101, ADL10-0116, and ADL 1-0398. More-still, the medicament is used (administered) in combination with one or more potent appetite suppressant drugs.

The use of N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide hydrochloride (Asimadoline), in particular, as modulatory compound and thus as a medicament or as active ingredient in medicaments has emerged as being particularly effective in all areas of indications described herein. This particularly high efficiency of Asimadoline in all indications described herein is preferably maintained in all preparation dosage forms.

The compounds used in the present invention are preferably selected from compounds that, due to their structure, are unable to cross the blood-brain barrier and therefore do not show the possibility of dependency. Moreover, no effect has been found to date which would limit the beneficial effects for the claimed indications.

The compounds used in the invention and/or their physiologically acceptable salts and/or their physiologically acceptable derivatives can therefore be used for the production of pharmaceutical compositions or preparations as follows: they are formulated together with at least one excipient or auxiliary, and if desired one or more further active compounds, into suitable dosage forms. The resulting composition or preparation can be used as a medicament in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (e.g. oral or rectal) or parenteral administration and do not react with the compounds used in the invention, for example water, vegetable oils, benzyl alcohol, polyethylene glycols, triacetin and other fatty acid glycerides, gelatin, soya lecithin, carbohydrates (e.g. lactose or starch), magnesium stearate, talc or cellulose.

For oral administration, in particular, tablets, coated tablets, capsules, syrups, oral liquids or drops are employed. Dosage forms of interest are, in particular, coated tablets and capsules having an enteric coating or capsule shell. For rectal administration, suppositories are used, and for parenteral administration, solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants are used.

The compounds for use in the present invention may also be freeze-dried and the resulting lyophilised product used, for example, in the manufacture of injectable preparations.

The compositions or preparations may be sterilized and/or contain adjuvants, such as preserving, stabilizing and/or wetting agents, emulsifying agents, salts for influencing osmotic pressure, buffer substances, colorants and/or flavorings. If desired, they may also contain one or more further active compounds, for example one or more vitamins, diuretics, anti-inflammatory agents or other compounds capable of modulating the tone of the GI tract but not selective opioid receptor modulators.

If the compound used in the present invention is a compound having a basic property, it is generally referred to as the base or free base of the compound. It may be advantageous to convert the free base into the relevant acid addition salt using an acid, for example by reaction with an equivalent amount of base in an inert solvent, for example ethanol, followed by evaporation. Acids suitable for this reaction are in particular those which form physiologically acceptable salts. Thus, it is possible to use inorganic acids, such as sulfuric acid, sulfurous acid, dithionic acid, nitric acid, hydrohalic acids (e.g. hydrochloric acid or hydrobromic acid), phosphoric acid (e.g. orthophosphoric acid), sulfamic acid, furthermore organic acids, in particular aliphatic, cycloaliphatic, araliphatic, aromatic or heterocyclic mono-or polycarboxylic acids, sulfonic acids or sulfuric acids, such as formic acid, acetic acid, propionic acid, caproic acid, caprylic acid, capric acid, palmitic acid, octadecanoic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, trimethoxybenzoic acid, adamantanecarboxylic acid, p-toluenesulfonic acid, glycolic acid, pamoic acid, chlorophenoxyacetic acid, aspartic acid, glutamic acid, proline, glyoxylic acid, palmitic acid, P-chlorophenoxyisobutyric acid, cyclohexanecarboxylic acid, glucose 1-phosphate, naphthalene monosulfonic acid, naphthalene disulfonic acid or lauryl sulfuric acid. Salts of physiologically unacceptable acids, such as picrates, can be used for isolating and/or purifying compounds of formula I. On the other hand, the compounds of the formula I can be converted into the corresponding metal salts, in particular alkali metal or alkaline earth metal salts, or into the corresponding ammonium salts, using bases, for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate. Suitable salts are, in addition, substituted ammonium salts, such as dimethyl-, diethyl-and diisopropylammonium salts, monoethanol-, diethanol-and diisopropylammonium salts, cyclohexyl-and dicyclohexyl-ammonium salts, dibenzylethylenediamine salts, and, in addition, salts of arginine or lysine.

Alternatively, compounds useful in the present invention having acidic properties may be converted into the relevant base addition salts using a base, for example by reaction of an equivalent amount of the acidic compound with a base in an inert solvent, for example ethanol, followed by evaporation. Examples of suitable bases are physiologically acceptable amines, hydroxides or carbonates, such as ethanolamine, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, which convert the compounds used in the present invention into the respective ammonium or metal salts.

On the other hand, the free bases of formula I or formula II can be liberated from their salts using bases such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, if desired.

Pharmaceutically acceptable derivatives of the compounds useful in the present invention include prodrugs, metabolites, and the like. Examples of such prodrugs and/or metabolites comprise compounds for use in the present invention modified by groups that are readily degradable/removable, such as alkyl, acyl, and/or biodegradable polymers, thereby releasing the compounds for use in the present invention from the respective derivatives. Examples of suitable biopolymers are described in the literature, for example int.j.pharm.115, 61-67 (1995).

The present invention further relates to pharmaceutical compositions comprising one or more potent selective opioid receptor modulator compounds as defined above and one or more potent appetite suppressant compounds as defined above.

The pharmaceutical compositions according to the invention may be obtained or produced according to or analogously to methods known in the art. Generally, the pharmaceutical compositions according to the invention are produced non-chemically, e.g. by mixing the active ingredients, i.e. the modulatory compound(s) (or salts thereof) and/or the potent appetite suppressant compound(s) (or salts thereof), and converting the mixture into the desired dosage form, e.g. into tablets by molding, or into a solution by dissolving the active ingredient in a solvent. In general, the active ingredient is converted into a pharmaceutical composition together with one or more excipients (e.g. solid, liquid and/or semi-liquid excipients) or one or more auxiliaries, if desired in combination with one or more further active ingredients.

These preparations can be used as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical administration and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, triacetin, gelatin, carbohydrates (e.g. lactose or starch), magnesium stearate, talc or vaseline. Suitable for oral administration are in particular tablets, pills, coated tablets, capsules, powders, granules, syrups, oral liquids or drops, suitable for rectal administration are suppositories, suitable for parenteral administration are solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, suitable for topical administration are ointments, creams or powders. The novel compounds may also be freeze-dried and the resulting lyophilisates used, for example, for the preparation of injection preparations. The preparations shown may be sterilized and/or contain auxiliaries, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for varying the osmotic pressure, buffer substances, dyes, flavorings and/or a number of further active ingredients, for example one or more vitamins.

For administration as an inhalation spray, it is possible to use a nebulizer in which the active ingredient is dissolved or suspended in a propellant gas or propellant gas mixture (e.g. CO)₂Or chlorofluorocarbons). The active ingredient is advantageously used here in its micronized form, in which case one or more further physiologically acceptable solvents, for example ethanol, may be present. The inhalation solution can be administered by means of a conventional inhaler.

The modulatory compounds according to the invention are generally administered in a dose of between about 0.001mg and 50mg, in particular between 0.01 and 30mg per dosage unit, analogously to other commercially available preparations known for the claimed indications. The daily dose is preferably between about 0.02 and 20mg/kg, more preferably between about 0.05 and 10mg/kg, even more preferably between about 0.1 and 5mg/kg, in particular between 0.2 and 4.0mg/kg body weight. In many cases, a daily dosage of about 0.3mg/kg, about 1.0mg/kg, about 2.0mg/kg, about 3.0mg/kg or about 4.0mg/kg, especially about 0.3mg/kg, about 1.0mg/kg or about 3.0mg/kg is advantageous. In many cases, it is advantageous to administer the daily dose in two separate portions, each containing half the amount of a given daily dose. In general, the mg dose of a modulatory compound is based on the pharmaceutically effective compound itself, or if the compound is administered as a salt, e.g., the hydrochloride salt, based on the weight of the compound salt. The dose in mg/kg is based on kg of body weight of the patient to whom the compound is administered.

The specific dosage for each individual patient, however, will depend upon a variety of factors such as the activity of the specific compound employed, the age, body weight, general health and sex, diet, time and route of administration, rate of excretion, drug combination and the severity of the particular disorder for which the therapy is applicable. Oral administration is preferred.

For the administration of Asimadoline, the following doses have proven beneficial:

0.1 to 2.0mg/kg per day, preferably 0.3 to 1.5mg/kg per day, especially 0.75 to 1.5mg/kg per day, for example about 1.0mg/kg per day, such a dose representing a "low dose" according to the invention;

1.75 to 6.0mg/kg per day, preferably 2.0 to 4.5mg/kg per day, in particular 2.5 to 3.5mg/kg per day, for example about 3mg/kg per day, which represents a "high dose" according to the invention "

The subject of treatment or administration according to the invention is each patient, preferably an animal, in particular a non-human mammal, particularly preferably a human, in need of such a treatment or administration.

Description of the drawings

FIG. 1 shows the results of satiety testing (ml number of maximum uptake volume depends on the dose of Asimadoline administered in part A study (three histograms, left to right: placebo → 1280 ml; 0.15mg/kg Asimadoline → 1425 ml; 0.5mg/kg Asimadoline → 1470ml) and part B study (two histograms, left to right: placebo → 1300 ml; 1.5mg/kg Asimadoline → 1390 ml)).

Fig. 2 shows the numerical values of total postprandial symptoms (VAS scores) as a result of taking a volume in the satiety test, depending on the administered dose of asimoranoline in the part a study (three bar graphs from left to right: placebo → VAS score 180; 0.15mg/kg asimoranoline → VAS score 187; 0.5mg/kg asimoranoline → VAS score 170) and the part B study (two bar graphs from left to right: placebo → VAS score 162; 1.5mg/kg asimoranoline → VAS score 192).

FIG. 3 shows the fasting volume (ml) of the colon at 0mm pressure as a result of the barocompensator test, which was dependent on the administered dose of Asimadoline in the study part A (three histograms, left to right: placebo → 1 ml; 0.15mg/kg Asimadoline → 8 ml; 0.5mg/kg Asimadoline → 21ml) and the study part B (two histograms, left to right: placebo → 6 ml; 1.5mg/kg Asimadoline → 24ml)

Figure 4 shows the swelling sensation values (VAS scores) as a result of the barocompensator test, depending on the pressure (mmHg) causing swelling and the dose of Asimadoline administered in the part a and part B studies (four groups, each consisting of five histograms; left to right:

under-8 mmHg

Placebo (part a) → 37;

0.15mg/kg Asimadoline (part A) → 38;

0.5mg/kg Asimadoline (part A) → 26;

placebo (part B) → 20;

1.5mg/kg Asimadoline (part B) → 31;

under-16 mmHg

Placebo (part a) → 43;

0.15mg/kg Asimadoline (part A) → 37;

0.5mg/kg Asimadoline (part A) → 37;

placebo (part B) → 23;

1.5mg/kg Asimadoline (part B) → 38;

under-24 mmHg

Placebo (part a) → 43;

0.15mg/kg Asimadoline (part A) → 45;

0.5mg/kg Asimadoline (part A) → 41;

placebo (part B) → 42;

1.5mg/kg Asimadoline (part B) → 41;

under-32 mmHg

Placebo (part a) → 54;

0.15mg/kg Asimadoline (part A) → 53;

0.5mg/kg Asimadoline (part A) → 47;

placebo (part B) → 51;

1.5mg/kg Asimadoline (part B) → 43.

Figure 5 shows the swelling pain values (VAS scores) as a result of barocompensator experiments, depending on the pressure (mmHg) causing swelling and the Asimadoline dosing in the part a and part B studies (four groups, each consisting of five histograms; left to right:

under-8 mmHg

Placebo (part a) → 22;

0.15mg/kg Asimadoline (part A) → 25;

0.5mg/kg Asimadoline (part A) → 18;

placebo (part B) → 14;

1.5mg/kg Asimadoline (part B) → 30;

under-16 mmHg

Placebo (part a) → 33;

0.15mg/kg Asimadoline (part A) → 28;

0.5mg/kg Asimadoline (part A) → 28;

placebo (part B) → 21;

1.5mg/kg Asimadoline (part B) → 37;

under-24 mmHg

Placebo (part a) → 38;

0.15mg/kg Asimadoline (part A) → 30;

0.5mg/kg Asimadoline (part A) → 32;

placebo (part B) → 30;

1.5mg/kg Asimadoline (part B) → 40;

under-32 mmHg

Placebo (part a) → 48;

0.15mg/kg Asimadoline (part A) → 42;

0.5mg/kg Asimadoline (part A) → 38;

placebo (part B) → 43;

1.5mg/kg Asimadoline (part B) → 47.

List of abbreviations used herein

AC ascending colon

Side effects of AE

ALT alanine aminotransferase

ANCOVA covariance analysis (statistical method)

ANOVA analysis of variance Applet (statistical method)

a.m. before noon; morning (am)

AST aspartate aminotransferase

AUC_0-tArea under concentration-time curve from time zero to time t

AUC_0-∞Total area under concentration-time curve

AUC τ area under steady state concentration-time curve

b.i.d. twice daily

BMI body mass index

C degree centigrade

C_avMean plasma concentration

cc cubic centimeter

CF Colon perfusion

Apparent overall clearance rate of CL/f plasma drug

C_maxMaximum concentration

COX2 cyclooxygenase-2

CNS central nervous system

CPMP patent and medical product Committee

C_preTrough plasma concentration

Clinical research and development organization of CRDO

CRF case report form

Coefficient of variance of CV

CYP cytochrome P

Descending colon of DC

dl deciliter

ECG electrocardiogram

EMD Merck KGaA, Darmstadt, Germany substance code

EMR Merck KGaA, Darmstadt, Germany research code (clinical practice)

Praise of bed research

F degree of Fahrenheit

FDA food and drug administration

g

G acceleration force

GC geometric center

Good clinical practice of GCP

GE gastric emptying

GI gastrointestinal tract

Good GMP production practices

HADS hospital anxiety and depression scale

hrs hour

IBS irritable bowel syndrome

IC₅₀50% inhibitory concentration

ICH International coordination conference

Non-detection of IND new medicine

IRB public review board

κ kappa

kcal

kg kilogram

KGaA Kommanditgesellschaft auf Aktien

L liter

LC-MS liquid chromatography-mass spectrometry

Micromole of mu mol

Micromole/l micromole per liter

mCi micro Curie

mEq/l milliequivalent per liter

mg of

mg/dl mg per deciliter

mg/kg

mg/ml milligram per milliliter

min for

ml of

ml/min

mm

mmHg mm Hg column

mRNA magnetic resonance

Mu micro

Number of N

No. No. 3

NSAID nonsteroidal anti-inflammatory drugs

PET electron emission tomography

pH hydrogen ion index

p.m. afternoon; afternoon/evening

PMX-CTM computer randomization procedure

QTc corrected QT interval

RS sigmoid colon

δ delta

Severe side effects of SAE

SAS statistical analysis system^TMNotes of SAS Institute, Inc

Volume trademark

TAT treatment area group

TC transverse colon

t_maxTime to maximum plasma concentration

T_1/2Apparent elimination half-life

U/l units per liter

UK United kingdom

VAS visual simulation scale

V_zApparent volume of final distribution of/f

Examples

A single-center, randomized, double-blind, placebo-controlled, parallel group phase I study was performed. This experiment evaluated the effect of 7-day treatment with 2 different doses of the peripherally selective opioid receptor modulator Asimadoline (N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide hydrochloride, EMD 61753) on gastrointestinal and colonic transit and sensorimotor function in healthy subjects compared to placebo.

The specific objective of the study was to compare gastrointestinal to colonic transit behavior and the effects on the following events:

1. composite sensory score of colon in response to distension

2. Threshold for colon response to first sensation of distension and pain sensation

3. Fasted colon compliance and tone

4. Postprandial stress response to standard dietary intake

The study included 60 healthy subjects with no history of gastrointestinal symptoms, and in particular no evidence of irritable bowel syndrome, randomized into one of the following treatment groups:

20 names of Asimadoline 0.15mg b.i.d. 7 days

20 name of Asimadoline 0.5mg b.i.d. 7 days

3. Placebo b.i.d. 7 days 20

Randomized arrangement was performed according to standard methods to ensure age and gender balance within treatment groups. The subjects (and initial investigators) were unaware of the treatment schedule, and the treatment groups were balanced in age and gender.

All subjects received a satiety test before and below drug treatment; scintillation mapped gastric and colonic transit testing; barometric pressure compensator testing after bowel preparation overnight to assess colonic compliance and colonic sensation before and after drug treatment; and fasted colon tone under drug treatment versus colon response to standardized diets.

The primary sensory endpoints in the study were pain, flatulence and complex (mean of pain and flatulence) sensory scores of the colon at four stages (randomized) distension (8, 16, 24 and 32 mmHg). The primary motor endpoints in the study were gastric emptying (remaining in the stomach at 2 hours), colon fullness (%) at 6 hours, colon Geometric Center (GC) at 24 hours and maximum filled volume.

Secondary analytical variables included the flatulence and pain sensation threshold, the overall flatulence score, the overall pain score and overall composite score, colon compliance, fasted colon tone, the tone response of the colon to standard dietary intake, colonic transit summarized by GC at 4 and 48 hours, and the percentage remaining in the stomach at 4 hours. In the satiety test, individual symptom scores (swelling, bloating, nausea, pain) were described. Safety assessments included recording side effects (AE). Subjects also received a complete physical examination, ECG recordings, and provided blood and urine samples for routine laboratory safety testing. In addition, quantitative determination of Asimadoline in plasma was performed.

A specific objective of this study was to compare the effect of 7 days of placebo treatment and three doses of Asimadoline on the following events as described above:

satiety after ingestion of nutritional beverages

Composite sensory score of the colon in response to distension in healthy subjects

Flatulence and pain perception thresholds of the colon in response to distension in healthy subjects

Fasted colon compliance and tone

Post-prandial stress response to standard dietary intake

A further objective of the study was to compare gastrointestinal to colonic transit behavior during the 7 day treatment period. Studies with lower doses (0.15mg/kg and 0.5mg/kg and placebo) were conducted alone as study part a and studies with higher doses (1.5mg/kg and placebo) were conducted alone as study part B (see figures 1 to 4).

The following results were obtained:

a) satiety test (see FIGS. 1 and 2)

0.15mg/kg Asimadoline slightly increased the maximum intake volume over placebo;

0.5mg/kg Asimadoline significantly increased the maximum intake volume over placebo;

establishing a dose response effect at the lower end of the dose range (0.15 mg/kg);

establishing an upper-limiting effect at higher concentrations (1.5 mg/kg);

higher volume of uptake at doses in the range of 0.5mg/kg is not associated with increased symptoms;

at a dose of 1.5mg/kg, symptoms increase with increasing volume ingested.

b) Air pressure compensator (Barostat) test (see FIGS. 3 to 5)

Fasted volume at 0.5mg/kg dose was significantly higher than placebo;

at a dose of 0.5mg/kg, the perception of distension is significantly reduced at low pressure (8 mmHg); this effect is reduced by the increase in pressure;

no significant reduction in pain perception was observed

Significantly higher pain and sensation scores were observed at the higher dose (1.5mg/kg) than for placebo.

The results clearly show that Asimadoline is suitable for dose-dependent appetite regulation. At lower doses, it promotes increased food intake, increases the volume of food ingested, and does not affect negative postprandial symptoms, i.e., does not increase swelling, bloating, nausea and/or pain.

Colon intubation test (pneumatic compensator test)

Preparation of the intestines

Using oral colonic lavage solution (2-5L polyethylene)Diol 3350 and electrolyte solution NuLytely^TMAbbott Laboratories, Chicago, IL) and 12 hour fasting, all subjects visit the General Clinical Research Center, Charlton 7, General Clinical Research Center at visit 3 after overnight bowel preparation.

Pipe placement

A tough colonoscopy was performed to evaluate the left side of the colon, and a teflon guide wire was placed in the proximal colon under fluoroscopic control. The endoscope is retracted.

The air pressure compensator catheter is inserted into the colon along the guide wire so that the air pressure compensator balloon is positioned in the upper sigmoid colon or the descending colon. The catheter and the barometric pressure compensator were connected using a universal 10cm long balloon (Hefty balloons, mobile Chemical co., Pittsford, NY) with a maximum capacity of 600cc, which balloon was connected to an electronic barometric pressure compensator with a rigid piston (Mayo rigid barometric pressure compensator, Mayo Foundation Engineering Department, Rochester, MN). The manometry part comprises six water-filling (0.4ml/min) gas-water sensors, three of which are positioned in the descending colon (sensor number 1-3) and three of which are positioned in the sigmoid colon (sensor number 4-6). The load cell was spaced 5cm apart, and the first and second sensors were located 5cm from the air bag at the mouth and tail ends, respectively. To reduce the effect of abdominal viscera on balloon volume, the study was conducted with the subject in a semi-prone position for the duration of the study.

Colonic compliance and sensation

Previous studies have shown that initial "conditioning" expansion to 20mmHg makes subsequent assessment of compliance and perception more reproducible [15.47.48 ]. Colon compliance and sensory thresholds were measured following conditional distension with ramp insufflation at 4mmHg increments, with step intervals from 0 to 44mmHg of 30 seconds; the threshold values for the first sensation and the pain sensation were thus determined using the uplink limitation method.

Shortly before colonic sensory evaluation, the level of arousal, anxiety or stress experienced by the subject was determined using four 100mm visual analogue scales, with the setpoints "fatigue-energetic", "calm-stressed", "anxious-relaxed" and "active-drowsy". This has previously been shown to be a significant covariate in the assessment of visceral sensory scores. Subsequently, the operating pressure was applied and inflated at randomized stages of 8, 16, 24 and 32mmHg above to measure the sensation of flatulence or pain.

In terms of sensory perception rating, participants were asked to score VAS for two separate abdominal pain and sensations of bloating at standardized times, i.e., 20 seconds after distention had begun. With the "unnoticeable" and "unsustainable" descriptions, the VAS is performed at the end. During sensory evaluation, verbal communication between the subject and the investigator was minimized.

Repeated measurement of colonic sensation

During colonic compliance measurements, colonic sensation was assessed before and 1 hour after drug administration. This equates to finding a threshold pressure or initial perception and perception of pain during successive increases in pressure using the ascending limit method. This method has been shown to provide a threshold evaluation method that is as accurate as tracking with or without random staircase method [49 ].

Colonic response to standard diet

Participants were allowed to rest for 15 minutes. Fasted colon tone and phase activity was then recorded for 30 minutes. Colonic tone was assessed in the presence of a constant operating pressure within the balloon, taking into account changes in balloon volume. The barometric pressure compensator bag was transportably inflated to a volume of 75ml to ensure that after the bag was stretched, it was deflated, inflated to a pressure of 1mmHg increments. The operating pressure is defined as 2mmHg above the minimum inflation pressure, which is the pressure at which respiratory escape is clearly recorded from the barometer's tracing, or at which the respiratory difference is not significant, i.e. at which the bag sub-volume is 25 ml.

Assessment of fasting colonic tone was followed by colonic tone measurement 90 minutes after feeding chocolate milkshake (35% carbohydrate, 53% fat and 12% protein) containing 1.000 kcal. This standard liquid high fat diet was administered to induce a response of the colon to food intake.

When the recording was terminated, the tube was carefully pulled and the test assembly removed.

Measurement for data analysis

Colonic antegrade before and under drug treatment, with a pressure increase of 4mmHg every 30 seconds, measured by means of slope insufflation

First sensation and pain sensation thresholds before and below drug treatment

Pain, flatulence and symptomatology scores at the four-stage swelling level before and under drug treatment

Fasted colon tone (ml) only under drug treatment

Post-prandial colonic tone changes only under drug treatment

Scintillation graphic transport test [42-45]

Method

At 7:00a.m. of the 5 th visit, subjects reached gastroenterology research Unit, fasted. Review of previously conducted pregnancy test results, administration of study medication and¹¹¹InCl₃and (4) making capsules. Breakfast is usually given after one hour^99mTc test meals, and gamma-photographic images were obtained for several hours after ingestion of the test meals (see below). Subjects remained in the study center at the end of the afternoon. He/she was asked to return for the 6 th and 7 th follow-up visits on the following 2 days for further photography.

Gastric emptying transport

At visit 5, subjects were studied after overnight fasting. After mixing and cookingDuring the course, add one (1.0) mCi to two raw eggs^99mTc sulphur colloid. Eggs were placed in a piece of butter bread, followed by a glass of 8 ounces milk (total calories: 296kcal, 32% protein, 35% fat, 33% carbohydrate). Front and back gamma-photographic images were obtained at 0, 1, 2, 3, 4 and 6 hours after ingestion of the meal at the 5 th follow-up visit.

Imaging time table for gastric emptying

Colonic transit test

Will be provided with¹¹¹InCl₃(0.10mCi) was mixed with 5mg of activated carbon slurry. The slurry was evaporated to dryness on a hot plate at 90 ℃ and the dried charcoal was placed IN a size capsule of gelatin (EliLilly, Indianapolis, IN) coated with isobutyrate (Eudragit S100), as IN previous studies [43, 45, 46 ]]. Markers for mapping the capsule position were placed on the anterior superior iliac crest of the subject. The capsules were dosed with one cup of 3 oz of water. Once imaging confirmed that the capsule had emptied from the stomach (as viewed by the position of the capsule relative to the iliac crest markers), the radiolabeled egg was prandial. This typically occurs within an hour; the capsule is rarely emptied. Even in these environments, the diet is administered after one hour because the study medication is administered on a timed basis and the effect of the study medication on gastric and small intestinal transit needs to be accurately assessed. At visits 5, 6 and 7, at¹¹¹InCl₃Front and back gamma-photographic images were obtained 4, 6, 8, 24, 32 and 48 hours after capsule ingestion.

Standardized diets (550kcal, chicken, potato and pudding) were given 4 hours after the radiolabeled diet intake. All other meals were taken ad libitum.

Colon transport imaging schedule

Data analysis

Data were analyzed as described in previous studies [15, 16, 43, 45 ].

Estimating emptying at 2 and 3 hours using geometric means relating to anterior and posterior gastric regions^99mTc ratio (gastric emptying). It is also estimated that colon is reached at 6 hours^99mTc ratio as a measure of oral blinded transport (surrogate for small bowel transport).

Geometric centers at 4, 24, 32 and 48 hours were estimated using geometric means (weighted by factors 1 to 5, respectively) in ascending, transverse, descending and sigmoid colon and feces. The geometric center at 34 hours is the primary variable.

The geometric center is a weighted average of the number of different colon regions (ascending (AC), Transverse (TC), Descending (DC), sigmoid (RS)) and stool. At any time, the proportion of the number of colon in each colon region multiplied by its weighting factor is as follows: (% ACx1 +% TCx2 +% DCx3 +% RSx4 +% stoo1x5)/100 ═ geometric center.

Thus, a high geometric center means faster colon transport; for example, a geometric center of 1 means that all isotopes are in the ascending colon, and a geometric center of 5 means that all isotopes are in the stool.

Statistical methods and analysis

Primary and secondary target variables

Primary sensory endpointAre the actual VAS values for pain, the sensation of flatulence or the combined sensation at 8, 16, 24 and 32mmHg barometric pressure compensator pressures.

End of primary motionGastric emptying at 2 hours, colon filling at 6 hours, 24 hoursColon transport geometric center and colon response to standardized dietary intake.

Primary endpoint in satiety testIs the difference from baseline in the composite satiety score 30 minutes after full satiety.

Secondary endpoint：

Compliance of the colon

Flatulence and pain perception thresholds of the colon in response to distension

Differences from baseline in the flatulence and pain sensation thresholds of the colon in response to distension

Pain, sensation of flatulence or combined sensation VAS values, averaged over all barometric pressure compensator pressures 8, 16, 24 and 32mmHg

Fasted colonic tone

Colonic tone in response to standard dietary intake

Colonic transport summarized by GC at 4 and 48 hours

4 h% emptying from stomach%

Difference in volume of nutritional drink taken from baseline at full satiation

Differences from baseline in individual symptom scores (swelling, fullness, nausea, pain) 30 minutes after complete satiety

All efficacy endpoints were calculated from the recorded raw data by means of the Mayo clinical Study statician.

Pharmacokinetic assessment

Pharmacokinetic parameters determined from the concentration-time data of Asimadoline were: c_max、C_pre、t_maxAnd AUC_0-t。

Descriptive statistics were performed on these parameters by Department of Clinical Pharmacology of Merck KGaA.

Definition of evaluability

Safety feature

The safety population included randomized subjects who all had received at least one dose of active treatment.

Intention to treat

The treatment intent population includes randomized subjects who all have received at least one dose of active treatment and provided any follow-up data for one or more efficacy target variables.

per scheme

The per regimen population includes all subjects who have been treated according to the regimen and meet the following criteria:

satisfy all admission/exclusion criteria, unless some criteria are waived

Absence of protocol violations related to factors that may affect treatment efficacy

Appropriate study drug treatment compliance

Measure most (> 90%) of the primary target variables at all follow-ups

Description of statistical analysis

The primary objective of this study was to compare responses (colonic sensation, Gastric Emptying (GE) and colonic transit) in three treatment groups (placebo, 0.15mg and 0.5 mg). Treatment schedules remain confidential to the initial investigator until all response data is compiled and recorded in SAS^TMAmong the databases, the database was developed by Section of Biostatistics of Mayo clinical.

A preliminary analysis of treatment efficacy included fully randomized subjects based on the treatment intent principle. For these analyses, randomized subjects with missing data were assigned an appropriate "treatment failure" value. Additional response data (treatment group) analysis and summary focused on those subjects with complete data and appropriate study drug treatment compliance (per protocol). A summary of subject characteristics (e.g., age, sex, Body Mass Index (BMI), satiety test) at baseline levels was obtained for all randomized subjects and treatment group assignments.

Assessment of colonic sensation (flatulence, pain and composite (mean of flatulence and pain) scores) was based on repeated measurement analysis of covariance. If the symmetric structure of the compound is not guaranteed, an unstructured variance-covariance matrix of four repeat values (scores at 8, 16, 24, and 32mmHg) is used. This analysis was performed on flatulence, pain and composite scores alone; alpha-levels (0.05) were not adjusted for the various types of reaction endpoints (different scores). Potential covariance in this analysis include age, gender, body mass index, pre-medication sensation score, corresponding inflation volume, and recorded anxiety and stress levels on the day of evaluation.

Analysis of the primary motor endpoints (percent gastric remnant at 2hrs, percent Colon Filling (CF) at 6hrs, and geometric center of colon at 24 hrs) and maximum filled volume (day 5) were based on either a one-way analysis of variance or analysis of covariance. These ratios (GE at 2hrs and CF at 6 hrs) ensure conversion prior to analysis (e.g. sin^-1V) to stabilize the differences between treatment groups. Analysis of filled volumes, except for BMI, used baseline values as covariances; or alternatively, BMI was used as a covariance to analyze relative changes (log [ day 5 volume/baseline volume)])。

Analysis of secondary response variables (colon compliance, fasted colon tone (i.e. volume), relative changes in colon volume in response to standard dietary intake, relative changes in the colonic flatulence and pain sensation thresholds, GE at 4hrs and GC values at 4 and 48 hrs) was also based on a one-way analysis of variance or covariance, with appropriate transformations applied as required.

For the primary and secondary analyses, simple non-parametric (Kruskal-Wallis test) comparisons between the three groups were also examined to supplement the previous analysis. Differences in mean response values between treatment groups were estimated using estimates of variance (pooled) analyzed by variance or covariance outcome with a confidence interval of 95%, with the exception of substantial heterogeneity in variance. All statistical tests used a two-sided alpha-level of 0.05. The alpha-levels of the various (types) endpoints were not adjusted, but multiple (pair-wise) comparisons between treatment groups (i.e., Bonferroni adjustments for three pair-wise comparisons) were made at the alpha-level of 0.017 for any one given endpoint. In addition, group mean differences at 95% confidence intervals were also calculated and reported to provide unadjusted pairwise comparisons.

Efficacy analysis was the responsibility of the statistical staff Alan Zinsmeister, a department of Biostatics Mayo clinical Rochester.

A summary of the incidence, type and severity of side effects, relevant laboratory values and other safety-related data is compiled by Merck KGaA, Darmstadt, Department corporation ebiometrics.

Sample size

The suggested sample size (N ═ 20 per treatment group) provided 80% (90%) intensity to test the following effect sizes between the two groups based on a simple two-sample t-test. Variance (or covariance) analysis provides similar strengths for smaller (overall) differences, depending on their mode.

The following table gives estimates of the magnitude of the effect from previous studies on individual barocompensator pressures and overall bloating, pain and composite scores, corresponding to 80% and 90% intensity of N-20 versus N-40 (e.g. placebo versus total drug):

¹differences between groups as a percentage of the overall mean

²Coefficient of variance

³Analysis of N-20 (placebo) versus N-40 (total drug)

⁴Average values over 8, 16, 24 and 32mmHg

To reduce variability in this study, the age (between 50 and 60 years) and gender of the treatment groups were balanced prior to study entry.

Claims (12)

1. Use of N-methyl-N- [ (1S) -1-phenyl-2- (3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide and/or a salt thereof in the manufacture of a medicament for the relief of post-prandial nausea in the treatment of digestive disorders.

2. Use according to claim 1, characterized in that the disorder is selected from the group consisting of gastroparesis, gastric atony, gastroparalysis and gastrointestinal stenosis.

3. The use according to claim 1, wherein the medicament is effective to modulate gastrointestinal tone.

4. Pharmaceutical composition comprising N-methyl-N- [ (1S) -1-phenyl-2- (3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide and/or a salt thereof and an appetite suppressant.

5. Process for the preparation of a pharmaceutical composition according to claim 4, characterized in that N-methyl-N- [ (1S) -1-phenyl-2- (3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide and/or a salt thereof, an appetite suppressant and one or more excipients and/or one or more auxiliaries are mixed together and converted into a pharmaceutical composition suitable for administration.

6. Pharmaceutical composition according to claim 4, characterized in that it comprises a therapeutically effective amount of N-methyl-N- [ (1S) -1-phenyl-2- (3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide hydrochloride.

7. Use according to claim 1, wherein the disorder of the digestive tract is gastroparesis and the medicament contains 0.001 to 50mg of N-methyl-N- [ (1S) -1-phenyl-2- (3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide and/or a salt thereof.

8. Use according to claim 7, characterized in that the medicament comprises N-methyl-N- [ (1S) -1-phenyl-2- (3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide hydrochloride.

9. Use according to claim 1, characterized in that the medicament comprises N-methyl-N- [ (1S) -1-phenyl-2- (3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide hydrochloride.

10. The use according to claim 1, wherein the medicament is effective to reduce satiety in a patient with digestive disorders.

11. The use according to claim 1, wherein the medicament is effective to reduce one or more postprandial symptoms, wherein the postprandial symptoms are selected from the group consisting of bloating, bloating after food intake, and pain.

12. Use according to claim 11, wherein the postprandial symptom is pain after food intake.