MXPA00005524A - (benzodioxan, benzofuran or benzopyran) derivatives having fundic relaxation properties - Google Patents

Abstract

The present invention of compounds of formula (I), a stereochemically isomeric form thereof, an N-oxide form thereof or a pharmaceutically acceptable acid addition salt thereof, wherein Alk1 is C1-6alkanediyl optionally substituted with hydroxy, C1-4alkyloxy or C1-4alkylcarbonyloxy;-Z1-Z2- is a bivalent radical;R1, R2 and R3 are each independently selected from hydrogen, C1-6alkyl, hydroxy, halo and the like;or when R1 and R2 are on adjacent carbon atoms, R1 and R2 taken together may form a bivalent radical;R4 is hydrogen or C1-6alkyl;A is a bivalent radical of formula -NR6-Alk2-(b-1), or -Npiperidinyl-(CH2)m(b-2) wherein m is 0 or 1;R5 is a radical of formula (A), wherein n is 1 or 2;p1 is 0, and p2 is 1 or 2;or p1 is 1 or 2, and p2 is 0;X is oxygen, sulfur or=NR9;Y is oxygen or sulfur;R7 is hydrogen, C1-6alkyl, C3-6cycloalkyl, phenyl or phenylmethyl;R8 is C1-6alkyl, C3-6cycloalkyl phenyl or phenylmethyl;R9 is cyano, C1-6alkyl, C3-6cycloalkyl, C1-6alkyloxycarbonyl or aminocarbonyl;R10 is hydrogen or C1-6alkyl;and Q is a bivalent radical. Processes for preparing said products, formulations comprising said products and their use as a medicine are disclosed, in particular for treating conditions which are related to impaired fundic relaxation.

Description

DERIVATIVES OF (BENZODIOXANO, BENZOFURANO OR BENZOPIRANO) THAT HAVE PROPERTIES OF FUNDAMENTAL RELAXATION DESCRIPTIVE MEMORY The present invention relates to new aminomethylchroman compounds which have fundic relaxation properties. The invention further relates to methods for preparing said compounds, as well as to the use of said compounds as a medicine. Aminomethylchroman derivatives structurally related in US Pat. No. 5,541, 199 are described as selective autoreceptor agonists useful as antipsychotic agents. Other structurally related aminomethylchroman derivatives having affinity for cerebral 5-hydroxytryptamine receptors of the 5-HT1 type; and therefore suitable for the treatment of disorders of the central nervous system are described in US Pat. No. 5,137,901. EP-0,546,388, published on June 16, 1993, describes structurally related aminomethylchroman derivatives that have affinity for cerebral 5-hydroxytryptamine receptors of the 5-HT? and for dopamine receptors of type D2. EP-0,628,310, published on December 14, 1994, covers the use of the same aminomethylchroman derivatives for the inhibition of the HIV protease.

DE-2,400,094, published on July 18, 1974, discloses 1- [1- [2- (1,4-benzod-oxan-2-yl) -2-hydroxyethyl] -4-pperidyl- 2-benzamidazolonones that have a blood pressure lowering activity. WO-93/17017 (corresponding to the Argentine patent application No.324,400), published on September 2, 1993, describes guanidine [(benzodioxane, benzofuran or benzopyran) alkylamino-alkyl substituted as selective vasoconstrictors useful for the treatment of related conditions with vasodilatation, such as, for example, migraine, cluster headache and headache associated with vascular disorders. WO-95/05383, published on February 23, 1995, encompasses dihydrobenzopyran-pyrimidine derivatives which also have vasoconstrictive activity. Other structurally related aminomethylchroman derivatives are described in WO 97/28157, published August 7, 1997, as a2 adrenergic receptor antagonists useful in the treatment of degenerative neurological conditions. The compounds of the present invention differ from the compounds known in the art cited, structurally, by the nature of the R5 substituent, and pharmacologically, by the fact that, unexpectedly, these compounds possess properties of fundic relaxation. In addition, the compounds of the present invention possess additional beneficial pharmacological properties, in that they have little or no vasoconstrictor activity.

During the consumption of a meal, the fundus, that is, the proximal part of the stomach, relaxes and provides a "reservoir" function. Patients who have a relaxation of damaged accommodation of the fundus with ingestion of food have been shown to be hypersensitive to gastric distension and exhibit dyspeptic symptoms. Therefore, it is believed that compounds that are capable of normalizing damaged fundic relaxation are useful in alleviating patients suffering from such dyspeptic symptoms. The present invention relates to compounds of formula a stereochemically isomeric form thereof, an N-oxide form thereof, or a pharmaceutically acceptable acid addition salt thereof, wherein Alk1 is C-alkylcarbonyl, C ^-C-alkylcarbonyl, carbonyl, C, _6 alkanediyl C, _6 alkylaryl optionally substituted with hydroxy, alkyloxy of CM. alkylcarbonyloxy of CM > CM-alkyloxycarbonyloxy alkylcarbonyloxy of CM, or C3-6 cycloalkylcarbonyloxy-alkyloxycarbonyloxy of CM; -Z1-Z2- is a bivalent radical of formula • CH2"(e-1), -CH = (e-6), -O-CH2- (E-2) -CH2-CH = (e-7), S-CH2" (e-3), - Crl2-CH-CH = (E-8), Cp2-CH2- (e-4), -CH = CH- (E-9); • CH2-CH2-CH2- (e-5), R \ n R2z and R3 are each independently selected from hydrogen, C-? 6 alkyl, C-? 6 alkenyl, C? -6 alkyloxy, trihalomethyl, trihalomethoxy, halo, hydroxy, cyano, nitro, amino, C 1-6 alkylcarbonylamino, C? -6-alkyloxycarbonyl, C-alkylcarbonyloxy, aminocarbonyl, mono- or di (C? -6-alkyl) aminocarbonyl, Ci-aminoalkyl . 6, mono- or di (C? -6 d) -aminoalkyl, alkylcarbonyloxy of CM alkyloxycarbonyloxy of CM, or C3-? Cycloalkylcarbonyloxy of C? -4 alkyloxycarbonyloxy, or when R1 and R2 are on adjacent carbon atoms, R1 and R2 taken together can form a bivalent radical of formula -CH2-CH2-CH2 (a-1), -O-CH2-CH2 (a-6); -CH2-CH2-CH2-CH2 (a-2), -O-CH2CH2-O- (a-7), -CH2-CH2-CH2-CH2-CH2 (a-3), -O-CH2-CH2- CH2 (a-8), -CH = CH-CH = CH- (a-4); -O-CH2-CH2CH2-CH2 (a-9), -O-CH2-O- (a-5), wherein optionally one or two hydrogen atoms on the same or different carbon atom can be replaced by hydroxy, alkyl of CM O CH2OH; R4 is hydrogen, C-? -6 alkyl, or a direct bond when the bivalent radical -Z1k- Z2- is of formula (e-6), (e-7) or (e-8); A is a bivalent radical of formula (b-1) (b-2) wherein the nitrogen atom is connected to Alk1, and m is 0 or 1; Alk2 is alkanediyl of C? _6, R6 is hydrogen, C? -6 alkyl, CM alkylcarbonyl, CM alkyloxycarbonyl; phenylmethyl, alkylaminocarbonyl of CM, alkylcarbonyloxy of CM-alkylcarbonyl of CM, or cycloalkylcarbonyloxy of C3-6-alkyloxycarbonyloxy of CM; R5 is a radical of formula (c-5) where n is 1 or 2; p1 is 0, and p2 is 1 or 2; or p1 is 1 or 2, and p2 is 0; X is oxygen, sulfur, NR9 or CHNO2; And it's oxygen or sulfur; R7 is hydrogen, C6-6alkyl, C3-6cycloalkyl, phenyl or phenylmethyl; R 8 is C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or phenylmethyl; R9 is cyano, C-? 6 alkyl, C3-6 cycloalkyl, C? -6 alkyloxycarbonyl or aminocarbonyl; R10 is hydrogen or C-i-β alkyl; and Q is a bivalent radical of the formula -CH2-CH2- (d-1), -CH = CH- (d-4), -CH2-CH2-CH2- (d-2), -CH2-CO- (d) -5), -CH2-CH2-CH2-CH2 (d-3), -CO-CH2- (d-6), wherein optionally one or two hydrogen atoms on the same or different carbon atom can be replaced by CM, hydroxy or phenyl alkyl, or Q is a bivalent radical of formula (d-7) (d-8) As used in the foregoing definitions, halo is generic for fluorine, chlorine, bromine and iodine; CM alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, 1-methyl-ethyl, 2-methylpropyl and the like; alkyl of C? _6 is intended to include alkyl of CM and the higher homologs thereof having 5 or 6 carbon atoms, such as, for example, 2-methyl-butyl, pentyl, hexyl and the like; C3-6 cycloalkyl is generic cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; C3-C alkenyl defines straight and branched chain unsaturated hydrocarbon radicals having from 3 to 6 carbon atoms, such as propenyl, butenyl, pentenyl, or hexenyl; alkanediyl of C -? - 2 defines methylene or 1, 2-ethanodiiIo; C2-4 alkanediyl defines bivalent straight or branched chain hydrocarbon radicals containing from 2 to 4 carbon atoms, such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the branched isomers of the same; alkanediyl of C? -5 defines bivalent straight or branched chain hydrocarbon radicals containing from 1 to 5 carbon atoms, such as, for example, methylene, 1,2-ethanediol, 1,3-propanediyl, 1,4-butanediyl, 1, 5-pentanediyl, and the branched isomers thereof; alkanediyl of C-i-β includes C-α-5 alkanediyl and the higher homologs thereof having 6 carbon atoms, such as, for example, 1,6-hexanediyl and the like. The thermal "CO" refers to a carbonyl group. Some examples of the R5 portion are: The term "stereochemically isomeric forms" as used above defines all possible isomeric forms that the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all the diastereomers and enantiomers of the basic molecular structure. More particularly, stereogenic centers may have the R or S configuration; substituents on bivalent cyclic (partially) saturated radicals can have either the cis or trans configuration. Compounds that span double bonds can have a stereochemistry E or Z in said double bond. The stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be encompassed within the scope of this invention. The pharmaceutically acceptable acid addition salts as mentioned above are intended to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are capable of forming. The pharmaceutically acceptable acid addition salts can be conveniently obtained by treating the base form with said appropriate acid. Suitable acids comprise, for example, inorganic acids such as hydrohalic acids, for example, hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and similar acids; or organic acids, such as acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (ie, ethanedioic), malonic, succinic (ie, butanedioic), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and similar acids. Conversely, said salt forms can be converted by treatment with an appropriate base, in the free base form.

The term "addition salt" as used above also comprises the solvates which the compounds of formula (I), as well as their salts, are capable of forming. Said solvates are for example, hydrates, alcoholates and the like. The? / -oxide forms of the compounds of formula (I), which can be prepared in manners known in the art, are intended to comprise those compounds of formula (I) wherein the bivalent radical of formula A represents a radical of formula (b-1), wherein R6 is other than hydrogen, or the bivalent radical of formula A represents a radical of formula (b-2), wherein the nitrogen atom is oxidized to the? / -oxide. Interesting compounds are those compounds of formula (I) wherein one or more of the following restrictions apply: a) the bivalent radical -Z1-Z2- is a radical of formula (e-4); b) R1, R2 and R3 are each independently selected from hydrogen, C1-6 alkyl) hydroxy or halo; c) R4 is hydrogen; and / or d) Alk1 is alkanediyl of C? _2 optionally substituted with hydroxy, in particular Alk1 is CH2. A first group of particular compounds consists of those compounds of formula (I) wherein the bivalent radical A is of formula (b-1). A second group of particular compounds consists of those compounds of formula (I) wherein the bivalent radical A is of formula (b-2). Preferred compounds are those compounds of formula (I) wherein R 5 is a radical of formula (c-1) wherein X is oxygen, and Q is a radical of formula (d-1) or (d-2) wherein optionally one or two hydrogen atoms in the same or different carbon atom can be replaced by alkyl CM- The most preferred compounds are those compounds of formula (I) wherein R4 is hydrogen; A is a radical of formula (b-1) wherein R6 is hydrogen or C6-alkyl, and Alk2 is C2-4 alkanediyl; and R5 is a radical of formula (c-1) wherein X is oxygen, R7 is hydrogen and Q is (d-2). Other more preferred compounds are those compounds of formula (I) wherein R 4 is hydrogen, A is a radical of formula (b-2) and R 5 is a radical of formula (c-1) wherein X is an oxygen, R 7 is hydrogen and Q is (d-2). The most preferred compounds are 1- [3 - [[(3,4-dihydro-2H-1-benzopyran-2-yl) methyl] amino] -propyl] -tetrahydro-2 (1 -) -pyrimidinone; a stereoisomeric form thereof or a pharmaceutically acceptable acid addition salt; (R) -1 - [3 - [[(3,4-dihydro-2 7-1 -benzopyran-2-yl) methyl] amino] -propyl] -tetrahydro-2 (1 - /) -pyrimidinone; or a pharmaceutically acceptable acid addition salt thereof; and (R) -1- [3 - [[(3,4-dihydro-2H-1-benzopyran-2-yl) methyl] amino] -propyl] -tetrahydro-2 (1 / -) -pyrimide none [R- (R, R)] - 2,3-dihydroxybutanedioate. The compounds of the present invention can generally be prepared by alkylation of an intermediate of formula (III) with an intermediate of formula (II), wherein W is an appropriate leaving group, such as, for example, halo, fluorine , chlorine, bromine, iodine, or in some cases W may also be a sulfonyloxy group, for example methanesulfonyloxy, benzenesulfonyloxy, trifluoromethanesulfonyloxy, and similar reactive exit groups. The reaction can be carried out in a solvent inert to the reaction, such as for example acetonitrile or tetrahydrofuran, and optionally in the presence of a suitable base such as, for example, sodium carbonate, potassium carbonate, calcium oxide or triethylamine. Agitation may improve the rate of the reaction. The reaction can conveniently be carried out at a temperature ranging from room temperature to the reflux temperature of the reaction mixture, and if desired, the reaction can be carried out in an autoclave at an increased pressure.

(II) (IN) The compounds of formula (I) can also be prepared by reductive alkylation of an intermediate of formula (IV), wherein Alk1 represents a direct bond, or alkanediyl of C? -5, following reductive alkylation procedures known in the art, with an intermediate of formula (III).

(IV) (III) Said reductive alkylation can be carried out in a solvent inert to the reaction, such as for example dichloromethane, ethanol, toluene or a mixture thereof, and in the presence of a reducing agent, such as for example sodium borohydride, sodium cyanoborohydride, or triacetoxy borohydride. In addition it may be convenient to use hydrogen as a reducing agent in combination with a suitable catalyst, such as, for example, palladium on carbon, rhodium on carbon or platinum on carbon. In the case that hydrogen is used as a reducing agent, it may be convenient to add a dehydrating agent to the reaction mixture, such as, for example, aluminum fer-butoxide. To avoid the undesired additional hydrogenation of certain functional groups in the reactants and reaction products, it may also be convenient to add an appropriate catalyst-poison to the reaction mixture, for example, thiophene or quinoline-sulfur. To improve the rate of the reaction, the temperature may rise in a range between room temperature and the reflux temperature of the reaction mixture, and optionally the pressure of the hydrogen gas may rise. Alternatively, the compounds of formula (I) can also be prepared by reacting an acid chloride of formula (V), wherein Alk1 represents C-α-5 alkanediyl or a direct bond, with an intermediate of formula (III) under conditions of reaction.

(V) (III) Said reaction can be carried out under hydrogenation conditions with hydrogen gas in the presence of a suitable catalyst, such as, for example, palladium on carbon, rhodium on carbon or platinum on carbon, in a suitable solvent, such as, for example, ethyl acetate, and in the presence of magnesium oxide. To avoid the undesired additional hydrogenation of certain functional groups in the reactants and reaction products, it may also be convenient to add an appropriate catalyst-poison to the reaction mixture, for example, thiophene or quinoline-sulfur. To improve the rate of the reaction, the temperature may rise in a range between room temperature and the reflux temperature of the reaction mixture, and optionally the pressure of the hydrogen gas may rise. The compounds of formula (Ia), defined as compounds of formula (I) wherein R 5 is a radical of formula (c-1) wherein R 7 is hydrogen, X 1 represents oxygen or sulfur, and Q is a bivalent radical of formula ( d-2), can be prepared by reacting an intermediate of formula (VI) with an intermediate of formula (VII) in a solvent inert to the reaction, such as, for example, tetrahydrofuran and the like.

(VI) (VII) (I-a) The compounds of formula (I) can additionally be prepared by conversion of the compounds of formula (I) to each other, according to group transformation reactions known in the art. For example, compounds of formula (I) wherein R6 is phenylmethyl can be converted into the corresponding compounds of formula (!) Wherein R6 is hydrogen, by means of debenzylation procedures known in the art. Said debencylation can be carried out following art-known procedures, such as catalytic hydrogenation using appropriate catalysts, for example, platinum on carbon, palladium on carbon, in suitable solvents such as methanol, ethanol, 2-propanol, diethyl ether, tetrahydrofuran and the like. In addition, the compounds of formula (I) wherein R6 is hydrogen can be alkylated using methods known in the art, such as, for example, reductive? / -alkylation with a suitable ketone or aldehyde, or the compounds of formula (I) wherein R6 is hydrogen can be reacted with an acyl halide or an acid anhydride. The compounds of formula (I) can also be converted to the corresponding A / -oxide forms following art-known procedures for the conversion of a trivalent nitrogen into its? / -oxide form. Said? / -oxidation reaction can generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Suitable inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides, for example sodium peroxide, potassium peroxide.; suitable organic peroxides may comprise peroxyacids, such as for example benzenecarbo-peroxoic acid or substituted benzenecarboperoxoic acid halo, for example, 3-chlorobenzene-carboperoxoic acid, peroxoalkanoic acids, for example, peroxoacetic acid, alkyhydroperoxides, for example, tert-butyl hydroperoxide . Suitable solvents include, for example, water, lower alkanols for example ethanol and the like, hydrocarbons, for example toluene, ketones, for example 2-butanone, halogenated hydrocarbons, for example dichloromethane, and mixtures of said solvents. The starting materials and some of the intermediates are known compounds, and can be obtained commercially or can be prepared according to conventional reaction procedures generally known in the art. For example, a number of intermediates of formula (II), (VI) or (V) can be prepared according to methodologies known in the art, which are described in WO-93/17017 and in WO-95/053837 . The compounds of formula (I) and some of the intermediates may have one or more stereogenic centers in their structure, present in an R or S configuration, such as, for example, the carbon atom having the substituent R4, and the carbon atom linked to the -AIk1-A-R5 portion. The compounds of formula (I) as prepared in the processes described above can be synthesized in the form of racemic mixtures of enantiomers that can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) can be converted to the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization, and the enantiomers are liberated therefrom by alkali. An alternative way of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will conveniently employ enantiomerically pure starting materials. The compounds of formula (I), the α-oxide forms, the pharmaceutically acceptable salts and the stereoisomeric forms thereof possess favorable fundic relaxation properties, as evidenced in pharmacological example C-1, the "Gastric Tone" test. measured by an electronic barostat in conscious dogs. " In addition, as demonstrated in the pharmacological example C-2"Basal artery vasoconstrictor activity", the compounds of the present invention possess additional pharmacological properties in that they possess little or no vascoconstricting activity. The amount of vasoconstrictor can cause unwanted side effects, such as coronary spasms that can induce chest pain. In view of the ability of the compounds of the present In order to relax the fundus, the subject compounds are useful for treating conditions related to a damaged or hindered fundus relaxation, such as dyspepsia, early satiety, distention and anorexia. Dyspepsia is described as a motility disorder. Symptoms may be caused by a delayed gastric evacuation or by a damaged relaxation of the fundus with the ingestion of food. Warm-blooded animals, including humans (usually referred to herein as a patient), who suffer from dyspeptic symptoms as a result of delayed gastric evacuation, usually have normal fundic relaxation, and can alleviate their dyspeptic symptoms by administering a prokinetic agent , as for example, cisapride. Patients may have dyspeptic symptoms without having an altered gastric evacuation. Their dyspeptic symptoms may be the result of a hypercontracted fundus, or of a hypersensitivity that produces a decreased docility and abnormalities in the molten relaxation of adaptation. A hypercontracted fundus can produce a lowered docility of the stomach. The "docility of the stomach" can be expressed as the relation of the volume of the stomach on the pressure exerted by the stomach wall. The docility of the stomach is related to the gastric tone, which is the result of the tonic contraction of muscle fibers of the nearby stomach. This proximal part of the stomach, exercising a regulated tonic contraction (gastric tone), acts as a reservoir of the stomach. Patients suffering from early satiety can not finish a normal meal, since they feel saturated before they can finish that normal meal. Normally, when a subject begins to eat, the stomach will exhibit an adaptive relaxation, that is, the stomach will relax to accept the food that is ingested. This adaptive relaxation is not possible when the docility of the stomach is hindered, which produces a damaged relaxation of the fundus. In view of the utility of the compounds of formula (I), it follows that the present invention further provides a method of treating warm-blooded animals, including humans (generally referred to herein as patients), suffering from damaged relaxation of the fundus. with the ingestion of food. Accordingly, a method of treatment is provided to relieve patients suffering from conditions such as dyspepsia, early satiety, bloating and anorexia. Therefore, the use of a compound of formula (I) as a medicine is provided, and in particular the use of a compound of formula (I) for the manufacture of a medicament for the treatment of conditions involving a damaged relaxation of the fundus. with the ingestion of food. Both prophylactic and therapeutic treatment are contemplated. Symptoms of impaired relaxation of the fundus may also arise due to the intake of chemicals, for example, Selective Serotonin Reuptake Inhibitors (SSRIs), such as fluoxetine, paroxetine, fluvoxamine, citalopram, and sertraline. Another functional gastrointestinal disorder is irritable bowel syndrome, whereby it is believed that one of its characteristics is related to the hypersensitivity of the intestine to distention. Accordingly, it is therefore believed that the modulation of said hypersensitivity by the compounds of the present invention having fundic relaxation properties, can produce a relationship of the symptoms in subjects suffering from IBS. Therefore, the use of a compound of formula (I) is provided for the manufacture of a medicament for the treatment of IBS (irritable bowel syndrome).

To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in the form of base or acid addition salt, as the active ingredient, is combined in intimate admixture with a pharmaceutically acceptable carrier., whose carrier can take a wide variety of forms according to the desired preparation form for administration. These pharmaceutical compositions are conveniently in unit dosage form suitable, preferably, for administration in oral, rectal, or by parenteral injection. For example, when preparing the compositions in oral dosage form, any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols and the like can be used in the case of oral liquid preparations, such as suspensions, syrups, elixirs. and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most convenient oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, although other ingredients may be included, for example, to aid in solubility. For example, injectable solutions can be prepared, in which the carrier comprises glucose solution or a mixture of saline and glucose. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents and the like may be employed. In compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, whose additives do not cause a significant adverse effect on the skin. Said additives may facilitate administration to the skin, and / or may be useful in the preparation of the desired compositions. These compositions can be administered in various ways, for example, as a transdermal patch, as a spot, as an ointment. The acid addition salts of (I), due to their increased solubility in water over the base form correspondence, are obviously more suitable in the preparation of aqueous compositions. It is especially convenient to formulate the pharmaceutical compositions mentioned above in unit dosage form for ease of administration and uniformity of dosage. The unit dosage form as used in the specification and claims herein refers to physically discrete units suitable as unit dosages; each unit contains a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, associated with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including divided or coated tablets), capsules, pills, powder packets, wafers, suspensions or injectable solutions, teaspoons, spoons, and the like, and segregated multiples thereof. For oral administration, the pharmaceutical compositions can take the form of solid dosage forms, for example, tablets (both swallow only and chewable forms), capsules or gel capsules, prepared by conventional means with pharmaceutically acceptable excipients, as binding agents. (for example pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (for example lactose, microcrystalline cellulose or calcium phosphate); lubricants, for example magnesium stearate, talc or silica); disintegrants (for example potato starch or sodium starch glycolate); or wetting agents (for example sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Said liquid preparations can be prepared by conventional means, optionally with pharmaceutically acceptable additives as suspending agents (for example sorbitol syrup, methylcululose, hydroxypropyl methylcellulose or hydrogenated edible fats); emulsifying agents (for example lecithin or acacia); non-aqueous vehicles (for example almond oil, oily esters or ethyl alcohol); and preservatives (for example methyl or propyl p-hydroxybenzoates or sorbic acid). The pharmaceutically acceptable sweeteners preferably comprise at least one intense sweetener, such as saccharin, sodium or calcium saccharine, aspartame, acesulfalme, potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monelin, stevioside or sucralose (4,1 ', 6'-trichlorcalcic and optionally a sweetener of magnitude such as sorbitol, mannitol , fructose, sucrose, maltose, isomalt, glucose, glucose-hydrogenated syrup, xylitol, caramel or honey.Interactive sweeteners are conveniently used in low concentrations.For example, in the case of sodium saccharin, the concentration can vary from 0.04% to 0.1% (w / v) based on the total volume of the final formulation, and preferably is approximately 0.06% in the low dosage formulations, and approximately 0.08% in the high dosage forms.The magnitude sweetener can be effectively used in larger amounts ranging from about 10% to about 35%, preferably from about 10% to 15% (w / v) The pharmaceutically acceptable flavors that can mask The bitter taste ingredients in the low dosage formulations are preferably fruity flavors, such as cherry, raspberry, blackcurrant or strawberry flavor. A combination of two flavors can produce very good results. In high dosage formulations, stronger flavors may be required, such as Caramel Chocolate flavor, Fresh Mint flavor, Fantasy flavor, and similar pharmaceutically acceptable strong flavors. Each flavor may be present in the final composition in a concentration ranging from 0.05% to 1% (w / v). The combinations of said strong flavors are conveniently used. Preferably, a flavor is used that does not undergo any change or loss of taste and color under the acidic conditions of the formulation. The compounds of the invention can also be formulated as depot preparations. Said long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly), or by intramuscular injection. Accordingly, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil), or ion exchange resins, or as sparingly soluble derivatives, for example as a sparingly soluble salt. The compounds of the invention can be formulated for parenteral administration by injection, conveniently intravenous, intramuscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion. Formulations for injection may be presented in unit dosage form, for example in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as isotonizing, suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The compounds of the invention can also be formulated in rectal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides. For intranasal administration, the compounds of the invention can be used, for example, as a liquid spray, as a powder or in the form of drops. The formulations of the present invention may optionally include an antiflatulent, such as simethicone, alpha-D-galactosidase and the like. In general, it is contemplated that a therapeutically effective amount would be from about 0.001 mg / kg to about 2 mg / kg of body weight, preferably from about 0.02 mg / kg to about 0.5 mg / kg of body weight. A method of treatment may also include the administration of the active ingredient in a regimen of between two or four intakes per day.

Experimental Part In the procedures described below the following abbreviations were used: "ACN" represents acetonitrile; "THF", which represents tetrahydrofuran; "DCM" represents dichloromethane; "DIPE" represents diisopropyl ether; and "DMF" means? /,? / - dimethylformamide. For some chemicals, the chemical formula was used, for example H2 for hydrogen gas, N2 for nitrogen gas, CH2CI2 for dichloromethane, CH3OH for methanol, NH3 for ammonia, HCl for hydrochloric acid, and NaOH for sodium hydroxide. In those cases the stereochemically isomeric form that was first isolated is designated as "A", and the second as "B", without further reference to the actual stereochemical configuration.

A. Preparation of intermediaries EXAMPLE A.1 a) A solution of (+) - (R) -a-methylbenzylamine (0.37 mol) in ethanol (100 ml) was added to a solution of 3,4-dihydro-2-l-benzopyran-2-carboxylic acid ( 0.36 mol) in ethanol (200 ml). The mixture was allowed to separate by crystallization. The precipitate was filtered off and dried. The residue was crystallized 4 times from ethanol. The precipitate was filtered off and dried. The residue was taken up in water, treated with 10% HCl and extracted with diethyl ether. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 8.6 g of (-) - (R) -3,4-dihydro-2 / -1-benzopyran-2-carboxylic acid (mp 85.5 ° C, [a] 20 D = 6.7 ° (c = 100 mg / 10 ml in methanol)) (interm. b) The intermediate (1) (2.14 mol) was stirred in toluene (1280 ml) under an inert atmosphere. Ethanol (640 ml) and sulfuric acid (21 ml, 96%) were added at room temperature. The reaction mixture was stirred and refluxed for 3.5 hours under an inert atmosphere. The reaction mixture was cooled to room temperature. A solution of NaHCO3 (68 g) in water (1900 ml) was added slowly, and this mixture was stirred for 15 minutes. The organic layer was separated, dried, filtered and the filtrate was concentrated to 600 ml volume. The concentrate, ethyl (-) - (R) -3,4-dihydro-2H-1-benzopyran-2-carboxylic ester, was used as such in the next reaction step (interm. 2). c) A mixture of toluene (1000 ml) and ethanol (absolute, 520 ml) was stirred. Sodium borohydride (2.13 moles) was added at room temperature under an inert atmosphere. The mixture was heated to 50 ° C. The intermediate (2) (2.14 mol) was added by dripping at 50 ° C in a period of 90 minutes (exothermic temperature rise of 15 ° C, cooling required). The reaction mixture was stirred for 90 minutes at 50 ° C. Water (1500 ml) was added while stirring. Then, 2-propanone (100 ml) was added dropwise under mild cooling. The mixture was decomposed with HCl (180 ml). The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 295 g of (-) - (R) -3,4-dihydro-2 - / - 1-benzopyran-2-methanol (interm. ). d) A mixture of intermediate (3) (0.18 mol) in toluene (110 ml) and α /, - -diethylethanamine (29 ml) was stirred and cooled in an ice bath. Methylsulfonyl chloride (0.20 mol) was added dropwise, and the reaction mixture was stirred for 30 minutes at room temperature. Water was added. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried (vacuum), yielding 31.4 g (72.0%) of (R) -3,4-dihydro-2H-1-benzopyran-2-methanol methanesulfonate (ester) (interm.

EXAMPLE A.2 a) A mixture of (±) -3,4-dihydro-2 - / - benzopyran-2-carbonichloride (0.5 mol) in? /,? / - dimethylacetamide (150 ml) and DIPE (350 ml) was hydrogenated with palladium on activated carbon (10%, 5.0 g) as catalyst in the presence of a solution of thiophene in methanol (4%, 4 ml). After uptake of H 2 (1 equivalent), the catalyst was removed by filtration. Potassium acetate (5 g) was added to the filtrate. Methanol (100 ml) was added to give a mixture (A). A mixture of [1- (phenylmethyl) -4-p-peridinyl] -carbamic acid, 1,1-dimethylethyl ester (0.45 mol) in methanol (500 ml) was hydrogenated with palladium on activated carbon (10%)., 5 g) as a catalyst. After absorption of hydrogen (1 eq.), The catalyst was removed by filtration and the filtrate was evaporated, to give residue (B). A mixture of residue (B) in mixture (A) and methanol (100 ml) was hydrogenated with palladium on activated carbon (5 g) as a catalyst in the presence of a solution of thiophene in methanol (4%, 3 ml). After absorption of hydrogen (1 eq.), The catalyst was removed by filtration and the filtrate was evaporated. The residue was taken up in water and extracted with diethyl ether. The separated organic layer was dried, filtered and the filtrate was treated with activated carbon, then filtered over dicalite, and the solvent was evaporated. The residue was crystallized from DIPE, separated by filtration and dried, yielding 64.4 g (41.8%) of product (fraction 1). Part (6.3 g) of this fraction was recrystallized from DIPE, separated by filtration and dried, yielding 4.53 g of product. The filtrate was concentrated, stirred and the resulting precipitate was filtered off and dried, yielding 35 g (22.4%) of (±) -1, 1-dimethylethyl [1 - [(3,4-dihydro-2H-1) -benzopyran-2-yl) methyl] -4-piperidinyl] carbamate (fraction 2) (interm. 5). b) A mixture of intermediate (5) (fractions 1 + 2) in methanol (1300 ml) and a solution of hydrochloric acid in 2-propanol (400 ml) was stirred overnight at room temperature. The precipitate was separated by filtration and dried, yielding 72.4 g of product. Part of this fraction was dissolved in water, alkalized, and extracted with diethyl ether. The separated organic layer was dried, filtered and the solvent was evaporated, yielding 36.9 g of (±) -1 - [(3,4-dihydro-2 - / - 1 -benzopyran-2-yl) methyl] -4 -piperidnamnam (interm 6). c) A mixture of intermediate (6) (0.047 mol) and acrylonitrile (0.047 mol) in ethanol (250 ml) was stirred and refluxed overnight.

The solvent was evaporated. The residue was purified on silica gel on a glass filter (eluent: CH 2 Cl 2 / CH 3 OH from 95/5 to 90/10). The desired fractions were collected and the solvent was evaporated. Toluene was added and azeotroped on the rotary evaporator, yielding 11.5 g (81.9%) of (±) -3 - [[1 - [(3,4-dihydro-2-l-benzopyran-2-yl) methyl] -4-pperidinyl] amino] propanenitrile (nterm.7). d) A mixture of intermediate (7) (0.013 mol) in a solution of ammonia in methanol (200 ml) was hydrogenated with Raney nickel (3.0 g) as a catalyst. After absorption of hydrogen (2 eq.), The catalyst was removed by filtration and the filtrate was evaporated, yielding 3.6 g of (±) -? / - [1 - [(3,4-dihydro-2H-1 - benzopyran-2-yl) methyl] -4-piperidinyl] -1,3-propanediamine (interm 8).

EXAMPLE A.3 a) A mixture of 1- [2-hydroxy-3-methyl-4- (phenylmethoxy) phenol] -ethanone (0.098 mol) and etonodioic acid, diethyl ester (0.11 mol) in toluene (100 ml) was added by trituration to a mixture of sodium methoxide (0.22 mol) in toluene (150 ml). The reaction mixture was stirred and refluxed for 2 hours. The solvent was evaporated. The residue was added to a mixture of acetic acid (150 ml) and hydrochloric acid (50 ml). The reaction mixture was stirred and refluxed for 1 hour. The mixture was poured over ice. The resulting precipitate was separated by filtration and dried (vacuum, 70 ° C), yielding 29 g (95.4%) of 8-methyl-4-oxo-7- (phenylmethoxy) -4H-1-benzopyran-2-carboxylic acid. (interm. 9): b) A mixture of intermediate (9) (0.093 mol) and methanesulfonic acid (11 g) in methanol (500 ml) was hydrogenated with palladium on activated carbon (3 g) as a catalyst. After uptake of H 2 (4 eq), the catalyst was removed by filtration. The filtrate was evaporated. The residue was dissolved in DCM and the organic solution was washed with water, dried, filtered and the solvent was evaporated, yielding 19.2 g of (±) -methyl-3,4-dihydro-7-hydroxy-8-methyl- 2 / - / - 1-benzopyran-2-carboxylate (interm. c) Reaction under N2 flow. A solution of diisobutylaluminium hydride in toluene (25%) was added dropwise to a mixture of intermediate (10) (0.077 mol) in toluene (250 ml) and THF (20 ml), stirred at -70 ° C. The reaction mixture was stirred for one hour at -70 ° C, then decomposed with methanol (35 ml). The reaction mixture was poured into water and this mixture was acidified with hydrochloric acid. The organic layer was separated and washed with water. The aqueous phase was extracted with DCM. The combined organic layers were dried, filtered and the solvent was evaporated, yielding 13 g (87.8%) of (±) -3,4-dihydro-7-hydroxy-8-methyl-2H-1-benzopyran-2. carboxaldehyde (interm 11).

EXAMPLE A.4 a) A mixture of? / - [1- (phenol-methyl) -4-piperidn'l] -1,3-propanediamine (0.035 mol) and 2,2-dioxide 1, 3.2 -benzodioxathiol (0.035 mol) in 1,4-dioxane (250 ml) was stirred and refluxed overnight, then stirred for 2 days at 20 ° C. The solvent was evaporated. The residue was crystallized from ACN / H2O. The precipitate was separated by filtration and dried, yielding 7.65 g of tetrahydro-2- [1- (phenylmethyl) -4-piperidinyl] -2 / - / - 1, 3,6-thiadiazine, 1,1-dioxide (interm 12). b) A mixture of intermediate (12) (0.021 mol) in methanol (150 ml) was hydrogenated with palladium on activated carbon (2.0 g) as a catalyst. After uptake of H 2 (1 eq.), The catalyst was removed by filtration and the filtrate was evaporated. The residue was crystallized from ACN. The precipitate was separated by filtration and dried, yielding 2.3 g (50.3%) of product. The filtrate was evaporated. Toluene was added and azetropeated on the rotary evaporator, yielding 1.4 g (30.6%) of tetrahydro-2- (4-piperidinyl) -2 - / ~ 1, 2,6-thiadiazine, 1, 1-dioxide (interm. 13).

EXAMPLE A.5 a) A mixture of 1- (phenylmethyl) -4-piperidynatanamine (0.076 mol) and acrylonitrile (0.076 mol) in ethanol (250 ml) was stirred and refluxed for 4 hours. The solvent was evaporated, yielding 20.0 g (102.4%, crude residue, using in the next reaction step, without further purification) of 3 - [[[1- (phenylmethyl-4-pyridinyl] methyl] -amino] -propanonitrile (interm ..) b) A mixture of intermediate (14) (0.078 mol) in a solution of ammonia in methanol (400 ml) was hydrogenated with Raney nickel (3 g) as a catalyst. After absorption of hydrogen (2 eq.), The catalyst was filtered off and the filtrate was evaporated, yielding 20.2 g (99.4%), used in the next reaction step, without further purification), of? / - [ [1 - (phenylmethyl) -4-pperidinyl] methyl] -1,3-propanediamine (interm. 15). c) A mixture of intermediate (15) (0.027 mol) and 1,1'-carbonylbis- '-imidazole (0.027 mol) was stirred and refluxed overnight. The solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / (CH3OH / NH3) 93/7). The desired fractions were collected and the solvent was evaporated, yielding 2.9 g of product. Part of this fraction (0.5 g) was recrystallized from ACN, separated by filtration and dried, yielding 0.14 g of tetrahydro-1 - [[1- (phenylmethyl) -4-piperidinyl] - methylene] -2 (7HJ-pyrmidinone (interm16) d) A mixture of intermediate (16) (0.0084 mol) in methanol (150 ml) was hydrogenated with palladium on activated charcoal (1 g) as a catalyst. After uptake of H 2 (1 eq.), The catalyst was filtered off and the filtrate was evaporated, yielding 1.25 g (75.9%) of tetrahydro-1- (4-piperidinylmethyl) -2 (7 / -) -p. Rimidinone (interm 17) B. Preparation of the final compounds EXAMPLE B.1 A mixture of intermediate (4) (0.011 mol), 1- (3-aminopropyl) -tetrahydro-2- (í - /) pyrimidinone (0.11 mol) and calcium oxide (1 g) in THF (50 ml) it was stirred overnight at 100 ° C (autoclave). The reaction mixture was filtered over dicalite and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / (CH3OH / NH3) 95/5). The pure fractions were collected and the solvent was evaporated. The residue was dissolved in ethanol and converted to the ethanedioic acid salt (1: 1). The precipitate was separated by filtration and dried (vacuum), yielding 2.2 g (50.8%) of (R) -1- [3 - [[(3,4-dihydro-2 - / - 1-benzopyran-2-yl. ) methyl] amino] propyl] -tetrahydro-2 ('- /) - pyrimidinone ethanedioate (1: 1); [a] = 54.56 ° (c = 0.1% in DMF) (comp.3).

EXAMPLE B.2 A mixture of 3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (0.015 mol) and 1- (3-aminopropyl) tetrahydro-2 (I / -) -pyrimidinationa (0.01 mol) in methanol (150 ml) was hydrogen for two days at room temperature (atmospheric pressure) with palladium on activated carbon ( 2 g) as a catalyst. After uptake of H 2 (1 eq.), The catalyst was removed by filtration and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / (CH3OH / NH3) 95/5). The pure fractions were collected and the solvent was evaporated. The residue (0.3 g) was dissolved in ethanol (30 ml) and converted to the ethanedioic acid salt (1: 1) with ethanedioic acid (0.3 g, 0.0124 mol). The precipitate was separated by filtration and dried (vacuum), yielding 0.3 g (7%) of (±) -1- [3 - [[(3,4-dihydro-2H-1-benzopyran-2-yl. ) methyl] amino] propyl] tetrahydro-2 (1 - /) - pyrimidnationate ethanedioate (1: 1); p. F. 217.6 ° C (comp.14) EXAMPLE B.3 A mixture of (-) - (R) -3,4-dihydro-2 / - / - 1-benzopyran-2-carbonyl chloride (0.2 ml) and magnesium oxide (40 g) in ethyl acetate (350 ml) hydrogen was added at 25 ° C with palladium on activated charcoal (10%) (5 ml). After uptake of H 2 (1 eq.), The catalyst was removed by filtration, and the filtrate was taken up in a mixture of potassium acetate (7 g) in methanol (200 ml). A mixture of 1- (3-aminopropyl) tetrahydro-2 (1 -) pyrimidinone (0.02 mol) in methanol (200 ml) was added, and the mixture was hydrogenated (16 hours at 25 ° C, 16 hours at 50 ° C. ) with rhodium on activated carbon (5%, 3 g) as a catalyst in the presence of a solution (4%) of thiophene in methanol (3 ml). After absorption of hydrogen, the catalyst was removed by filtration and the filtrate was evaporated. The residue was stirred in water, treated with 50% NaOH, and extracted with DMC. The separated organic layer was dried, filtered and the solvent was evaporated. The residue rested overnight in 2-propanone (500 ml). The supernatant was separated by decantation and the residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / (CH 3 OH / NH 3) 95/5). The desired fractions were collected and their solvent was evaporated, yielding (R) -1- [3 - [[(3,4-dihydro-2 / -1-benzopyran-2-yl) methyl] amino] propyl] tetrah Dro-2 (7H) -p¡rimindinone (comp.2) EXAMPLE B.4 1, 1'-carbonylbis-7 - / - imidazole (0.02 mol) was added to a solution of (±) - / V- (3-aminopropyl) -? / - [(3,4-d) hydrox-2 / - / - 1-benzopyran-2-yl) methyl] -? / - (phenylmethyl) -1,3-propanediamine (0.02 mol) in THF (100 ml). The reaction solution was stirred for 17 hours at room temperature. The solvent was evaporated. Water was added to the residue and the mixture was extracted with toluene. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized from ethyl acetate (50 ml). The precipitate was separated by filtration and dried, yielding 3.3 g (42%) of (+) - 1- [3 - [[(3,4-dihydro-2H-1-benzopyran-2-yl) methyl] ] (phenylmethyl) amino] propyl] tetrahydro-2 ('-) - pyrimidinone (Compound 13); p. F. 94.7 ° C.

EXAMPLE B.5 Diphenyl cyanocarbonimidic acid ester (0.01 mol) was added to a solution of (±) - / V- (3-aminopropyl) -? / - [(3,4-dihydro-2 / -1-benzopyran-2-yl) ) methyl] -1,3-propanediamine (0.01 mol) in DMC (100 ml), stirred at room temperature. The reaction mixture was stirred for 17 hours at room temperature. The solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / (CH3OH / NH3) 95/25). The pure fractions were collected and the solvent was evaporated. The residue was dissolved in ethanol (50 ml) and converted to the ethanodoic acid salt (1: 1) with ethanedioic acid (1.27 g, 0.01 mol). The precipitate was separated by filtration and dried (vacuum), yielding 2.5 g (59.9%) of (±) - [1- [3 - [[(3,4-dihydro-2H-1-benzopyran- 2- l) methyl] amino] propyl] hexahydro-2-pyrimidinylidene] cyanamide ethanediotan (1: 1) (Compound 21); p. F. 177.5 ° C.

EXAMPLE B.6 A solution of compound (13) (0.009 mol) in methanol (150 ml) was hydrogenated at 50 ° C with palladium on activated carbon (2 g) as a catalyst. After uptake of H 2 (1 eq.), The catalyst was separated by filtration and the filtrate was evaporated. The residue was dissolved in ethanol (100 ml) and converted to the ethanedioic acid salt (1: 1) with ethanedioic acid (1.16 g, 0.009 mol). The precipitate was separated by filtration and dried under vacuum, yielding 2.8 g (79.1%) of (±) -1- [3 - [[(3,4-dihydro-2H-1-benzopyran-2-yl) methylene] amino] propyl] tetrahydro-2 (AAV) -pyrimidinone ethanedioate (1: 1) (Compound 1); p. F. 226.3 ° C.

EXAMPLE B.7 A mixture of compound (2) (0.0125 mol) and 2-propanone (0.017 mol) in methanol (150 ml) was hydrogenated at 50 ° C with palladium on activated carbon (2 g) as a catalyst in the presence of a solution (4 g). %) of thiophene in methanol (2 ml). After uptake of H 2 (1 eq.), The catalyst was removed by filtration and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / (CH3OH / NH3) 94/5/1). The pure fractions were collected and the solvent was evaporated. The residue was dried, yielding 2226 g of (R) -1- [3 - [[(3,4-dihydro-2-1-benzopyran-2-yl) methyl] (1-methylethyl) amino] propyl] tetrahydro-2 (i - /) - pyrimidinone ethanedioate (Compound 12).

EXAMPLE B.8 A solution of (RR, SS) -3,4-dihydro-2-oxiranyl-2 - / - 1-benzopyran (2.5 g) and 1- (4-piperidinyl) -2-imidazolidinone (2.4 g) in ethanol (70 ml) was stirred for 16 hours at reflux temperature. The reaction mixture was allowed to cool to room temperature and evaporated to dryness, yielding 3.7 g of (RR, SS) -1- [1- [2- (3,4-dihydro-2H-1-benzopyran-2-! l) -2-hydroxyethyl] -4-piperidinyl] -2-imidazolidinone (compound 20).

EXAMPLE B.9 A mixture of N "-cyano-N- [1 - [(3,4-dihydro-2H-1-benzopyran-2-yl) methyl] -4-piperidn'l] -N? 2, 2-dimethoxyethyl) guanidine (0.0153 mol) and HCl (0.5 N, 46 ml) in THF (160 ml) was stirred and refluxed for 100 minutes, ice water was added, NaCO3 was added in In order to obtain a clear separation, the organic layer was separated, DCM was added, everything was washed with water, dried, filtered and the solvent was evaporated, the residue was separated and purified by gel column chromatography. Silica (separation first compound: eluent: CH2Cl2 / (CH3OH 95/5, second compound separation: CH2CI2 / (CH3OH / NH3) 90/10.) The two groups of pure fractions were collected and their solvent evaporated. from ACN. Each precipitate was filtered off and dried, yielding 1.75 g [1- [1 - [(3,4-dihydro-2H-1-benzopyran-2-yl) methyl] -4-piperidinyl] - 1H-imidazol-2-yl] cyanamide (compound 59), and 0.48 g of (±) - [1- [1 - [(3,4-dihydro-2H ~ 1-be nzopyran-2-yl) methyl] -4-p-peridinyl] -i / - / -imidazoI-2-yl] urea (compound 66).

EXAMPLE B.10 Compound (139) (0.0039 mol), BBr3 (0.03 mol, 1 M in DCM, 30 ml) and DCM (50 ml) were mixed and cooled in an ice bath. The reaction mixture was stirred for 2 hours at 20 ° C. The mixture was decomposed with H2O / NH4OH (50/50, 100 ml), while cooling in an ice bath. The mixture was stirred, dried, filtered and the solvent was evaporated. The residue was crystallized from ethanol. The precipitate was separated by filtration and dried, yielding 0.60 g of (±) - (R *, S *) - 1- [1- [2- (3,4-dihydro-8-hydroxy-2H-1-benzopyran -2-yl) -2-hydroxyethyl] -4-piperidinyl] -3,4,5,6-tetrahydro-2 (l / - /) pyrimidinone (compound 141).

EXAMPLE B.11 A mixture of compound (150) (0.0028 mol) in methanol (100 ml) was hydrogenated with Pd / C (10%), 1.0 g) as a catalyst. After absorption of hydrogen (1 equivalent), the catalyst was removed by filtration and the filtrate was evaporated. The residue was dissolved in methanol / DIPE and converted to the ethanedioic acid salt (1: 1). The precipitate was separated by filtration and dried, yielding 0.56 g (46.7%) of [R (R *, R *)] - 1- [3 - [[2- (3,4-dihydro-2H-1-benzopyran -2-yl) -2-hydroxyethyl] amino] propyl] -3,4,5,6-tetrahydro-2 (H) -pyrimidinone ethanodiate (1: 1) (compound 145).

EXAMPLE B.12 A mixture of compound (34) (0.0066 mol), Pd (OAc) 2 (0.050 g), 1,3-propanediyl-bis [diphenylphosphine] (DPPP) (0.200 g) and NH3 (20 g; gas) in THF ( 100 ml) was stirred overnight at 150 ° C under carbon monoxide at a pressure of 0.51 106 Pa (5 atm). The reaction mixture was filtered and the filtrate was evaporated and purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / (CH 3 OH / NH 3) 95/5). The pure fractions were collected and the solvent was evaporated, yielding (±) -2 - [[[(3-hexahydro-2-oxo-1-pyrimidinyl) propyl] (phenylmethyl) amino] methyl] -3,4- dihydro-2H-1-benzopyran-6-carboxamide (compound 51).

EXAMPLE B.13 Triethylamine (0.01 mol) was added to compound (3) (0.0066 mol) in DCM (50 ml). Acetyl chloride (0.0066 mol) was added and the reaction mixture was stirred for 24 hours at room temperature. The mixture was washed with water, then dried, filtered and the solvent was evaporated, yielding 1.91 g of ethyl (R) - [3,4-dihydro-2H-1-benzopyran-2-yl) methyl] [3- hexahydro-2-oxo-1-pyrimidinyl) propyl] carbamate (compound 56). Serving The compounds of formula (I) are numbered as follows: Table F-1 to F-8 lists the compounds that were prepared according to one of the above examples. The following abbreviations were used in the tables: .C4H6O5 represents the salt of 2-hydroxybutanedioic acid (salt of mélic acid), .C2H2O4 represents the salt of ethanedione, C4H6O6 represents the salt of acid [R- (R *, R *)] -2,3-dihydroxy-butanediido (salt of L-tartaric acid),. (E) - C4H4O4 represents acid salt (E) -2-butanedioic acid (salt of fumaric acid),. (Z) - C4H4O4 represents (Z) -2-butanedioic acid salt (maleic acid salt), .C2HeO means ethanolate, .C3H8O2-propanolate, and c.CdHn represents cyclohexyl. TABLE F-1 ADRO F-2 TABLE F-3 TABLE F-4 TABLE F-5 TABLE F-6 (*): point of union to the nitrogen that has the group R SQUARE F-7 TABLE F-8 C. Pharmacological examples C.1. Gastric tone measured by an electronic barostat in conscious dogs Gastric tone can not be measured by manometric methods. Therefore, an electronic barostat was used. This allows the study of the physiological pattern and regulation of gastric tone in conscious dogs and the influence of evaluation compounds on that tone. The barostat consists of an air projection system that is connected by a double-lumen 14-French polyvinyl tube to an ultra-thin flaccida polyethylene bag (maximum volume: ± 700 ml). Gastric tone variations were measured by recording changes in the volume of air within an intragastric bag, maintained at a constant pressure, or at varying pressure levels. The barostat maintains a constant pressure (preselected) inside a bag full of flaccid air introduced into the stomach, changing the volume of air inside the bag by means of an electrical feedback system. Thus, the barostat measures gastric motor activity (contraction or relaxation) as changes in intragastric volume (decrease resp. Increase) at a constant intragastric pressure. The barostat consists of an effort marker connected by an electronic developer to an air injection-aspiration system. Both the stress marker and the injection system are connected by means of a double-lumen polyvinyl tube to an ultra-thin polyethylene bag. A dial on the barostat allows the selection of the pressure level to be maintained within the intragastric bag. Female hound dogs weighing 7-17 kg were trained to stand still in Pavlov frames. They were implanted a gastric cannula under general anesthesia and aseptic precautions. After a median laparotomy, an incision was made through the gastric wall in the longitudinal direction between the major and minor curve, 2 cm above the Latarjet nerves. The cannula was secured to the gastric wall by means of a double bag ring suture and was launched by means of a rubbing wound in the left quadrant of the hypochondrium. The dogs were allowed a recovery period of two weeks. At the beginning of the experiment, the cannula was opened to remove any gastric juice or food debris. If necessary, the stomach was cleaned with 40 to 50 ml of warm water. The ultra-thin bag of the barostat was placed in the fundus of the stomach through the gastric cannula. To ensure easy deployment of the intragastric bag during the experiment, a volume of 150-200 ml was injected into the bag raising the pressure to a maximum of 14 mm Hg (approximately 1.87 kPa) very briefly. This procedure was repeated twice. A stabilization period of 1 hour was left. After a stabilization period of 30 minutes at an intragastric pressure of 2 mm Hg (approximately 0.27 kPa), intragastric pressure curves with steps of 2 mm Hg (0.27 kPa) (maximum 14 mm Hg (approximately 1.87 kPa)) were constructed. (11 minutes at 2 mm Hg (0.27 kPa) and 3 minutes at each pressure step). These pressure changes could be established either manually, or could be installed by means of a computer program (LabVIEW). At least 2 stable curves had to be observed before the administration of the drug. Then, the evaluation compound was administered subcutaneously between the first 3-5 minutes at 2 mm Hg (0.27 kPa). The evaluation compounds were screened at 0.63 mg / kg s.c. Other doses and routes were evaluated if an evaluation compound proved to be active during the screening procedure. Then, four new pressure-volume curves were constructed to evaluate the effect induced by the compound. Table C-1 summarizes the percentage effect on the relaxation of the fundus, 1 hour after the administration of the evaluation compound.

TABLE C-1 C.2 Vasconstrictive activity on basal artery Segments of basal arteries taken from pigs (anesthetized with sodium pentobarbital) were mounted for recording of isometric tension in organ baths. The preparations were bathed in Krebs-Henseleit solution. The solution was maintained at 37 ° C and gassed with a mixture of 95% O2-5% CO2. The preparations were stretched until a stable basal tension of 2 grams was obtained. The preparations were narrowed with serotonin (3x10 7M) The response to the serotonin addition was measured and subsequently the serotonin was removed by washing.This procedure was repeated until stable responses were obtained.The evaluation compound was then administered to the bath of organ and the construction of the preparation was measured.This constrictive response was expressed as a percentage of the response to serotonin as measured above.The ED5o value (molar concentration) is defined as the concentration at which an evaluation compound causes 50 % of the constrictive response obtained with serotonin, these ED50 values are estimated from experiments on three different preparations, a greater number of compounds were evaluated.The following compounds had ED50 values higher than 1.00x10"6 M: 1, 3, 6 , 9, 11, 13, 14, 17, 20, 23, 26, 38.41, 43.45,47,48,50,52,53,54,55,59,60,61, 64,65,66 , 67,72,73,75,76,79,80,83, 86,87,88,89 , 90,92,93,95,96,109,114,115,117,118,119,121, 125,127,128,129,1 31, 133, 137, 138, 141, 143, 147, 148, 156, 164. Compound 10 had an ED50 value of 1.13x10"06 M, and the compound 21 had an ED50 value of 5.90x10"07 M.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula (I) a stereochemically isomeric form thereof, a N-oxide form thereof or a pharmaceutically acceptable acid addition salt thereof, wherein Alk1 is C-alkylcarbonyl, CM-C-alkylcarbonyl, carbonyl, CM-carbonyl-alkyl, or C6-C6alkaryl, optionally substituted with hydroxy, C- alkyloxy, CM-alkylcarbonyloxy, C1-4-alkylcarbonyloxy-C-alkyloxycarbonyloxy. Or C3-6-cycloalkylcarbonyloxycarboxyloxy of C? -; -Z1-Z2- is a bivalent radical of the formula -CH2- (e-1), -O-CH2- (e-2), -S-CH2- (e-3), -CH2-CH2- (e- 4), -CH2-CH2-CH2- (e-5), -CH = (e-6), -CH2-CH = (e-7), -CH2-CH2-CH = (e-8),. CH = CH- (e-9); R1, R2 and R3 are each independently selected from hydrogen, C6-6 alkyl, C3-6 alkenyl. C? -6 alkyloxy, trihalomethyl, trihalomethoxy, halo, hydroxy, cyano, nitro, amino, C? -6 alkylcarbonylamino, C? -6-alkyloxycarbonyl, CM-alkylcarbonyloxy, aminocarbonyl, mono- or di (C? 6) aminocarbonyl, aminoalkyl of C? -6, mono- or di (C? -6 d-ylaminoalkyl, CM-alkyloxycarbonyloxycarbonyloxy of CM, or C3-6cycloalkylcarbonyloxy-alkyloxycarbonylloxy) CM, O when R1 and R2 are on adjacent carbon atoms, R1 and R2 taken together can form a bivalent radical of the formula -CH2-CH2-CH2- (a-1), -CH2-CH2CH2-CH2- (a-2) ), -CH2-CH2-CH2-CH2-CH2- (a-3), -CH = CH-CH = CH- (a-4), -O-CH2-O- (a-5), -O- CH2-CH2- (a-6), -O-CH2-CH2-O- (a-7), -O-CH2-CH2-CH2- (a-8), -O-CH2-CH2-CH2-CH2 - (a-9), wherein optionally one or two hydrogen atoms on the same or different carbon atom can be replaced by hydroxy, CH2OH CO alkyl, R4 is hydrogen, C6-6 alkyl, or a direct bond when the bivalent radical -Z1-Z2- is formula (e-6), (e-7) or (e-8); A is a bivalent radical of formula (b-1) (b-2) wherein the nitrogen atom is connected to Alk1, and m is 0 or 1; Alk2 is Ci ^ alkanediyl; R6 is hydrogen, C- [alpha] 6 alkyl, C- alkylcarbonyl, CM alkyloxycarbonyl, phenylmethyl, CM alkylaminocarbonyl, C1-4 alkylcarbonyloxy-C-M-alkyloxycarbonyl, C3-6-cycloalkylcarbonyloxy, -alkyloxycarbonyloxy of CM; R5 is a radical of formula - N-R7 (c-1) (c-3) (o4) (c-5) wherein n is 1 or 2; p is 0, and p2 is 1 or 2; or p1 is 1 or 2, and p2 is 0; X is oxygen, sulfur, NR9 or CHNO2; And it's oxygen or sulfur; R7 is hydrogen, C-i-β alkyl, C3-6 cycloalkyl, phenyl or phenylmethyl; R 8 is C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or phenylmethyl; R9 is cyano, C-? 6 alkyl, C3-6 cycloalkyl, C-? 6 alkyloxycarbonyl or aminocarbonyl; R10 is hydrogen or C-? -6 alkyl; and Q is a bivalent radical of the formula -CH2-CH2- (d-1), -CH2-CH2-CH2- (d-2), -CH2-CH2-CH2-CH2 (d-3), -CH = CH - (d-4), -CH-CH2-CO- (d-5), -CO-CH2- (d-6), wherein optionally one or two hydrogen atoms on the same or different carbon atom may be replaced by C, hydroxy or phenyl alkyl, or Q is a bivalent radical of formula (d-7) (d-8)

2. A compound according to claim 1, wherein the bivalent radical A is of formula (b-1).

3. A compound according to claim 1, wherein the bivalent radical A is of formula (b-2).

4. A compound according to claim 1, wherein R4 is hydrogen; A is a radical of formula (b-1) wherein R6 is hydrogen or C6-alkyl, and Alk2 is C2-4 alkanediyl; or A is a radical of formula (b-2); and R5 is a radical of formula (c-1) wherein X is oxygen, R7 is hydrogen and Q is (d-1) or (d-2), wherein optionally one or two hydrogen atoms in the same or different Carbon atom can be replaced by CM alkyl.

5. A compound according to claim 1, wherein the compound is 1- [3 - [[3,4-dihydro-2H-1-benzopyran-2-yl) methyl] amino] -propyl] -tetrahydro- 2 (1 H) -pyrimidinone; a stereoisomeric form or a pharmaceutically acceptable acid addition salt thereof.

6. A compound according to claim 5, Wherein the compound is (R) -1- [3 - [[(3,4-dihydro-2 / - / - 1-benzopyran-2-yl) methyl] amino] propyl] tetrahydro-2 (1H) - pyrimidinone [R- (R *, R *)] - 2,3-dihydroxybutanedioate.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to any of claims 1 to 6.

8. A process for preparing a pharmaceutical composition according to claim 7, wherein a therapeutically effective amount of a compound according to any of claims 1 to 6 is intimately mixed with a pharmaceutically acceptable carrier.

9. A compound according to any of claims 1 to 6, for use as a medicament.

10. A process for preparing a compound of formula (I) wherein a) an intermediate of formula (II) is alkylated with an intermediate of formula (III) in a reaction-inert solvent and optionally in the presence from a proper base, (II) (III) b) an intermediate of formula (IV), wherein Alk1 represents a direct bond or alkanediyl of C -? - 5, is reductively alkylated with an intermediate of formula (III); (IV) (III) c) an intermediate of formula (V), wherein Alk1 represents a direct bond or alkanediyl of C? -5, is reacted with an intermediate of formula (III); + H- A- R5- (I) (IV) (III) wherein in the above reaction schemes, the radicals A, R1, R2, R3, R4 and R5 are as defined in claim 1, and W is an appropriate exit group; d) or, the compounds of formula (I) are converted to each other following transformation reactions known in the art; or if desired, a compound of formula (I) is converted to an acid addition salt, or conversely, an acid addition salt of a compound of formula (I) is converted to a free base form with alkali; and if desired, the preparation of stereochemically isomeric forms thereof. SUMMARY OF THE INVENTION The present invention of compounds of formula (I) a stereochemically isomeric form thereof, an N-oxide form or a pharmaceutically acceptable acid addition salt thereof, wherein Alk1 is Ci-β alkanediyl optionally substituted with hydroxy, CM alkyloxy, or CM alkyl alkylcarbonyloxy; -Z1-Z2- is a bivalent radical; R1, R2 and R3 are each independently selected from hydrogen, C-? -6 alkyl, halo, hydroxy and the like; or when R1 and R2 are on adjacent carbon atoms, R and R2 taken together can form a bivalent radical; R4 is hydrogen or C? -6 alkyl; A is a bivalent radical of the formula -NR6-Alk2- (b-1), or -? / Piperidnil- (CH2) m (b-2) wherein m is 0 or 1; R5 is a radical of formula (c-1) (c-2) (c-3) (c-4) (c-5) wherein n is 1 or 2; p1 is 0, and p2 is 1 or 2; or p1 is 1 or 2, and p2 is 0; X is oxygen, sulfur, or = NR9; And it's oxygen or sulfur; R7 is hydrogen, C-i-e alkyl, C3-6 cycloalkyl phenyl or phenylmethyl; R8 is C6_6 alkyl, C3_6 cycloalkyl, phenyl or phenylmethyl; R9 is cyano, C6-6alkyl, C3-6 cycloalkyl, C-? 6alkyloxycarbonyl or aminocarbonyl; R10 is hydrogen or C-t-6 alkyl; and Q is a bivalent radical; there is described a process for the preparation of said products, formulations comprising said products, and their use as a medicament, in particular for the treatment of conditions that are related to a damaged fundic relaxation. JANSSEN / xal * aom * jtc * pbg * yac * lrb * osu * asg * P00 / 427F