MXPA97002356A - Derivatives of phenyl-oxy-alkyl- (4-piperidinyl) benzo - Google Patents

Abstract

The present invention relates to novel benzoate derivatives having the formula (I), the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein R1 is halo or C1-6 alkylsulfonylamino. 6, R2 is hydrogen and R3 is C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, or R2 and R3 taken together form a bivalent radical of the formula -CH = CH- (a), - ( CH2) 2- (b) or - (CH2) 3- (c); in the bivalent radicals of the formula (a), (b) or (c) one or more hydrogen atoms may be replaced by C1-alkyl 6; Alk is C 1-6 alkanediyl, R 4 is hydrogen or C 1-6 alkyloxy, R 5, R 6 and R 7 each independently is hydrogen, halo, C 1-6 alkyl, C 1-6 alkyloxy, or R 5 and R 6 taken together they can also form a bivalent radical of the formula: -NR8C (O) NR9-, -NH-C (NHR10) = N-, -O- (CH2) mO-; R8 and R9 each independently is hydrogen or alkyl C1-6; R10 is hydrogen, alkylcarb C 1-6 onyl, C 1-6 alkyloxycarbonyl, m is 1 or 2, the pharmaceutical compositions comprising said compounds, methods for preparing the compounds and compositions as well as the use of a medicine are described, in particular for the treatment of intestinal disturbances involving decreased mobility of cabbage

Description

DERIVATIVES OF FENIL-OXO-OLQUIL- (-PIPERIDINIL) BENZOATO DESCRIPTIVE MEMORY The present invention relates to novel benzoate derivatives, pharmaceutical compositions comprising said novel compounds, processes for preparing the compounds and compositions, and to the use thereof as a medicine, in particular in the treatment of conditions involving decreased susceptibility. of the colon. In EP-0, 389.037-0, published on September 26, 1990, the N- (3-hydroxy-4-piperidinyl) (dihydrobenzofuran or dihydro-2H-benzo-iran) carboxamide derivatives are described as having stimulant properties of gastrointestinal In EP-0,445,852-0, published on September 11, 1991, the N- (4-? I? Eridinyl) (dihydrobenzofuran or dihydro-2H-benzopyran) carboxarnide derivatives are also described as having gastrointestinal irritant properties. UO 93/03725 (SrnithKline Beecharn), published on March 4, 1993, generally describes the use as SHT * receptor antagonists of esters of the general formula X-CO-YZ, wherein X can be a substituted phenyl, and can be oxygen, and Z may be a substituted piperidine moiety. WO 94/08995. SmithKline Beecharn), published on April 28, 1994, generally discloses, for example, substituted 7-benzofuran carboxylates which also have 5HT antagonistic activity. The last two patent applications describe the use of the 5HTβ antagonist compounds in the treatment of irritable bowel syndrome (IBS), in particular the diarrhea aspects of IBS. Unexpectedly it has been discovered that the present novel compounds show intestinal prokinetic activity. In this manner, the presently described compounds show utility in the treatment of conditions involving a lowered bowel movement, especially the colon. The present invention relates to novel benzoate derivatives having the formula the N-oxide forms, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein: i is halo or C 1 -C 6 alkylarylamyl amino; R2 is hydrogen and R3 is alkyl of C6-6, alkenyl of C2-6 or alkinyl of C2-6; R2 and R3 together form a bivalent radical of the formula: -CH2CH- (a), - (CH2) 2- (b), or - (CH2? 3- (O; In the bivalent radicals of formula (a), (b) or (c) one or two volumes of hydrogen can be replaced by alkylene of C? -6; 5 Alk is alkanedyl of Ci-e; R is hydrogen or Ci-β alkyloxy; RS, R6 and 7 each independently are hydrogen, halo, Ci-β alkyl, Ci-β alkyloxy, or R5 and Rβ together can also form a radical - 'Or bivalent of the formula: 0 NR8-C-NR9 (d), 15 NH-R1 NH C-N (e), or 20 0 (CH2) m "O-- (f); Rβ and R9 each independently are hydrogen or alky of C? -6; RÍO s hydrogen, alkylcarbomlo of Ci-ß, 25 alki Lox carbo ilo of C? -6; and rn is 1 or? . As used in the above definitions and below, halo is rich in fluorine, chlorine, bromine and iodine; to the ilo of C? -6 defines radicals of saturated hydrocarbons in chain straight and branched having 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentiio, hexyl, 1 -methyl] ethyl, 2-methoxy and the like; alkenyl of C2-6 defines straight and branched chain hydrocarbon radicals containing a double bond and having from 2 to 6 carbon atoms such as ethenyl, 2-propemyl, 3-butenyl, 2-butenyl, 2- Pentelo, 3-? entenlo, 3-rnet? i-2-butenyl, 3-hexene, and the like; C2-6 alkynyl defines straight and branched chain hydrocarbon radicals containing a triple ligation having from 2 to 6 carbon atoms such as, for example, ethynyl, 2-? rophenyl, 3-butyl, 2 -But it, 2-pendent, 3-pendent, 3-hex, and similar; Ci-β alkanyl defines bivalent straight or branched chain hydrocarbon radicals containing from 1 to 6 carbon atoms such as, for example, rnetileno, 1,2-etanedulo, 1,3-pro? aned? lio, 1, 4-butanediol, 1,5-pentanedulo, 1, 6-hexanedi lio. The pharmaceutically acceptable addition salts as mentioned above should comprise the therapeutically active non-toxic acid addition salt forms which the compounds of the formula (I) are capable of forming. The latter can conveniently be obtained by using the base form with said appropriate acid. Suitable acids include, for example, inorganic acids such as hydroalic acids, for example, inorganic acids such as hydrococides, for example hydrochloric acid or brornhydride.; sulfuric, nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanic, hydroxyacetic, lactic, propanic, hydroxyacetic, lactic, pyruvic, oxalic, rnalonic, succinic, rnaleic, fumaric, rnálico, tartaric, citric, rnetansul phonic, ethanesulphonic, benzensul phonic, p-toluensul phonic, cycloalic, salicylic, p-5 aminosalicylic , Parnoic and similar acids. The term "addition salt" as used herein also encompasses the solvates that the compounds of the formula (I) as well as the salts thereof are capable of forming. Said solvates are for example hydrates, alcoholates and the like. Conversation, The salt form can be converted by the alkali treatment into the free base form.The term "isomeric ether-chemical forms" as used above, defines all possible isomeric forms of the compounds of the formula (I) can you own, fl Unless mentioned or indicated to the contrary, the chemical designation of the compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereors and enantiomers of the basic molecular structure. More in particular, the centers stereogénicos can have the configuration R- or S-; Substitutes in saturated (partially) cyclic divalent radicals may have the cis or trans configuration and the alkenyl radicals of C 2-6 may have the E- or Z- configuration. The stereochemically isomeric forms of the The compounds of the formula (I) obviously must be within the scope of this invention. Some of the compounds of the formula (I) can also exist in their tautornic form. Said forms although explicitly not indicated in the above formula should be included within the scope of the present invention. For example, the compounds of the formula 5 (I) wherein R5 and R6 are taken together to form a bivalent radical of the formula (d) wherein R8, R9 or both are hydrogen may exist in their corresponding tautomeric form. The N-oxide forms of the compounds of the formula / «* £ • > (I) must comprise those compounds of the formula (T) wherein one or several nitrogen atoms are oxidized in the so-called N-oxide, particularly those N-oxides wherein the piperidine nitrogen is N-oxidized. Ri is suitably fluorine, chlorine or bromine, preferably R1 is chlorine; R3, not being taken together with R2, is suitably alkyl of C? -6, preferably methyl; When R2 and R3 are taken together a bivalent radical of the formula (b) is preferred; Alk is suitably 1, 2-ethanediyl, 1,3-propanediyl, or 1,4-butanediyl, preferably 1,3-pro-anediyl; R is suitably hydrogen or rnetoxy; 5. ß and R7 are suitably hydrogen, alkyl of C? -6 / alkyloxy of Ci-e. or chlorine, preferably methyl, rnetoxy or hydrogen; When R5 and Rß are all together a radical bivalent of the formula (d) or (e) is preferred, especially a radical of the formula (d). The interesting compounds of the formula (I) are those compounds of the formula (I) wherein R 1 is chloro. Other interesting compounds of the formula (I) are those compounds of the formula (I) wherein R2 and R3 taken together form a bivalent radical of the formula (b). More interesting compounds are those interesting compounds where Alk is 1, 3-pro? Anediiio. Preferred compounds are those more interesting compounds wherein R5, R6 and R7 are methoxy. Also the preferred compounds are those more interesting compounds wherein R7 is hydrogen and RS and R6 are taken together to form a radical of the formula (d) wherein Rß and R * are hydrogen. Other preferred compounds are those interesting compounds where R5 and R7 are methyl and R * is methoxy. The most preferred compounds are: cis-3-rnedhoxy-l-C4-oxo-4- (3,4,5-trimetroxife il) butyl] ~ 4-? Ip ridinyl 4-amino-5-chloro- 2, 3- dihydro-7-benzofurancarboxylate; 1 - C 4-0X0- 4 - (3, 4, 5 - 1 rimetox i feni 1) but i 1] - 4 - pi pe ri di ni 1 4 -amino-5-chloro- 2, 3 -dihydro - 7-benzo fu rne rbox i lato; 1-C4- (2, 3-dihydro-2-oxo-lH-benzirnidazo.l-5-yl) -4-oxobutyl] -4-pi? Eridinyl 4-arnino-5-chloro-2, -dihydro- 7-benzo fu ane rbox i lato; Y l ~ C4- (4-R-methoxy-3,5-dimethyl-enyl) -4-oxo-butyl] -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzofuranecarboxylate; The stereoisomeric forms thereof and the pharmaceutically acceptable acid addition salts. To simplify the structural representations of the compounds of the formula (I) and certain intermediates thereof, the radical of the formula later on it will be represented by the symbol D and the radical Hereafter will be represented by L. In the following preparations, the reaction products can be isolated from the reaction mixture and, if necessary further purified according to the methodologies generally known in the art such as, for example, distillation extraction , crystallization, 5 trituration or chromatography. The compounds of the formula (I) can be N-Alkylating a piperidine of the formula (II) with an intermediate of the formula (III). L-U + H-D N-Alkylation 5 (III) (II) (I) W1 in the intermediary of formula (III) is an appropriate leaving group such as, for example, halo, For example chlorine, bromine or iodine, or a sulfonyloxy group, for example rnetansulfonyloxy, tol-ensulfonyloxy and the like leaving groups; the reaction of N-alkylation of (II) with (III) is conveniently carried out following the alkylation procedures known in the art. The compounds of the formula (I) can also be prepared by the esterification of an alcohol of the formula (IV) wherein * Y L are co or defined above, with a carboxylic acid of the formula (V) wherein R 1, R 2 and R 3 are as defined above, as a functional derivative of The same, such as an acyllable, a symmetrical or mixed anhydrous or an ester, preferably an activated ester, following the procedures known in the art.

(IV) (V) It may be convenient to protect the amino group of the intermediate of the formula (V) during the course of the reaction to avoid unwanted side reactions. Said amino protecting group is removed after the esterification ends. Suitable protecting groups include reachable groups such as C 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonyl, phenyl ethyl and the like protecting groups. The compounds of the formula (I) wherein RS and R6 are taken together and form a radical of the formula (d), said compounds being represented by the formula (Id), can be prepared by reacting an intermediate of the formula ( VI) with 1, 1 '-carbonylbis-1H-imidazole or a functional derivative thereof, followed by reaction procedures known in the art.

(VI) s «o The compounds of the formula (I) wherein R '"and β are taken together and form a radical of the formula (e), said compounds being represented by the formula (Ie), can be prepared by reacting an intermediate of the formula (VI) wherein R8 and R9 both are hydrogen, said intermediates being represented by the formula (Vi-a), with an intermediate of the formula (VII), followed by reaction procedures known in the art.

(VI-a) (VII) (I-e) The compounds of the formula (I) can also be converted to each. For example, the compounds of the formula (I), wherein R or is hydrogen can be converted to compounds of the formula (I), wherein R ° is Ci-β alkylcarbonyl or C?-6alkyloxycarbonyl, by of N-acylation reactions known in the art. The compounds of the formula (I) wherein R3 is C2-6 alkenyl or C2-6 alkynyl can be converted into compounds of the formula (I) in which > R3 is the corresponding saturated alkyl radical by means of hydrogenation techniques known in the art. The compounds of the formula (I) can also be converted to the corresponding forms of N-oxide followed by procedures known in the art for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction can generally be carried out by making reacting the starting material of the formula (I) with an appropriate organic or inorganic peroxide. Suitable morganic peroxides comprise, for example, hydrogen peroxide, alkali metal peroxides or alkaline earth metal, for example sodium peroxide, potassium peroxide; Suitable organic peroxides may comprise peroxyacids such as, for example, benzenecarboperoxyacid or halo substituted benzenecarboxyperoxicacid, for example, 3-eiobenzenecarboperoxyaic acid, peroxoalkanoic acids, for example peroxoacetic acid, alkyl roperoxide, for example tert-butylhydroperoxide. Suitable solvents are, 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 intermediates of the formula (II) can be derived from an appropriately substituted piperidine of the formula (VIII) with an intermediate acid of the formula (V) or a functional derivative thereof, followed by to form ether known in the art, and subse- quently remove the protecting group P, following procedures known in the art. P represents a protective group that can be replaced, such as C1-4 alkylcarbonyl, Ci-1alkyloxycarbonyl, phenylmercury and similar protective groups. 25 (vm) (V) The preparation of the intermediate acids of the formula (V) is described in EP-0,389.03 -A. The intermediates of the formula (Vi-a) can be prepared by reducing an intermediate of the formula (IX) with a suitable reducing agent such as, for example, a combination of platinum in carbon and hydrogen. activated, in a reaction-inert solvent such as, for example, te rahi urano.

(K) Said intermediates of the formula (IX) can be prepared by N-alkylating a pipepdine of the formula (II) with an intermediate of the formula (X) wherein l is an appropriate leaving group, such as, by € > atom, a halogen atom, analogously to the compounds of the formula (I) are prepared from intermediates (II) and (TU).

(X) (D) The intermediates of the formula (VIII '), wherein Pl represents P as defined above as well as hydrogen, J- can be prepared by reducing an intermediate of the formula (XI) following the methods known in the art. In particular, the intermediates of the formula (VIII '), wherein R * is C? -6 alkyloxy, said intermediates being represented by the formula (VlII'-a), and Wherein R * and the hydroxyl group have a cis configuration can be prepared by means of the reduction of an intermediate of the formula (Xl-a) using a reducing agent such as substituted borohydrate, for example lithium tris-sec-butylborohydrate, potassium tris-sec-butylborohydrate, hydrates substituted aluminum, lithium tris-tert-butoxyaluminum hydroxide and the like, in a reaction-inert solvent such as, for example, tetrahydrofuran. It may be advantageous to carry out the reaction at a lower temperature, preferably at a temperature below -70 ° C. Using reagervtes When the stereochemistry is pure, said reaction can be performed stereospecifically. 1. 5 (X) (VIII ') (XI-a): R "is Ci-β alkyl (VIII'-a): R4 is C? -6 alkyl J * The diastereomeric cis and trans racernates of the compounds of the formula (I), or any of the other intermediates can also be resolved in their optical isomers, cis (+), cis (-), trans (+) and trans ( -) by the application of methodologies known in the art. The diastereomers can be separated by physical separation methods such as selective co-location and chromatographic techniques, for example distribution of counting current and enantiomers can be separated from each by crystallization. selective of its diastereomeric salts with enantiomerically pure acids or their enantiomerically derived derivatives. The compounds of the formula (I) and the intermediates of the formulas (II) and (VI), the N-oxide forms, the salts Pharmaceutically acceptable and the stereoisomeric forms thereof possess mobility-stimulating properties favorable intestinal In particular, the present compounds show significant mobility enhancing effects in the large intestine and small intestine. The latest properties are verified by the results obtained in test 5"Guinea Pig Lleurn Coaxial Stirnulation" and the test "Colon rnotility in conscious dog". Both tests are described later. Some of the compounds also show activity in the "Lida idine test in dogs" test. In view of its mobility-enhancing properties A < Useful intestinal, the subject compounds can be formulated in various forms for administration purposes. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in the form of a base or salt. addition acid, as the ingredient .15 active is combined in intimate admixture as a pharmaceutically acceptable carrier, said carrier can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unit dosage form Suitable, preferably, for administration orally, rectally or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the common pharmaceutical media can be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, tonics, and solutions; or vehicles solids such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Due to the ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, wherein solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will generally comprise sterile water, at least in large part, although other ingredients, for example, to aid solubility, v ") may be included.Injectable solutions, for example, may be prepared in wherein the vehicle comprises saline solution, glucose solution or a mixture of saline solution and glucose.The injectable suspensions can also be prepared wherein the appropriate liquid carriers, suspending agents and the like can be employed. percutaneous administration, the vehicle optionally comprises a penetration enhancing agent and / or a suitable moisturizing agent, optionally combined with suitable additives of any nature in minor proportions, said additives do not cause a significant detrimental effect to the skin. facilitate administration to the skin and / or may be useful for to prepare the desired compositions. These compositions can be administered in various ways, for example, as a transdermal patch. , co or a local application, as an ointment. The acid addition salts of (I), (II) or (VI) they are obviously more suitable in the preparation of aqueous compositions due to their increased solubility of water on the corresponding base form. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in the dosage unit form for ease of administration and uniformity of dosage. The dosage form as used in the specification and claims herein, refers to physically discrete units suitable as unit doses., each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including coated or labeled tablets, capsules, pills, powder packets, wafers, injectable solutions or suspensions, tablespoons, large tablespoonfuls and the like, and segregated multiples thereof. ability to stimulate the mobility of the intestinal system and in particular its ability to improve colonic mobility, the compound subjects are useful for normalizing or improving bowel transit in subjects suffering from symptoms related to distorted mobility, for example a decreased pepstalisis of the intestine large and small alone or in combination with delayed gastric emptying In view of the utility of the compounds of the present invention, a method is provided for treating warm-blooded animals suffering from disturbances of intestinal system mobility such as, for example, constipation, pseudo-obstruction, intestinal atony, post-compulsory intestinal atony, irritable bowel syndrome (IBS), delayed induced drug transit, and in particular colonic transit. Said method comprises the systemic administration of an effective amount for stimulating the intestine of a compound of the formula (I), an N-oxide, a pharmaceutically acceptable acid addition salt or a possible stereoisomeric form thereof, "for animals of hot blood. Thus, the use of a compound of the formula (I) as a medicine is provided, and in particular the use of a compound of the formula (I) for the manufacture of a medicine to treat conditions involving decreased mobility of the colon. In general, it is contemplated that a therapeutically effective amount would be from about 0.01 mg / kg to about 10 mg / kg body weight, preferably from about 0.02 mg / kg to about 5 mg / kg body weight. A treatment method can also include the administration of the active ingredient in a regimen of between 2 or 4 doses per day.

? R EXPERIMENTAL PART A. PREPARATION OF INTERMEDIARIES EXAMPLE 1 a) Sodium borohydrate (7.7 g) was added in portion form to a stirred solution of 3-methoxy-1- (phenylmethyl) -4-piperidinone (44.8 g) in ethanol. (610 mi). Upon completion, the whole mixture was cooled to room temperature and stirring continued for 3 hours at room temperature. The reaction mixture was concentrated to a volume of approximately 150 ml. The water (300 ml) was added to the concentrate and all traces of ethanol were evaporated. After cooling, the mixture was extracted with diethyl ether. The extract was washed with water, dried, filtered and evaporated. The oily residue was purified by column chromatography on silica gel (eluent: CHCl3 / CH3OH 96/4). The pure fractions were collected and the eluent was evaporated. The residue was separated by column chromatography on silica gel (eluent: hexane CHCl3 / (CH3? H / NH3) 50/50/1). The first fraction was collected and the eluent evaporated, yielding 11.5 g (25.5%) of trans-3-rnetoxy-i- (phenyltrnetii) -4-? Iperidinol (intermediate 1). The second fraction was collected and the eluent evaporated, yielding 7.7 g (17.1%) of cis-3-methoxy-1- (phenylmethyl) -4- piperidinol (intermediate 2). a ') A solution of 3-methoxy-1- (phenylmethyl) -4-piperidinone (4.4 g) in tetrahydrofuran was cooled to -75 ° C. The lithium tris-sec-butylborohydrate was added in the form of drops and the reaction mixture was stirred for two hours at -70 ° C. 10% acetic acid (100 ml) was added as drops at room temperature. The organic solvent was evaporated. The aqueous residue was alkalized with NH 4 OH, then extracted twice with diisopropyl ether. The separated organic layer was washed with water, dried over filtered HgSO4 and the solvent was evaporated. The residue was purified by means of short column chromatography on silica gel (eluent: CH2Cl2 / CH30H 95/5 adding up to 98/2), yielding 1.3 g (29.4%) of cis-3-methoxy-1 (phenyl). lrnet.il) -4-piperidinol (intermediate 2). b) A mixture of 11.5 g of the intermediate (2) and 150 rnl of methanol was hydrogenated at normal pressure and at room temperature with 2 g of palladium on carbon catalyst (.1.0%). After the calculated amount of hydrogen was absorbed, the catalyst was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (eluent: CHCl3 / CH3OH / NH3) 85/15). The pure fractions were collected and the eluent was evaporated, yielding 3.6 g (53%) of cis-3-methoxy-4-piperidinol as an oily residue. (intermediary 3). c) A solution of bisil, l'-d? met? let? l) d? carbonate (65.5 g) in CHCl3 (100 rnl) was added in the form of drops to a solution of intermediate (3) (34 g) in trichloroethane (350 rnl) and the reaction mixture was stirred for three hours at room temperature. The reaction mixture was washed with water and ammonia then with water. The separated organic layer was dried over ngSO *, filtered and the solvent was evaporated. The residue (79 g) was purified by column chromatography on silica gel (eluent: CH2Cl2 / CH3OH / NH3) 97/3, adding ~~ to 95/5). The pure fractions were collected and the solvent was evaporated, yielding 58 g of (±) -l, 1-d? Met? Let? L? S-4? H? Drox? -3-rnetox? -1-p? Per? D? carboxylate (96.4% crude residue) (intermediate 4). d) Sodium hydrate (4g) was added to a solution of the intermediate (4) (19.4 g) in tetrahydrofuran (400 ml). The mixture was stirred and refluxed for 3 hours (solution I). 1, 1'-carbonyl bis-lH ~? Rn? Dazole (13.6 g) was added to a suspension of 4-amino-5-chloro-2,3-d? -hydro-7-benzofurancarboxylic acid (18 g) in acetonitrile (400 ml) and this The mixture was stirred for 2 hours at room temperature. The solvent was evaporated. The residue was dissolved in tet rahydrofuran (400 ml), giving solution II. At room temperature, the solution (II) was poured into a solution (1) and the reaction mixture was stirred for 2 hours at room temperature. atmosphere. The solvent was evaporated. The residue was divided between CH2Cl2 and H2O. The organic layer was separated and the layer aqueous was extracted twice with CH2Cl2. The separated organic layer was dried over M O ^, filtered and the solvent was evaporated. The residue was purified by means of short column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 98/2). The desired fractions were collected and the solvent was evaporated, yielding 32 g (±) -c? SlC (1,1-d? Met? I-ethoxy) carbonyl] -3 -? Netox? -4 - ?? per? D ? nLl 4-arn? no-5 ~ chloro-? , 3-d? H? Dro-7-benzofurancarbox? Lato (87%) (intermediate 5). e) A mixture of intermediate (5) (32 g) in tetrahydrofuran (500 ml) and hydrochloric acid (50 ml) was stirred and refluxed for 30 minutes. The reaction mixture was cooled and alkalized with NH 4 OH. The layers were separated. The aqueous layer was extracted with tetrahydrofuran. The separated organic layer was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / (CH30H / NH3) 93/7). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from acetom tp lo. The precipitate was filtered and dried (vacuum 80 ° C), yielding 6.4 g of (±) -c? E-3-rnetox? ~ 4-p? pep dinil 4-am? no-5-chloro-2, 3-d? hi-dro-7-benzofurancarboxylate (26%) (intermediate 6).

EXAMPLE 2 a) A mixture of 4-amino-5-chloro-2, 3-d? h acid? dro-7-benzofurancarboxylic (4.3 g) in thiomyl chloride (100 ml) and CHC13 (200 ml) was stirred and refluxed for 2 hours. The mixture was cooled and the solvent was evaporated. Once more toluene was added and evaporated, yielding 4.8 g of 4-amino-5-chloro-2,3-d? H? dro-7 -benzofurancarbomlo (100% crude waste) 5 (i termediario 7). b) A solution of l, l-d? met? let l-4-h? drox? -1 - pipepdincarboxy lato (4.02 g) and N, N-d? Met? L-4-?? pepd? Nam? Na (3.7 g) in dichloromethane (200 nl) was stirred at room temperature. A solution of the intermediate (7) (4.8 g) in CH2Cl2 * 3 (200 rnl) was poured into the solution, the reaction mixture was stirred for 3 hours at room temperature, the mixture was washed with water, a 5% NaOH solution and once with water. The residue was separated, dried over MgSO 4, filtered and the solvent was evaporated.

Purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 4.7 g of 1, 1-d? Rnet? Let? 4 ~ [C (4-arn? No ~ 5-chloro- 2, 3-d? -7 - benzo f uram 1) ca rbom llox 1] - 1 - pi pe pd 1 nc rbox 1 lato (59%) (intermediary 8). c) A mixture of intermediate (8) (7 g) in tetrahydrofuran (20 ml) and hydrochloric acid (20 ml) was stirred and refluxed for 2 hours. The reaction mixture was cooled and alkalized with Ni-OH. The organic layer was removed by decanting and the solvent was evaporated. The residue was purified by means of column chromatography on gel R silica (eluent CH2Cl2 / (CH3? H / NH3) 92/8). The pure fractions were collected and the solvent was evaporated. The residue (5.5 g) was recovered by means of high performance liquid chromatography (column 200 g Kromasil; 10 j-im; 10 A; eluent: (0.5% NI-UOOAc in water) / methanol 70/30). The pure fractions were collected and extracted with NH3 / CH2CI2. The extract was evaporated. The residue was crystallized from acetomtplo. The precipitate was filtered and dried (vacuum, 70 ° C), yielding 2.60 g of 4-p? Per? D? N? 1 4-am? No-5 ~ chloro ~, 3-d? H? Dro-7-benzofurancarbox? Lato (54%) (i termediario 9).

EXAMPLE 3 a) A mixture of cyclopropyl (4 ~ amin-3-m-trophin) rnetanone (80 g), prepared as described in US Pat. No. 3, 657, 267, and concentrated with CH1 (420) was stirred and refluxed for 30 minutes. The reaction mixture was cooled and water was added. The precipitate was filtered, washed with water and dried, yielding 80 g (84.5%) of l- (-aromethyl-3-nitropheni-1) -4-chloro-1-butanone; pf. 150 ° C (intermediate 10). b) A mixture of intermediate (9) (14.8 g), intermediate (10) (12.13 g) and N, Nd? et? letanarn? na (8.3 nl) in N, Nd? met? lformam? da (150 ml) was stirred for 20 hours at ± 70 ° C. The solvent was evaporated. The residue was diluted with water and this mixture was extracted twice with CH2Cl2. The separated organic layer was washed with water, dried over HgSO «, filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 90/10). The desired fractions were collected and the solvent was evaporated. The residue (10 g) was crystallized from ether diisopropyl. The precipitate was filtered and dried, yielding 8.3 g (33%) of 1-C4- (4-arnino-3-nitrophenyl) -4-oxobutyl] -4-piperid.i.nil 4-amino-5-chloro -2, 3- dihydro-7-benzofurancarboxylate (intermediate 11). c) A mixture of. intermediary (11) (8.2 g) in * "'<) tetrahydrofuran (150 ml) was hydrogenated with platinum on activated carbon (5%) (2 g) as a catalyst.After H2 absorption (3 equivalents), the catalyst was filtered on dicalite and the filtrate was The residue was diluted with water and this mixture was extracted twice with CH2CI - The separated organic layer was washed with water, dried over M SO4, filtered and the solvent was evaporated. The residue (8 g) was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 3) 92/8). The pure fractions were collected and the solvent was evaporated. The residue (7.5 g) was crystallized from CH3CN The precipitate was filtered and dried, yielding 5.43 g (70.5%) of l-C4- (3,4-diaminophenyl) -4-oxobutyl] -4-piperidinyl 4-amino-5-chloro-2,3-dihydro-7. -benzofurancarboxylate; pf. 173.4 ° C (intermediate 12).

B. PREPARATION OF FINAL COMPOUNDS A mixture of intermediate (6) (2.3 g), 4-chloro-l- (, 4, 5 ~ tprnetox? Phen? L) - 1-butanone (2 g), sodium carbonate 5 (2.1 g) and iodide of potassium (catalytic amount) in 4-rnet? l-2-pentanone (150 ml, previously dried over Mg? 4) was stirred and refluxed overnight. The reaction mixture was cooled, washed with water, dried over MgSO4 *, filtered and the filtrate was evaporated. The residue was purified by means of Column chromatography on silica gel (eluent: OH2Cl2, adding up to CH2Cl2 / CH3OH / NH3) 97/3) The pure fractions were collected and the solvent was evaporated, the residue was dissolved in methanol and converted to the ethanedioic acid salt with ethanedioic acid (0.6 g) The mixture was boiled, then cooled and the precipitate was filtered and recrystallized from 2-propanol. The precipitate was dissolved in Nf-U OH / CH2 C I2 - The organic layer was separated, dried over n Cj, filtered and the solvent was evaporated. The residue was stirred in boiling, cooled ether dioxopropyl and the precipitate The resulting mixture was filtered and dried (vacuum, 80 ° C), yielding 1.10 g of (±) -c? S-3-methox? -l-C4-oxo-4- (3,4,5-trinethoxyphenyl) ) but? l] ~ 4-pipen dini1 4- a? no-5-chloro-2, 3-d? h? dro? 7-beni'o-furancarbonxi Jato (28%); pf. 132 ° C (compound 1). In a similar way they were also prepared: 25 1-1.4-oxo-4- (3,4,5-tr? Rneto? Phen? L) but? L- | -4-pi pep-dini l 4-am? No -5-chloro-2, 3-d? H? Dro -7-benzo furancarbox? Lato etanedioate (1: 1); pf. 177.8 ° C (compound 2); l- [4- (4-ethylphenyl) -4-oxo-butyl] -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate; pf. 1.21.3 ° C (compound 3); 1- C4- (3, 5-dichlorophenyl) -4-oxobutii3-4-piperidinyl 4-amino-5-chloro-2,3-dihydro-benzofurancarboxylate; pf. 122.6 ° C (compound); l-C4- (3,4-di-ethoxyphenyl) -4-oxobutyl] -4-? iperi-yl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate; pf. 156.3 ° C (compound 5); l-C4- (4-methoxyphenyl) -4-oxobutyl-I-4-? iperidinyl 4-arnino-5-chloro-2,3-dihydro-7-benzofurancarbo-xylate; pf. I * 136.4 ° C (compound 6); 1-C4- (4-ethoxy-rr 3, 5-dimethyl phenyl?) -4 - oxobutyl] -4-piperidinyl 4-amino-5-chloro-2, 3 -di hi ro- 7- benzofurancarboxylate (E) - 2-butanedioate (1: 1); pf. 171.2 ° C (compound 7).

EXAMPLE 5 4- (4-hydroxy-piperidinyl) -l- (3,4,5-tri ethoxy phenyl) -1-butanone (3.3 g) was added to a solution of sodium hydrate (0.4 g) in tetrahydrofuran (.1.00 rnl) (solution I) under a flow of N2. A mixture of 5 -arnino-6-chloro-3, 4- dihydro-2H-l-benzopyran-8-carboxylic acid (2.14 g) and 1,1'-carbonylbis-lH-i idazol (2 g) in acetonitrile ( 100 rnl) was stirred for 2 hours at room temperature and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (100 rnl) (solution II). At room temperature, the solution (II) was poured into the solution (I) and the reaction mixture was stirred for 4 hours at room temperature. The solvent was evaporated. The residue was diluted with water and extracted twice with CH2Cl2. The separated organic layer was washed with water, dried over MgSO ^, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / hexane / (CH3OH / NH3) 50/42/3). 1.-1- 4-0x0-4- (3,4, 5-trimethoxyphenyl) butii] -4-piperidinyl 4-arnino-5-chloro-2,3-dihydro-2-, dimethyl-1-7-benzofurancarboxylate; rnp. 154.2 ° C (compound 9) .: .1. ~ l_4-oxo - 4 ~ (3,4,5-trimethoxyphenyl) util] -4-piperidinyl 4-amino-5-chloro-2-rnetoxybenzoate rnonohydrate; p.f. 90 ° C (compound 10); l- [4-Oxo-4- (3,4,5-trimethoxyphenyl) butyl-] - 4-pip-ridinyl-4-amino-5-chloro-2-methyl-7-benzofurancarboxylate; f. , 128.6 ° C (compound 11).

EXAMPLE 6 A mixture of the intermediate (12) (2.4 g) and hydrochloric acid (few drops) in water (50 ml) was stirred at room temperature. A solution of potassium isocyanate (2.5 g) in water (50 ml) was added and the resulting reaction mixture was stirred and refluxed for 2 hours. The reaction mixture was cooled, alkalized with NH 4 OH, and then extracted twice with CH 2 Cl 2. The separated organic layer was dried over r1gSO < 4, filtered, and the solvent was evaporated. The residue (2.5 g) was mixed with 1,1 '-carbonylbis-lH-i idazole (0.93 g) in tetrahydrofuran (80 ml). The reaction mixture was stirred and refluxed for 2 hours. The solvent was evaporated. The residue was diluted with water and this mixture was extracted twice with CH2Cl2. The separated organic layer was washed with water, dried over MgSO, filtered and the solvent evaporated. The residue was crystallized from 2-propanol / methanol. The precipitate was filtered and dried, yielding 0.53 g of l- [4- (2,3-dihydro-2-oxo-IH-benzirnidazol-5-yl) -4-oxobutyl] -4-? Iperidinyl 4-amino-5 ~ chloro-2,3-dihydro-7-benzofurancarboxylate (21.2%), mp 272. ° C '1 (compound 12).

EXAMPLE 7 A mixture of intermediate (12) (1.8 g) methyl (a- 5 irnino-to-metoxirnetii) carbarnato (0.5 g) and acetic acid (0.75 mi) in CHCl3 (100 rnl) was stirred and refluxed for 2 days. The reaction mixture was alkalized with NH 4 OH. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, dried 0 over NgSO, filtered and the solvent was evaporated. The residue was crystallized twice from methanol. The precipitate was filtered and dried, yielding 0.4 g of 1-C4-C2-C (methoxycarbonyl) amino] -lH-benzimidazol-5-ylC-4-oxobutii] -4-piperidinyl 4-arnino-5-chloro rnonohydrate. -2,3-dihydro-7- 5 benzofurancarboxylate [18.7%]; p.f. 201.6 ° C (compound .1.3).

C. PHARMACOLOGICAL EXAMPLE EXAMPLE 8: COAXIAL STIMULATION OF INDIAN CONEJILLO The Dunkin Hartley guinea pigs of both 5 sexes (body weight + _ 500 g) were killed by decapitation. The ileum was removed and cleaned with heated and oxygenated Krebs Henselei solution. The intact, non-terminal ileum segments, 4.5 cm long, of the guinea pig were vertically suspended with a preload of g • l in 100 ml in Krebs-Henseleit solution (37.5 ° C), gassed with a mixture of 95% O and 5% CO2 - Transrnural excitation was applied over the total length of the ileum segment by means of two Platinum electrodes, the anode threaded through the lumen of the ileum, the cathode in the bath solution. The preparation was excited with individual rectangular stimulus Cl msg; 0.1 Hz, submaxirm response (current driving 80% of the maximum response)] from a programmable stimulator. The contractions were measured isometrometrically. During the 30 minute stabilization period, the strips were repeatedly drawn at a tension of 2 g, to obtain a steady-state voltage of lg. Before starting electrical stimulation, a cumulative dose response curve of acetyloline was given. The electrical stimulation started at the supra-anxarian current to determine the amplitude maximum of the contraction responses. When these responses were stable, a submaxin stimulation for obtain 80% of the maximum responses was given until the contraction responses were constant for at least 15 minutes, then an individual dose of the test compound was added to the bath fluid. The amplitude of the contraction response 5 minutes after the administration of the test compound is compared to the amplitude before administration of the test compound. Compounds 1,2,7 and 13 showed an increase in contraction response amplitude of more than 5% at a concentration of 3.10-9M.

EXAMPLE 9 MOBILITY OF THE COLON IN THE CONSCIOUS DOG The female hound dogs, weighing 7-17 kg, were implanted with isometric force transducers, under general anesthesia and aseptic conditions. To study colonic mobility, the transducers were sutured in the colon at 8, 1.6, 24 and 32 cm away from the ileocecal valve. The dogs were left during a recovery period of at least 2 weeks. The experiments began after a period of fasting of + _ 20 hours, during which water was available ad libitum. During the experiments, the dogs were free to move in their cages, using a telemetric system (without wires). The cages were built in a special room, equipped with glass so that the light entered in one direction, that is, the observer could see two dogs while the dogs were not They could see the observer. Through this system it was possible to observe the dogs for behavioral changes and to determine defecation events. The information from the transducers was transmitted in digital form by a specially constructed small transmitter box. This box was placed in a llaqueta worm by the dog. The signals were received by means of a microphone on each box and were transmitted to a central computer system. One of the parameters in this test is the defecation of dogs. During the first three hours after administration of the test compound, the dogs were observed to determine when the defecation occurred. Compounds 1,2,5,6,12 and 13 gave defecation in at least 50% of the test animals at doses of 0.31 rng / l-g for 5 said first three hours.

D. EXAMPLES OF COMPOSITION The following formulations exemplify the typical pharmaceutical compositions in the form of dosage units suitable for the systernical or topical administration to warm-blooded animals according to the present invention. "active ingredient" (A.T). as used throughout these examples, it refers to a compound of the formula (I), an N-oxide form, a pharmaceutically acceptable addition salt or a stereochemically Isomeric of the same.

EXAMPLE 10; ORAL SOLUTIONS 9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate were dissolved in 4 1 of boiling purified water. In 3 1 of this solution were first dissolved 10 g of 2,3-dihydroxybutanedioic acid and then 20 g of the AI The last solution is combined with the remaining part of the first solution and 12 1 of 1, 2, 3-propanetriol and 3L of sorbitol 70% of the solution were added to it. 40 g of sodium saccharin were dissolved in 0.5 1 of gua and 2 ml of raspberry and 2 rnl of gooseberry essence are added. The last solution is combined with the first one, water is added q.s. at a volume of 2.0 1 by providing an oral solution comprising 5 m of A. I. per tablespoon (5 ml). The resulting solution is filled into suitable containers.

EXAMPLE 11. CAPSULES g of A. I., 6 g of sodium lauryl sulfate, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide, and 1.2 g of magnesium stearate were vigorously stirred together. The resulting mixture is subsequently filled into suitable hardened gelatin capsules, each comprising 20 mg of A. I.

EXAMPLE 12: COATED TABLETS OF FILM PREPARATION OF THE TABLET NUCLEUS A mixture of 100 g of A. I., 570 g of lactose and 200 g of starch is mixed well and then combined with a solution of 5 g of sodium dodecyl sulfate and 10 g of polyvinyl pyrrolidone in approximately 200 ml of water. The wet powder mix is screened, dried and sieved once more. After adding 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil. The whole mixture is mixed well and compressed into tablets, giving 10. 00 tablets, each comprising 10 ng of the active ingredient.

COATING To a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol was added a solution of 5 g of ethyl cellulose in 15 ml of dichloromethane. Then 75 rnl of dichloromethane and 2.5 rnl of 1, 2, -propanetriol were added. 10 g of polyethylene glycol were melted and dissolved in 75 ml of dichloromethane. The latter solution is added to the former and then 2.5 g of magnesium octadecanoate, 5 g of polyvinyl pyrrolidone and 30 ml of concentrated color suspension are added and the total mixture is homogenized. The cores of the tablet are coated with the mixture in this manner obtained in a coating apparatus.

EXAMPLE 13: INJECTABLE SOLUTION 1. 8 g of methyl 4-hydroxybenzoate and 0.2 g of propyl 4-hydroxybenzoate were dissolved in approximately 0.5 1 of boiling water for injection. After cooling to about 50 ° C, 4 g of lactic acid, 0.05 g of propylene glycol and 4 g of A were added during stirring. The solution was cooled to room temperature and supplemented with water for injection q.s. ad 1 1 volume, giving a solution ^) 4 mg / ml of A. I. The solution was sterilized by filtration (U.S.P. XVII page 811) and filled in sterile containers.

EXAMPLE 14: SUPPOSITORIES 3 g of A. I. was dissolved in a solution of 3 g of acid, 3-dihydroxybutanedione in 25 ml of polyethylene glycol 400. 12 G of surfactant in triglycerides q.s. ad 300 g were melted together. The last mixture was mixed well with the last solution. The mixture thus obtained was poured into molds at a temperature of 37-38 ° C to form 1.00 suppositories, each containing 30 mg of the active ingredient.

Claims (11)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula (I) a N-oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein: R1 is halo or Ci-β alkylsulfonyl-amino; R 2 is hydrogen and R 3 is C 6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; or R2 and R3 taken together form a bivalent radical of the formula: -CH = CH- (a), ~ (CH2) 2- (b), or - (CH2) 3- (O; in the bivalent radicals of the formula (a), (b) or (c), one or two hydrogen atoms can be replaced by Ci-s alkyl, Alk is Ci-β alkynediyl, R * is hydrogen or Ci-e alkyloxy, RS, Rβ and R7 each independently is hydrogen, halo, Ci-β alkyl, Ci-β alkyloxy, or R5 and R- taken together can also form a bivalent radical of the formula: O II -NR8-C-NR9- (d). -O- (CH2) m -O- (0; i '- * Rβ R9 each independently is hydrogen or alkyl Ci-ß; R10 is hydrogen, Ci-s alkylcarbonyl, Ci-β alkyloxycarbonyl; rn is 1 or

2. 2. A compound according to claim 1, further characterized in that R1 is chloro. 15 3.- A compound in accordance with the claim 1, further characterized in that R2 and R3 taken together form a bivalent radical of the formula (b). 4. A compound according to claim 1, further characterized in that Alk is 1,3-propanediyl. 5. A compound in accordance with the claim 1, further characterized in that the compound is cis-3-methoxy-l- [4 -oxo- 4 - (3, 4, 5 - 1 rimeto i feni 1) bu i 1] - 4 - pi pe ri dinil 4 -ami non-5-chloro-2,3-dihydro-7-benzofurancarboxylate; l- [4-oxo-4- (3,4,5-t rirnetox i feni 1) but. i. i] - 4-pi peri-dinyl-4-arni non-5-cyclo-2, 3-dihydro-7-benzofurancarboxylate; l - [4- (2, 3-dihydro-2-oxo-lH-benznunidazol-5-yl) -4-oxobutyl] -4-piperidinyl 4-amino-5-chloro- 2, -dihydro-7-benzofurancarboxylate; 1-C4- (4-methoxy-3, 5-dirnet.-phenyl) -4- oxobutyl-4-piperidinyl 4-arnino-5-chloro-2,3-dihydro-7-benzofurancarboxylate; a stereoisomeric form thereof or a pharmaceutically acceptable acid addition salt thereof. 6. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. 7. A process for preparing a pharmaceutical composition according to claim 6, further characterized in that the compound according to claim 1 is intimately mixed with a pharmaceutically acceptable carrier. 8. A compound in accordance with the claim 1, further characterized because it is used as a medicine. 9. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of intestinal disturbances involving decreased mobility of the colon. 10.- An intermediary of the formula a N-oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein R a R *, R7 and Alk are as defined in claim 1. 11. A process for preparing a compound according to claim 1, further characterized in that a) a piperidine of the formula (II) is N-alkylated with an intermediate of the formula (III), N-alkylation L-LJi HD (I) (III) ( II) where H is an appropriate leaving group, L is a radical of the formula wherein Alk and R5 to R7 are as defined in claim 1, and D is a radical of the formula wherein R1 to R * are as defined in claim 1; b) an alcohol of the formula (IV) is reacted with a carboxylic acid of the formula (V) or a functional derivative of the ism, such as an acyl halide, a symmetrical or mixed anhydrous or an ester; (IV) (V) '3 c) an intermediate of the formula (VI) is reacted with 1,1' -carbonylbis-1H-imidazole or a functional derivative thereof, thus preparing a compound of the formula ( Id); 0 d) an intermediate of the formula (Vi-a) is reacted with an intermediate of the formula (VII), thus preparing a compound of the formula (I-e); and optionally converting the compounds of the formula (I) into each other by a functional group transformation reaction; and, if desired, converting a compound of the formula (I) to a pharmaceutically acceptable acid addition salt, or conversely, converting an acid addition salt to a free base form with alkali; and / or preparing stereochemically isomeric forms thereof.