MXPA97006622A - Oxadiazoles procineti - Google Patents

Abstract

The present invention relates to a compound having the formula (I) an N-oxide form, a pharmaceutically acceptable addition form or a stereochemically isomeric form, wherein: R 1 is hydrogen or halogen, R 2 is C 1-6 alkyl , C2-6 alkenyl or C2-6 alkynyl, R3 is hydrogen, or R2 and R3 taken together can form a C2-3 alkanediyl radical wherein one or more hydrogen atoms can be replaced by C1-4 alkyl; hydrogen, hydroxy or C1-6alkyloxy; X is a bivalent radical of the formula (a-1) (a-2), L is a radical of the formula: -Alk-R5 (b), -Alk-O- R6 (c), Alk is C1-12 alkanediyl, R5 is hydrogen, cyano, C1-6 alkylcarbonyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, aryl, arylcarbonyl, tetrahydrofuran, dioxolane, alkyl substituted dioxolane, C1-6, dioxane, dioxane substituted with C1-6 alkyl, R6 is hydrogen, aryl, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkylcarbonyl, aryl is defined as phenyl or phenyl substituted with up to three substituents selected from halogen, C 1-6 alkyl or C1 alkyloxy

Description

PROCINETIC OXIDES DESCRIPTIVE MEMORY The present invention relates to novel prokinetic oxadiazole derivatives. In addition, it relates to pharmaceutical compositions comprising the same, to processes for preparing said compounds and compositions, and to the use thereof as a medicament, in particular under conditions involving decreased mobility of the colon. EP-0,076,530, EP-0,389,037 and EP-0,445,862 describe N- (4-piperidinyl) benzamide derivatives having gastrointestinal motility stimulating properties. UO-94/12494 describes the use of dimethylbenzofurans and di-ethylbenzopyrans as 5-HT3 antagonists. UO 93/02677 describes oxadiazoles as 5-HT4 receptor antagonists. UO 94/08994 discloses a number of bicyclic ester derivatives benzoic l-butyl-4-piperidinylmethyl substituted as 5-HT * receptor antagonists. UO 94/08995 discloses other bicyclic ester derivatives benzoic l-butyl-4-piperidinylmethyl substituted as 5-HT4 receptor antagonists. The compounds of the present invention differ from the prior art compounds by the presence of an oxadiazole moiety that is directly linked to the piperidinyl ring. The present compounds unexpectedly show favorable intestinal mobility stimulating properties. More particularly, they show effects that improve mobility in the colon. This invention relates to the compounds of the formula The N-oxide forms, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein: R 1 is hydrogen or halogen R 2 is C 1 6 alkyl, C 2-6 alkenyl, or C 2 alkynyl -6; R3 is hydrogen; or R2 and R3 together can form a C2-C3 alkanediyl radical wherein one or two hydrogen atoms can be replaced by C1-4 alkyl; R * is hydrogen, hydroxy or Ci-βXalkyloxy is a bivalent radical of the formula (a-1) (^ L is a radical of the formula: -Alk-RS ib), -Alk-O-R * (c), Alk is C1-12 alkanediyl; RS is hydrogen, cyano, Ci-g alkylcarbonyl, Ci-6 alkylsulfinyl, Ci -6 alkylsulfonyl, aryl, arylcarbonyl, tetrahydrofuran, dioxolane, dioxolane substituted with Ci-β alkyl, dioxane, cycloalkyl substituted dioxane, H.H; R6 is hydrogen, aryl, Ci-alkyl & , hydroxyalkyl of Ci - & , Ci-β alkylcarbonyl; Aryl is defined as phenyl or substituted phenyl with up to three substituents selected from halogen, Ci-alkyl & or Ci-βalkyloxy. As used in the above definitions halogen is generic to fluorine, chlorine, bromine and iodine; C? - "alkyl defines straight and branched saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, and the like; Ci-β alkyl defines C 1-4 alkyl and higher homologs having 5 or 6 carbon atoms such as, for example, pentyl, hexyl and the like; C2-6 alkylene defines straight or branched hydrocarbon radicals having a double bond and having from 2 to 5 carbon atoms such as, for example, ethenyl, 2-pentene, 3-butenyl, 2-butenyl, 2-pentenyl, 3-methyl-2-butenyl and the like; C2-6 alkynyl defines straight or branched hydrocarbon radicals having a triple bond and having from 2 to 6 carbon atoms such as, for example ethynyl, 2-propynyl, 3-butynyl, 2-butynyl, 2-pentynyl, 3-methyl-2-butynyl and the like; C2-3 alkanediyl defines straight or branched bivalent hydrocarbon radicals containing from 2 to 3 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl and the like; C1-12 alkanediyl defines C2-3 alkanediyl, the lower homologue, ie 1,1-methanediyl, and the higher homologs having 4 12 carbon atoms such as, for example, 1,4-butanediyl, , 5-pentanediyl, 1,6-hexanediyl, 1,7-heptanediyl, 1,8-octanediyl 1,9-nonanediyl, 1,10-decanediyl, 1,11-undecanediyl, 1,12-dodecanediyl and the branched isomers thereof. The pharmaceutically acceptable acid 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 be conveniently obtained by treating the base form with said appropriate acid. Suitable acids comprise, for example, inorganic acids such as hydraulic acids, for example, hydrochloric or hydrobromic acid; sulfuric, nitric, phosphoric and the like; or organic acids such as, for example, acetic, propanic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulonic, benzenesulonic, p-toluenosulonic, cyclic acid ico, salicylic, p-aminosalicylic, parnico and the like. The term "addition salt" as used also comprises the solvates that the compounds of the formula (I) as well as the salts thereof, are capable of forming. Such solvates, for example, are hydrates, alcoholates and the like. Conversely, the salt form can be converted by the alkali treatment into the free base form. 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 diastereors and enantiomers of the basic molecular structure. More particularly, stereogenic centers may have the R or S configuration; the substituents on the saturated, cyclic, bivalent radicals may have the cis or trans configuration. The stereochemically isomeric forms of the compounds of the formula (I) obviously must be found within the scope of this invention.

The N-oxide forms of the compounds of the formula (I) must comprise those compounds of the formula (I) wherein one or more nitrogen atoms are oxidized in the so-called N-oxide, particularly those N-oxides wherein the Piperidine nitrogen is N-oxidized. When used further, the term "compounds of the formula (I)" should also include the N-oxide forms, the pharmaceutically acceptable acid addition salts and all stereochemically isomeric forms thereof. Interesting compounds are those compounds of the formula (I) wherein R * is hydrogen. Another group of interesting compounds includes those compounds of the formula (I) wherein R is halogen, preferably chlorine. Also interesting compounds are those compounds of the formula (I) wherein L is a radical of the formula (b) wherein RS is preferably cyano or tetrahydrofuran; or L is a radical of the formula (c) wherein ß is preferably Ci-β alkyl, Ci-e hydroxyalkyl, or phenyl substituted with a halogen. Particular compounds are those in which R2 and R3 together form a C2-3 alkanediyl radical, preferably an ethanediyl radical, wherein one or two hydrogen atoms can be replaced by C1-4 alkyl. Also the particular compounds are those compounds wherein R2 is Ci-β alkyl, suitably methyl, and 3 is hydrogen. The preferred compounds are those compounds of the formula (I) wherein R 1 is chloro; R2 is methyl; R3 and R4 are hydrogen; L is a radical of formula (b) wherein RS is tetrahydrofuran, or a radical of formula (c) wherein R is 4-fluoro enyl. Also preferred compounds are those compounds of formula (I) wherein R 1 is chloro; R2 and R3 together form a radical of disubstituted ethanediyl geminate with methyl; R * is hydrogen; and L is a radical of formula (b) wherein RS is cyano. Other preferred compounds are those compounds of the formula (I) wherein R 1 is chloro; R2 and R3 together form an ethanediyl radical; R * is hydrogen; and L is a radical of the formula (c) wherein Rβ is methyl. The most preferred compounds are: 2-chloro-5-methoxy-4-C3-Cl-C (tetrahydro-2-furanyl) methyl] -4-piperidinyl] -l, 2,4-oxadiazol-5-yl-3-benzenedin; 5-chloro-2,3-dihydro-7-C3-Cl- (3-methoxypropyl) -4-piperidinyl] -l, 2,4-oxadiazol-5-yl3-4-benzofuranamine; 5-chloro-2,3-dihydro-7-C5-Cl- (3-methoxypropyl) -4-? Iperidinyl-1,2, -oxadiazol-3-yl-f-4-benzofuranamine; the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof. In order to simplify the structural representations of the compounds of the formula (I) and certain starting materials and intermediates thereof, the radical it will be represented later by the symbol D. In the following preparations, the reaction products can be isolated from the reaction mixture and, if necessary, further purified in accordance with the methodologies generally known in the art such as, for example, , extraction, distillation, crystallization, trituration and chromatography. The compounds of the formula (I) can be prepared by N-alkylating a piperidine of the formula (II), wherein D is as defined above, with an intermediate of the formula (III), wherein U1 is an appropriate leaving group such as, for example, halogen, for example, chlorine, bromine or iodine, or a sulfonyloxy group, for example, methanesulfonyloxy, 4-methylbenzenesulfonyloxy and the similar leaving groups. The N-alkylation reaction of (II) and (III) is conveniently carried out following the alkylation procedures known in the art.

N-alkylation L-Ui + H-D (I) (III) (II) The compounds of the formula (I) can also be prepared by converting the compounds of the formula (I) one into the other. The compounds of the formula (I) can also be converted to the corresponding N-oxide forms following the procedures known in the art for converting a trivalent nitrogen into its N-oxide form. Said reaction of N-oxidation can be carried out generally by reacting the starting material of the formula (I) with an appropriate organic or inorganic peroxide. Suitable inorganic peroxides comprise, for example, hydrogen peroxide, or alkali metal or alkaline earth metal peroxides, for example, sodium peroxide, potassium peroxide; Suitable organic peroxides may comprise peroxyacids such as, for example, benzenecarboperoxyacid or halobenzenecarboperoxyacid substituted by, for example, 3-chlorobenzenecarboxyperoxyacid, peroxoalkane acids, for example peroxoacetic acid, alkylperoxides, for example, t. Butil hydroped gone. Suitable solvents are, for example, water, lower alkanols, for example, ethane 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), wherein X is a radical of the formula (a-1), said intermediates being represented HD * (II-a-1), can be derived from an appropriately substituted piperidine of the formula (IV ) with an intermediate carboxylic ester of the formula (V), wherein R? is Ci-β alkyl, following the cyclization procedures known in the art, and subsequently removing the protecting group P, following the procedures known in the art. P represents a removable protective group such as Ci-C "alkylcarbonyl, Ci-C-alkyloxycarbonyl; , phenylaryl, and the similar N-protecting groups known in the art.

P (V) The intermediates of the formula (II), wherein X is a radical of the formula (a-2), said intermediates being represented by H-D2 (II-a-2), can be derived from an appropriately substituted piperidine of the formula (VI), wherein R7 is C? -6 alkyl, with an intermediate of the formula (VID, following the cyclization procedures known in the art, and subsequently removing the protective group P, as defined above, following the procedures known in the art.

The intermediates of the formula (IV) can be prepared by reacting an intermediate of the formula (VIII) with hydroxylamine in a solvent inert to the reaction in the presence of a strong base, for example, sodium methoxide.

(V? D v The compounds of the formula (I) can also be prepared by the formation of oxadiazole in an analogous manner as described for the intermediates (II-a-1) and (II-a-2). The intermediate carboxylic esters of the formula (V) can be prepared from the corresponding carboxylic acids following ester formation methods known in the art. Said corresponding carboxylic acids are known from, for example, EP-0,075,530, EP-0,389,037 and EP-0, 445, 86. The intermediates of the formula (VID) can be prepared by dehydrating an intermediate of the formula (VIII) using an appropriate dehydrating agent such as, for example, phosphorus pentoxide, phosphorus oxychloride or thionylchloride, and subsequently reacting the nitrile thus formed with hydroxylamine in a solvent inert to the reaction and in the presence of a strong base such as, for example, sodium methoxide.

(Vffl) (vn) The racemates of the compounds of the formula (I), or any of the other intermediates, can also be resolved into their optical isomers, by applying the methodologies known in the art. The diastereoisomers can be separated by physical separation methods such as selective crystallization and chromatography techniques, eg, counting current distribution, and the enantiomers can be separated from one another by the selective crystallization of their diastereoprene salts with enantiomerically pure acids or their derivatives enantiomerically pure. The compounds of the formula (I), the N-oxide forms, the pharmaceutically acceptable salts and the stereoisomeric forms thereof possess favorable intestinal motility-stimulating properties. In particular, the present compounds show significant effects that improve mobility in the small and large intestine. The stimulatory effect of the present compounds of the formula (I) on the mobility of the intestinal system, in particular the effects that improve mobility in the colon, can be tested by the "Colon Motility in the Conscious Dog" test as described further ahead. In view of their useful properties that improve intestinal mobility, the present compounds can be formulated in different forms for the purposes of administration. As suitable pharmaceutical compositions, mention may be made of all of the compositions usually employed for the systemic administration of drugs. To prepare the pharmaceutical compositions of this invention, a therapeutically effective amount of the particular compound, optionally in the form of acid addition salt, as the active ingredient, is combined in intimate admixture with a pharmaceutically acceptable carrier, which can take a variety of forms depending on of the desired preparation form for administration. These pharmaceutical compositions are desirably in a unit dosage form suitable, preferably, for oral, rectal or parenteral injection. For example, in the preparation of 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 employed 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 in administration, tablets and capsules represent the most advantageous oral unit dosage 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. Injectable solutions, for example, can be prepared wherein the vehicle comprises saline solution, 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 hydroidifying agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a detrimental effect significant to the skin. Said additives may facilitate administration to the skin and / or may be useful for preparing the desired compositions. These compositions may be administered in various ways, for example, as a transdermal patch, as a spot, or as an ointment. The acid addition salts of the compounds of the formula (I) due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions. It is particularly advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form to facilitate administration and uniformity of dosage. The unit dosage form as used in the specification and claims herein refers to suitable discrete physical units as unit doses, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect, in association with the vehicle Pharmaceutical required Examples of such unit dosage forms are tablets (including labeled or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, cradles, spoons and the like, and segregated multiples thereof. In view of the ability of the compounds of the present invention to stimulate the mobility of the intestinal system and, in particular its ability to improve colon mobility, the present compounds are useful for normalizing or improving bowel emptying in subjects suffering from a distorted mobility, for example, decreased peristalsis of the small and / or large intestine. In view of the utility of the compounds of the formula (I), the present invention also provides a method for treating warm-blooded animals suffering from disturbances of intestinal system mobility such as, for example, pseudo-obstruction, and in particular impaired transit of the colon. Said method comprises the systemic administration of an effective amount that stimulates the intestine of a compound of the formula (I) to warm-blooded animals. In this way, the use of a compound of the formula (I) as a medicament is provided, and in particular the use of a compound of the formula (I) for the manufacture of a medicament for treating conditions involving decreased mobility of the colon.

Those skilled in the treatment of such mobility disturbances can determine the effective stimulant amount from the test results presented below. An effective amount would be from about 0.01 rg / kg to about 10 ng / kg in body weight, most preferred from about 0.1 mg / kg to about 5 mg / kg in body weight. A method of treatment may also include the administration of the active ingredient in a regimen of between two to four ingestions per day. The following examples should illustrate and not limit the scope of the present invention. Hereinafter, "DIPE" means diisopropyl ether and "RT" means room temperature.

EXPERIMENTAL PART A. Preparation of Intermediate Compounds EXAMPLE 1 Sulfuric acid (18 mL) was added dropwise to cooled methane (90 mL). 4-Amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (20 g) was added to the mixture which was subsequently stirred and refluxed for 3 hours. The reaction mixture was cooled and alkalized with CH3OH / NH3. The solvent was evaporated and the residue was stirred in water. The precipitate was filtered and washed with water and DIPE. The remaining solid was dried, yielding 17.2 g (81%) of methyl 4-arnino-5-chloro-2,3-dihydro-7-benzof? -carboxylate (intermediate 1: mp 135.4 ° C).

EXAMPLE 2 Ethane (150 ml) was added to a solution of hydroxylamine hydrochloride (17.25 g) in water (48 ml). Ethyl 4-cyano-l-piperidinecarboxylate (45 g) was added and the mixture was cooled. Sodium methoxide (44.4 g) was added dropwise at RT and the reaction mixture was stirred for 30 minutes at 60 ° C. The reaction mixture was cooled, filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 95/5). The pure fractions were collected and the solvent evaporated, yielding 25 g (40%) of ethyl 4-Way (hydroxyimino) methyl] -l-piperidinecarboxylate. This fraction was redissolved in 2-propanone and converted to the hydrochloric acid salt (1: 1) with HCl / 2-propane. The precipitate was filtered and dried, yielding 22 g (35%) of 4- [amino (hydroxyimino) methylJ-1-piperidino-ethyl carboxylate hydrochloride (intermediate 2).

EXAMPLE 3 a) A mixture of intermediate 2 (10.07 g), sodium ethoxide (5.42 g) and molecular sieves (45 g) in ethanol (150 ml) was stirred for 30 minutes at room temperature. Intermediate 1 (9.1 g) was added and the reaction mixture was stirred and refluxed for 10 hours. The reaction mixture was cooled, filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 95/5). The pure fractions were collected and the solvent evaporated, yielding 11.6 g (74%) of 4-C5- (4-amino-5-chloro-2,3-dihydro-7-benzofurani-1, 2,4-oxadiazole-3 ethyl-l-K-piperidinocarboxylate (intermediary 3, mp 162.4ßC). b) A mixture of intermediate 3 (10g) and potassium hydroxide (14g) in 2-propane (200ml) was stirred and refluxed for 6 hours. The reaction mixture was cooled and the solvent evaporated. Water was added to the residue and evaporated once more. The residue was stirred in water and the resulting precipitate was filtered, washed with water and purified by column chromatography on silica gel (eluent: CH2Cl2 / (CH3? H / H3) 90/10). The pure fractions were collected and the solvent evaporated, yielding 5.14 g (64%) of 5-chloro-2,3-dihydro-7-C3- (4-? Iperidinyl) -l, 2,4-oxadiazol-5-yl3 -4-benzofarrannine (intermediate 4, mp 219.0 ° C). In the same way as intermediate 4 was prepared from the intermediate l, 5-chloro-2,3-dihydro-2,2-dimethyl-7- [3- (4-? I? Eridinyl) -l, 2,4- oxadiazol-5-yl3-4-benzofuranamine (intermediate 5; mp 198.8 ° C) was prepared from ethyl 4-arnino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxylate; and 2-chloro-5-methoxy-4-C3- (4-ylperidinyl-1, 2,4-oxadiazol-5-yl) benzenamine (intermediate 6, mp 160.2 ° C) was prepared from 4- C 5 9-arni non-ethyl 5-chloro-2-methoxyphene 1-1, 2, 4-oxadiazol-3-yl] -l-piperidinecarboxylate.

EXAMPLE 4 a) Triethylamine (0.16 mol) was added to a solution of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (0.16 mol) in chloroform (600 ml) at a temperature below 10 ° C. Ethyl chloroformate (15.3 ml) was then added and the reaction mixture was stirred for 40 minutes, while cooling in an ice bath. The gaseous ammonia was allowed to bubble through the mixture and the reaction mixture was stirred for 3 hours at room temperature. The precipitate was filtered and washed consecutively with water; 5% NaOH solution, and water one more time, and dried, yielding 23.5 g (69%) of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxyamide (intermediate 7). b) Intermediate 7 (0.12 mol) was added to phosphorus oxychloride (120 ml) and the reaction mixture was stirred for 45 minutes at 100 ° C. The mixture was cooled and the solvent evaporated. The residue was added to ice and the mixture was extracted with CH2Cl2 and methane. The organic layer was dried over t S0", filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 99/1). The pure fractions were collected and the solvent evaporated, yielding 14.5 g (63%) of 4-a-ino-5-chloro-2,3-dihydro-benzofurane-neutritrile (intermediate 8). c) A solution of hydroxylamine hydrochloride (5.3 g) in methane (80 nl) was added to a solution of sodium (1.75 g) in methane (80 ml). The reaction mixture was stirred for 30 minutes at room temperature. The precipitate was filtered and washed with methanol (80 ml). Intermediate 8 (14.5 g) was added in the portion form to the filtrate. The reaction mixture was stirred and refluxed for 7 hours. The mixture was cooled and the solvent evaporated, the residue was dissolved in 2-ropanone and converted to the hydrochloric acid salt (1: 1) with HC1 / 2-propane. The mixture was first boiled, after which it was cooled to 0 ° C. The precipitate was filtered and dried, yielding 14 g (70%) of 4-amino-5-chloro-2,3-dihydro-N'-hydroxy-7-benzofurancarboxyimidamide monohydrochloride (intermediate 9). d) A mixture of intermediate 9 (13.5 g), sodium ethoxide (7.5 g) and molecular sieves 4 A (30 g) in ethanol (120 ml) was stirred for 30 minutes at room temperature. Ethyl 4-piperidinocarboxylate (5.2 g) was added and the reaction mixture was stirred and refluxed for 6 hours. The mixture is 00 the filtrate was cooled, filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / (CH3? H / NH3) 95/5). The pure fractions were collected and the solvent evaporated. A sample (1 g) was crystallized from CH 3 CN. The precipitate was filtered and dried, yielding 0.5 g (19.4%) of 5-chloro-2,3-dihydro-7-C5- (4-piperidinyl) -l, 2,4-oxadiazol-3-yl3-4-benzofuranamine. (intermediary 10). In the same way as intermediate 10 was prepared from 4-arnino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid, 5-chloro-2,3-dihydro-2,2-dirnethyl was prepared -7-C5- (4-piperidinyl) -l, 2,4-oxadiazol-3-yl3 ~ 4-benzofibran ina (intermediate 11, mp 230.8ßC) from 4-arnino-5-chloro-2 , 3-dihydro-2,2-dimethyl-7-benzofurancarboxylate. 2-Chloro-5-methoxy-4-C5- (4-piperidinyl) -1,4-oxadiazol-3-yl-3-benzenamine (intermediate 12, pf. 174. 2 ° C) from 4-arnino-5-chloro-2-methoxy-N'-hydroxy-7-benzenecarboxyimidamide monohydrochloride, described in UO 93/02677, following the same procedure 4 d).

B. Preparation of the compounds of the formula (I) EXAMPLE 5 A mixture of methyl (3-chloropropyl) ether (1.6 g), intermediate 4 (3.9 g), triethylamine (5 ml) and potassium iodide (a catalytic amount in dimethylformamide (60 rnl) for 48 hours at 60 ° C was stirred. The reaction mixture was cooled and the solvent evaporated.The residue was partitioned between CH2Cl2 and a saturated aqueous NaCl solution.The organic layer was separated, dried over hgSO4, filtered and the solvent was evaporated.The residue was purified by column over silica gel (eluent: CH 2 Cl 2 / CH 3 OH 90/10) The desired fractions were collected and the solvent was evaporated, the residue was solidified in DIPE, filtered, dissolved in 2-propane and converted to the hydrochloric acid salt ( 1: 1) with HC1 / 2-propane The precipitate was filtered and dried, yielding 1.14 g (22.1% 5-chloro-2,3-dihydro-7- [3- [l- (3-methoxypropyl) -4-piperidinyl-3, 2,4-oxadiazol-5-yl3 ~ 4 helohydrate hemihydrate. ~ benzofuranami a (compound 1; mp 244. ° C).

EXAMPLE 6 A mixture of intermediate 5 (4 g), 4-bromobutanonitrile (2.2 g) and triethylamine (4.2 ml) in dimethylformamide (70 ml) was stirred for 2 hours at 70 ° C. The mixture was cooled and the solvent evaporated. The residue was partitioned between CH2Cl2 and NH2 / H2O. The organic layer was separated, dried over MgSO 4, filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 95/5). The desired fractions were collected and the solvent evaporated. The residue was solidified in DIPE at 0 ° C, filtered and dried, yielding 1.89 g (38%) of 4-C5- (4-arnino-5-chloro-2,3-dihydro-2,2-dimethyl-7-). benzofuranyl) -1,2,4-oxadiazol-3-yl3-l-piperidinobutanonitrile (compound 3, mp 151.4 ° C).

EXAMPLE 7 A mixture of tetrahydrofurfuryl rnesylate (2.34 g), intermediate 12 (2.7 g) and sodium carbonate (2.8 g) in 4-methyl-pentanone (180 rnl) was stirred and refluxed for 24 hours. Additional tetrahydrofurfuryl mesylate (1 g) was added and the reaction mixture was stirred and refluxed for 24 hours. The reaction mixture was cooled, washed with water, dried over MgSO4, filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 95/5). The pure fractions were collected and the solvent evaporated. The residue was crystallized from CH3CN. The precipitate was filtered and dried, yielding 1.34 g (39%) of 2-chloro-5-methoxy-4-C5-Cl-C (tetrahydro-2-furanyl) methyl3-4-piperidini. -l, 2,4-oxadiazol-3-yl-3-benzenednine (compound 7, mp 148.5 ° C).

C. Pharmacological example EXAMPLE 8: MOBILITY OF THE COLON IN THE CONSCIOUS DOG Female hound dogs, weighing from 7 to 17 kg, were implanted with iso-electric force transducers under general anesthesia and aseptic precautions. To study the mobility of the colon, the transducers were sutured in the colon 8, 16, 24 and 32 cm away from the ileocecal valve. The dogs were left in a recovery period of at least two weeks. Experiments were initiated after a fasting period of ± 20 hours, during which water was available ad libitum. During the experiments, the dogs could move in their cages, thanks to the telemetric (wireless) system. The cages were built in a special room, provided with diaphanous glass in one direction, that is, the observer can see the dogs while the dogs can not see the observer. Through this system it was possible to observe the dogs for behavioral changes and to determine defecation cases. The information from the transducers was transmitted in digital form by a specially constructed small transmitter box. This box was placed in a jacket put on by the dog. The signals were received via a microphone on each cage and transmitted to a central computing 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 and 8 induced defecation in 60% or more of the test animals at a dose of 0.31 mg / kg during those first three hours.

D. Examples of Composition The following formulations exemplify typical pharmaceutical compositions in a unit dose form suitable for systemic or topical administration to warm-blooded animals in accordance with the present invention. "Active Ingredient" (A.I.) as used in these examples refers to a compound of the formula (I), a pharmaceutically acceptable acid addition salt, or an isomerically eetereochemically isomeric form thereof.

EXAMPLE 9: ORAL SOLUTIONS 9 g of methyl-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate were dissolved in 4 1 of boiling purified water. In 3 1 of this solution, 10 g of acid 2 were first dissolved., 3-dihydroxybutanedioic 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? -panpanotriol and 3 1 of sorbitol 70% of the solution are added to the isma . Dissolve 40 g of sodium saccharin in 0.5 1 of water and add 2 ml of raspberry and 2 ml of thorn grape essence. The last solution is combined with the first, water is added q.s. to a volume of 20 1 giving an oral solution comprising 5 rng of A. I. per teaspoon (5 ml). The resulting solution is filled into suitable containers.

EXAMPLE 10: CAPSULES g of A. I-, 6 g of sodium lauryl sulfate, 56 g of starch, 56 g of lactose, 0.8 g of colloid silicon dioxide, and 1.2 g of magnesium stearate are stirred vigorously together. The resulting mixture is subsequently filled into 1000 suitable hardened gelatin capsules, each comprising 20 mg of A. I ..

EXAMPLE 11: TABLETS COATED WITH FILM Preparation of the tablet core A mixture of 100 g of AI, 570 g of lactose and 200 g of starch is mixed well and then mixed with a solution of 5 g of sodium dodecylsulfate and 10 g of polyvinyl pyrrolidone in approximately 200 ml. of water. The wet powder mix is screened, dried and sieved once more. Then, 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil are added. Everything is mixed well and compressed into tablets, giving 100,000 tablets, each comprising 10 mg of the active ingredient. Coating To a solution of 10 g of rilethylcellulose in 75 ml of denatured ethane is added a solution of 5 g of ethylcellulose in 150 ml of dichloromethane. Then, 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol are added. 10 g of polyethylene glycol are melted and dissolved in 75 ml of dichloromethane. The last solution is added to the first one and then 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated color suspension are added and the whole is ovenified. The tablet cores are coated with the mixture thus obtained in a coating apparatus.

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound that has the formula a form of N-oxide, a pharmaceutically acceptable acid addition form or a stereochemically isomeric form, wherein: R1 is hydrogen or halogen; R2 is C6-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; R3 is hydrogen; or R2 and R3 together can form a C2-3 alkanediyl radical wherein one or more hydrogen atoms can be replaced by C1-4 alkyl; R * is hydrogen, hydroxy or Ci-βalkyloxy; X is a bivalent radical of the formula N-O O-N N ^ N (a-1) (a-2) L is a radical of the formula: -Alk-R 5 (b), -Alk-O-R * (c), Alk is C 1-12 alkanediyl; Re is hydrogen, cyano, C alqu-β alkylcarbonyl > C1-6 alkylsulfinyl, Ci-alkylsulfonyl- & , aryl, arylcarbonyl, tetrahydrofuran, dioxolane, dioxolane substituted with C 1-6 alkyl, dioxane, dioxane substituted with Ci-β alkyl; Rβ is hydrogen, aryl, Ci-alkyl & , Ci-β hydroxyalkyl, Ci-β alkylcarbonyl; Aryl is defined as phenyl or phenyl substituted with up to three substituents selected from halogen, Ci-β alkyl or Ci-e alkyloxy.

2. A compound according to claim 1, further characterized in that R * is chloro.

3. A compound according to claim 1, further characterized in that R * is hydrogen.

4. A compound in accordance with the claim 1, further characterized in that R1 is chloro; R2 is methyl; R3 and R * are hydrogen; and L is a radical of the formula (b) wherein R5 is tetrahydrofuran, or a radical of the formula Ce) wherein R is 4-fl-orophenyl.

5. A compound in accordance with the claim 1, further characterized in that R * is chloro; R2 and R3 together form an ethanediyl radical; R * is hydrogen; and L is a radical of the formula (c) wherein f is is methyl.

6. A compound according to claim 1, further characterized in that the compound is selected from 2-chloro-5-methoxy-4-C3-Cl-C (tetrahydro-2-f? RaniD ethyl 3-4-piperidinyl) -l, 2,4-oxadiazol-5-yl benzenamine; 5-chloro-2,3-dihydro-7-r3-C.l- (3-rintotoxipropyl) -4-piperidinyl-l, 2,4-oxadiazol-5-yl-4-benzofuranamine; 5-chloro-2,3-dihydro-7- [5-Cl- (3-methoxypropyl) -4-piperidinyl3,1,2,4-oxadiazol-3-yl-4-benzofuranamine; the N-oxide forms, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof.

7. A composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound as claimed in any of claims 1 to 6.

8. A process for preparing a composition in accordance with claim 1. 6, further characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as claimed in any one of the claims. 1 to 6.

9. A compound as claimed in any of claims 1 to 6 for use as a medicament. 10.- An intermediary of the formula a stereochemically isomeric form, or a pharmaceutically acceptable acid addition salt thereof wherein R *, R2, R3, R < and X are useful as defined in claim 1. 11. A process for preparing a compound according to claim 1, further characterized in that an intermediate of the formula (II) is alkylated with an intermediate of the formula (III) ), N-alkylation L-Ul + H-D (I) (III) (II) and optionally converts the compounds of the formula (I) one into the other by a functional group transformation reaction; and, if desired, converts a compound of the formula (I) to a pharmaceutically acceptable acid addition salt, or conversely, converts an acid addition salt to a free base form with alkali; and / or preparing stereochemically isomeric forms thereof. SUMMARY OF THE INVENTION The present invention relates to novel oxadiazole derivatives of the formula (I), the N-xido forms, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein R 1 is hydrogen or halogen; R2 is C6-6 alkyl / C2-6 alkenyl or C2-6 alkynyl; R3 is hydrogen; or R2 and R3 together can form a C2-3 alkanediyl radical wherein one or two hydrogen atoms can be replaced by Ci- alkyl; R * is hydrogen or Ci-βalkyloxy; X is a bivalent radical of the formula Ca-1), or (a-2), L is a radical of the formula -Alk-R5 or -Alk-0-R6, Alk is C1-12 alkanediyl; R 5 is hydrogen, cyano, Ci-β alkylcarbonyl, C 1-6 alkylsulfinyl Ci-β alkylsulfonyl, aryl, arylcarbonyl, tetrahydrofuran, dioxolane, dioxolane substituted with C 1-6 alkyl / dioxane, Ci-β alkyl substituted dioxane; R6 is hydrogen, aryl, Ci-s alkyl, C1-6 hydroxyalkyl, Ci-β alkylcarbonyl; aryl is defined as phenyl or phenyl substituted with up to three substituents selected from halogen, Ci-e alkyl or Ci-β alkyloxy; it further relates to pharmaceutical compositions comprising them, to processes for preparing said compounds and compositions, and to the use thereof as a medicament, in particular under conditions involving decreased mobility of the colon. BS / apro * 1prn * arnm * P97 / 709F