Novel N-substituted 4-((-4'-aminobenzoyl)-oxymethyl)-piperidines having gastric prokinetic properties

The use of a compound of formula (I)

• 57
• the N-oxide forms, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
• R1 is C1-6alkyloxy, C2-6alkenyloxy or C2-6alkynyloxy;
• R2 is hydrogen or C1-6alkyloxy,
• or when taken together R1 and R2 may form a bivalent radical of formula
• —O—CH2—O— (a-1),—O—CH2—CH2— (a-2),—O—CH2—CH2—O— (a-3),—O—CH2—CH2—CH2— (a-4),—O—CH2—CH2—CH2—O— (a-5),—O—CH2—CH2—CH2—CH2— (a-6),
• wherein in said bivalent radicals one or two hydrogen atoms may be substituted with C1-6alkyl;
• R3 is hydrogen or halo;
• L is C3-6cycloalkyl, C5-6cycloalkanone, C2-6alkenyl optionally substituted with Ar, or L is a radical of formula
• -Alk—R4 (b-1),-Alk—NR5R6 (b-2),
• 58 -Alk—X—R7 (b-4),-Alk—Y—C(═O)—R9 (b-5),or-Alk—Y—C(═O)—NR11R12 (b-6),
• wherein Alk is C1-12alkanediyl;
• R4 is hydrogen, C1-6alkylsulfonylamino, C3-6cycloalkyl, C5-6cycloalkanone, Ar-, di(Ar)methyl, Ar-oxy- or Het1;
• R5 is hydrogen or C1-6alkyl;
• R6 is Het2;
• R7 is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C3-6cycloalkyl, Ar or Het2;
• X is O, S, SO2 or NR8;
• said R8 being hydrogen, C1-6alkyl or Ar;
• R9 is hydrogen, C1-6alkyl, C3-6cycloalkyl, Ar, ArC1-6alkyl, di(Ar)methyl, C1-6alkyloxy or hydroxy;
• Y is NR10 or a direct bond;
• said R10 being hydrogen, C1-6alkyl or Ar;
• R11 and R12 each independently are hydrogen, C1-6alkyl, C3-6cycloalkyl, Ar or ArC1-6alkyl, or R11 and R12 combined with the nitrogen atom bearing R11 and R12 may form a pyrrolidinyl or piperidinyl ring both being optionally substituted with C1-6alkyl, amino or mono or di(C1-6alkyl)amino, or said R11 and R12 combined with the nitrogen bearing R11and R12 may form a piperazinyl or 4-morpholinyl radical both being optionally substituted with C1-6alkyl;
• each Ar being unsubstituted phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, amino-sulfonyl, C1-6alkylcarbonyl, nitro, trifluoromethyl, amino or aminocarbonyl;
• and
• Het1 and Het2 each independently are selected from furan;
• furan substituted with C1-6alkyl or halo;
• tetrahydrofuran;
• a tetrahydrofuran substituted with C1-6alkyl;
• a dioxolane;
• a dioxolane substituted with C1-6alkyl, a dioxane;
• a dioxane substituted with C1-6alkyl;
• tetrahydropyran;
• a tetrahydropyran substituted with C1-6alkyl;
• pyrrolidinyl;
• pyrrolidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, or C1-6alkyl;
• pyridinyl;
• pyridinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C1-6alkyl;
• pyrimidinyl;
• pyrimidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C1-6alkyl, C1-6alkyloxy, amino and mono and di(C1-6alkyl)amino;
• pyridazinyl;
• pyridazinyl substituted with one or two substituents each independently selected from hydroxy, C1-6alkyloxy, C1-6alkyl or halo;
• pyrazinyl;
• pyrazinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C1-6alkyl, C1-6alkyloxy, amino, mono- and di(C1-6alkyl)amino and C1-6alkyloxycarbonyl;
• Het1 can also be a radical of formula
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• Het1 and Het2 each independently can also be selected from the radicals of formula
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• R13 and R14 each independently are hydrogen or C1-4alkyl;
• with the proviso that L is other than n-butyl when R1 and R2 are taken together to form a bivalent radical of formula (a-2);
• for the manufacture of a medicine for treating conditions involving a decreased motility of the stomach.

A process for preparing a compound of formula (I′) characterized by

• a) reacting an intermediate of formula (II) with an carboxylic acid derivative of formula (III) or a reactive functional derivative thereof, such as for example an acid chloride,
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• b) N-alkylating an intermediate of formula (IV), wherein W represents an appropriate leaving group such as halo, with a reagent of formula (V).
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• c) reacting an appropriate ketone or aldehyde intermediate of formula L′═O (IV-a), said L′═O represents a derivative of formula L—H wherein two geminal hydrogen atoms are replaced by oxygen, with a piperidine of formula (V)
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• d) carbonylating an intermediate of formula (XII), wherein X is bromo or iodo, in the presence,of an intermediate of formula (II)
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• in a reaction-inert solvent such as, e.g. acetonitrile or tetrahydrofuran, in the presence of a suitable catalyst, such as palladium-on-carbon, and a tertiary amine such as, e.g. triethylamine, and at a temperature ranging between room temperature and the reflux temperature of the reaction mixture,
• and, if desired, converting compounds of formula (I) into each other following art-known transformations;
• and further, if desired, converting the compounds of formula (I′), into a therapeutically active non-toxic acid addition salt by treatment with an acid, or conversely, converting the acid addition salt form into the free base by treatment with alkali;
• and, if desired, preparing stereochemically isomeric forms or N-oxide forms thereof.