Novel substituted N-(1-alkyl-3-hydroxy-4-piperidinyl)benzamides

Claim 2

A chemical compound having the formula a N -oxide form, a pharmaceutically acceptable acid addition salt of a stereoisomeric form thereof, wherein R¹ is hydrogen, C₁₋₆ alkyl, aryl C₁-C₆alkyl, alkylcarbonyl, C₁-C₆ alkyloxycarbonyl, aryloxycarbonyl, aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, aminocarbonyl, mono- or di(C₁₋₆alkyl)­aminocarbonyl, pyrrolidinylcarbonyl or piperidinylcarbonyl; R² is hydrogen or C₁₋₆alkyl; R³, R⁴ and R⁵ each independently are hydrogen, C₁₋₆alkyl, C₁₋₆alkyl­oxy, halo, hydroxy, cyano, nitro, amino, trifluoromethyl, mono- or di­(C₁₋₆alkyl)amino, aminocarbonyl, arylcarbonylamino, C₁₋₆alkylcarbonyl­amino, C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy, aminosulfonyl, C₁₋₆alkylaminosulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl, C₁₋₆alkyl­thio, mercapto, arylC₁₋₆alkyloxy or aryloxy; R⁶ is hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, halo or amino; L is a radical of formula wherein Alk is C₁₋₆alkanediyl or C₃₋₆alkenediyl; Y¹ is O, S or NR⁷; whereas Y is O, S, NR⁷ or a direct bond; said R⁷ being hydrogen or C₁₋₆alkyl; R⁸ and R⁹ each independently are hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy, aryl, C₃₋₆cycloalkyl, arylC₁₋₆alkyl or (C₃₋₆cycloalkyl)C₁₋₆alkyl; provided that R⁸ and R⁹ are other than hydrogen when R⁷ is hydrogen; R¹⁰ is C₁₋₆alkyl, C₃₋₆cycloalkyl, aryl C₁₋₆alkyl, C₁₋₆alkyloxy or (C₃₋₆cycloalkyl)C₁₋₆alkyl; R¹¹ is aryl, arylC₁₋₆alkyl, C₁₋₆alkyloxy or (C₃₋₆cycloalkyl)C₁₋₆alkyl; R¹² is C₁₋₆alkyl, aryl or arylC₁₋₆alkyl; R¹³ is C₁₋₆alkyl, C₃₋₆cycloalkyl, aryl, arylC₁₋₆alkyl or (C₃₋₆cyclo­alkyl)C₁₋₆alkyl; R¹⁴ is arylC₁₋₆alkyl wherein the C₁₋₆alkyl moiety is substituted with hydroxy or C₁₋₆alkylcarbonyloxy; R¹⁵ and R¹⁶ each independently are hydrogen, C₁₋₆ alkyl, hydroxy, C₁₋₆alkyloxy, amino, mono- or di(C₁₋₆alkyl)amino, hydroxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, aminocarbonyl, mono- or di(C₁₋₆alkyl)aminocarbonyl or 2-C₁₋₆alkyl-1,3-dioxolan-2-yl; or R¹⁵ and R¹⁶ combined with the carbon atom bearing said R¹⁵ and R¹⁶ may form a carbonyl or a 1,3-dioxolan-2-ylidene radical; s is the integer 1,2 or 3; A is O, S or NR¹⁹; said R¹⁹ being hydrogen, C₁₋₆alkyl, aryl, pyridinyl, pyrimidinyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl or arylC₁₋₆alkyl; R¹⁷ and R¹⁸ each independently are hydrogen or C₁₋₆alkyl, or when A is NR¹⁹ R¹⁷ and R¹⁸ taken together may form a fused benzene residue being optionally substituted with halo or C₁₋₆alkyl; t is the integer 1 or 2; R²⁰ is hydrogen or C₁₋₆alkyl; B is a bivalent radical of formula -CH₂-CH₂-, -C(=O)-CH₂- or -CH₂-CH₂-CH₂-, wherein each hydrogen atom independently may be replaced by C₁₋₆alkyl substituents, or when R²⁰ is C₁₋₆alkyl said bivalent radical may also be 1,2-benzenediyl optionally substituted with halo or C₁₋₆alkyl; E is a bivalent radical of formula -CH₂-CH₂-, -CH₂-N(R²¹)- or -CH₂-CH₂-CH₂-, wherein each hydrogen atom independently may be replaced by C₁₋₆alkyl, or said bivalent radical may also be 1,2-benzenediyl optionally substituted with halo or C₁₋₆alkyl; said R²¹ being hydrogen or C₁₋₆alkyl; R²², R²³ and R²⁴ each independently are hydrogen or C₁₋₆alkyl; n and m are both independently 0 or 1; G is carbionyl, carboxymethylene, C₁₋₆alkyloxycarbonylmethylene, C₁₋₆alkylcarbonylmethylene, 5,5-dimethyl-1,3-dioxan-2-ylidene or 1,3-­dioxolan-2-ylidene; and aryl is phenyl optionally substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyl­oxy, aminosulfonyl, C₁₋₆alkylcarbonyl, nitro, trifluoromethyl, amino, aminocarbonyl and phenylcarbonyl.

Claim 3

A chemical compound according to claim 1 wherein R¹ is hydrogen, C₁₋₆alkyl, aryloxycarbonyl, mono- or di(C₁₋₆alkyl)aminocarbonyl, pyrrolidinylcarbonyl or piperidinylcarbonyl; R² is hydrogen; and R³, R⁴ and R⁵ each independently are hydrogen, halo, C₁₋₆alkyloxy, amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkylcarbonylamino, nitro, aminosulfonyl, C₁₋₆alkylaminosulfonyl or C₁₋₆alkylsulfonyl.

Claim 4

A chemical compound according to claim 2 wherein the substituents on the 3- and the 4- position of the piperidine ring have the cis configuration.

Claim 5

A chemical compound according to claim 3 wherein aryl is phenyl optionally substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, C₁₋₄alkyl and C₁₋₄alkyloxy; Alk is a C₁₋₄alkanediyl radical; and L is a radical of formula (a) wherein Y¹ is NR⁷, said R⁷ being hydrogen or C₁₋₄alkyl, and R⁸ and R⁹ are both C₁₋₄alkyl; or (b) wherein R¹⁰ is C₁₋₄alkyl and R¹¹ is aryl or C₁₋₄alkyloxy; or (c) wherein Y¹ is NR⁷, said R⁷ being hydrogen or C₁₋₄alkyl and R¹² is C₁₋₄alkyl; or (d) wherein R¹³ is C₁₋₄alkyl, C₃₋₆cycloalkyl or aryl; or (e) wherein Y¹ is NR⁷, said R⁷ being hydrogen or C₁₋₄alkyl; or (f) wherein Y is O, NR⁷ or a direct bond, R¹⁵ is hydrogen, C₁₋₄alkyl, hydroxy, C₁₋₄alkyloxy, amino, mono- or di(C₁₋₄alkyl)amino, hydroxyC₁₋₄alkyl, C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl or aminocarbonyl and R¹⁶ is hydrogen or C₁₋₄alkyl, or R¹⁵ and R¹⁶ combined with the carbon atom bearing said R¹⁵ and R¹⁶ may form a carbonyl or a 1,3-dioxolan-2-ylidene radical; or (g) wherein Y is O, NR⁷ or a direct bond and A is O or NR¹⁹, said R¹⁹ being hydrogen, C₁₋₆alkyl, aryl, pyridinyl pyrimidinyl, C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl or arylC₁₋₄alkyl; or (h) wherein B is 1,2-ethanediyl or when R¹⁰ is C₁₋₄alkyl B may also be 1,2-benzenediyl optionally substituted with halo or C₁₋₄alkyl; or (i) wherein E is 1,3-propanediyl optionally substituted with C₁₋₄alkyl, 1,2-benzenediyl optionally substituted with halo or C₁₋₄alkyl, or a bivalent radical of formula -CH₂-N(R²¹)-, said R²¹ being hydrogen or C₁₋₄alkyl; or (j) wherein R²³ and R²⁴ are both hydrogen; or L is a radical of formula (k) wherein G is carbonyl, C₁₋₄alkyloxycarbonylmethylene, C₁₋₄alkyl­carbonylmethylene, 5,5-dimethyl-1,3-dioxan-2-ylidene or 1,3-­dioxolan-2-ylidene.

Claim 6

A chemical compound according to claim 4 wherein the benzamide part is substituted on the meta position with R³ being chloro, bromo, C₁₋₄alkylaminosulfonyl, aminosulfonyl or C₁₋₄alkylsulfonyl, on the para position with R⁴ being amino and on the ortho position with R⁵ being hydroxy or C₁₋₄alkyloxy.

Claim 7

A pharmaceutical composition comprising a suitable pharmaceutical carrier and as active ingredient a therapeutically effective amount of a compound as claimed in any one of claims 1 to 5.

Claim 8

A gastrointestinal stimulating pharmaceutical composition comprising a suitable pharmaceutical carrier and as active ingredient an effective gastrointestinal stimulating amount of a compound as claimed in any one of claims 1 to 5.

Claim 10

A compound as claimed in any one of claims 1 to 5 for use as a medicine.

Claim 11

A compound as claimed in any one of claims 1 to 5 for use as a gastrointestinal stimulating medicine.

Claim 12

A process for preparing a chemical compound as claimed in any one of claims 1 to 5, characterized by a) N -alkylating a piperidine of formula H-D      (II) with an intermediate of formula L-W      (III) wherein W represents a reactive leaving group, in a reaction-inert solvent, optionally in the presence of a base and/or a iodide salt; or b) reacting a piperidine of formula or a functional derivative thereof, in a reaction-inert medium, optionally in the presence of a reagent capable of forming amides; or c) reacting a piperidine of formula W-C(O)-Y²-Alk-D (VI) wherein W is a reactive leaving group, with an alcohol or amine of formula T¹H (VII) in a reaction-inert solvent, thus preparing a compound of formula T¹-C(O)-Y²-Alk-D (I-a-1), wherein T¹- denotes a radical of formula and Y² denotes O, S, NR⁷ or a direct bond; or d) reacting a piperidine of formula H-Y³-Alk-D (VIII) with a reagent of formula T²-C(O)-W (IX) wherein W is a reactive leaving group, in a reaction-inert solvent, thus preparing a compound of formula T²-C(O)-Y³-Alk-D (I-a-2) wherein T² denotes a radical of formula and Y³ denotes O, S or NR⁷; or e) reacting an isocyanate of formula O=C=N-Alk-D (X) with an alcohol or amine of formula T³-H (XI) in a reaction-inert solvent, thus preparing a compound of formula T³-C(O)-NH-Alk-D (I-a-3) wherein T³ denotes a radical of formula f) reacting an isocyanate of formula R⁹-N=C=O (XII) with a piperidine of formula H-Y³-Alk-D (VIII) in a reaction-inert solvent thus, preparing a compound of formula R⁹-NH-C(O)-Y³-Alk-D (I-a-4), wherein Y³ denotes O, S or NR⁷; or g) reacting a carboxylic acid of formula T⁴-C(O)-OH or a functional derivative thereof with a piperidine of formula H-Y³-Alk-D (VIII) in a reaction-inert solvent, thus preparing a compound of formula T⁴-C(O)-Y³-Alk-D (I-a-5) wherein T⁴- denotes a radical of formula R¹³- or R¹⁴- and Y³ is O, S or NR⁷; or h) N -alkylating an amine of formula T⁵-H (XV) with a piperidine derivative of formula W-Alk-D (XIV) wherein W represents a reactive leaving group, thus preparing a compound of formula T⁵-Alk-D (I-a-6), wherein T⁵- denotes a radical of formula i) reacting an anhydride of formula with an amine of formula H₂N-Alk-D      (XVII) in a reaction-inert solvent, thus preparing a compound of formula j) cyclizing a reagent of formula R²²-C(O)-Alk-D (XVIII) in the presence of potassium cyanide and ammonium carbonate, thus preparing a hydantoin derivative of formula k) reductively N -alkylating a compound of formula H-D (II) with a ketone or aldehyde of formula L′=O (XIX), wherein L′=O is a compound of formula L-H wherein two geminal hydrogen atoms in said C₁₋₆alkane­diyl or C₅₋₆cycloalkanediyl are replaced by =O, in a reaction-inert solvent; thus preparing a compound of formula (I); or l) reacting a 7-oxa-3-azabicyclo[4.1.0)heptane of formula in a reaction-inert medium, thus preparing a compound wherein the substituents in the 3- and 4- position of the piperidine ring are in the trans configuration and, optionally O -alkylating or O -­acylating (I-b-1) with a reagent R 1-a (XXII) wherein W represents a reactive leaving group, thus preparing a compound of formula wherein R 1-a is defined as R¹, provided that it is other then hydrogen; or m) reacting a piperidone of formula with an amide of formula (XXI) thus preparing a compound of formula wherein the substituents in the 3- and 4-positions of the piperidine ring are in the cis configuration; wherein D represents a radical of formula wherein R¹, R², R³, R⁴, R⁵ and R⁶ have the previously described meanings; or optionally converting the compounds of formula (I) into each other following art-known grouptransformation procedures, and, if desired, converting the compounds of formula (I) into a therapeutically active non-toxic acid-addition salt form by treatment with an appropriate acid or, conversely, converting the acid-addition salt into the free base form with alkali; and/or preparing stereochemically isomeric forms thereof; and/or preparing the N -oxide forms thereof.