Patent EA-003608-B1 (EA)
Title: 4-(aminomethyl)-piperidine benzamides for treating gastrointestinal disorders
Inventor: BOSMANS JEAN-PAUL
IPC: A61P1/10
Filed: 1999-12-14
Abstract: 1. A compound of formula (I) a stereochemically isomeric form thereof, an N-oxide form thereof, a prodrug thereof, or a pharmaceutically acceptable acid or base addition salt thereof, wherein -R<1>-R<2>- is 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), -O-CH2-CH2-CH2-CH2-O- (a-7), -O-CH2-CH2-CH2-CH2-CH2- (a-8), wherein in said bivalent radicals optionally one or two hydrogen atoms on the same or a different carbon atom may be replaced by C1-6alkyl or hydroxy, R<3> is hydrogen or halo; R<4> is hydrogen or C1-6alkyl; R<5> is hydrogen or C1-6alkyl; L is C3-6cycloalkyl, oxoC5-6cycloalkyl, or C2-6alkenyl, or L is a radical of formula -Alk-R<6> (b-1), -Alk-X-R<7> (b-2), -Alk-Y-C(=O)-R<9> (b-3), or -Alk-Y-C(=O)-NR<11>R<12> (b-4), wherein each Alk is C11-12alkanediyl; and R<6> is hydrogen, cyano, amino, C1-6alkylsulfonylamino, C3-6cycloalkyl, oxoC5-6cycloalkyl, aryl or Het<1>; R<7> is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C3-6cycloalkyl, aryl or Het<2>; X is O, S, SO2 or NR<8>; said R<8> being hydrogen or C1-6alkyl; R<9> is hydrogen, C1-6alkyl, C3-6cycloalkyl, C1-6alkyloxy, hydroxy or aryl; Y is a direct bond, NR<10>, O, S, O-(CH2)n-, S-(CH2)n-, or -NR<10>-(CH2)n-, wherein n is an integer from 1 to 6, and R<10> being hydrogen or C1-6alkyl; R<11> and R<12> each independently are hydrogen, C1-6alkyl, C3-6cycloalkyl, or R<11> and R<12> combined with the nitrogen atom bearing R<11> and R<12> may form a pyrrolidinyl or piperidinyl ring both being optionally substituted with C1-6alkyl, amino or mono or di(C1-6alkyl)amino, or said R<11> and R<12> combined with the nitrogen bearing R<11> and R<12> may form a piperazinyl or 4-morpholinyl radical both being optionally substituted with C1-6alkyl; and each aryl represents unsubstituted phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, C1-6alkyl, C1-6alkylaxy, amino-sulfonyl, C1-6alkylcarbonyl, nitro, trifluoromethyl, amino or aminocarbonyl; and Het<1> and Het<2> each independently are selected from furan; furan substituted with C1-6alky1 or halo; tetrahydrofuran; tetrahydrofuran substituted with C1-6alkyl; dioxolane; dioxolane substituted with C1-6alkyl; dioxane; dioxane substituted with C1-6alkyl; tetrahydropyran; 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 ore two substituents each independently selected from halo, hydroxy, cyano, C1-6alkyl, C1-6alkyloxy, amino, mono- and di(C1-6alkyl)amino and C1-6alkyloxycarbonyl; Het<1> can also be a radical of formula Het<1> and Het<2> each independently can also be selected from the radicals of formula R<13> and R<14> each independently are hydrogen or C1-4alkyl. 2. A compound as claimed in claim 1 wherein the -OR<4> radical is situated at the 3-position of the piperidine moiety having the trans configuration. 3. A compound as claimed in claim 1 wherein the -OR<4> radical is situated at the 4-position of the piperidine moiety. 4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound according to any of claims 1 to 3. 5. A process for preparing a pharmaceutical composition according to claim 4 wherein a therapeutically active amount of a compound according to any of claims 1 to 3 is intimately mixed with a pharmaceutically acceptable carrier. 6. A compound according to any of claims 1 to 3 for use as a medicine. 7. A compound of formula (III) a pharmaceutically acceptable acid addition salt thereof or a stereochemically isomeric form thereof, wherein R<1>, R<2>, R<3>, R<4> and R<5> are as defined in claim. 8. A process for preparing a compound of formula (I) wherein an intermediate of formula (II) is N-alkylated with an intermediate of formula (III) in a reaction-inert solvent and, optionally in the presence of a suitable base, wherein L, R<1>, R<2>, R<3>, R<4> and R<5> have a values defined in claim 1 and W is an appropriate leaving group; with following conversion, if desired, of one compound into another by art known methods; and/or if desired, or if desired; a compound of formula (I) is converted into a pharmaceutically acceptable acid addition salt, or conversely, an acid addition salt of a compound of formula (I) is converted into a free base form with alkali; and, if desired, preparing stereochemically isomeric forms thereof. 9. A process for preparing a compound of formula (I) wherein an appropriate intermediate ketone or aldehyde intermediate of formula L'=O (IV), said L'=O being a compound of formula L-H, wherein two geminal hydrogen atoms in the C1-12alkanediyl moiety are replaced by =O, is reacted with an intermediate of formula (III); wherein L, R<1>, R<2>, R<3>, R<4> and R<5> have a values defined in claim 1, with following conversion, if desired, of one compound into another by art known methods; and/or if desired, or if desired; a compound of formula (I) is converted into a pharmaceutically acceptable acid addition salt, or conversely, an acid addition salt of a compound of formula (I) is converted into a free base form with alkali; and, if desired, preparing stereochemically isomeric forms thereof. 10. A process for preparing a compound of formula (I) wherein an intermediate of formula (V) is reacted with an carboxylic acid derivative of formula (VI) or a reactive functional derivative thereof; wherein L, R<1>, R<2>, R<3>, R<4> and R<5> have a values defined in claim 1, with following conversion, if desired, of one compound into another by art known methods; and/or if desired, or if desired; a compound of formula (I) is converted into a pharmaceutically acceptable acid addition salt, or conversely, an acid addition salt of a compound of formula (I) is converted into a free base form with alkali; and, if desired, preparing stereochemically isomeric forms thereof. 11. A process for preparing a compound of formula (I) wherein an intermediate of formula (VII), wherein X is bromo or iodo, is carbonylated in the presence of an intermediate of formula (V) in a reaction-inert solvent in the presence of a suitable catalyst and a tertiary amine, and at a temperature ranging between room temperature and the reflux temperature of the reaction mixture; wherein L, R<1>, R<2>, R<3>, R<4> and R<5> have a values defined in claim 1, with following conversion, if desired, of one compound into another by art known methods; and/or if desired, or if desired; a compound of formula (I) is converted into a pharmaceutically acceptable acid addition salt, or conversely, an acid addition salt of a compound of formula (I) is converted into a free base form with alkali; and, if desired, preparing stereochemically isomeric forms thereof 12. A process for preparing a compound of formula (III) wherein an intermediate of formula (VIII), wherein PG is an appropriate protective group, is reacted with an acid of formula (VI), or an appropriate reactive functional derivative thereof, in a reaction-inert solvent and subsequent deprotection of the protecting group PG yielding compounds of formula (III); wherein L, R<1>, R<2>, R<3>, R<4> and R<5> are as defined in claim 1 with following conversion, if desired, of one compound into another by art known methods; and/or if desired, or if desired; a compound of formula (I) is converted into a pharmaceutically acceptable acid addition salt, or conversely, an acid addition salt of a compound of formula (I) is converted into a free base form with alkali; and, if desired, preparing stereochemically isomeric forms thereof 13. A compound of formula (XXXIV) wherein L and R<4> are as defined in claim 1.