Patent EA-002619-B1 (EA)
Title: Gastrokinetic bicyclic benzamides of 3- or 4-substituted 4-(aminomethyl)-piperidine derivatives
Inventor: BOSMANS JEAN-PAUL RENE MARIE A
IPC: A61P1/14
Filed: 1998-07-07
Abstract: 1. A compound of formula (I)   a stereochemically isomeric form thereof, an N-oxide form thereof or a pharmaceutically acceptable acid or base addition salt thereof, wherein R<1> and R<2> taken together 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, R<3> is hydrogen or halo; R<4> is hydrogen or C1-6alkyl; R<5> is hydrogen or C1-6alkyl; L is C3-6cycloalkyl, C5-6cycloalkanone, 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 C1-12alkanediyl; and R<6> is hydrogen, hydroxy, cyano, C1-6alkylsulfonylamino, C3-6cycloalkyl, C5-6cycloalkanone, or Het<1>; R<7> is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C3-6cycloalkyl, 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 or hydroxy; Y is NR<10> or a direct bond; said 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 Het<1> and Het<2> 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 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 central 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 central piperidine moiety. 4. A compound as claimed in any of Claims 1 to 3 wherein L is C3-6cycloalkyl or C2-6alkenyl; or L is a radical of formula (b-l), wherein each Alk is C1-6alkanediyl, and R<6> is hydrogen, hydroxy, cyano, amino, C1-6alkylsulfonylamino, C3-6cycloalkyl or Het<1>, wherein Het<1> is tetrahydrofuran; dioxolane; dioxolane substituted with C1-6alkyl; tetrahydropyran; pyridazinyl substituted with one or more substituents selected from hydroxy, halo and C1-6alkyl; or a radical of formula (c-l), (c-3) or (c-4) wherein R<13> is C1-4alkyl; or L is a radical of formula (b-2), wherein Alk is C1-6alkanediyl, X is O, and R<7> is C1-6alkyl or hydroxyC1-6alkyl; or L is a radical of formula (b-2), wherein Alk is C1-6alkanediyl, R<7> is Het<2> wherein Het<2> is pyrazinyl substituted with C1-6alkyl, and X is NR<8> wherein R<8>.is hydrogen or C1-6alkyl; or L is a radical of formula (b-3) wherein Y is a direct bond, and R<9> is C1-6alkyl, hydroxy or C1-6alkyloxy; or L is a radical of formula (b-4) wherein Y is a direct bond, and R<11> and R<12> combined with the nitrogen atom bearing R<11> and R<12> form pyrrolidinyl. 5. A compound as claimed in Claim 4 wherein L is butyl; propyl substituted with methoxy, methylcarbonyl or 2-methyl-1,3-dioxolane; ethyl substituted with 4-methyl-2-pyridazinone or tetrahydropyranyl; or methyl substituted with tetrahydrofuranyl or tetrahydropyranyl. 6. A compound as claimed in Claim 1 wherein the compound is (trans)-(-)-4-amino-5-chloro-2,3-dihydro-N-[[3-hydroxy-1-(3-methoxypropyl)-4-piperidinyl]methyl]-2,2-dimethyl-7-benzofurancarboxamide; a pharmaceutically acceptable acid addition salt or an N-oxide form thereof. 7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound according to any of Claims 1 to 6. 8. A process for preparing a pharmaceutical composition according to Claim 7 wherein a therapeutically active amount of a compound according to any of Claims 1 to 6 is intimately mixed with a pharmaceutically acceptable carrier. 9. 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 1 for compounds of formula (I). 10. 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,   and optionally one compound of formula (I) is converted into each other compound of formula (I) following art-known transformation reactions; 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) by means of an appropriate 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)   and optionally one compound of formula (I) is converted into each other compound of formula (I) following art-known transformation reactions; 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 (I) by means of an intermediate of formula (V) with an carboxylic acid derivative of formula (VI) or a reactive functional derivative thereof   and optionally one compound of formula (I) is converted into each other compound of formula (I) following art-known transformation reactions; 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 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 in the above reaction schemes the radicals L, R<1>, R<2>, R<3>, R<4> and R<5> are as defined in Claim 1 and W is an appropriate leaving group; and optionally one compound of formula (I) is converted into each other compound of formula (I) following art-known transformation reactions; 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. 14. 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 in the above reaction schemes the radicals L, R<1>, R<2>, R<3>, R<4> and R<5> are as defined in Claim 1 and W is an appropriate leaving group; and optionally one compound of formula (III) is converted into each other compound of formula (III) following art-known transformation reactions; or if desired; a compound of formula (III) is converted into an acid addition salt, or conversely, an acid addition salt of a compound of formula (III) is converted into a free base form with alkali; and, if desired, preparing stereochemically isomeric forms thereof.