Bicyclic benzamides of 3- or 4-substituted 4-(aminomethyl)-piperidine derivatives
First Claim
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 R1 and R2 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,R3 is hydrogen or halo;
R4 is hydrogen or C1-6alkyl;
R5 is hydrogen or C1-6alkyl;
L is C3-6cycloalkyl, C5-6cycloalkanone, or C2-6alkenyl, Or L is a radical of formula —
Alk—
R6 (b-1), —
Alk—
X—
R7 (b-2), —
Alk—
Y—
C(═
O)—
R9 (b-3), or —
Alk—
Y—
C(═
O)—
NR11R12 (b-4), wherein each Alk is C1-12alkanediyl; and
R6 is hydrogen, hydroxy, cyano, C16alkylsulfonylamino, C3-6cycloalkyl, C56cycloalkanone, or Het1;
R7 is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C3-6cycloalkyl, or Het2;
X is O,S, SO2 or NR8;
said R8 being hydrogen or C1-6alkyl;
R9 is hydrogen, C1-6alkyl, C3-6cycloalkyl, C1-6alkyloxy or hydroxy;
Y is NR10 or a direct bond;
said R10 being hydrogen or C1-6alkyl;
R11 and R12 each independently are hydrogen, C1-6alkyl, C3-6cycloalkyl, 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 R11 and R12 may form a piperazinyl or 4-morpholinyl radical both being optionally substituted with C16alkyl; 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;
pyriniidinyl pyrimidinyl substituted with one or two substituents each indepentently 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 bearadical of formula Het1 and Het2 each independently can also be selected from the radicals of formula R13 and R14 each independently are hydrogen or C1-4 alkyl; and
wherein the —
OR4 radical is situated at the 4-position of the central piperidine moiety.
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Abstract
The present invention of compounds of formula (I)
a stereochemically isomeric form thereof, an N-oxide form thereof or a pharmaceutically acceptable acid addition salt thereof, R1 and R2 taken together form a bivalent radical of formula wherein in said bivalent radicals one or two hydrogen atoms may be substituted with C1-6alkyl; R3 is hydrogen or halo; R4 is hydrogen or C1-6alkyl; R5 is hydrogen or C1-6alkyl; L is C3-6cycloalkyl, C5-6cycloalkanone, C2-6alkenyl, or L is a radical of formula —Alk—R6—, Alk—X—R7, —Alk—Y—C(═O)—R9, or —Alk—Y—C(═O)— NR11R12 wherein each Alk is C1-12alkanediyl; and R6 is hydrogen, cyano, C1-6alkylsulfonylamino, C3-6cycloalkyl, C5-6cycloalkanone, or a heterocyclic ringsystem; R7 is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C3-6cycloalkyl, or a heterocyclic ringsystem; X is O, SO2 or NR8; said R8 being hydrogen or C1-6alkyl; R9 is hydrogen, C1-6alkyl, C3-6cycloalkyl, C1-6alkyloxy or hydroxy; Y is NR10 or a direct bond; said R10 being hydrogen, or C1-6alkyl; R11 and R12 each independently are hydrogen, C1-6alkyl, C3-6cycloalkyl, or R11 and R12 combined with the nitrogen atom may form an optionally substituted pyrrolidinyl, piperidinyl, piperazinyl or 4-morpholinyl ring. Processes for preparing said products, formulations comprising said products and their use as a medicine are disclosed, in particular for treating conditions which are related to impairment of gastric emptying.
25 Citations
10 Claims
-
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 R1 and R2 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, R3 is hydrogen or halo;
R4 is hydrogen or C1-6alkyl;
R5 is hydrogen or C1-6alkyl;
L is C3-6cycloalkyl, C5-6cycloalkanone, or C2-6alkenyl, Or L is a radical of formula —
Alk—
R6 (b-1),—
Alk—
X—
R7 (b-2),—
Alk—
Y—
C(═
O)—
R9 (b-3), or—
Alk—
Y—
C(═
O)—
NR11R12 (b-4),wherein each Alk is C1-12alkanediyl; and R6 is hydrogen, hydroxy, cyano, C16alkylsulfonylamino, C3-6cycloalkyl, C56cycloalkanone, or Het1;
R7 is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C3-6cycloalkyl, or Het2;
X is O,S, SO2 or NR8;
said R8 being hydrogen or C1-6alkyl;
R9 is hydrogen, C1-6alkyl, C3-6cycloalkyl, C1-6alkyloxy or hydroxy;
Y is NR10 or a direct bond;
said R10 being hydrogen or C1-6alkyl;
R11 and R12 each independently are hydrogen, C1-6alkyl, C3-6cycloalkyl, 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 R11 and R12 may form a piperazinyl or 4-morpholinyl radical both being optionally substituted with C16alkyl; 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;
pyriniidinyl pyrimidinyl substituted with one or two substituents each indepentently 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 C1-6alkyloxycarbonylHet1 can also bearadical of formula Het1 and Het2 each independently can also be selected from the radicals of formula R13 and R14 each independently are hydrogen or C1-4 alkyl; and
wherein the —
OR4 radical is situated at the 4-position of the central piperidine moiety.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10)
a pharmaceutically acceptable acid addition salt thereof or a stereochemically isomeric form thereof, wherein R1, R2, R3, R4 and R5 are as defined in claim 1 for compounds of formula (I). -
9. A process for preparing a compound of formula (I) wherein
a) 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, b) 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);
c) an intermediate of formula (V) is reacted with an carboxylic acid derivative of formula (VI) or a reactive functional derivative thereof;
d) 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, R1, R2, R3, R4 and R5 are as defined in claim 1 and W is an appropriate leaving group;
e) or, compounds of formula (I) are converted into each other 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.
- ═
-
10. A process for preparing a compound of formula (III) wherein
a) 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, R1, R2, R3, R4 and R5 are as defined in claim 1 and W is an appropriate leaving group;
b) or, compounds of formula (III) are converted into each other 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.
-
- O—
Specification