Bicyclic benzamides of 3- or 4-substituted 4-(aminomethyl)-piperidine derivatives

• US 20020086879A1
• Filed: 02/22/2001
• Published: 07/04/2002
• Est. Priority Date: 07/11/1997
• Status: Active Grant

• Current Assignee: Jean-Paul Rene Marie Andre Bosmans, Michel Anna Jozef De Cleyn, Michel Surkyn
• Original Assignee: Jean-Paul Rene Marie Andre Bosmans, Michel Anna Jozef De Cleyn, Michel Surkyn
• Inventors: De Cleyn, Michel Anna Jozef, Surkyn, Michel, Bosmans, Jean-Paul Rene Marie Andre
• Granted Patent: US 6,635,643 B2
• Time in Patent Office: Days
• US Class Current: 514/320
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 211/42 attached in position 3 or 5
• CPC Class Codes: C07D 211/44 attached in position 4
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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 C_1-6alkyl; R³ is hydrogen or halo; R⁴ is hydrogen or C_1-6alkyl; R⁵ is hydrogen or C_1-6alkyl; L is C_3-6cycloalkyl, C_5-6cycloalkanone, C_2-6alkenyl, 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 C_1-12alkanediyl; and R⁶ is hydrogen, cyano, C_1-6alkylsulfonylamino, C_3-6cycloalkyl, C_5-6cycloalkanone, or a heterocyclic ringsystem; R⁷ is hydrogen, C_1-6alkyl, hydroxyC_1-6alkyl, C_3-6cycloalkyl, or a heterocyclic ringsystem; X is O, SO₂ or NR⁸; said R⁸ being hydrogen or C_1-6alkyl; R⁹ is hydrogen, C_1-6alkyl, C_3-6cycloalkyl, C_1-6alkyloxy or hydroxy; Y is NR¹⁰ or a direct bond; said R¹⁰ being hydrogen, or C_1-6alkyl; R¹¹ and R¹² each independently are hydrogen, C_1-6alkyl, C_3-6cycloalkyl, 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.

Claims

1. A compound of formula (I)

2. A compound as claimed in claim 1 wherein the —

OR⁴ 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 —

OR⁴ 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 C_3-6cycloalkyl or C_2-6alkenyl;

or L is a radical of formula (b-1), wherein each Alk is C_1-6alkanediyl, and R⁶ is hydrogen, hydroxy, cyano, amino, C_1-6alkylsulfonylamino, C_3-6cycloalkyl or Het¹, wherein Het¹ is tetrahydrofuran;

dioxolane;

dioxolane substituted with C_1-6alkyl;

tetrahydropyran;

pyridazinyl substituted with one or more substituents selected from hydroxy, halo and C_1-6alkyl;

or a radical of formula (c-1), (c-3) or (c4) wherein R¹³ is C_1-4alkyl;

or L is a radical of formula (b-2), wherein Alk is C_1-6alkanediyl, X is O, and R⁷ is C_1-6alkyl or hydroxyC_1-6alkyl;

or L is a radical of formula (b-2), wherein Alk is C_1-6alkanediyl, R⁷ is Het² wherein Het² is pyrazinyl substituted with C_1-6alkyl, and X is NR⁸ wherein R⁸ is hydrogen or C_1-6alkyl;

or L is a radical of formula (b-3) wherein Y is a direct bond, and R⁹ is C_1-6alkyl, hydroxy or C_1-6alkyloxy;

or L is a radical of formula (b-4) wherein Y is a direct bond, and R¹¹ and R¹² are C_1-6alkyl, or R¹¹ and R¹² combined with the nitrogen atom bearing R¹¹ and R¹² 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 according to any of claims 1 to 6 for use as a medicine.

10. A compound of formula (III)

11. 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 C_1-12alkanediyl 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.

12. 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.