Bicyclic Benzamides of 3-or 4-Substituted 4-(Aminomethyl)-Piperidine Derivatives

• US 20100210657A1
• Filed: 05/04/2010
• Published: 08/19/2010
• Est. Priority Date: 07/11/1997
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: De Cleyn, Michel Anna Jozef, Bosmans, Jean-Paul René Marie André, Surkyn, Michel
• Granted Patent: US 8,063,070 B2
• Time in Patent Office: Days
• US Class Current: 514/248
• 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. 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)

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—

CH₂—

CH₂—

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, or C_2-6alkenyl,

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 C_1-12alkanediyl; and

R⁶ is hydrogen, hydroxy, cyano, C_1-6alkylsulfonylamino, C_3-6cycloalkyl, C_5-6cycloalkanone, or Het¹;

R⁷ is hydrogen, C_1-6alkyl, hydroxyC_1-6alkyl, C_3-6cycloalkyl, or Het²;

X is O, S, 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 bearing R¹¹ and R¹² may form a pyrrolidinyl or piperidinyl ring both being optionally substituted with C_1-6alkyl, amino or mono or di(C_1-6alkyl)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 C_1-6alkyl; and

Het¹ and Het² each independently are selected from furan;

furan substituted with C_1-6 alkyl or halo;

tetrahydrofuran;

a tetrahydrofuran substituted with C_1-6alkyl;

a dioxolane;

a dioxolane substituted with C_1-6 alkyl, a dioxane;

a dioxane substituted with C_1-6alkyl;

tetrahydropyran;

a tetrahydropyran substituted with C_1-6alkyl;

pyrrolidinyl;

pyrrolidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, or C_1-6alkyl;

pyridinyl;

pyridinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C_1-6alkyl;

pyrimidinyl;

pyrimidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C_1-6 alkyl, C_1-6alkyloxy, amino and mono and di(C_1-6alkyl)amino;

pyridazinyl;

pyridazinyl substituted with one or two substituents each independently selected from hydroxy, C_1-6alkyloxy, C_1-6 alkyl or halo;

pyrazinyl;

pyrazinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C_1-6alkyl, C_1-6alkyloxy, amino, mono- and di(C_1-6alkyl)amino and C_1-6alkyloxycarbonyl;

Het¹ can also be a radical of formula

Het¹ and Het² each independently can also be selected from the radicals of formula

R¹³ and R¹⁴ each independently are hydrogen or C_1-4alkyl.

2. A compound according to claim 1, wherein the —

OR⁴ radical of the central piperidine moiety has the trans configuration.

3. A compound as claimed in claim 1 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 (c-4) 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.

4. A compound according to claim 1 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.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound according to claim 1.

6. A process for preparing a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound according to claim 1 comprising intimately mixing the compound according to claim 1 with a pharmaceutically acceptable carrier.

7. A method of treating decreased gastro-intestinal motility comprising administering to a subject in need thereof an effective amount of a compound according to claim 1.