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

• US RE40,793 E1
• Filed: 10/26/2005
• Issued: 06/23/2009
• Est. Priority Date: 07/11/1997
• Status: Expired due to Term

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: DeCleyn, Michel Anna Jozef, Bosmans, Jean-Paul Renë Marie Andrë, Surkyn, Michel
• Primary Examiner(s): CHANG, CELIA C
• Application Number:
  US11/259,719
• Time in Patent Office: 1,336 Days
• Field of Search: 514/248, 514/258, 514/320, 514/321, 546/196, 546/197, 546/205, 546/207, 546/214, 544/235, 544/237, 544/278
• US Class Current: 514/248
• 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 ring-system; 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)

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 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 C₁₆alkyl; and

Het¹ and Het² each independently are selected from furan;

furan substituted with C_1-6alkyl or halo;

tetrahydrofuran;

a tetrahydrofuran substituted with C_1-6alkyl;

a dioxolane;

a dioxolane substituted with C_1-6alkyl 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;

pyriniidinyl;

pyrimidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C_1-6alkyl, 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_1-6alkyl or halo;

pyrazinyl;

pyrazinyl substituted with one ore 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 bearadical 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; and

wherein the —

OR⁴ radical is situated at the 4-position of the central piperidine moiety.

4. 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.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound according to any of claims 1-4 3.

6. A process for preparing a pharmaceutical composition according to claim 5 wherein a therapeutically active amount of a compound according to any of claims 1-4 3 is intimately mixed with a pharmaceutically acceptable carrier.

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

8. A compound of formula (III)

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) as claimed in claim 1 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.

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.

11. The method of claim 7 wherein the decreased gastro-intestinal motility is decreased gastric emptying.

2. 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 (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.

3. A compound as claimed in claim 2 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.