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

• US 7,790,750 B2
• Filed: 10/20/2006
• Issued: 09/07/2010
• Est. Priority Date: 07/11/1997
• Status: Expired due to Fees

• 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
• Primary Examiner(s): CHANG, CELIA C
• Application Number:
  US11/584,732
• Publication Number:
  US 20070037850A1
• Time in Patent Office: 1,418 Days
• Field of Search: 514/248, 514/258, 514/320, 514/321, 544/237, 544/278, 546/196, 546/197, 546/205, 546/207, 546/214
• 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, 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 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. The compound as claimed in claim 1 wherein the —

OR⁴ radical has the transconfiguration.

3. The 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 tetrahydrofiaran;

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 Het²wherein Het²is 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. The compound as claimed in 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 compound of formula (III)

7. 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,

8. 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);

9. 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.

10. A process for preparing a pharmaceutical composition comprising mixing a therapeutically effective amount of a compound according to claim 1 with a pharmaceutically acceptable carrier.