Substituted tetrahydropyran spiro pyrrolidinone and piperidinone, preparation and therapeutic use thereof
AssigneeSanofi
InventorsZhongli GAO, Ryan HARTUNG, David STEFANY
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Abstract
The present disclosure relates to a series of substituted N-phenyl-bipyrrolidine carboxamides of formula (I): wherein R1, R2, m, n and p are as described herein. More specifically, the compounds of this invention are modulators of H3 receptors and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases modulated by H3 receptors including diseases associated with the central nervous system. Additionally, methods of preparation of substituted N-phenyl-bipyrrolidine carboxamides and intermediates therefore are disclosed.
Claims8
A process for preparing a compound of formula (18):
- wherein m is 1 or 2;
- n is 1 or 2;
- p is 1 or 2;
- R1 is hydrogen, (C1-C4)alkyl, CF3, or (C1-C4)alkoxy-(C1-C4)alkyl;
- and R2 is hydrogen, halogen, (C1-C4)alkyl or CF3;
- said method comprising
- a) condensing an aldehyde of formula (16):
- wherein n is as defined for the compound of formula (18);
- with a compound of formula (12):
- wherein R1, R2, m and p are as defined for the compound of formula (18);
- in the presence of a reducing agent, to provide the compound of formula (17):
- wherein R1, R2, m, n, and p are as defined for the compound of formula (18);
- and
- b) cyclizing the compound of formula (17) in the presence of a base to provide the compound of formula (18).
A process to prepare a compound of formula (18):
- wherein n is 1 or 2;
- p is 1 or 2;
- R1 is hydrogen, (C1-C4)alkyl, CF3, or (C1-C4)alkoxy-(C1-C4)alkyl;
- and R2 is hydrogen, halogen, (C1-C4)alkyl or CF3;
- said method comprising
- a) condensing an aldehyde of formula (16):
- with a bromide of formula (19):
- wherein R2 is as defined for the compound of formula (18);
- in the presence of a reducing agent;
- to provide a compound of formula (20):
- wherein n and R2 are as defined for the compound of formula (18);
- and
- b) cyclizing the compound of formula (20) in the presence of a base to provide a compound of formula (21):
- wherein n and R2 are as defined for the compound of formula (18);
- and
- c) condensing the compound of formula (21) with a compound of formula (4):
- wherein p, m and R1 are as defined for the compound of formula (18), or condensing the compound of formula (21) with a with a compound of formula (9):
- wherein p, m, and R1 are as defined for the compound of formula (18);
- to provide the compound of formula (18).
Dependencies are inferred from the claim text.