Substituted tetrahydropyran spiro pyrrolidinone and piperidinone, preparation and therapeutic use thereof
View Patent ↗The present disclosure relates to a series of substituted N-phenyl-bipyrrolidine carboxamides of formula (I): wherein R 1 , R 2 , 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.
1. 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; R 1 is hydrogen, (C 1 -C 4 )alkyl, CF 3 , or (C 1 -C 4 )alkoxy-(C 1 -C 4 )alkyl; and R 2 is hydrogen, halogen, (C 1 -C 4 )alkyl or CF 3 ;
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).
2. The process according to claim 1 , wherein the reducing agent is triacetoxyborohydride.
3. The process according to claim 1 , wherein the base is present in a catalytic amount.
4. The process according to claim 3 , wherein the base is potassium t-butoxide.
5. A process to prepare a compound of formula (18):
wherein n is 1 or 2; p is 1 or 2; R 1 is hydrogen, (C 1 -C 4 )alkyl, CF 3 , or (C 1 -C 4 )alkoxy-(C 1 -C 4 )alkyl; and R 2 is hydrogen, halogen, (C 1 -C 4 )alkyl or CF 3 ;
said method comprising
a) condensing an aldehyde of formula (16):
with a bromide of formula (19):
wherein R 2 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 R 2 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 R 2 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 R 1 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 R 1 are as defined for the compound of formula (18); to provide the compound of formula (18).
6. The process according to claim 5 , wherein the reducing agent is triacetoxyborohydride.
7. The process according to claim 5 , wherein the base is present in a catalytic amount.
8. The process according to claim 7 , wherein the base is potassium t-butoxide.