Substituted N-heteroaryl spirolactam bipyrrolidines, preparation and therapeutic use thereof
The present disclosure relates to a series of substituted N-heteroaryl spirolactam bipyrrolidines of formula (I). Wherein R 1 , R 2 , Q 1 , Q 2 , Q 3 , Q 4 , X, m, n, p and s 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, this disclosure also relates to methods of preparation of substituted N-heteroaryl spirolactam bipyrrolidines of formula (I) and intermediates therefor.
1. A compound of formula (I):
wherein:
m, p=1;
n, s=1;
X is O, NR 3 or CR 4 R 5 ;
Q 1 to Q 4 are independently CH or N provided that one of Q 1 to Q 4 is N;
R 1 is hydrogen, (C 1 -C 4 )alkyl, CF 3 or (C 1 -C 4 )alkoxy;
R 2 is hydrogen, halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy or CF 3 ;
R 3 is hydrogen or (C 1 -C 6 )alkyloxycarbonyl;
R 4 is hydrogen; and
R 5 is hydrogen or OH;
or a salt thereof or an enantiomer or a diastereomer thereof.
2. The compound according to claim 1 , wherein
m, p, n and s are 1;
X is O;
R 1 is CH 3 ; and
R 2 is CH 3 ;
or a salt thereof or an enantiomer or a diastereomer thereof.
3. The compound according to claim 1 , wherein
m, p and s are 1;
n is 1;
X is NH, NCOOBu t , CH 2 or CHOH;
R 1 is CH 3 ; and
R 2 is CH 3 ;
or a salt thereof or an enantiomer or a diastereomer thereof.
4. The compound of claim 1 selected from the group consisting of:
2[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-8-oxa-2-aza-spiro[4.5]decan-1-one;
2[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;
8-hydroxy-2-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-2-aza-spiro[4.5]decan-1-one;
2[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-2-aza-spiro[4.5]decan-1-one;
2-[2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-8-oxa-2-aza-spiro[4.5]decan-1-one;
2-[2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-2,8-diaza-spiro[4.5]decan-1-one;
2-[2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-2,8-diaza-spiro[4.5]decan-1-one;
2-[5-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-2-yl]-8-oxa-2-aza-spiro[4.5]decan-1-one; and
2[2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;
or a salt thereof.
5. The compound according to claim 1 which has the formula (II):
wherein R 1 , R 2 , Q 1 , Q 2 , Q 3 , Q 4 , X, m, n, p and s are as defined in claim 1 .
6. A pharmaceutical composition comprising a compound of formula (I):
wherein:
m, p =1;
n, s =1;
X is O, NR 3 or CR 4 R 5 ;
Q 1 to Q 4 are independently CH or N provided that one of Q 1 to Q 4 is N;
R 1 is hydrogen, (C 1 -C 4 )alkyl, CF 3 or (C 1 - C 4 )alkoxy;
R 2 is hydrogen, halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy or CF 3 ;
R 3 is hydrogen or (C 1 -C 6 )alkyloxycarbonyl;
R 4 is hydrogen; and
R 5 is hydrogen or OH; or
a pharmaceutically acceptable salt thereof or an enantiomer or a diastereomer thereof in combination with at least one pharmaceutically acceptable excipient, diluent or a carrier.
7. The composition according to claim 6 , wherein the compound is selected from the group consisting of:
2-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-8-oxa-2-aza-spiro[4.5]decan-1-one;
2[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;
8-hydroxy-2-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-2-aza-spiro[4.5]decan-1-one;
2[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-2-aza-spiro[4.5]decan-1-one;
2[2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-8-oxa-2-aza-spiro[4.5]decan-1-one;
2-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-2,8-diaza-spiro[4.5]decan-1-one;
2[2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-2,8-diaza-spiro[4.5]decan-1-one;
2-[5-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-2-yl]-8-oxa-2-aza-spiro[4.5]decan-1-one; and
2-[2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester; or
a pharmaceutically acceptable salt thereof.
8. The composition according to claim 6 , wherein the compound has the formula (II):
wherein R 1 , R 2 , Q 1 , Q 2 , Q 3 , Q 4 , X, m, n, p and s are as defined in claim 6 .