Substituted N-heterocycloalkyl bipyrrolidinylphenyl amide derivatives, preparation and therapeutic use thereof
The present disclosure relates to a series of substituted N-heterocycloalkyl bipyrrolidinylphenyl amide derivatives of formula (I). wherein R, R 1 , R 2 , R 3 , R 4 , X, 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, this disclosure relates to methods of preparation of substituted N-heterocycloalkyl bipyrrolidinylphenyl amide derivatives of formula (I) and intermediates therefor.
1. A compound of formula (I):
wherein
n is 0 or 1;
m is 1;
p is 1;
X is O or HH;
Ar is phenyl or naphthyl;
R 1 is H or CH 3 ;
R 2 is H, halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, CF 3 or OCF 3 ; and
R 3 and R 4 are the same or different and independently of each other selected from the group consisting of hydrogen, tetrahydropyranyl, and unsubstituted or substituted piperidine, wherein the substituents are selected from the group consisting of (C 1 -C 6 )alkoxycarbonyl and (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl; or
R 3 and R 4 taken together with the nitrogen atom to which they are attached form piperidine, which is optionally substituted with (C 1 -C 4 )alkyl-NH—CO;
or a salt thereof or an enantiomer or a diastereomer thereof.
2. The compound according to claim 1 , wherein
n is 0;
m and p are 1;
X is O;
Ar is phenyl;
R 1 is CH 3 ;
R 2 is H, halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, CF 3 or OCF 3 ;
R 3 and R 4 are the same or different and independently of each other selected from the group consisting of hydrogen, tetrahydropyranyl, and unsubstituted or substituted piperidine, wherein the substituents are selected from the group consisting of (C 1 -C 6 )alkoxycarbonyl and (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl;
or a salt thereof or an enantiomer or a diastereomer thereof.
3. The compound according to claim 1 , wherein
n is 0 or 1;
m and p are 1;
X is O;
Ar is naphthyl;
R 1 is CH 3 ;
R 2 is H, halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, CF 3 or OCF 3 ; and
R 3 and R 4 taken together with the nitrogen atom to which they are attached form piperidine, which is optionally substituted with (C 1 -C 4 )alkyl-NH—CO;
or a salt thereof or an enantiomer or a diastereomer thereof.
4. The compound of claim 1 selected from the group consisting of:
2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-N-(tetrahydro-pyran-4-yl) -acetamide;
6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-naphthalene-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide;
4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-N-(tetrahydro-pyran-4-yl)-benzamide;
2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-N-(tetrahydro-pyran-4-yl) -benzamide;
4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-N-(tetrahydro-pyran-4-ylmethyl) -benzamide;
4-{2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-acetylamino}-piperidine -1-carboxylic acid tert-butyl ester;
2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl -1′-yl)-phenyl]-N-piperidin-4-yl-acetamide;
4-{2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-acetylamino}-piperidine -1-carboxylic acid ethyl ester;
N-(1-cyclopentylmethyl-piperidin-4-yl)-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-acetamide; and
1-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl -1′-yl)-benzyl]-piperidine-4-carboxylic acid methylamide;
or a salt thereof.
5. The compound according to claim 1 which has the formula (II):
wherein R 1 , R 2 , R 3 , R 4 , X, m, n and p are as defined in claim 1 .
6. A pharmaceutical composition comprising a compound of formula (I):
wherein
n is 0 or 1;
m is 1;
p is 1;
X is O or HH;
Ar is phenyl or naphthyl;
R 1 is H or CH 3 ;
R 2 is H, halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, CF 3 or OCF 3 ; and
R 3 and R 4 are the same or different and independently of each other selected from the group consisting of hydrogen, tetrahydropyranyl, and unsubstituted or substituted piperidine, wherein the substituents are selected from the group consisting of (C 1 -C 6 )alkoxycarbonyl and (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl; or
R 3 and R 4 taken together with the nitrogen atom to which they are attached form piperidine, which is optionally substituted with (C 1 -C 4 )alkyl-NH—CO; 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-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl- 1′-yl)-phenyl]-N-(tetrahydro-pyran-4-yl) -acetamide;
6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-naphthalene-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide;
4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-N-(tetrahydro-pyran-4-yl)-benzamide;
2-methyl-4-((2S,3′S)-2-methyl-[3′]bipyrrolidinyl-1′-yl)-N-(tetrahydro-pyran-4-yl) -benzamide;
4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-N-(tetrahydro-pyran-4-ylmethyl) -benzamide;
4-{2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-acetylamino}-piperidine -1-carboxylic acid tert-butyl ester;
2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl -1′-yl)-phenyl]-N-piperidin-4-yl-acetamide;
4-{2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-acetylamino}-piperidine -1-carboxylic acid ethyl ester;
N-(1-cyclopentylmethyl-piperidin-4-yl)-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-acetamide; and
1-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl -1′-yl)-benzyl]-piperidine-4-carboxylic acid methylamide; 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 , R 3 , R 4 , X, m, n and p are as defined in claim 6 .