Hydroxymethyl pyrrolidines as β3 adrenergic receptor agonists
The present invention provides compounds of Formula (I), pharmaceutical compositions thereof, and method of using the same in the treatment or prevention of diseases mediated by the activation of β3-adrenoceptor.
1. A compound of Formula Ia, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof:
wherein
n is 0, 1 or 2;
Y is selected from the group consisting of methylene, —CH(CH 3 )— and a bond;
Z is selected from the group consisting of
R 3 is selected from the group consisting of:
(1) methyl,
(2) oxo, and
(3) —NH 2 .
2. The compound of claim 1 wherein Z is selected from the group consisting of:
3. The compound of claim 2 ,
wherein n is 1;
Y is a bond;
Z is
R 3 is oxo.
4. A compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof.
5. A compound of claim 4 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof.
6. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
7. A method for the treatment or prevention of a disease or disorder selected from the group consisting of (1) overactive bladder, (2) urinary incontinence, (3) urge urinary incontinence, and (4) urinary urgency, wherein said method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
8. A method for the treatment or prevention of a disease or disorder selected from the group consisting of (1) overactive bladder, (2) urinary incontinence, (3) urge urinary incontinence, and (4) urinary urgency, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 and a second active agent.
9. The method of claim 8 , wherein the second active agent is a muscarinic receptor antagonist.
10. The compound of claim 1 having the following chemical structure:
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 having the following chemical structure:
or a pharmaceutically acceptable salt thereof.
12. A compound having the following chemical structure:
13. A compound having the following chemical structure:
14. A pharmaceutical composition comprising a compound of claim 1 , a second active agent and a pharmaceutically acceptable carrier.
15. The pharmaceutical composition of claim 14 , wherein the second active agent is a muscarinic receptor antagonist.
16. The pharmaceutical composition of claim 15 , wherein the second active agent is a tolterodine.