Hydroxymethyl pyrrolidines as β3 adrenergic receptor agonists
View Patent ↗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.