COMBINATION THERAPY FOR THE TREATMENT-OF LOWER URINARY TRACT SYMPTOMS
This invention concerns compositions for the treatment of Lower Urinary Tract Symptoms (LUTS), and especially LUTS which results from benign prostatic hypertrophy. The compositions of the invention comprise a Beta-3 agonist described below, optionally in combination with a 5-alpha reductase inhibitor, or an NK-1 antagonist or an alpha-1 adrenergic antagonist or an anti-muscarinic agent. The invention also includes compositions comprising a beta-3 agonist and two additional active agents selected from a 5-alpha reductase inhibitor, an NK-1 antagonist, an alpha-1 adrenergic antagonist or an anti-muscarinic agent.
1 . A pharmaceutical composition for the treatment of lower urinary tract symptoms (LUTS), comprising a therapeutically effective amount of a beta 3 agonist selected from
N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-(3-cyclopentylpropyl)-5-tetrazolon-1-yl]benzenesulfonamide; and
2N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide or a pharmaceutically acceptable salt thereof and
a pharmaceutically acceptable carrier, and optionally a therapeutically effective amount of a 5-alpha reductase inhibitor, or an NK-1 antagonist or an alpha-1 adrenergic antagonist or an antimuscarinic agent.
2 . A pharmaceutical composition according to claim 1 comprising a beta 3 agonist and one additional active agent selected from 5-alpha reductase inhibitor, or an NK-1 antagonist or an alpha-1 adrenergic antagonist or an anti-muscarinic agent.
3 . A pharmaceutical composition according to claim 2 comprising a beta 3 agonist and 5-alpha reductase inhibitor wherein the 5-alpha reductase inhibitor is selected from the group consisting of finasteride, dutasteride, turosteride and epristeride.
4 . A pharmcceutical composition according to claim 2 wherein the 5-alpha reductase inhibitor is finasteride or dutasteride.
5 . A pharmaceutical composition according to claim 2 comprising a beta 3 agonist and an alpha-1 adrenergic antagonist, wherein the alpha-1 adrenergic antagonist is selected from amsulosin, terazosin, doxazosin, alfuzosin, indoramin and prazosin.
6 . A pharmaceutical composition according to claim 5 comprising a beta 3 agonist and an alpha-1 adrenergic antagonist, wherein the alpha-1 adrenergic antagonist is selected from amsulosin and alfuzosin.
7 . A pharmaceutical composition according to claim 2 comprising a beta 3 agonist and an NK-1 antagonist, wherein the NK-1 antagonist is selected from
(a) an antagonist of the NK-1 receptor selected from:
or pharmaceutically acceptable salt thereof;
(b) an antagonist of the NK-1 receptor selected from
or pharmaceutically acceptable salt thereof
8 . A composition according to claim 7 wherein the NK-1 receptor antagonist is selected from group (a).
9 . A composition according to claim 7 wherein the NK-1 receptor antagonists are selected from group (b).
10 . A pharmaceutical composition according to claim 7 wherein the beta 3 agonist is selected from
N-[4-[2- [[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-(3-cyclopentylpropyl)-5-tetrazolon-1-yl]benzenesulfonamide; and
2N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide, or a pharmaceutically acceptable salt thereof, and the NK-1 receptor antagonist is selected from
or a pharmaceutically acceptable salt thereof.
11 . A pharmaceutical composition according to claim 2 comprising a beta 3 agonist and an anti-muscarinic agent.
12 . A pharmaceutical composition according to claim 11 wherein the antimuscarinic agent is selected from tolterodine, oxybutynin, trospium, vamicamide, solifenacin, propiverine, S-oxybutynin, temiverine, sanctura, staybla and fesoterodine.
13 . A pharmaceutical composition according to claim 12 wherein the anti-muscarinic agent is selected from tolterodine, and oxybutynin.
14 . Use of a composition according to claim 1 for the treatment of Lower urinary Tract Symptoms.
15 . A method of treating lower urinary tract symptoms in a patient in need of such treatment comprising the administration of a therapeutically effective amount of a composition according to claim 1 .
16 . A method of treating lower urinary tract symptoms in a patient in need of such treatment comprising the administration of a therapeutically effective amount of a beta 3 agonist selected from
N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-(3-cyclopentylpropyl)-5-tetrazolon-1-yl]benzenesulfonamide; and
2N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide, or a pharmaceutically acceptable salt thereof and
optionally a therapeutically effective amount of a 5-alpha reductase inhibitor, or an NK-1 antagonist or an alpha-1 adrenergic antagonist or an anti-muscarinic agent.