Biphenyl derivatives
This invention provides biphenyl derivatives of formula I: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , W, a, b and c are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The biphenyl derivatives of this invention possess both β 2 adrenergic receptor agonist and muscarinic receptor antagonist activity and therefore, such biphenyl derivatives are useful for treating pulmonary disorders, such as chronic obstructive pulmonary disease and asthma.
1. A compound of the formula:
2. Biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1, 2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenyl-carbamoyl) ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 , wherein the compound is in the form of a pharmaceutically acceptable salt.
4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition comprising:
(a) biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof;
(b) a steroidal anti-inflammatory agent; and
(c) a pharmaceutically acceptable carrier.
6. A pharmaceutical composition comprising an isotonic aqueous solution comprising from about 0.05 μg/mL to about 10 mg/mL of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising:
(a) biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenyl-carbamoyl) ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof; and
(b) a pharmaceutically acceptable carrier;
wherein the pharmaceutical composition is a dry powder.
8. The pharmaceutical composition of claim 7 , wherein the carrier is lactose or starch.
9. A pharmaceutical composition comprising:
(a) micronized particles of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenylcarbamoyl) ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof; and
(b) dry lactose having a particle size between about 1 μm and about 100 μm.
10. A pharmaceutical composition comprising:
(a) biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenyl-carbamoyl) ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof; and
(b) a propellant.
11. The pharmaceutical composition of claim 10 , wherein the propellant is a hydrofluoroalkane.
12. A method of treating a pulmonary disorder, the method comprising administering to a patient in need of treatment a therapeutically effective amount of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenylcarbamoyl)-ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
13. A method of treating a pulmonary disorder, the method comprisingadministering to a patient in need of treatment a therapeutically effective amount of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenylcarbamoyl)-ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a steroidal anti-inflammatory agent.
14. A method of treating chronic obstructive pulmonary disease, the method comprising administering to a patient in need of treatment a therapeutically effective amount of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenyl-carbamoyl) ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
15. A method of treating asthma, the method comprising administering to a patient in need of treatment a therapeutically effective amount of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethylamino]methyl}-2-methylphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
16. A method of producing bronchodilation in a patient, the method comprising administering to the patient a bronchodilation-producing amoun of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethylamino]methyl}-2-methylphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
17. A method of antagonizing a muscarinic receptor in a biological system or sample having a muscarinic receptor, the method comprising contacting the biological system or sample with a muscarinic receptor antagonizing-amount of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethylamino]methyl}-2-methylphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
18. A method of agonizing a β 2 adrenergic receptor in a biological system or sample having a β 2 adrenergic receptor, the method comprising contacting the biological system or sample with a β 2 adrenergic receptor agonizing-amount of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethylamino]methyl}-2-methylphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
19. A method of antagonizing a muscarinic receptor and agonizing a β 2 adrenergic receptor in a biological system or sample having a muscarinic receptor and a β 2 adrenergic receptor, the method comprising contacting the biological system or sample with a muscarinic receptor antagonizing- and β 2 adrenergic receptor agonizing-amount of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenylcarbamoyl)ethyl]-piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.