Biphenyl derivatives
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Accused Products
Abstract
This invention provides biphenyl derivatives of formula I:
wherein R1, R2, R3, R4, R5, R6, R7, 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 β2 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.
66 Citations
19 Claims
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1. A compound of the formula:
- 2. Biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenyl-carbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
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4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
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5. A pharmaceutical composition comprising:
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(a) biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof; (b) a steroidal anti-inflammatory agent; and (c) a pharmaceutically acceptable carrier.
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6. A pharmaceutical composition comprising an isotonic aqueous solution comprising from about 0.05 μ
- g/mL to about 10 mg/mL of biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
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7. A pharmaceutical composition comprising:
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(a) biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenyl-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. - View Dependent Claims (8)
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9. A pharmaceutical composition comprising:
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(a) micronized particles of biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof; and (b) dry lactose having a particle size between about 1 μ
m and about 100 μ
m.
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10. A pharmaceutical composition comprising:
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(a) biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenyl-carbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof; and (b) a propellant. - View Dependent Claims (11)
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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-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
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13. 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-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof;
- and a therapeutically effective amount of a steroidal anti-inflammatory agent.
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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-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenyl-carbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
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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-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]-piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
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16. A method of producing bronchodilation in a patient, the method comprising administering to the patient a bronchodilation-producing amount of biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]-piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
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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-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]-piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
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18. A method of agonizing a β
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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-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenyl-carbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
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2 adrenergic receptor in a biological system or sample having a β
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19. A method of antagonizing a muscarinic receptor and agonizing a β
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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-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenyl-carbamoyl) ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
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2 adrenergic receptor in a biological system or sample having a muscarinic receptor and a β
Specification