Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-11-12
2003-11-25
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S653000, C546S157000, C564S218000, C564S360000, C564S365000
Reexamination Certificate
active
06653323
ABSTRACT:
FIELD OF THE INVENTION
The invention is directed to novel &bgr;
2
adrenergic receptor agonists. The invention is also directed to pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with &bgr;
2
adrenergic receptor activity, and processes and intermediates useful for preparing such compounds.
BACKGROUND OF THE INVENTION
&bgr;
2
Adrenergic receptor agonists are recognized as effective drugs for the treatment of pulmonary diseases such as asthma and chronic obstructive pulmonary disease (including chronic bronchitis and emphysema). &bgr;
2
Adrenergic receptor agonists are also useful for treating pre-term labor, and are potentially useful for treating neurological disorders and cardiac disorders. In spite of the success that has been achieved with certain &bgr;
2
adrenergic receptor agonists, current agents possess less than desirable potency, selectivity, speed of onset, and/or duration of action. Thus, there is a need for additional &bgr;
2
adrenergic receptor agonists having improved properties. Preferred agents may possess, among other properties, improved duration of action, potency, selectivity, and/or onset.
SUMMARY OF THE INVENTION
The invention provides novel compounds that possess &bgr;
2
adrenergic receptor agonist activity. Accordingly, this invention provides compounds of formula (I):
wherein:
R
1
is methoxy or ethoxy and R
2
is hydrogen or phenyl; or R
1
is hydrogen and R
2
is phenyl; and
R
3
is —CH
2
OH or —NHCHO and R
4
is hydrogen; or R
3
and R
4
taken together are —NHC(═O)CH═CH—;
or a pharmaceutically-acceptable salt or solvate or stereoisomer thereof.
The invention also provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically-acceptable carrier.
The invention also provides a method of treating a disease or condition associated with &bgr;
2
adrenergic receptor activity (e.g. a pulmonary disease, such as asthma or chronic obstructive pulmonary disease, pre-term labor, a neurological disorder, a cardiac disorder, or inflammation) in a mammal, comprising administering to the mammal, a therapeutically effective amount of a compound of the invention.
The invention also provides a method of treating a disease or condition associated with &bgr;
2
adrenergic receptor activity in a mammal, comprising administering to the mammal, a therapeutically effective amount of a pharmaceutical composition of the invention.
This invention also provides a method of modulating a &bgr;
2
adrenergic receptor, the method comprising contacting a &bgr;
2
adrenergic receptor with a modulating amount of a compound of the invention.
In separate and discrete aspects, the invention also provides synthetic processes and intermediates, including compounds of formulas (V), (VI), and (IX) described herein, which are useful for preparing compounds of the invention.
The invention also provides a compound of the invention as described herein for use in medical therapy, as well as the use of a compound of the invention in the manufacture of a formulation or medicament for treating a disease or condition associated with &bgr;
2
adrenergic receptor activity (e.g. a pulmonary disease, such as asthma or chronic obstructive pulmonary disease, pre-term labor, a neurological disorder, a cardiac disorder, or inflammation) in a mammal.
Preferred compounds of the invention are shown in Table I.
TABLE I
Preferred Compounds of The Invention
Compound
Structure
1
N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-
2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine
2
N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-
hydroxymethyl-4-hydroxyphenyl)ethylamine
3
N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-
hydroxymethyl-4-hydroxyphenyl)ethylamine
4
N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-
hydroxymethyl-4-hydroxyphenyl)ethylamine
5
N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-
formamido-4-hydroxyphenyl)ethylamine
6
N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-
hydroxy-2(1H)-quinolinon-5-yl)ethylamine
7
N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-
hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine
8
N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-
2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine
9
N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-
hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine
10
N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-
hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine
11
N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-
hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine
12
N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-
hydroxy-2(1H)-quinolinon-5-yl)ethylamine
13
N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-
hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine
14
N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-
hydroxymethyl-4-hydroxyphenyl)ethylamine
15
N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-
hydroxymethyl-4-hydroxyphenyl)ethylamine
16
N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-
formamido-4-hydroxyphenyl)ethylamine
17
N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-
formamido-4-hydroxyphenyl)ethylamine
18
N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-
hydroxy-2(1H)-quinolinon-5-yl)ethylamine
19
N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-
hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine
20
N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-
hydroxymethyl-4-hydroxyphenyl)ethylamine
21
N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-
(3-hydroxymethyl-4-hydroxyphenyl)ethylamine
22
N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-
2-(3-formamido-4-hydroxyphenyl)ethylamine
23
N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-
formamido-4-hydroxyphenyl)ethylamine
24
N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-
formamido-4-hydroxyphenyl)ethylamine
25
N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-
(3-formamido-4-hydroxyphenyl)ethylamine
26
N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-
formamido-4-hydroxyphenyl)ethylamine
27
N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-
hydroxy-2(1H)-quinolinon-5-yl)ethylamine
28
N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-
hydroxy-2(1H)-quinolinon-5-yl)ethylamine
29
N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-
(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine
30
N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-
hydroxy-2(1H)-quinolinon-5-yl)ethylamine
DETAILED DESCRIPTION OF THE INVENTION
When describing the compounds, compositions and methods of the invention, the following terms have the following meanings, unless otherwise indicated.
The term “methoxy” or “—OMe” refers to a group of the formula —OCH
3
, and the term “ethoxy” or “—OEt” refers to a group of the formula —OCH
2
CH
3
.
The term “therapeutically effective amount” refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
The term “treatment” as used herein refers to the treatment of a disease or medical condition in a patient, such as a mammal (particularly a human) which includes:
(a) preventing the disease or medical condition from occurring, i.e., prophyl
Aggen James B.
Jacobsen John R.
Moran Edmund J.
Boone David E.
Hagenah Jeffrey A.
Saxon Roberta P.
Seaman D. Margaret
Theravance Inc.
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