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
2003-12-30
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S157000, C546S229000, C546S312000, C564S086000, C564S336000, C548S193000, C544S128000, C544S158000, C544S297000, C514S235200, C514S237800, C514S275000, C514S331000, C514S352000, C514S370000, C514S649000
Reexamination Certificate
active
06670376
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:
each of R
1
-R
5
is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and R
a
;
or R
1
and R
2
, R
2
and R
3
, R
3
and R
4
, or R
4
and R
5
are joined together to form a group selected from the group consisting of —C(R
d
)═C(R
d
)C(═O)NR
d
—, —CR
d
R
d
—CR
d
R
d
—C(═O)NR
d
—, —NR
d
C(═O)C(R
d
)═C(R
d
)—, —NR
d
C(═O)CR
d
R
d
—CR
d
R
d
—, —NR
d
C(═O)S—, —SC(═O)NR
d
—, —(CR
d
R
d
)
p
—, —S(CR
d
R
d
)
q
—, —(CR
d
R
d
)
q
S—, —S(CR
d
R
d
)
r
O—, —O(CR
d
R
d
)
r
S—, and —NHC(R
j
)═C(R
k
)—;
R
6
is hydrogen, alkyl, or alkoxy;
R
7
is hydrogen or alkyl;
R
8
is hydrogen or alkyl; or R
8
together with R
9
is —CH
2
— or —CH
2
CH
2
—;
R
9
is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and R
a
, or R
9
together with R
8
is —CH
2
— or —CH
2
CH
2
—;
R
10
is hydrogen or alkyl;
each R
11
, R
12
, and R
13
is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —NO
2
, halo, —NR
d
R
e
, —C(═O)R
d
, —CO
2
R
d
, —OC(═O)R
d
, —CN, —C(═O)NR
d
R
e
, —NR
d
C(═O)R
e
, —OC(═O)NR
d
R
e
, —NR
d
C(═O)OR
e
, —NR
d
C(═O)NR
d
R
e
, —OR
d
, —S(O)
m
R
d
, —NR
d
—NR
d
—C(═O)R
d
, —NR
d
N═CR
d
R
d
, —N(NR
d
R
e
)R
d
, and —S(O)
2
NR
d
R
e
;
or R
11
and R
12
together with the atoms to which they are attached form a fused benzo ring, which benzo ring can optionally be substituted with 1, 2, 3, or 4 R
c
;
or R
11
and R
12
together with the atoms to which they are attached form a heterocyclic ring;
wherein for R
1
-R
6
, R
9
, and R
11
-R
13
, each alkyl, alkenyl, and alkynyl is optionally substituted with R
m
, or with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from R
b
; for R
1
-R
6
, R
9
, and R
11
-R
13
each aryl and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R
c
, and for R
1
-R
6
, R
9
, and R
11
-R
13
each cycloalkyl and heterocyclic ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R
b
and R
c
;
each R
a
is independently —OR
d
, —NO
2
, halo, —S(O)
m
R
d
, —S(O)
2
OR
d
, —S(O)
m
NR
d
R
e
, —NR
d
R
e
, —O(CR
f
R
g
)
n
NR
d
R
e
, —C(═O)R
d
, —CO
2
R
d
, —CO
2
(CR
f
R
g
)
n
—CONR
d
R
e
, —OC(═O)R
d
, —CN, —C(═O)NR
d
R
e
, —NR
d
C(═O)R
e
, —OC(═O)NR
d
R
e
, —NR
d
C(═O)OR
e
, —NR
d
C(═O)NR
d
R
e
, —CR
d
(═N—OR
e
), —CF
3
, or —OCF
3
;
each R
b
is independently R
a
, oxo, or ═N—OR
e
;
each R
c
is independently R
a
, alkyl, alkenyl, or alkynyl; wherein each alkyl, alkenyl and alkynyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R
b
;
each R
d
and R
e
is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from R
h
; or R
d
and R
e
together with the atoms to which they are attached form a heterocyclic ring having from 5 to 7 ring atoms, wherein the heterocyclic ring optionally contains 1 or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
each R
f
and R
g
is independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R
h
; or R
f
and R
g
together with the carbon atom to which they are attached form a ring having from 5 to 7 ring atoms, wherein the ring optionally contains 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
each R
h
is independently halo, C
1-8
alkyl, C
1-8
alkoxy, —S—C
1-8
alkyl, aryl, (aryl)-C
1-6
alkyl, (aryl)-C
1-8
alkoxy, heteroaryl, (heteroaryl)-C
1-6
alkyl, (heteroaryl)-C
1-8
alkoxy, hydroxy, amino, —NHC
1-6
alkyl, —N(C
1-6
alkyl)
2
, —OC(═O)C
1-6
alkyl, —C(═O)C
1-6
alkyl, —C(═O)OC
1-6
alkyl, —NHC(═O)C
1-6
alkyl, —C(═O)NHC
1-6
alkyl, carboxy, nitro, —CN, or —CF
3
;
R
j
and R
k
together with the carbon atoms to which they are attached form a phenyl ring that is optionally substituted with 1, 2, 3, or 4 R
c
;
each R
m
is independently aryl, heteroaryl, cycloalkyl or heterocyclyl; wherein each aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of R
c
, and wherein each cycloalkyl and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents selected from R
b
;
m is 0, 1, or 2;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
p is 3, 4, or 5;
q is 2, 3, or 4;
r is 1, 2, or 3;
w is 0, 1, 2, 3, or 4;
or a pharmaceutically-acceptable salt or solvate or stereoisomer thereof.
The invention also provides compounds of formula (II):
wherein:
R
4
is —CH
2
OH or —NHCHO and R
5
is hydrogen; or R
4
and R
5
taken together are —NHC(═O)CH═CH—;
R
11
is phenyl or heteroaryl, wherein each phenyl is optionally substituted with 1 or 2 substituents selected from halo, —OR
d
, —CN, —NO
2
, —SO
2
R
d
, —C(═O)R
d
, —C(═O)NR
d
R
e
, and C
1-3
alkyl, wherein C
1-3
alkyl is optionally substituted with 1 or 2 substituents selected from carboxy, hydroxy, and amino, and each R
d
and R
e
is independently hydrogen or C
1-3
alkyl; and wherein each heteroaryl is optionally substituted with 1 or 2 C
1-3
alkyl substituents; and
R
12
is hydrogen or —OC
1-6
alkyl;
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 (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 amou
Aggen James
Church Timothy J.
Jacobsen John R.
Leadbetter Michael R.
Moran Edmund J.
Aulakh Charanjit S.
Boone David E.
Hagenah Jeffrey A.
Saxon Roberta P.
Theravance Inc.
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