Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-25
2003-01-28
Rao, Deepak R. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252140, C514S252180, C514S253040, C514S302000, C544S127000, C544S331000, C544S362000, C546S115000, C546S116000
Reexamination Certificate
active
06511977
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to indanes and benzopyrans and analogues thereof which are potassium channel inhibitors and thus are useful as antiarrhythmic agents.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, novel indanes and benzopyrans and analogues thereof are provided which are potassium channel inhibitors and have the structure
including pharmaceutically acceptable salts thereof, prodrug esters thereof, and all stereoisomers thereof, wherein
A, B and D are independently selected from CH or N;
X
1
is
(where n is 1, 2 or 3), O, NR
5
, S, SO, SO
2
,
wherein the hetero atom in each of the above groups is linked to the aromatic ring;
(where R
3
and R
4
are independently H, alkyl, arylalkyl or cycloalkyl, or R
3
and R
4
can be taken together with the carbon to which they are attached to form a 5 to 8 carbon containing ring; and R
5
is H, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl);
R is H, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl, or cycloalkylalkyl;
R
1
is alkyl, arylalkyl, aryl, alkenyl, heterocyclo, heterocycloalkyl,
(where R
5a
can be any of the R
5
groups), cycloalkyl, cycloalkylalkyl or
(where R
6
and R
7
are independently selected from H, aryl, alkyl, arylalkyl or cycloalkyl, or R
6
and R
7
can be taken together with the nitrogen atom to which they are attached to form a 5 to 8 membered ring); or R and R
1
can be taken together with the —N—S— atoms to form a 5- to 8-membered ring;
X
2
is a single bond,
or —O— (where R
8
is H, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl);
R
2
is H, alkyl, arylalkyl,
(where R
10
and R
11
are independently selected from H, alkyl, arylalkyl or cycloalkyl, or R
10
and R
11
can be taken together with the nitrogen to which they are attached to form a 5- to 8-membered ring); and
(where R
12
is alkyl, arylalkyl, aryl,
heterocycle, heterocycloalkyl,
(where R
14
can be any of the R
8
groups), alkoxy, CF
3
, aryloxy, arylalkoxy, cycloalkyl or cycloalkylalkyl, and where R
15
and R
16
are independently selected from H, alkyl, arylalkyl, aryl, heterocyclo, cycloalkyl, amino, aminoalkyl, or heterocycloalkyl, or R
15
and R
16
can be taken together with the nitrogen to which they are attached to form a 5- to 8-membered ring which may optionally contain an additional nitrogen atom in the ring and/or an amino group or an aminoalkyl group attached to the ring); and
R
13
is
(wherein this moiety is as defined with respect to R
12
);
with the proviso that where X
1
is
and A, B and D are all carbon, then
(1) where Q is
and R
12
or R
13
is
at least one of R
15
or R
16
is, aryl, arylalkyl, heterocycle or heterocycloalkyl, or alkyl of 4 to 12 carbons; and/or
(2) Q is other than
(where R
12
is methyl, ethyl, CF
3
or alkoxy); and/or
(3) where Q is
and R
12
is
then heterocycle is a monocyclic or bicyclic heterocycle ring containing from 5 to 10 ring members, containing one to five nitrogen atoms, and/or one or two oxygen atoms, and/or one sulfur atom; and/or
(4) where Q is
and R
12
is
then at least one of R
15
and R
16
contains an additional amino group or R
15
and R
16
taken together with the nitrogen atom to which they are attached form a ring which contains an additional nitrogen atom in the ring and/or an amino group or an aminoalkyl group attached to the ring; and/or
(5) where Q is
and R
13
is
then at least one of R
15
and R
16
contains an additional amino group or R
15
and R
16
taken together with the nitrogen atom to which they are attached form a ring which contains an additional nitrogen atom in the ring and/or an amino group or an aminoalkyl group attached to the ring.
Preferred compounds of formula I of the invention can have the following structural formulae:
Preferred are compounds of formula I wherein Q is
wherein heterocycle is a monocyclic ring (cycloheteroalkyl ring or heteroaryl ring) containing 5 or 6 ring members which include one or two nitrogen atoms in the ring and/or one oxygen atom in the ring.
Also preferred are compounds of formula I where
R is H;
R
1
is aryl or alkyl;
X
2
is O or a single bond;
R
2
is H;
X
1
is
where R
3
and R
4
are each H and/or alkyl;
A and B are each CH;
D is N or CH; and
Q is
where R
15
and R
16
are H, aryl, aralkyl or aminoalkyl.
Still more preferred are compounds of formula I where
R is H;
R
1
is aryl;
X
2
is O or a single bond;
R
2
is H;
X
1
is
A and B are each CH;
D is N or CH; and
Q is
In addition, in accordance with the present invention, a method for preventing, inhibiting or treating cardiac arrhythmia, including atrial arrhythmia, is provided, wherein a compound of formula I is administered in a therapeutically effective amount which inhibits the IKur potassium channel.
The formula I compound employed in the above method has the structure
including pharmaceutically acceptable salts thereof, prodrug esters thereof, and all stereoisomers thereof, wherein
A, B and D are independently selected from CH or N;
X
1
is
(where n is 1, 2 or 3), O, NR
5
, S, SO, SO
2
,
wherein the heteroatom in each of the above groups is linked to the aromatic ring;
(where R
3
and R
4
are independently H, alkyl, arylalkyl or cycloalkyl, or R
3
and R
4
can be taken together with the carbon to which they are attached to form a 5 to 8 carbon containing ring; and R
5
is H, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl);
R is H, alkyl, alkenyl, aryl, arylalkyl, heterocycloalkyl, cycloalkyl, or cycloalkylalkyl;
R
1
is alkyl, arylalkyl, aryl, alkenyl, heterocyclo, heterocycloalkyl,
(where R
5a
can be any of the R
5
groups), cycloalkyl, cycloalkylalkyl or
(where R
6
and R
7
are independently selected from H, aryl, alkyl, arylalkyl or cycloalkyl, or R
6
and R
7
can be taken together with the nitrogen atom to which they are attached to form a 5 to 8 membered ring); or R and R
1
can be taken together with the —N—S— atoms to form a 5- to 8-membered ring;
X
2
is a bond,
or —O—
(where R
8
is H, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl);
R
2
is H, alkyl, arylalkyl,
(where R
10
and R
11
are independently selected from H, alkyl, arylalkyl or cycloalkyl, or R
10
and R
11
can be taken together with the nitrogen to which they are attached to form a 5- to 8-membered ring); and
Q is
(where R
12
is alkyl, arylalkyl, aryl,
heterocycle, heterocycloalkyl,
where R
14
can be any of the R
8
groups), alkoxy, aryloxy, arylalkoxy, cycloalkyl or cycloalkylalkyl, and where R
15
and R
16
are independently selected from H, alkyl, arylalkyl, heterocyclo, cycloalkyl or heterocycloalkyl, or R
15
and R
16
can be taken together with the nitrogen to which they are attached to form a 5- to 8-membered ring (which may optionally contain an additional nitrogen in the ring and/or an amino group or an aminoalkyl group attached to the ring); and
R
13
is
(wherein this moiety is as defined with respect to R
12
).
DETAILED DESCRIPTION OF THE INVENTION
The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.
Unless otherwise indicated, the term “lower alkyl”, “alkyl” or “alk” as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 40 carbons, preferably 1 to carbons, more preferably 1 to 12 carbons, in the normal chain,such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various additional branched chain isomers thereof, and the like as well as such groups including 1 to 4 substituents which may be halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido,
Atwal Karnail S.
Finlay Heather J.
Gross Michael F.
Lloyd John
Spear Kerry L.
Bristol--Myers Squibb Company
Rao Deepak R.
Rodney Burton
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