Oxabispidine compounds useful in the treatment of cardiac...

Details Oxabispidine compounds useful in the treatment of cardiac... Oxabispidine compounds useful in the treatment of cardiac...

2000-10-16

2003-05-06

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S469000, C540S472000, C544S074000, C544S080000

Reexamination Certificate

active

06559143

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel pharmaceutically useful compounds, in particular compounds which are useful in the treatment of cardiac arrhythmias.
BACKGROUND AND PRIOR ART
Cardiac arrhythmias may be defined as abnormalities in the rate, regularity, or site of origin of the cardiac impulse or as disturbances in conduction which causes an abnormal sequence of activation. Arrhythmias may be classified clinically by means of the presumed site of origin (i.e. as supraventricular, including atrial and atrioventricular, arrhythmias and ventricular arrhythmias) and/or by means of rate (i.e. bradyarrhythmias (slow) and tachyarrhythmias (fast)).
In the treatment of cardiac arrhythmias, the negative outcome in clinical trials (see, for example, the outcome of the Cardiac Arrhythmia Suppression Trial (CAST) reported in New England Journal of Medicine, 321, 406 (1989)) with “traditional” antiarrhythmic drugs, which act primarily by slowing the conduction velocity (class I antiarrhythmic drugs), has prompted drug development towards compounds which selectively delay cardiac repolarization, thus prolonging the QT interval. Class III antiarrhythmic drugs may be defined as drugs which prolong the trans-membrane action potential duration (which can be caused by a block of outward K
+
currents or from an increase of inward ion currents) and refractoriness, without affecting cardiac conduction.
One of the key disadvantages of hitherto known drugs which act by delaying repolarization (class III or otherwise) is that they all are known to exhibit a unique form of proarrhythnia known as torsades de pointes (turning of points), which may, on occasion be fatal. From the point of view of safety, the mininisation of this phenomenon (which has also been shown to be exhibited as a result of administration of non-cardiac drugs such as phenothiazines, tricyclic antidepressants, antihistamines and antibiotics) is a key problem to be solved in the provision of effective antiarrhythmic drugs.
Antiarrhythmic drugs based on bispidines (3,7-diazabicyclo[3.3.1]nonanes), are known from inter alia international patent applications WO 91/07405 and WO 99/31100, European patent applications 306 871, 308 843 and 655 228 and U.S. Pat. Nos. 3,962,449, 4,556,662, 4,550,112, 4,459,301 and 5,468,858, as well as journal articles including inter alia J. Med. Chem. 39, 2559, (1996), Pharmacol. Res., 24, 149 (1991), Circulation, 90, 2032 (1994) and Anal Sci, 9, 429, (1993). Oxabispidine compounds are neither disclosed nor suggested in any of these documents.
Certain oxabispidine compounds are disclosed as chemical curiosities in Chem. Ber., 96, 2872 (1963). That these compounds may be used in the treatment of arrhythmias is neither mentioned nor suggested.
We have surprisingly found that a novel group of oxabispidine-based compounds exhibit electrophysiological activity, preferably class III electrophysiological activity, and are therefore expected to be useful in the treatment of cardiac arrhythmias.
DISCLOSURE OF THE INVENTION
According to the invention there is provided compounds of formula I,
wherein
R
1
represents C
1-12
alkyl (which alkyl group is optionally substituted and/or terminated by one or more groups selected from halo, cyano, nitro, aryl, Het
1
, —C(O)R
5a
, —OR
5b
, —N(R
6
)R
5c
, —C(O)XR
7
, —C(O)N(R
8
)R
5d
, and —S(O)
2
R
9
), or R
1
represents —C(O)XR
7
, —C(O)N(R
8
)R
5d
or —S(O)
2
R
9
;
R
5a
to R
5d
independently represent, at each occurrence, H, C
1-6
alkyl (which latter group is optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro, aryl and Het
2
), aryl or Het
3
, or R
5d
, together with R
8
, represents C
3-6
alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C
1-3
alkyl groups);
R
6
represents H, C
1-6
alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl, —C(O)R
10a
, —C(O)OR
10b
or —C(O)N(H)R
10c
;
R
10a
, R
10b
and R
10c
independently represent C
1-6
alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl, or R
10a
represents H;
R
7
represents C
1-12
alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro, aryl, C
1-6
alkoxy and Het
4
);
R
8
represents H, C
1-12
alkyl, C
1-6
alkoxy (which latter two groups are optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro, C
1-4
alkyl and C
1-4
alkoxy), —D-aryl, —D-aryloxy, —D-Het
5
, —D—N(H)C(O)R
11a
, —D—S(O)
2
R
12a
, —D—C(O)R
11b
, —D—C(O)OR
12b
, —D—C(O)N(R
11c
)R
11d
, or R
8
, together with R
5d
, represents C
3-6
alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C
1-3
alkyl groups);
R
11a
to R
11d
independently represent H, C
1-6
alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl, or R
11c
and R
11d
together represent C
3-6
alkylene;
R
9
, R
12a
and R
12b
independently represent C
1-6
alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl) or aryl;
D represents a direct bond or C
1-6
alkylene;
X represents O or S;
R
2
represents H, halo, C
1-6
alkyl, —OR
13
, —E—N(R
14
)R
15
or, together with R
3
, represents═O;
R
3
represents H, C
1-6
alkyl or, together with R
2
, represents═O;
R
13
represents H, C
1-6
alkyl, —E-aryl, —E-Het
6
, —C(O)R
16a
, —C(O)OR
16b
or —C(O)N(R
17a
)R
17b
;
R
14
represents H, C
1-6
alkyl, —E-aryl, —E-Het
6
, —C(O)R
16a
, OR
16b
, —S(O)
2
R
16c
, —[C(O)]
p
N(R
17a
)R
17b
or —C(NH)NH
2
;
R
15
represents H, C
1-6
alkyl, —E-aryl or —C(O)R
16d
;
R
16a
to R
16d
independently represent, at each occurrence when used herein, C
1-6
alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het
7
), aryl, Het
8
, or R
16a
and R
16d
independently represent H;
R
17a
and R
17b
independently represent, at each occurrence when used herein, H or C
1-6
alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het
9
), aryl, Het
10
, or together represent C
3-6
alkylene, optionally interrupted by an O atom;
E represents, at each occurrence when used herein, a direct bond or C
1-4
alkylene;
p represents 1 or 2;
Het
1
to Het
10
independently represent five- to twelve-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which groups are optionally substituted by one or more substituents selected from —OH, oxo, halo, cyano, nitro, C
1-6
alkyl, C
1-6
alkoxy, aryl, aryloxy, —N(R
18a
)R
18b
, —C(O)R
18c
, —C(O)OR
18d
, —C(O)N(R
18e
)R
18f
, —N(R
18g
)C(O)R
18h
and —N(R
18i
)S(O)
2
R
18j
;
R
18a
to R
18j
independently represent C
1-6
alkyl, aryl or R
18a
to R
18i
independently represent H;
A represents a direct bond, —J—, —J—N(R
19
)— or —J—O— (in which latter two groups, N(R
19
)— or O— is attached to the carbon atom bearing R
2
and R
3
);
B represents —Z—, —Z—N(R
20
)—, —N(R
20
)—Z—, —Z—S(O)
n
—, —Z—O— (in which latter two groups, Z is attached to the carbon atom bearing R
2
and R
3
), —N(R
20
)C(O)O—Z—, (in which latter group, —N(R
20
) is attached to the carbon atom bearing R
2
and R
3
) or —C(O)N(R
20
)— (in which latter group, —C(O) is attached to the carbon atom bearing R
2
and R
3
);
J represents C
1-6
alkylene optionally substituted by one or more substituents selected from —OH, halo and amino;
Z represents a direct bond or C
1-4
alkylene;
n represents 0, 1 or 2;
R
19
and R
20
independently represent H or C
1-6
alkyl;
G represents CH or N;
R
4
represents one or more optional substituents selected from —OH, cyano, halo, nitro, C
1-6
alkyl (optionally terminated by —N(H)C(O)O

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