Azabicyclooctane derivatives useful in the treatment of...

Details Azabicyclooctane derivatives useful in the treatment of... Azabicyclooctane derivatives useful in the treatment of...

2001-02-28

2003-05-06

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...

C546S112000, C546S124000, C514S304000

Reexamination Certificate

active

06559162

ABSTRACT:

This application is a 371 of PCT/SE00/02064 filed Dec. 19, 2000, now WO 01/47893 Jul. 5, 2000.
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 m or otherwise) is that they all are known to exhibit a unique form of proarrhythmia known as torsades de pointes (turning of points), which may, on occasion be fatal. From the point of view of safety, the minimisation of this phenomenon (which has also been shown to be exhibited as a result of administration of noncardiac drugs such as phenotiazines, 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 665 228 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). 3-Azabicyclo[3.2.1]octane compounds are neither disclosed nor suggested in any of these documents.
Compounds based on 3-azabicyclo[3.2.1]octanes are known for use in a variety of other medical applications including serotonin antagonism (as described in EP 212 802 and EP 645 391), neurokinin-I receptor antagonism (as described in WO 98/18788), nitric oxide synthase inhibition (as described in WO 97/36871) and analgesia (as described in Rico, B, et al.,
J. Heterocycl. Chem
. 31(2), 313-318 (1994)). None of these documents either disclose or suggest the use of 3-azabicyclo[3.2.1]octane-based compounds as antiarrhythmic agents.
We have surprisingly found that a novel group of 3-azabicyclo[3.2.1]octane-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
the wavy bond represents optional endo- or exo-stereochemistry;
one of R
1
and R
2
represents R
1a
and the other represents a fragment of the formula Ia,
R
1a
represents C
1-12
alkyl (optionally substituted and/or terminated by one or more groups selected from halo, cyano, nitro, aryl, Het
1
, —C(O)R
7a
, —OR
7b
, —N(R
8
)R
7c
, —C(O)XR
9
, —C(O)N(R
10
)R
7d
and —S(O)
2
R
11
), Het
2
, —C(O)R
7a
, —C(O)XR
9
, —C(O)N(R
10
)R
7d
or —S(O)
2
R
11
;
R
7a
to R
7d
independently represent, at each occurrence when used herein, H, C
1-6
alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, C
1-6
alkoxy, halo, cyano, nitro, aryl, Het
3
and —NHC(O)R
12
), aryl or Het
4
, or R
7d
, together with R
10
, 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
12
represents H, C
1-4
alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, cyano, aryl and —NHC(O)R
13
) or aryl;
R
13
represents H, C
1-4
alkyl or aryl;
R
8
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
14a
or —C(O)OR
14b
;
R
14a
and R
14b
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, or R
14a
represents H;
X represents O or S;
R
9
represents, at each occurrence when used herein, C
1-12
alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro, aryl, C
1-4
alkoxy, —SO
2
R
15
and Het
5
);
R
15
represents C
1-6
alkyl or aryl;
R
10
represents, at each occurrence when used herein, 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
6
, —D—N(H)C(O)R
16a
, —D—S(O)
2
R
17a
, —D—C(O)R
16b
, —D—C(O)OR
17b
, —D—C(O)N(R
16c
)R
16d
, or R
10
, together with R
7d
, represents C
3-4
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
16a
to R
16d
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
16c
and R
16d
together represent C
3-6
alkylene;
R
17a
and R
17b
independently represent C
1-4
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;
R
11
represents, at each occurrence when used herein, C
1-6
alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl or Het
7
;
R
4
represents H, halo, C
1-6
alkyl, —OR
18
, —E—N(R
19
)R
20
OR together with
R
5
, represents ═O;
R
5
represents H, C
1-6
alkyl or, together with R
4
, represents ═O;
R
18
represents H, C
1-6
alkyl, —E-aryl, —E—Het
8
, —C(O)R
21a
, —C(O)OR
21b
or —C(O)N(R
22a
)R
22b
;
R
19
represents H, C
1-6
alkyl, —E-aryl, —E—Het
8
, —C(O)R
21a
, —C(O)OR
21b
, —S(O))
2
R
21c
, —[C(O)]
p
N(R
22a
)R
22b
or —C(NH)NH
2
;
R
20
represents H, C
1-6
alkyl, —E-aryl or —C(O)R
21d
;
R
21a
to R
21d
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
9
), aryl, Het
10
, or R
21a
and R
21d
independently represent H;
R
22d
and R
22b
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
11
), aryl, Het
12
, 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
12
independently represent, at each occurrence when used herein, 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, cy

Affiliated with

Also associated with

Rating

Azabicyclooctane derivatives useful in the treatment of... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Azabicyclooctane derivatives useful in the treatment of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Azabicyclooctane derivatives useful in the treatment of... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3008847