Bispidine compounds useful in the treatment of cardiac...

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

2000-09-07

2002-10-15

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S122000, C546S018000, C514S278000

Reexamination Certificate

active

06465481

ABSTRACT:

This application is a 371 of PCT/SE00/01251 filed Jun. 15, 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 III 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 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 application WO 91/07405, ye European patent applications 306 871, 308 843 and 655 228 and US 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). Known bispidine-based antiarrhythmic compounds include bisaramil (3-methyl-7-ethyl-9&agr;, 4′-(Cl-benzoyloxy)-3,7-diazabicyclo[3.3.1]nonane), tedisamil (3′, 7′-bis(cyclopropylmethyl)spiro-(cyclopentane-1,9′)-3,7-diazabicyclo[3.3.1]nonane), SAZ-VII-22 (3-(4-chlorobenzoyl)-7-isopropyl-3,7-diazabicyclo[3.3.1]nonane), SAZ-VII-23 (3-benzoyl-7-isopropyl-3,7-diazabicyclo[3.3.1]nonane), GLG-V-13 (3-[4-(1H-imidazol-1-yl)benzoyl]-7-isopropyl-3,7-diazabicyclo[3.3.1]nonane), KMC-IV-84 (7-[4′-(1H-imidazol-1-yl)benzenesulfonyl]-3-isopropyl-3,7-diaza-bicyclo[3.3.1]nonane dihydroperchlorate and ambasilide (3-(4-aminobenzoyl)-7-benzyl-3,7-diazabicyclo[3.3.1]nonane).
We have surprisingly found that a novel group of bispidine-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, —(CH
2
)
a
-aryl, or —(CH
2
)
a
-Het
1
(all of which are optionally substituted and/or terminated (as appropriate) by one or more substituents selected from —OH, halo, cyano, nitro, C
1-4
alkyl and/or C
1-4
alkoxy);
a represents 0, 1, 2, 3, or 4;
Het
1
represents a five to ten-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, and which also optionally includes one or more ═O sub stituents;
X represents O or S;
R
5a
and R
5b
independently represent H or C
1-3
alkyl;
R
2
and R
3
independently represent H, C
1-4
alkyl (optionally substituted and/or terminated with one or more nitro or cyano groups), OR
7
, N(R
7a
)R
7b
, OC(O)RS or together form —O—(CH
2
)
2
—O—, —(CH
2
)
3
—, —(CH
2
)
4
— or —(CH
2
)
5
—;
R
7
and R
8
independently represent H, C
1-6
alkyl or —(CH
2
)
b
-aryl (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/or C
1-4
alkoxy);
R
7a
and R
7b
independently represent H or C
1-6
alkyl;
b represents 0, 1, 2, 3 or 4;
R
4
represents H or C
1-6
alkyl;
R
9
represents —C(O)R
10
, C
1-6
alkyl, —(CH
2
)
d
-aryl or —(CH
2
)
d
-Het
2
(which latter three groups are optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, C
1-4
alkyl, C
1-4
alkoxy, C(O)R
11
, C(O)OR
12
and/or —N(H)S(O)
e
R
13
);
R
10
, R
11
and R
12
independently represent H, C
1-6
, alkyl, Het
3
or —(CH
2
)
f
-aryl (which latter three groups are optionally substituted and/or terminated (as appropriate) by one or more substituents selected from —OH, cyano, halo, amino, nitro, C
1-6
, alkyl, C
1-6
alkoxy, C(O)R
14
, C(O)OR
15
and/or N(H)S(O)
2
R
16
);
R
13
represents C
1-6
alkyl or —(CH
2
)
g
-aryl (both of which are optionally substituted and/or terminated (as appropriate) by one or more substituents selected from halo, nitro, C
1-6
alkyl and/or C
1-6
alkoxy);
R
14
and R
15
independently represent H, C
1-6
alkyl or aryl;
R
16
represents C
1-6
alkyl or aryl;
e represents 0, 1 or 2;
d, f and g independently represent 0, 1, 2, 3 or 4;
Het
2
and Het
3
independently represent five to ten-membered heterocyclic rings containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, and which also optionally includes one or more ═O substituents;
R
6
represents one or more optional substituents selected from —OH, cyano, halo, amino, nitro, C
1-6
alkyl (optionally terminated by N(H)C(O)OR
18a
), C
1-6
alkoxy, —C(O)N(H)R
19
, —NHC(O)N(H)R
20
, —N(H)S(O)
2
R
21
and/or —OS(O)
2
R
22
;
R
19
and R
20
independently represent H or C
1-6
alkyl;
R
18a
, R
21
and R
22
independently represent C
1-6
alkyl;
A represents a single bond, C
1-6
alkylene or —(CH
2
)
j
C(H)(OR
23
)(CH
2
)
k
— (in which latter group, the —(CH
2
)
j
— group is attached to the bispidine nitrogen atom and which latter two groups are optionally substituted by one or more —OH groups);
B represents a single bond, C
1-4
alkylene, —(CH
2
)
m
N(R
24
)—, —(CH
2
)
m
S(O)
n
—, —(CH
2
)
m
O— (in which three latter groups, the —(CH
2
)
m
— group is attached to the carbon atom bearing OR
9
and R
4
), —C(O)N(R
24
)— (in which latter group, the —C(O)— group is attached to the carbon atom bearing OR
9
and R
4
), —N(R
24
)C(O)O(CH
2
)
m
— or —N(R
24
)(CH
2
)
m
— (in which latter two groups, the N(R
24
) group is attached to the carbon atom bearing OR
9
and R
4
);
j represents 1, 2, 3 or 4;
k and m independently represent 0, 1, 2, 3 or 4;
n represents 0, 1 or 2;
R
23
represents H, C
1-6
alkyl or C(O)R
25;
R
24
represents H or C
1-6
alkyl;
R
25
represents H, C
1-6
alkyl, Het
4
or —(CH
2
)
p
-aryl (which latter two groups are optionally substituted and/or terminated (as appropriate) by one or more substituents selected from —OH, cyano, halo, amino, nitro, C
1-6
alkyl and/or C
1-6
alkoxy);
Het
4
represents a five to ten-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, and which also optionally includes one or more ═O substituents;
p represents 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable derivative thereof;
provided that m does not represent 0 when B represents —(CH
2
)
m
N(R
24
), —(CH
2
)
m
S(O)
n
— or —(CH
2
)
m
O—,
which compounds are referred to hereinafter as “the compounds of th

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