Bispidine antiarrhythmic compounds

Details Bispidine antiarrhythmic compounds Bispidine antiarrhythmic compounds

1999-01-12

2001-09-18

Huang, Evelyn Mei (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S122000

Reexamination Certificate

active

06291475

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 antiarrhythtmic 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 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.
Most antiarrhythmic drugs (including class III antiarrhythmic drugs) have a duration of action of between 3 and 12 hours. For example, the recently registered (approved, as of December 1997, in the US, Sweden, the UK, Denmark, Belgium, Netherlands, Finland, Italy and Austria) selective class III antiarrhythmic drug ibutilide (Pharmacia Upjohn) has a half-life of elimination which averages at around 6 hours when the drug is administered intravenously to a human patient.
In the minimisation of the side effects (including torsades de pointes) associated with antiarrhythmic drugs, compounds which are effective, yet short acting, when administered intravenously, are expected to be of benefit. Accordingly, compounds which have a duration of action which is relatively short (hereinafter referred to as “short acting compounds”) may be expected to have clinical advantages when used in the acute conversion of arrhythmias, including reduced monitoring and hospitalisation time. By “short acting” in this context, we mean a half life (t
½
), as measured in the test described below, of between 1 and 120 minutes, preferably between 1 and 60 minutes, more preferably between 1 and 30 minutes and especially between 1 and 15 minutes.
Antiarrhythmic drugs based on bispidines (3,7-diazabicyclo[3.3.1]nonanes), are known from inter alia international patent application WO 91/07405, 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). Known bispidine-based antiarrhythmic compounds include bisaramil (3-methyl-7-ethyl-9&agr;,4′-(C1-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-imidazolo-1-yl)benzenesulphonyl]-3-isopropyl-3,7-diaza-bicyclo[3.3.1]nonane dihydro-perchlorate 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 in particular short-acting 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 a compound of formula I,
wherein
R
1
and R
2
independently represent H, C
1-4
alkyl or together form —O—(CH
2
)
2
—O—, —(CH
2
)
4
— or —(CH
2
)
5
—;
R
9
represents C
1-12
alkyl, phenyl, naphthyl, C
1-3
alkylphenyl (which four groups are all optionally substituted or terminated by one or more substituents selected from —OH, halo, cyano, nitro, C
1-4
alkyl or C
1-4
alkoxy) or —(CH
2
)
q
Cy
1
;
R
10
represents H or —OH;
R
11
represents H or C
1-4
alkyl;
R
12
represents one or more optional substituents selected from OH, cyano, halo, amino, nitro, C
1-6
alkyl, C
1-6
alkoxy, —N(H)S(O)
2
R
16
, —OS(O)
2
R
16a
, —N(H)C(O)N(H)R
17
or —C(O)N(H)R
18
;
A represents a single bond, C
1-4
alkylene, —(CH
2
)
n
N(R
20
)—, —(CH
2
)
n
S(O)
p
—, —(CH
2
)
n
O— (in which three latter groups, the —(CH
2
)
n
— group is attached to the carbon atom bearing R
10
and R
11
), —C(O)N(R
20
)— (in which latter group, the —C(O)— group is attached to the carbon atom bearing R
10
and R
11
),
—N(R
20
)C(O)O(CH
2
)
n
—, —N(R
20
)(CH
2
)
n
— (in which two latter groups, the N(R
20
) group is attached to the carbon atom bearing R
10
and R
11
) or
—(CH
2
)
m
C(H)(OH)(CH
2
)
n
— (in which latter group, the —(CH
2
)
m
— group is attached to the carbon atom bearing R
10
and R
11
);
B represents a single bond, C
1-6
alkylene, —N(R
23
)(CH
2
)
r
— or —O(CH
2
)
r
— (in which two latter groups, the —(CH
2
)
r
— group is attached to the bispidine nitrogen atom);
m represents 1, 2 or 3;
n and r independently represent 0, 1, 2, 3 or 4;
p represents 0, 1 or 2;
q represents 0, 1, 2 or 3;
X represents O or S;
Cy
1
represents a five to seven-membered heterocyclic ring containing one or more heteroatom selected from O, N or S, which ring is optionally 15 substituted by one or more substituent selected from C(O)R
21
or C(O)OR
22
;
R
16
, R
16a
, R
20
and R
23
independently represent H or C
1-4
alkyl; and
R
17
, R
18
, R
21
and R
22
independently represent H or C
1-6
alkyl;
or a pharmaceutically acceptable derivative thereof.
Pharmaceutically acceptable derivatives include salts and solvates. Salts which may be mentioned include acid addition salts. Pharmaceutically acceptable derivatives also include, at the bispidine nitrogens, C
1-4
alkyl quaternary ammonium salts and N-oxides, provided that, when a N-oxide is present at a bispidine nitrogen, X does not represent S and/or p does not represent 0 when A represents —(CH
2
)
n
S(O)
p
—.
The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimeris

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