3-phenyl-3,7-diazabicyclo[3.3.1] nonane compounds,...

Details 3-phenyl-3,7-diazabicyclo[3.3.1] nonane compounds,... 3-phenyl-3,7-diazabicyclo[3.3.1] nonane compounds,...

2002-06-27

2003-08-05

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...

C514S300000, C546S018000, C546S122000

Reexamination Certificate

active

06602880

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to novel 3,7,9,9-tetrasubstituted 3,7-diazabicyclo[3.3.1]nonane compounds which bear a substituted phenyl radical in position 3, and to their salts and to pharmaceutical preparations containing these compounds and to processes for the preparation of these compounds and to the use of these compounds for inhibiting cardiac arrhythmia in mammals.
3-Benzoyl-3,7-diazabicyclo[3.3.1]nonane derivatives with antiarrhythmic properties are already known from U.S. Pat. No. 5,532,251 (=EP 665,014).
Furthermore, 3-phenylsulfonyl-3,7-diazabicyclo [3.3.1 ]nonane derivatives and medicaments containing them with antiarrhythmic properties are known from U.S. Pat. No. 5,576,327 and 5,635,511 (=EP 665,228).
Despite the efforts of the art, however, there has remained a need for active substances with effective antiarrhythmic activity.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide new antiarrhythmic active substances with an improved activity profile.
Furthermore, it is an object of the invention to provide new 3,7-diazabicyclo[3.3.1]nonane compounds having valuable pharmacological properties.
These and other objects are achieved in accordance with the present invention by providing a compound corresponding to the formula I:
wherein
R
1
is an alkyl group with 1-6 carbon atoms or a cycloalkylalkyl group with 4-7 carbon atoms,
R
2
is lower alkyl, and
R
3
is lower alkyl, or
R
2
and R
3
together form an alkylene chain with 3-6 carbon atoms, and
R
4
represents a phenyl radical monosubstituted in the ortho or para position by nitro, cyano or lower alkanoyl or disubstituted in the ortho and para positions by nitro;
or a physiologically compatible acid addition salt thereof.
It has now been found that the novel 3,7,9,9-tetrasubstituted 3,7-diazabicyclo[3.3.1]nonane compounds bearing a substituted phenyl radical in position 3 possess valuable pharmacological properties for the treatment and/or prophylaxis of cardiac arrhythmias and exhibit an antiarrhythmic action profile which makes them particularly suitable for the treatment of cardiac arrhythmias, in particular tachycardic arrhythmias.
The invention therefore relates to novel compounds of the general formula I
wherein
R
1
is an alkyl group with 1-6 carbon atoms or a cycloalkylalkyl group with 4-7 carbon atoms,
R
2
is lower alkyl, and
R
3
is lower alkyl, or
R
2
and R
3
together form an alkylene chain with 3-6 carbon atoms, and
R
4
represents a phenyl radical monosubstituted in the ortho or para position by nitro, cyano or lower alkanoyl or disubstituted in the ortho and para position by nitro,
and their physiologically compatible acid addition salts.
If R
1
in the compounds of Formula I represents an alkyl group, this may be straight-chain or branched and contain 1 to 6, preferably 3 to 5, in particular 4, carbon atoms. A cycloalkylalkyl group R
1
may preferably be cyclopropylmethyl. Alkyl radicals with 3 to 5 carbon atoms have proved particularly suitable radicals R
1
.
If the substituents R
2
and R
3
represent lower alkyl, these alkyl groups may be straight-chain or branched and contain 1 to 4, preferably 1 to 3, carbon atoms and in particular represent methyl.
If R
2
and R
3
together form an alkylene group, this may contain 3 to 6, preferably 4 to 5, carbon atoms. In particular, those compounds in which R
2
and R
3
together represent an alkylene chain with 4 to 5 carbon atoms have proved suitable.
The substituent R
4
represents a substituted phenyl group, in which the substituents of the phenyl group are arranged in the ortho or para position. A lower alkanoyl substituent may contain 2 to 5, preferably 2 to 3, carbon atoms. Preferably R
4
represents a phenyl group substituted in the para position by cyano or lower alkanoyl, in particular cyano.
According to the invention, the novel compounds of Formula I and their acid addition salts are obtained by reacting compounds of the general formula II
wherein R
1
, R
2
and R
3
have the above meanings, in known manner with compounds of the general formula III
R
4
—X  III
wherein R
4
has the above meaning and X is halogen, and optionally free bases of Formula I are converted into their acid addition salts or the acid addition salts are converted into the free bases of Formula I.
The reaction of the compounds of Formula II with compounds of Formula III can take place in known manner under conventional conditions for the substitution of aromatic halides by amines. In particular chlorine or fluorine are considered as halogens in the compounds of Formula II. The reaction is carried out in an organic solvent which is inert under the reaction conditions, at temperatures between room temperature and the boiling temperature of the reaction mixture. Suitable organic solvents include, for example, ethers, in particular cyclic ethers such as tetrahydrofuran, lower alkanols such as butanol, lower aliphatic ketones such as acetone, dimethyl sulfoxide, dimethyl formamide, aromatic hydrocarbons such as benzene or toluene or mixtures of the above solvents. Advantageously, the reaction may be carried out under basic conditions e.g. in the presence of an at least equivalent amount of a base. Examples of suitable bases include inorganic bases such as alkali metal hydroxides, alkali metal carbonates, alkali metal amides or alkali metal hydrides and organic bases such as tertiary lower alkylamines.
The compounds of Formula I may be isolated from the reaction mixture and purified in a known manner. Acid addition salts can be converted into the free bases in conventional manner, and these may if desired be converted in known manner into pharmacologically compatible acid addition salts.
Suitable pharmacologically acceptable acid addition salts of the compounds of Formula I include, for example, the salts thereof with the usual inorganic acids, e.g. hydrohalic acids, in particular hydrochloric acid, sulfuric acid or phosphoric acids, or with organic acids, for example lower aliphatic mono-, di- or tricarboxylic acids such as maleic acid, fumaric acid, lactic acid, tartaric acid, acetic acid or citric acid, or with sulfonic acids, for example lower alkanesulfonic acids such as methanesulfonic acid or benzenesulfonic acids optionally substituted in the benzene ring by halogen or lower alkyl, such as p-toluenesulfonic acid.
If the substituents R
2
and R
3
are different in the compounds of Formula I, the compounds contain an asymmetric center and may exist in two optically, active forms or as a racemate. The present invention includes both the racemic mixtures and the optical isomers of these compounds of Formula I. The optically active compounds can be obtained from the racemic mixtures in a known manner by customary separation processes, e.g. by chromatography on chiral separating materials or by fractional crystallisation of suitable salts using optically active acids. Enantiomerically pure compounds can also be prepared by synthesis from corresponding enantiomerically pure starting compounds of Formula II.
The starting compounds of Formula II are known from published German patent application no. DE 26 58 558, U.S. Pat. No. 4,450,112 (=EP 103,833), and U.S. Pat. No. 4,912,113 (=EP 306,871) and/or can be prepared in a known manner by the methods described in these specifications or analogously to the methods described in these specifications.
The starting compounds of Formula III are known and/or can be prepared using known processes or analogously to known processes.
It has now surprisingly been found that the compounds of Formula I according to the invention and their physiologically acceptable acid addition salts have particularly beneficial antiarrhythmic effects. In particular, they exhibit class III antiarrhythmic properties, which cause a prolongation of the QT interval in the ECG and effect prolongation of the effective refractory period in the heart. The compounds have a beneficial activity profile with good compatibility, a

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