Amine derivatives, processes for producing them and a use of them as antiarrhythmic drugs

A process for producing an amine derivative of the general formula (I) or a salt thereof,

• (A) reacting a compound of the general formula (II) set forth below or a salt thereof with a compound of the general formula (III) set forth below or a salt thereof;
• (B) reducing a compound of the general formula (Ia) set forth below or a salt thereof to produce a compound of the general formula (Ib) or a salt thereof;
• (C) reacting a compound of the general formula (Ic) set forth below or a salt thereof with an alkanesulfonyl halide to produce a compound of the general formula (Id) set forth below or a salt thereof;
• (D) reacting a compound of the general formula (II) set forth below or a salt thereof with a compound of the general formula (IV) set forth below or a salt thereof to produce a compound of the general formula (V) set forth below or a salt thereof and reacting the thus produced compound (V) with a compound of the general formula (VI) set forth below or a salt thereof to produce a compound of the general formula (Ie) or a salt thereof;
• or
• (E) reacting a compound of the general formula (VII) set forth below or a salt thereof with a compound of the general formula (VIII) set forth below or a salt thereof to produce a compound of the general formula (If) set forth below or a salt thereof:
• ##STR11## (wherein A denotes a group of the general formula --(CH.sub.2).sub.m --, --(CH.sub.2).sub.m --O--, --(CH.sub.2).sub.m --NH-- or --(CH.sub.2).sub.m --SO.sub.2 --, where a hydrogen atom in the --(CH.sub.2).sub.m -- moiety may be substituted by no more than one hydroxy group;
• B denotes a group of the general formula --(CH.sub.2).sub.n --, --NR.sub.7 --(CH.sub.2).sub.n -- or --CONH--(CH.sub.2).sub.n --;
• R.sub.1, R.sub.2, R.sub.3 and R.sub.4 denote each independently a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, a lower alkanoyl group, a nitro group, a hydroxy group, a lower alkylsulfonyloxy group, a phenoxymethyl group, a heterocyclic group or a group of the general formula --NR.sub.5 R.sub.6, where R.sub.5 and R.sub.6 denote each independently a hydrogen atom, a lower alkanoyl group, a lower alkyl group or a heterocyclic group;
• R.sub.9 denotes a hydrogen atom, a halogen atom, a nitro group, an amino group, a lower alkyl group, a lower alkanoylamino group or a lower alkylamino group;
• R.sub.8a and R.sub.8b denote the same halogen atom or lower alkoxy group or, alternatively, when R.sub.8a denotes a hydrogen atom, R.sub.8b denotes a lower alkylsulfonylamino group or a halogen atom (provided that when R.sub.8a is a hydrogen atom and R.sub.8b is a lower alkylsulfonylamino group, R.sub.1 denotes a group of the general formula --NR.sub.5 R.sub.6 or a heterocyclic group);
• R denotes a lower alkyl group or an aryl group;
• R.sub.7 denotes a hydrogen atom or a lower alkyl group;
• X denotes a group of the general formula --NR.sub.10 R.sub.11, a nitro group, a cyano group or a heterocyclic group, where R.sub.10 and R.sub.11 denote each independently a hydrogen atom or a lower alkylsulfonyl group;
• m denotes an integer of 0-3;
• n denotes an integer of 0-3;
• L denotes a reactive leaving group;
• A' has the same meaning as A, except that it is not --(CH.sub.2).sub.m --;
• one of R.sub.10a and R.sub.11a is a hydrogen atom while the other is a lower alkylsulfonyl group;
• R.sub.1a, R.sub.2a, R.sub.3a, R.sub.4a, R.sub.9a and X.sub.a have the same meanings as the above R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.9 and X, respectively, provided that at least one of them is a nitro group;
• and
• R.sub.1b, R.sub.2b, R.sub.3b, R.sub.4b, R.sub.9b and X.sub.b have the same meanings as the above R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.9 and X, respectively, provided that at least one of them is an amino group.

A process for producing an amine derivative of the general formula (I) or a salt thereof reacting a compound of the general formula (II) set forth below or a salt thereof with a compound of the general formula (III) set forth below or a salt thereof:

• ##STR12## wherein A denotes a group of the general formula --(CH.sub.2).sub.m --, --(CH.sub.2).sub.m --O--, --(CH.sub.2).sub.m --NH-- or --(CH.sub.2).sub.m --SO.sub.2 --, where a hydrogen atom in the --(CH.sub.2).sub.m -- moiety may be substituted by no more than one hydroxy group;
• B denotes the general formula --(CH.sub.2).sub.n --, --NR.sub.7 --(CH.sub.2).sub.n -- or --CONH--(CH.sub.2).sub.n ;
• R.sub.1, R.sub.2, R.sub.3 and R.sub.4 denote each independently a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, a lower alkanoyl group, a nitro group, a hydroxy group, a lower alkylsulfonyloxy group, a phenoxymethyl group, a heterocyclic group or a group of the general formula --NR.sub.5 R.sub.6, where R.sub.5 and R.sub.6 denote each independently a hydrogen atom, a lower alkanoyl group, a lower alkyl group or a heterocyclic group;
• R.sub.9 denotes a hydrogen atom, a halogen atom, a nitro group, an amino group, a lower alkyl group, a lower alkanoylamino group or a lower alkylamino group;
• R.sub.8a and R.sub.8b denote the same halogen atom or lower alkoxy group or, alternatively, when R.sub.8a denotes a hydrogen atom, R.sub.8b denotes a lower alkylsulfonylamino group or a halogen atom (provided that when R.sub.8a is a hydrogen atom and R.sub.8b is a lower alkylsulfonylamino group, R.sub.1 denotes a group of the general formula --NR.sub.5 R.sub.6 or a heterocyclic group);
• R denotes a lower alkyl group or an aryl group;
• R.sub.7 denotes a hydrogen atom or a lower alkyl group;
• X denotes a group of the general formula --NR.sub.10 R.sub.11, a nitro group, a cyano group or a heterocyclic group, where R.sub.10 and R.sub.11 denote each independently a hydrogen atom or a lower alkylsulfonyl group;
• m denotes an integer of 0-3;
• n denotes an integer of 0-3;
• and
• L denotes a reactive leaving group.

A process for producing an amine derivative of the general formula (I) or a salt thereof reducing a compound of the general formula (Ia) set forth below or a salt thereof to produce a compound of the general formula (Ib) set forth below or a salt thereof:

• ##STR13## (wherein A denotes a group of the general formula --(CH.sub.2).sub.m --, --(CH.sub.2).sub.m --O--, --(CH.sub.2).sub.m --NH-- or --(CH.sub.2).sub.m --SO.sub.2 --, where a hydrogen atom in the --(CH.sub.2).sub.m -- moiety may be substituted by at least one hydroxy group;
• B denotes a group of the general formula --(CH.sub.2).sub.n --, --NR.sub.7 --(CH.sub.2).sub.n -- or --CONH--(CH.sub.2).sub.n --;
• R.sub.1, R.sub.2, R.sub.3 and R.sub.4 denote each independently a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, a lower alkanoyl group, a nitro group, a hydroxy group, a lower alkylsulfonyloxy group, a phenoxymethyl group, a heterocyclic group or a group of the general formula --NR.sub.5 R.sub.6, where R.sub.5 and R.sub.6 denote each independently a hydrogen atom, a lower alkanoyl group, a lower alkyl group or a heterocyclic group;
• R.sub.9 denotes a hydrogen atom, a halogen atom, a nitro group, an amino group, a lower alkyl group, a lower alkanoylamino group or a lower alkylamino group;
• R.sub.8a and R.sub.8b denote the same halogen atom or a lower alkoxy group or, alternatively, when R.sub.8a denotes a hydrogen atom, R.sub.8b denotes a lower alkylsulfonylamino group or a halogen atom (provided that when R.sub.8a is a hydrogen atom and R.sub.8b is a lower alkylsulfonylamino group, R.sub.1 denotes a group of the general formula --NR.sub.5 R.sub.6 or a heterocyclic group);
• R denotes a lower alkyl group or an aryl group;
• R.sub.7 denotes a hydrogen atom or a lower alkyl group;
• X denotes a group of the general formula --NR.sub.10 R.sub.11, a nitro group, a cyano group or a heterocyclic group, where R.sub.10 and R.sub.11 denote each independently a hydrogen atom or a lower alkylsulfonyl group;
• m denotes an integer of 0-3;
• n denotes an integer of 0-3;
• R.sub.1a, R.sub.2a, R.sub.3a, R.sub.4a, R.sub.9a and X.sub.a have the same meanings as the above R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.9 and X, respectively, provided that at least one of them is a nitro group;
• and
• R.sub.1b, R.sub.2b, R.sub.3b, R.sub.4b, R.sub.9b and X.sub.b have the same meanings as the above R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.9 and X, respectively, provided that at least one of them is an amino group.

A process for producing an amine derivative of the general formula (I) or a salt thereof by reacting a compound of the general formula (Ic) set forth below or a salt thereof with an alkanesulfonyl halide to produce a compound of the general formula (Id) set forth below or a salt thereof:

• ##STR14## (wherein A denotes a group of the general formula --(CH.sub.2).sub.m --, --(CH.sub.2).sub.m --O--, --(CH.sub.2).sub.m --NH-- or --(CH.sub.2).sub.m --SO.sub.2 --, where a hydrogen atom in the --(CH.sub.2).sub.m -- moiety may be substituted by at least one hydroxy group;
• B denotes a group of the general formula --(CH.sub.2).sub.n --, --NR.sub.7 --(CH.sub.2).sub.n -- or --CONH--(CH.sub.2).sub.n --;
• R.sub.1, R.sub.2, R.sub.3 and R.sub.4 denote each independently a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, a lower alkanoyl group, a nitro group, a hydroxy group, a lower alkylsulfonyloxy group, a phenoxymethyl group, a heterocyclic group or a group of the general formula --NR.sub.5 R.sub.6, where R.sub.5 and R.sub.6 denote each independently a hydrogen atom, a lower alkanoyl group, a lower alkyl group or a heterocyclic group;
• R.sub.9 denotes a hydrogen atom, a halogen atom, a nitro group, an amino group, a lower alkyl group, a lower alkanoylamino group or a lower alkylamino group;
• R.sub.8a and R.sub.8b denote the same halogen atom or lower alkoxy group or, alternatively, when R.sub.8a denotes a hydrogen atom, R.sub.8b denotes a lower alkylsulfonylamino group or a halogen atom (provided that when R.sub.8a is a hydrogen atom and R.sub.8b is a lower alkylsulfonylamino group, R.sub.1 denotes a group of the general formula --NR.sub.5 R.sub.6 or a heterocyclic group);
• R denotes a lower alkyl group or an aryl group;
• R.sub.7 denotes a hydrogen atom or a lower alkyl group;
• X denotes a group of the general formula --NR.sub.10 R.sub.11, a nitro group, a cyano group or a heterocyclic group, where R.sub.10 and R.sub.11 denote each independently a hydrogen atom or a lower alkylsulfonyl group;
• m denotes an integer of 0-3;
• n denotes an integer of 0-3;
• and
• one of R.sub.10a and R.sub.11a is a hydrogen atom while the other is a lower alkylsulfonyl group.

A process for producing an amine derivative of the general formula (I) or a salt thereof reacting a compound of the general formula (II) set forth below or a salt thereof with a compound of the general formula (IV) set forth below or a salt thereof to produce a compound of the general formula (V) set forth below or a salt thereof and reacting the thus produced compound (V) with a compound of the general formula (VI) set forth below or a salt thereof to produce a compound of the general formula (Ie) set forth below or a salt thereof:

• ##STR15## (wherein A denotes a group of the general formula --(CH.sub.2).sub.m --, --(CH.sub.2).sub.m --O--, --(CH.sub.2).sub.m --NH-- or --(CH.sub.2).sub.m --SO.sub.2 --, where a hydrogen atom in the --(CH.sub.2).sub.m -- moiety may be substituted by at least one hydroxy group;
• B denotes a group of the general formula --(CH.sub.2).sub.n --, --NR.sub.7 --(CH.sub.2).sub.n -- or --CONH--(CH.sub.2).sub.n --;
• R.sub.1, R.sub.2, R.sub.3 and R.sub.4 denote each independently a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, a lower alkanoyl group, a nitro group, a hydroxy group, a lower alkylsulfonyloxy group, a phenoxymethyl group, a heterocyclic group or a group of the general formula --NR.sub.5 R.sub.6, where R.sub.5 and R.sub.6 denote each independently a hydrogen atom, a lower alkanoyl group, a lower alkyl group or a heterocyclic group;
• R.sub.9 denotes a hydrogen atom, a halogen atom, a nitro group, an amino group, a lower alkyl group, a lower alkanoylamino group or a lower alkylamino group;
• R.sub.8a and R.sub.8b denote the same halogen atom or lower alkoxy group or, alternatively, when R.sub.8a denotes a hydrogen atom, R.sub.8b denotes a lower alkylsulfonylamino group or a halogen atom (provided that when R.sub.8a is a hydrogen atom and R.sub.8b is a lower alkylsulfonylamino group, R.sub.1 denotes a group of the general formula --NR.sub.5 R.sub.6 or a heterocyclic group);
• R denotes a lower alkyl group or an aryl group;
• R.sub.7 denotes a hydrogen atom or a lower alkyl group;
• X denotes a group of the general formula --NR.sub.10 R.sub.11, a nitro group, a cyano group or a heterocyclic group, where R.sub.10 and R.sub.11 denote each independently a hydrogen atom or a lower alkylsulfonyl group;
• m denotes an integer of 0-3;
• n denotes an integer of 0-3;
• L denotes a reactive leaving group;
• and
• A' has the same meaning as A, except that it is not --(CH.sub.2).sub.m --.

A process for producing an amine derivative of the general formula (I) or a salt thereof reacting a compound of the general formula (VII) set forth below or a salt thereof with a compound of the general formula (VIII) set forth below or a salt thereof to produce a compound of the general formula (If) set forth below or a salt thereof:

• ##STR16## (wherein A denotes a group of the general formula --(CH.sub.2).sub.m --, --(CH.sub.2).sub.m --O--, --(CH.sub.2).sub.m --NH-- or --(CH.sub.2).sub.m --SO.sub.2 --, where a hydrogen atom in the --(CH.sub.2).sub.m -- moiety may be substituted by at least one hydroxy group;
• B denotes a group of the general formula --(CH.sub.2).sub.n --, --NR.sub.7 --(CH.sub.2).sub.n -- or --CONH--(CH.sub.2).sub.n --;
• R.sub.1, R.sub.2, R.sub.3 and R.sub.4 denote each independently a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, a lower alkanoyl group, a nitro group, a hydroxy group, a lower alkylsulfonyloxy group, a phenoxymethyl group, a heterocyclic group or a group of the general formula --NR.sub.5 R.sub.6, where R.sub.5 and R.sub.6 denote each independently a hydrogen atom, a lower alkanoyl group, a lower alkyl group or a heterocyclic group;
• R.sub.9 denotes a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, an amino group, a lower alkanoylamino group or a lower alkylamino group;
• R.sub.8a and R.sub.8b denote the same halogen atom or lower alkoxy group or, alternatively, when R.sub.8a denotes a hydrogen atom, R.sub.8b denotes a lower alkylsulfonylamino group or a halogen atom (provided that when R.sub.8a is a hydrogen atom and R.sub.8b is a lower alkylsulfonylamino group, R.sub.1 denotes a group of the general formula --NR.sub.5 R.sub.6 or a heterocyclic group);
• R denotes a lower alkyl group or an aryl group;
• R.sub.7 denotes a hydrogen atom or a lower alkyl group;
• X denotes a group of the general formula --NR.sub.10 R.sub.11, a nitro group, a cyano group or a heterocyclic group, where R.sub.10 and R.sub.11 denote each independently a hydrogen atom or a lower alkylsulfonyl group;
• m denotes an integer of 0-3;
• n denotes an integer of 0-3;
• and
• L denotes a reactive leaving group.