Alkylamine-substituted dicyanopyridine and amino acid ester prodrugs thereof
The present application relates to novel 6-alkylamino-substituted dicyanopyridines, to their amino acid ester prodrugs, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, preferably for the treatment and/or prevention of cardiovascular disorders.
1. A compound of formula (VII)
wherein,
R 1 represents hydrogen or (C 1 -C 4 )-alkyl,
R 2 represents (C 1 -C 6 )-alkyl, (C 2 -C 4 )-alkenyl, (C 2 -C 4 )-alkynyl or (C 3 -C 7 )-cycloalkyl,
where (C 1 -C 6 )-alkyl may be substituted by 1 to 3 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkoxy, (C 1 -C 4 )-alkylsulfanyl and (C 1 -C 4 )-alkylsulfonyl,
and
where (C 2 -C 4 )-alkenyl and (C 2 -C 4 )-alkynyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 )-alkyl, trifluoromethoxy and (C 1 -C 4 )-alkoxy,
and
where (C 3 -C 7 )-cycloalkyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, (C 1 -C 4 )-alkyl, trifluoromethoxy and (C 1 -C 4 )-alkoxy,
or
R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S,
where the 4- to 7-membered heterocycle may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, oxo, trifluoromethyl, (C 1 -C 4 )-alkyl, trifluoromethoxy and (C 1 -C 4 )-alkoxy,
R 4 represents hydrogen or the side group of a natural α-amino acid or its homologs or isomers,
R 5 represents hydrogen or methyl,
R 6A represents hydrogen, (C 1 -C 4 )-alkyl, or an amino protective group,
R 7A represents hydrogen, (C 1 -C 4 )-alkyl, or an amino protective group,
or
R 6A and R 7A together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle,
where the 5- or 6-membered heterocycle may be substituted by 1 or 2 substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, amino, hydroxyl and (C 1 -C 4 )-alkoxy,
or
R 7A together with R 4 and the atoms, to which they are attached, forms a pyrrolidine or piperidine ring,
or a salt thereof.
2. The compound of claim 1 , wherein
R 1 represents hydrogen, methyl, or ethyl;
R 2 represents (C 1 -C 3 )-alkyl, cyclopropyl, or cyclobutyl,
where (C 1 -C 3 )-alkyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl;
or
R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain a further heteroatom from the group consisting of N, O, and S,
where the 4- to 6-membered heterocycle may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, methoxy, and ethoxy;
R 4 represents methyl or 3-aminopropan-1-yl;
R 5 represents hydrogen;
R 6A represents hydrogen, methyl, or an amino protecting group; and
R 7A represents hydrogen, or an amino protecting group; or
R 7A together with R 4 and the atoms, to which they are attached, forms a pyrrolidine ring.
3. The compound of claim 1 , wherein
R 1 represents hydrogen, methyl, or ethyl;
R 2 represents methyl, ethyl, or n-propyl, where methyl, ethyl, and n-propyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, trifluoromethyl, and methoxy;
or
R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, or piperidinyl ring, where the azetidinyl, and piperidinyl ring may be substituted by a methoxy substituent.
4. The compound of claim 1 , wherein
R 1 represents hydrogen, methyl or ethyl,
R 2 represents (C 1 -C 3 )-alkyl, cyclopropyl or cyclobutyl,
where (C 1 -C 3 )-alkyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl.
5. A compound of formula (VIII)
wherein
R 1 represents hydrogen or (C 1 -C 4 )-alkyl,
R 2 represents (C 1 -C 6 )-alkyl, (C 2 -C 4 )-alkenyl, (C 2 -C 4 )-alkynyl or (C 3 -C 7 )-cycloalkyl,
where (C 1 -C 6 )-alkyl may be substituted by 1 to 3 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkoxy, (C 1 -C 4 )-alkylsulfanyl and (C 1 -C 4 )-alkylsulfonyl,
where (C 2 -C 4 )-alkenyl and (C 2 -C 4 )-alkynyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 )-alkyl, trifluoromethoxy and (C 1 -C 4 )-alkoxy,
and
where (C 3 -C 7 )-cycloalkyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, (C 1 -C 4 )-alkyl, trifluoromethoxy and (C 1 -C 4 )-alkoxy,
or
R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S,
where the 4- to 7-membered heterocycle may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, oxo, trifluoromethyl, (C 1 -C 4 )-alkyl, trifluoromethoxy and (C 1 -C 4 )-alkoxy;
L 2 represents (C 2 -C 6 )-alkanediyl;
R 17A represents hydrogen, (C 1 -C 4 )-alkyl, or an amino protective group, and
R 18A represents hydrogen, (C 1 -C 4 )-alkyl, or an amino protective group; or
R 17 and R 18 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, where the 5- or 6-membered heterocycle may be substituted by 1 or 2 substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, amino, hydroxyl, and (C 1 -C 4 )-alkoxy.
6. The compound of claim 5 , wherein
R 1 represents hydrogen, methyl, or ethyl;
R 2 represents (C 1 -C 3 )-alkyl, cyclopropyl, or cyclobutyl, where (C 1 -C 3 )-alkyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl;
or
R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain a further heteroatom from the group consisting of N, O, and S,
where the 4- to 6-membered heterocycle may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, methoxy, and ethoxy;
L 2 represents ethane-1,2-diyl or propane-1,3-diyl,
R 17 represents hydrogen, methyl, or an amino protecting group; and
R 18 represents hydrogen, methyl, or an amino protecting group.
7. The compound of claim 5 , wherein
R 1 represents hydrogen, methyl, or ethyl;
R 2 represents methyl, ethyl, or n-propyl, where methyl, ethyl, and n-propyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, trifluoromethyl, and methoxy;
or
R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, or piperidinyl ring, where the azetidinyl, and piperidinyl ring may be substituted by a methoxy substituent.