Substituted 4-aryl-1,4-dihydro-1,6-naphthyridine amides and their use
View Patent ↗The present application relates to novel substituted 4-aryl-1,4-dihydro-1,6-naphthyridine-3-carboxamides, a process for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for the manufacture of medicaments for the treatment and/or prophylaxis of diseases, especially cardiovascular disorders.
1. A method of treatment of diabetic neuropathy comprising administering to a human or animal in need thereof an effective amount of a compound of formula (I)
in which
D is N or C—R 4 , in which
R 4 is hydrogen, fluorine, trifluoromethyl or (C 1 -C 4 )-alkyl,
Ar is a group of the formula
in which
* is the linkage point,
R 5 is hydrogen, fluorine, chlorine, cyano, nitro, trifluoromethyl or (C 1 -C 4 )-alkyl,
R 6 is hydrogen or fluorine,
R 7 is halogen, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy or trifluoromethoxy,
R 8 is cyano or nitro,
R 9 is hydrogen, halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio or di-(C 1 -C 4 )-alkylamino, it being possible for the alkyl group in said (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy and (C 1 -C 4 )-alkylthio radicals in each case to be substituted up to three times by fluorine,
or
phenyl, which may be substituted by halogen, (C 1 -C 4 )-alkyl or trifluoromethyl,
R 10 is hydrogen, halogen or (C 1 -C 4 )-alkyl,
E is CH, C—R 7 or N,
and
n is the number 0, 1 or 2,
it being possible in the case where the substituent R 7 occurs more than once for its meanings to be identical or different,
R 1 is (C 1 -C 4 )-alkyl which may be substituted up to three times by fluorine,
R 2 is (C 1 -C 6 )-alkyl which may be substituted by (C 3 -C 7 )-cycloalkyl or up to three times by fluorine, or is a group of the formula —SO 2 —R 11 in which
R 11 is (C 1 -C 6 )-alkyl, trifluoromethyl, (C 3 -C 7 )-cycloalkyl, phenyl or 5- or 6-membered heteroaryl having up to two heteroatoms from the series N, O and/or S,
it being possible for phenyl and heteroaryl in turn each to be substituted once or twice, identically or differently, by halogen, cyano, nitro, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy and/or trifluoromethoxy,
and
R 3 is hydrogen, fluorine, trifluoromethyl or (C 1 -C 4 )-alkyl,
or a salt thereof.
2. The method of claim 1 , wherein
D is C—R 4 in which
R 4 is hydrogen, methyl or trifluoromethyl,
Ar is a group of the formula
in which
* is the linkage point,
R 5 is hydrogen, fluorine, chlorine or cyano,
R 8 is cyano or nitro,
and
R 9 is chlorine, bromine, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, (C 1 -C 4 )-alkylthio or trifluoromethylthio,
R 1 is methyl or trifluoromethyl,
R 2 is (C 1 -C 4 )-alkyl, trifluoromethyl or a group of the formula —SO 2 —R 11 in which
R 11 is (C 1 -C 4 )-alkyl or trifluoromethyl,
and
R 3 is hydrogen, methyl or trifluoromethyl,
or a salt thereof.
3. The method of claim 1 , wherein
D is C—R 4 in which
R 4 is hydrogen or methyl,
Ar is a group of the formula
in which
* is the linkage point
and
R 9 is ethyl, methoxy or trifluoromethoxy,
R 1 is methyl or trifluoromethyl,
R 2 is methyl, ethyl, n-propyl or isopropyl
and
R 3 is hydrogen or methyl,
or a salt thereof.
4. The method of claim 1 , wherein the compound of formula (I) has a structure selected from the group consisting of
or a salt thereof.
5. The method of claim 1 , wherein the compound of formula (I) has a structure selected from the group consisting of
or a salt thereof.
6. A method for the treatment of aldosteronism, high blood pressure, chronic heart failure, the sequelae of a myocardial infarction, cirrhosis of the liver, renal failure and stroke comprising administering to human or animal in need thereof an effective amount of at least one compound of formula (I)
in which
D is N or C—R 4 , in which
R 4 is hydrogen, fluorine, trifluoromethyl or (C 1 -C 4 )-alkyl,
Ar is a group of the formula
in which
* is the linkage point,
R 5 is hydrogen, fluorine, chlorine, cyano, nitro, trifluoromethyl or (C 1 -C 4 )-alkyl,
R 6 is hydrogen or fluorine,
R 7 is halogen, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy or trifluoromethoxy,
R 8 is cyano or nitro,
R 9 is hydrogen, halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio or di-(C 1 -C 4 )-alkylamino, it being possible for the alkyl group in said (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy and (C 1 -C 4 )-alkylthio radicals in each case to be substituted up to three times by fluorine,
or
phenyl, which may be substituted by halogen, (C 1 -C 4 )-alkyl or trifluoromethyl,
R 10 is hydrogen, halogen or (C 1 -C 4 )-alkyl,
E is CH, C—R 7 or N,
and
n is the number 0, 1 or 2,
it being possible in the case where the substituent R 7 occurs more than once for its meanings to be identical or different,
R 1 is (C 1 -C 4 )-alkyl which may be substituted up to three times by fluorine,
R 2 is (C 1 -C 6 )-alkyl which may be substituted by (C 3 -C 7 )-cycloalkyl or up to three times by fluorine, or is a group of the formula —SO 2 —R 11 in which
R 11 is (C 1 -C 6 )-alkyl, trifluoromethyl, (C 3 -C 7 )-cycloalkyl, phenyl or 5- or 6-membered heteroaryl having up to two heteroatoms from the series N, O and/or S,
it being possible for phenyl and heteroaryl in turn each to be substituted once or twice, identically or differently, by halogen, cyano, nitro, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy and/or trifluoromethoxy,
and
R 3 is hydrogen, fluorine, trifluoromethyl or (C 1 -C 4 )-alkyl,
or a salt thereof.
7. The method of claim 6 , wherein
D is C—R 4 in which
R 4 is hydrogen, methyl or trifluoromethyl,
Ar is a group of the formula
in which
* is the linkage point,
R 5 is hydrogen, fluorine, chlorine or cyano,
R 8 is cyano or nitro,
and
R 9 is chlorine, bromine, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, (C 1 -C 4 )-alkylthio or trifluoromethylthio,
R 1 is methyl or trifluoromethyl,
R 2 is (C 1 -C 4 )-alkyl, trifluoromethyl or a group of the formula —SO 2 —R 11 in which
R 11 is (C 1 -C 4 )-alkyl or trifluoromethyl,
and
R 3 is hydrogen, methyl or trifluoromethyl,
or a salt thereof.
8. The method of claim 6 , wherein:
D is C—R 4 in which
R 4 is hydrogen or methyl,
Ar is a group of the formula
in which
* is the linkage point
and
R 9 is ethyl, methoxy or trifluoromethoxy,
R 1 is methyl or trifluoromethyl,
R 2 is methyl, ethyl, n-propyl or isopropyl
and
R 3 is hydrogen or methyl,
or a salt thereof.
9. The method of claim 6 , wherein
or a salt thereof.
10. The method of claim 6 , wherein the compound of formula (I) has a structure selected from the group consisting of:
or a salt thereof.
11. The method of claim 6 , wherein the compound of formula (I) has the structure:
or a salt thereof.
12. The method of claim 1 , wherein the compound of formula (I) has the structure:
or a salt thereof.