Substituted arylimidazolone and triazolone as inhibitors of vasopressin receptors
View Patent ↗The present application relates to novel, substituted 4-arylimidazol-2-ones and 5-aryl-1,2,4-triazolones, processes for the production thereof, the use thereof alone or in combinations for the treatment and/or prevention of diseases and the use thereof for the production of medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of cardiovascular diseases.
1. A compound of the formula (I)
in which
A stands for N or C—R 4 , wherein
R 4 means hydrogen or (C 1 -C 4 ) alkyl,
R 1 stands for (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl or (C 2 -C 6 ) alkynyl, which can each be singly to triply, similarly or differently, substituted with residues selected from the range halogen, cyano, oxo, trifluoromethyl, (C 3 -C 7 ) cycloalkyl, phenyl, —OR 10 , —NR 11 R 12 , —C(═O)—OR 13 and —C(═O)—NR 14 R 15 , wherein
(i) (C 3 -C 7 ) cycloalkyl can be up to doubly, similarly or differently, substituted with (C 1 -C 4 ) alkyl, oxo, hydroxy, (C 1 -C 4 ) alkoxy and/or amino,
(ii) phenyl can be up to triply, similarly or differently, substituted with residues selected from the range halogen, cyano, nitro, (C 1 -C 4 ) alkyl, trifluoromethyl, hydroxy, hydroxymethyl, (C 1 -C 4 ) alkoxy, trifluoromethoxy, (C 1 -C 4 ) alkoxymethyl, hydroxycarbonyl, (C 1 -C 4 ) alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 ) alkylaminocarbonyl and di-(C 1 -C 4 ) alkylaminocarbonyl,
(iii) R 10 , R 11 , R 12 , R 13 , R 14 and R 15 mutually independently on each single occurrence mean hydrogen, (C 1 -C 6 ) alkyl or (C 3 -C 7 ) cycloalkyl, wherein (C 1 -C 6 ) alkyl can itself be up to doubly, similarly or differently, substituted with amino, hydroxy, (C 1 -C 4 ) alkoxy, hydroxycarbonyl and/or (C 1 -C 4 ) alkoxycarbonyl
and
(C 3 -C 7 ) cycloalkyl can itself be up to doubly, similarly or differently, substituted with (C 1 -C 4 ) alkyl, oxo, hydroxy, (C 1 -C 4 ) alkoxy and/or amino,
and/or
(iv) R 11 and R 12 and also R 14 and R 15 respectively in pairs together with the nitrogen atom to which they are bound form a 4 to 7-membered heterocycle, which can contain a further hetero atom from the range N, O and S and be up to doubly, similarly or differently, substituted with (C 1 -C 4 ) alkyl, oxo, hydroxy, (C 1 -C 4 ) alkoxy and/or amino,
or
R 1 stands for (C 3 -C 7 ) cycloalkyl, which can be up to doubly, similarly or differently, substituted with (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, hydroxy, amino and/or oxo,
R 2 stands for phenyl, naphthyl, thienyl, benzothienyl, furyl or benzofuryl, which can each be singly to triply, similarly or differently, substituted with residues selected from the range halogen, cyano, nitro, (C 1 -C 4 ) alkyl, trifluoromethyl, hydroxy, (C 1 -C 4 ) alkoxy, trifluoromethoxy and phenyl,
wherein the last-named phenyl residue can itself be up to doubly, similarly or differently, substituted with residues selected from the range halogen, cyano, nitro, (C 1 -C 4 ) alkyl, trifluoromethyl, hydroxy, (C 1 -C 4 ) alkoxy, trifluoromethoxy, hydroxy-(C 1 -C 4 ) alkyl and (C 1 -C 4 ) alkylthio,
L 1 stands for a group of the formula —(CR 5A R 5B ) m —, wherein
m means the number 1, 2 or 3
and
R 5A and R 5B mutually independently mean hydrogen or (C 1 -C 4 ) alkyl
or
two residues R 5A and R 5B bound to the same carbon atom are linked to one another and together form a —(CH 2 ) n bridge, wherein
n means the number 2, 3, 4 or 5,
or, in the event that m stands for the number 2 or 3,
two residues bound to adjacent (1,2- or 1,3-) or non-adjacent (1,3-) carbon atoms R 5A and/or R 5B are linked to one another and together form a —(CH 2 ) p bridge, wherein
p means the number 1, 2, 3 or 4,
where, in the event that the group —CR 5A R 5B — occurs several times, the individual meanings of R 5A and R 5B can in each case be the same or different,
or
L 1 stands for a group of the formula
L 2 stands for a group of the formula *—CR 6A R 6B —(CR 7A R 7B ) q — or *—CR 6A R 6B —CR 7A R 7B —O—, wherein
* means the binding site with the N atom of the amide group,
q means the number 0, 1 or 2,
R 6A means hydrogen or (C 1 -C 4 ) alkyl,
R 6B means hydrogen, (C 1 -C 4 ) alkyl, trifluoromethyl, (C 3 -C 6 ) cycloalkyl or phenyl, which can be up to doubly, similarly or differently, substituted with halogen, (C 1 -C 4 ) alkyl and/or trifluoromethyl, or a residue of the formula —C(═O)—OR 16 or —C(═O)—NR 17 R 18 , wherein
R 16 , R 17 and R 18 mutually independently represent hydrogen, (C 1 -C 4 ) alkyl or (C 3 -C 6 ) cycloalkyl
or
R 17 and R 18 together with the nitrogen atom to which they are bound form a 4 to 6-membered heterocycle, which can contain a further hetero atom from the range N, O and S and be up to doubly, similarly or differently, substituted with (C 1 -C 4 ) alkyl, hydroxy and/or (C 1 -C 4 ) alkoxy,
or
R 6A and R 6B are linked to one another and together form a —(CH 2 ) r bridge, wherein
r means the number 2, 3, 4 or 5
and one CH 2 group of the bridge can be exchanged for —O—, —S— or —N—R 19 , wherein
R 19 represents hydrogen or (C 1 -C 4 ) alkyl,
R 7A means hydrogen, fluorine, (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkoxy,
R 7B means hydrogen, fluorine, (C 1 -C 4 ) alkyl, hydroxy-(C 1 -C 4 ) alkyl or a residue of the formula —OR 20 , —NR 21 R 22 , —C(═O)—OR 23 or —C(═O)—NR 24 R 25 , wherein
R 20 , R 21 , R 22 , R 23 , R 24 and R 25 mutually independently represent hydrogen, (C 1 -C 4 ) alkyl or (C 3 -C 6 ) cycloalkyl
or
R 21 and R 22 and also R 24 and R 25 respectively in pairs together with the nitrogen atom to which they are bound form a 4 to 6-membered heterocycle, which can contain a further hetero atom from the range N, O and S and be up to doubly, similarly or differently, substituted with (C 1 -C 4 ) alkyl, hydroxy and/or (C 1 -C 4 ) alkoxy,
or
R 7A and R 7B together form an oxo group
or
R 7A and R 7B are linked to one another and together form a —(CH 2 ) s bridge, wherein
s means the number 2, 3, 4 or 5
and one CH 2 group of the bridge can be exchanged for —O—, —S— or —N—R 26 , wherein
R 26 represents hydrogen or (C 1 -C 4 ) alkyl,
where, in the event that the group —CR 7A R 7B — occurs several times, the individual meanings of R 7A and R 7B can in each case be the same or different,
or
L 2 stands for a group of the formula
wherein
* means the binding site with the N atom of the amide group,
x means the number 1, 2, 3 or 4,
where one CH 2 group of the ring can be exchanged for —O—, —S— or —N—R 27 , wherein
R 27 represents hydrogen or (C 1 -C 4 ) alkyl,
and
R 6B and R 7B each have the aforesaid meanings,
R 3 stands for phenyl, naphthyl or 5 to 10-membered heteroaryl with up to three hetero atoms from the range N, O and/or S, which can each be singly to triply, similarly or differently, substituted with residues selected from the range halogen, cyano, nitro, (C 1 -C 4 ) alkyl, trifluoromethyl, hydroxy, (C 1 -C 4 ) alkoxy, trifluoromethoxy, (C 1 -C 4 ) alkylthio, (C 1 -C 4 ) alkylsulfinyl, (C 1 -C 4 ) alkylsulphonyl, di-(C 1 -C 4 ) alkylamino and phenyl,
wherein the last-named phenyl residue can itself be up to doubly, similarly or differently, substituted with halogen, cyano, nitro, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, trifluoromethyl and/or trifluoromethoxy,
or the grouping
L 2 -R 3 together forms a group of the formula
wherein
* means the binding site with the N atom of the amide group,
D means CH 2 or O,
E means NH, N—CH 3 , O or S,
t means the number 0 or 1,
R 8 means a substituent selected from the range halogen, cyano, nitro, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, trifluoromethyl and trifluoromethoxy,
u means the number 0, 1 or 2,
where, in the event that the substituent R 8 occurs several times, its meanings can be the same or different,
and
R 9 means hydrogen or (C 1 -C 4 ) alkyl,
and salts thereof.
2. The compound of the formula (I) according to claim 1 , in which
A stands for N or C—R 4 , wherein
R 4 means hydrogen or (C 1 -C 4 ) alkyl,
R 1 stands for (C 1 -C 6 ) alkyl, which can be substituted with hydroxy, (C 1 -C 6 ) alkoxy, (C 3 -C 7 ) cycloalkyl or phenyl, or for (C 3 -C 7 ) cycloalkyl,
wherein the said cycloalkyl residues can themselves be up to doubly, similarly or differently, substituted with (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, hydroxy, amino and/or oxo
and
the phenyl residue up to triply, similarly or differently, with halogen, cyano, nitro, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, trifluoromethyl and/or trifluoromethoxy,
R 2 stands for phenyl, naphthyl, thienyl, benzothienyl, furyl or benzofuryl, which can each be substituted up to triply, similarly or differently, with halogen, cyano, nitro, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, trifluoromethyl, trifluoromethoxy and/or phenyl,
wherein the last-named phenyl residue can itself be up to doubly, similarly or differently, substituted with halogen, cyano, nitro, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, trifluoromethyl and/or trifluoromethoxy,
L 1 stands for a group of the formula —(CR 5A R 5B ) m —, wherein
m means the number 1, 2 or 3
and
R 5A and R 5B mutually independently mean hydrogen or (C 1 -C 4 ) alkyl
or
two residues R 5A and R 5B bound to the same carbon atom are linked to one another and together form a —(CH 2 ) n bridge, wherein
n means the number 2, 3, 4 or 5,
or, in the event that m stands for the number 2 or 3,
two residues bound to adjacent (1,2- or 2,3-) or non-adjacent (1,3-) carbon atoms R 5A and/or R 5B are linked to one another and together form a —(CH 2 ) p bridge, wherein
p means the number 1, 2, 3 or 4,
where, in the event that the group —CR 5A R 5B — occurs several times, the individual meanings of R 5A and R 5B can in each case be the same or different,
or
L 1 stands for a group of the formula
L 2 stands for a group of the formula *—CR 6A R 6B —(CR 7A R 7B ) q — or *—CR 6A R 6B —CR 7A R 7B —O—, wherein
* means the binding site with the N atom of the amide group,
q means the number 0, 1 or 2,
R 6A means hydrogen or (C 1 -C 4 ) alkyl,
R 6B means hydrogen, (C 1 -C 4 ) alkyl, trifluoromethyl, (C 3 -C 6 ) cycloalkyl or phenyl, which can be up to doubly, similarly or differently, substituted with halogen, (C 1 -C 4 ) alkyl and/or trifluoromethyl
or
R 6A and R 6B are linked to one another and together form a —(CH 2 ) r bridge, wherein
r means the number 2, 3, 4 or 5,
and
R 7A and R 7B mutually independently mean hydrogen or (C 1 -C 4 ) alkyl,
where, in the event that the group —CR 7A R 7B — occurs several times, the individual meanings of R 7A and R 7B can in each case be the same or different,
R 3 stands for phenyl, naphthyl or 5 to 10-membered heteroaryl with up to three hetero atoms from the range N, O and/or S, which can each be substituted up to triply, similarly or differently, with halogen, cyano, nitro, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, trifluoromethyl, trifluoromethoxy, di-(C 1 -C 4 ) alkylamino and/or phenyl,
wherein the last-named phenyl residue can itself be up to doubly, similarly or differently, substituted with halogen, cyano, nitro, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, trifluoromethyl and/or trifluoromethoxy,
or the grouping
L 2 -R 3 together forms a group of the formula
wherein
* means the binding site with the N atom of the amide group,
D means CH 2 or O,
E means NH, N—CH 3 , O or S,
t means the number 0 or 1,
R 8 means a substituent selected from the range halogen, cyano, nitro, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, trifluoromethyl and trifluoromethoxy,
u means the number 0, 1 or 2,
where, in the event that the substituent R 8 occurs several times, its meanings can be the same or different,
and
R 9 means hydrogen or (C 1 -C 4 ) alkyl,
and salts thereof.
3. The compound of the formula (I) according to claim 1 , in which
A stands for N or C—R 4 , wherein
R 4 means hydrogen or (C 1 -C 4 ) alkyl,
R 1 stands for (C 1 -C 6 ) alkyl, which can be singly to triply, similarly or differently, substituted with residues selected from the range fluorine, chlorine, cyano, oxo, trifluoromethyl, (C 3 -C 6 ) cycloalkyl, phenyl, —OR 10 , —NR 11 R 12 , —C(═O)—OR 13 and —C(═O)—NR 14 R 15 , wherein
(i) (C 3 -C 6 ) cycloalkyl can be up to doubly, similarly or differently, substituted with (C 1 -C 4 ) alkyl, oxo, hydroxy, (C 1 -C 4 ) alkoxy and/or amino,
(ii) phenyl can be up to triply, similarly or differently, substituted with residues selected from the range fluorine, chlorine, cyano, (C 1 -C 4 ) alkyl, trifluoro-methyl, hydroxy, hydroxymethyl, (C 1 -C 4 ) alkoxy, trifluoromethoxy, (C 1 -C 4 ) alkoxymethyl, hydroxycarbonyl, (C 1 -C 4 ) alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 ) alkylaminocarbonyl and di-(C 1 -C 4 ) alkylaminocarbonyl,
(iii) R 10 , R 11 , R 12 , R 13 , R 14 and R 15 mutually independently on each single occurrence mean hydrogen, (C 1 -C 4 ) alkyl or (C 3 -C 6 ) cycloalkyl, wherein
(C 1 -C 4 ) alkyl can itself be up to doubly, similarly or differently, substituted with amino, hydroxy, (C 1 -C 4 ) alkoxy, hydroxycarbonyl and/or (C 1 -C 4 ) alkoxycarbonyl
and
(C 3 -C 6 ) cycloalkyl can itself be up to doubly, similarly or differently, substituted with (C 1 -C 4 ) alkyl, oxo, hydroxy, (C 1 -C 4 ) alkoxy and/or amino,
and/or
(iv) R 11 and R 12 and also R 14 and R 15 respectively in pairs together with the nitrogen atom to which they are bound form a 4 to 6-membered heterocycle, which can contain a further hetero atom from the range N and O and be up to doubly, similarly or differently, substituted with (C 1 -C 4 ) alkyl, oxo, hydroxy, (C 1 -C 4 ) alkoxy and/or amino,
or
R 1 stands for (C 2 -C 6 ) alkenyl, which can be substituted with hydroxy, (C 1 -C 4 ) alkoxy, hydroxycarbonyl or (C 1 -C 4 ) alkoxycarbonyl,
or
for (C 3 -C 6 ) cycloalkyl, which can be up to doubly, similarly or differently, substituted with (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, hydroxy, amino and/or oxo,
R 2 stands for phenyl or thienyl, which can be singly to triply, similarly or differently, substituted with residues selected from the range fluorine, chlorine, cyano, (C 1 -C 4 ) alkyl, trifluoromethyl, hydroxy, (C 1 -C 4 ) alkoxy, trifluoromethoxy and phenyl,
wherein the last-named phenyl residue can itself be up to doubly, similarly or differently, substituted with residues selected from the range fluorine, chlorine, cyano, (C 1 -C 4 ) alkyl, trifluoromethyl, (C 1 -C 4 ) alkoxy and trifluoromethoxy,
L 1 stands for a group of the formula —CR 5A R 5B —, wherein
R 5A and R 5B mutually independently mean hydrogen or (C 1 -C 4 ) alkyl,
L 2 stands for a group of the formula *—CR 6A R 6B —(CR 7A R 7B ) q —, wherein
* means the binding site with the N atom of the amide group,
q means the number 0 or 1,
R 6A means hydrogen or (C 1 -C 4 ) alkyl,
R 6B means hydrogen, (C 1 -C 4 ) alkyl, trifluoromethyl, (C 3 -C 6 ) cycloalkyl or phenyl, which can be up to doubly, similarly or differently, substituted with fluorine, chlorine, (C 1 -C 4 ) alkyl and/or trifluoromethyl, or a residue of the formula —C(═O)—OR 16 or —C(═O)—NR 17 R 18 , wherein
R 16 , R 17 and R 18 mutually independently represent hydrogen, (C 1 -C 4 ) alkyl or (C 3 -C 6 ) cycloalkyl
or
R 17 and R 18 together with the nitrogen atom to which they are bound form a 4 to 6-membered heterocycle, which can contain a further hetero atom from the range N and O and be up to doubly, similarly or differently, substituted with (C 1 -C 4 ) alkyl, hydroxy and/or (C 1 -C 4 ) alkoxy,
or
R 6A and R 6B are linked to one another and together form a —(CH 2 ), bridge, wherein
r means the number 2, 3, 4 or 5
and one CH 2 group of the bridge can be exchanged for —O—,
R 7A means hydrogen, fluorine or (C 1 -C 4 ),
R 7B means hydrogen, fluorine, (C 1 -C 4 ) alkyl, hydroxy-(C 1 -C 4 ) alkyl or a residue of the formula —OR 20 , —NR 21 R 22 , —C(═O)—OR 23 or —C(═O)—NR 24 R 25 , wherein
R 20 , R 21 , R 22 , R 23 , R 24 and R 25 mutually independently represent hydrogen, (C 1 -C 4 ) alkyl or (C 3 -C 6 ) cycloalkyl
or
R 21 and R 22 and also R 24 and R 25 respectively in pairs together with the nitrogen atom to which they are bound form a 4 to 6-membered heterocycle, which can contain a further hetero atom from the range N and O and be up to doubly, similarly or differently, substituted with (C 1 -C 4 ) alkyl, hydroxy and/or (C 1 -C 4 ) alkoxy,
or
R 7A and R 7B together form an oxo group
or
R 7A and R 7B are linked to one another and together form a —(CH 2 ) s bridge, wherein
s means the number 2, 3, 4 or 5
and one CH 2 group of the bridge can be exchanged for —O—,
or
L 2 stands for a group of the formula
wherein
* means the binding site with the N atom of the amide group,
x means the number 1, 2, 3 or 4,
where one CH 2 group of the ring can be exchanged for —O—,
and
R 6B and R 7B each have the aforesaid meanings,
and
R 3 stands for phenyl, naphthyl or 5 to 10-membered heteroaryl with up to two hetero atoms from the range N, O and/or S, which can each be singly to triply, similarly or differently, substituted with residues selected from the range fluorine, chlorine, cyano, (C 1 -C 4 ) alkyl, trifluoromethyl, hydroxy, (C 1 -C 4 ) alkoxy, trifluoromethoxy, (C 1 -C 4 ) alkylthio, (C 1 -C 4 ) alkylsulphonyl, di-(C 1 -C 4 ) alkylamino and phenyl,
wherein the last-named phenyl residue can itself be up to doubly, similarly or differently, substituted with fluorine, chlorine, cyano, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, trifluoromethyl and/or trifluoromethoxy,
and salts thereof.
4. The compound of the formula (I) according to claim 1 , in which
A stands for N or C—R 4 , wherein
R 4 means hydrogen or (C 1 -C 4 ) alkyl,
R 1 stands for (C 1 -C 6 ) alkyl, which can be substituted with hydroxy, (C 1 -C 4 ) alkoxy, (C 3 -C 6 ) cycloalkyl or phenyl, or for (C 3 -C 6 ) cycloalkyl,
wherein the said cycloalkyl residues can themselves be up to doubly, similarly or differently, substituted with (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, hydroxy and/or amino
and
the phenyl residue can be up to doubly, similarly or differently, substituted with halogen, cyano, nitro, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, trifluoromethyl and/or trifluoromethoxy,
R 2 stands for phenyl, naphthyl, thienyl or benzothienyl, which can each be up to triply, similarly or differently, substituted with halogen, cyano, nitro, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, trifluoromethyl, trifluoromethoxy and/or phenyl,
wherein the last-named phenyl residue can itself be up to doubly, similarly or differently, substituted with halogen, cyano, nitro, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, trifluoromethyl and/or trifluoromethoxy,
L 1 stands for a group of the formula —(CR 5A R 5B ) m —, wherein
m means the number 1, 2 or 3
and
R 5A and R 5B mutually independently mean hydrogen or methyl
or
two residues R 5A and R 5B bound to the same carbon atom are linked to one another and together form a —(CH 2 ) n bridge, wherein
n means the number 2, 3, 4 or 5,
or, in the event that m stands for the number 2 or 3,
two residues bound to adjacent (1,2- or 2,3-) or non-adjacent (1,3-) carbon atoms R 5A and/or R 5B are linked to one another and together form a —(CH 2 ) p bridge, wherein
p means the number 1, 2, 3 or 4,
where, in the event that the group —CR 5A R 5B — occurs several times, the individual meanings of R 5A and R 5B can in each case be the same or different,
or
L 1 stands for a group of the formula
L 2 stands for a group of the formula *—CR 6A R 6B —(CH 2 ) q —, wherein
* means the binding site with the N atom of the amide group,
q means the number 0 or 1,
R 6A means hydrogen or methyl,
R 6B means hydrogen, (C 1 -C 4 ) alkyl, trifluoromethyl or (C 3 -C 6 ) cycloalkyl
or
R 6A and R 6B are linked to one another and together form a —(CH 2 ) r bridge, wherein
r means the number 2, 3, 4 or 5,
and
R 3 stands for phenyl, naphthyl or 5 to 10-membered heteroaryl with up to two hetero atoms from the range N, O and/or S, which can each be substituted up to triply, similarly or differently, with halogen, cyano, nitro, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, trifluoromethyl, trifluoromethoxy and/or phenyl,
wherein the last-named phenyl residue can itself be up to doubly, similarly or differently, substituted with halogen, cyano, nitro, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, trifluoromethyl and/or trifluoromethoxy,
and salts thereof.
5. The compound of the formula (I) according to claim 1 , in which
A stands for N or C—R 4 , wherein
R 4 means hydrogen or methyl,
R 1 stands for (C 1 -C 6 ) alkyl, which can be singly or doubly, similarly or differently, substituted with residues selected from the range fluorine, oxo, trifluoromethyl, (C 3 -C 6 ) cycloalkyl, phenyl, —OR 10 , —C(═O)—OR 13 and —C(═O)—NR 14 R 15 , wherein
(i) (C 3 -C 6 ) cycloalkyl can be up to doubly, similarly or differently, substituted with (C 1 -C 4 ) alkyl, hydroxy and/or (C 1 -C 4 ) alkoxy,
(ii) phenyl can be up to doubly, similarly or differently, substituted with residues selected from the range fluorine, chlorine, cyano, (C 1 -C 4 ) alkyl, trifluoromethyl, hydroxymethyl, (C 1 -C 4 ) alkoxy, hydroxycarbonyl, (C 1 -C 4 ) alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 ) alkylaminocarbonyl and di-(C 1 -C 4 ) alkylaminocarbonyl,
and
(iii) R 10 , R 13 , R 14 and R 15 mutually independently on each single occurrence mean hydrogen, (C 1 -C 4 ) alkyl or (C 3 -C 6 ) cycloalkyl, wherein
(C 1 -C 4 ) alkyl can itself be up to doubly, similarly or differently, substituted with hydroxy, (C 1 -C 4 ) alkoxy, hydroxycarbonyl and/or (C 1 -C 4 ) alkoxycarbonyl
and
(C 3 -C 6 ) cycloalkyl can itself be up to doubly, similarly or differently, substituted with (C 1 -C 4 ) alkyl, hydroxy and/or (C 1 -C 4 ) alkoxy,
or
R 1 stands for (C 2 -C 6 ) alkenyl, which can be substituted with hydroxycarbonyl or (C 1 -C 4 ) alkoxycarbonyl,
or
for (C 3 -C 6 ) cycloalkyl, which can be up to doubly, similarly or differently, substituted with (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy and/or hydroxy,
R 2 stands for phenyl or thienyl, which can be singly to doubly, similarly or differently, substituted with residues selected from the range fluorine, chlorine, (C 1 -C 4 ) alkyl, trifluoromethyl, (C 1 -C 4 ) alkoxy and trifluoromethoxy,
L 1 stands for a group of the formula —CR 5A R 5B —, wherein
R 5A and R 5B mutually independently mean hydrogen or methyl,
L 2 stands for a group of the formula *—CR 6A R 6B —(CR 7A R 7B ) q —, wherein
* means the binding site with the N atom of the amide group,
q means the number 0 or 1,
R 6A means hydrogen or methyl,
R 6B means hydrogen, methyl, trifluoromethyl or a residue of the formula —C(═O)—OR 16 or —C(═O)—NR 17 R 18 , wherein
R 16 , R 17 and R 18 mutually independently represent hydrogen, (C 1 -C 4 ) alkyl or (C 3 -C 6 ) cycloalkyl
or
R 17 and R 18 together with the nitrogen atom to which they are bound form a 4 to 6-membered heterocycle, which can contain an O atom as a further hetero atom,
or
R 6A and R 6B are linked to one another and together form a —(CH 2 ), bridge, wherein
r means the number 2, 3, 4 or 5
and one CH 2 group of the bridge can be exchanged for —O—,
R 7A means hydrogen, fluorine or methyl,
R 7B means hydrogen, fluorine, methyl or a residue of the formula —C(═O)—OR 23 or —C(═O)—NR 24 R 25 , wherein
R 23 , R 24 and R 25 mutually independently represent hydrogen, (C 1 -C 4 ) alkyl or (C 3 -C 6 ) cycloalkyl
or
R 24 and R 25 together with the nitrogen atom to which they are bound form a 4 to 6-membered heterocycle, which can contain an O atom as a further hetero atom,
or
R 7A and R 7B together form an oxo group
or
R 7A and R 7B are linked to one another and together form a —(CH 2 ), bridge, wherein
s means the number 2, 3, 4 or 5
and one CH 2 group of the bridge can be exchanged for —O—,
or
L 2 stands for a group of the formula
wherein
* means the binding site with the N atom of the amide group,
x means the number 1, 2, 3 or 4,
where one CH 2 group of the ring can be exchanged for —O—,
and
R 6B and R 7B each have the aforesaid meanings,
and
R 3 stands for phenyl, naphthyl, pyridyl, quinolinyl or isoquinolinyl, which can each be singly to doubly, similarly or differently, substituted with residues selected from the range fluorine, chlorine, cyano, (C 1 -C 4 ) alkyl, trifluoromethyl, (C 1 -C 4 ) alkoxy, trifluoromethoxy, (C 1 -C 4 ) alkylthio and phenyl,
wherein the last-named phenyl residue can itself be up to doubly, similarly or differently, substituted with fluorine, chlorine, cyano, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, trifluoromethyl and/or trifluoromethoxy,
and salts thereof.
6. The compound of the formula (I) according to one of claim 1 , in which
A stands for N or CH,
R 1 stands for (C 1 -C 6 ) alkyl, which can be singly or doubly, similarly or differently, substituted with residues selected from the range fluorine, oxo, hydroxy, (C 1 -C 4 ) alkoxy, trifluoromethyl, (C 3 -C 6 ) cycloalkyl and phenyl,
where phenyl can itself be up to doubly, similarly or differently, substituted with residues selected from the range fluorine, chlorine, cyano, (C 1 -C 4 ) alkyl, trifluoromethyl, hydroxymethyl, (C 1 -C 4 ) alkoxy, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl and di-(C 1 -C 4 ) alkylaminocarbonyl,
or
R 1 stands for (C 2 -C 4 ) alkenyl or (C 3 -C 6 ) cycloalkyl,
R 2 stands for phenyl or thienyl, which can be singly to doubly, similarly or differently, substituted with residues selected from the range fluorine, chlorine, bromine, (C 1 -C 4 ) alkyl and (C 1 -C 4 ) alkoxy,
L 1 stands for —CH 2 —, —CH(CH 3 )— or —CH 2 CH 2 —,
L 2 stands for a group of the formula *—CR 6A R 6B —(CR 7A R 7B ) q —, wherein
* means the binding site with the N atom of the amide group,
q means the number 0 or 1,
R 6A means hydrogen or methyl,
R 6B means hydrogen, methyl, trifluoromethyl or a residue of the formula —C(═O)—NR 17 R 18 , wherein
R 17 and R 18 mutually independently represent hydrogen, (C 1 -C 4 ) alkyl or (C 3 -C 6 ) cycloalkyl
or
R 17 and R 18 together with the nitrogen atom to which they are bound form a 4 to 6-membered heterocycle, which can contain an O atom as a further hetero atom,
or
R 6A and R 6B are linked to one another and together form a —(CH 2 ) r bridge, wherein
r means the number 2, 3, 4 or 5
and one CH 2 group of the bridge can be exchanged for —O—,
R 7A means hydrogen, fluorine or methyl,
R 7B means hydrogen, fluorine, methyl or a residue of the formula —C(═O)—OR 23 or —C(═O)—NR 24 R 25 , wherein
R 23 , R 24 and R 25 mutually independently represent hydrogen or (C 1 -C 4 ) alkyl
or
R 24 and R 25 together with the nitrogen atom to which they are bound form a 4 to 6-membered heterocycle, which can contain an O atom as a further hetero atom,
or
R 7A and R 7B together form an oxo group
or
R 7A and R 7B are linked to one another and together form a —(CH 2 ) s bridge, wherein
s means the number 2, 3, 4 or 5
and one CH 2 group of the bridge can be exchanged for —O—,
or
L 2 stands for a group of the formula
wherein
* means the binding site with the N atom of the amide group,
x means the number 1, 2, 3 or 4
and
R 6B and R 7B each have the aforesaid meanings,
and
R 3 stands for phenyl or pyridyl, which can be singly to doubly, similarly or differently, substituted with residues selected from the range fluorine, chlorine, (C 1 -C 4 ) alkyl, trifluoromethyl, (C 1 -C 4 ) alkoxy and trifluoromethoxy, or for naphthyl,
and salts thereof.
7. The compound of the formula (I) according to claim 1 , in which
A stands for N or CH,
R 1 stands for (C 1 -C 6 ) alkyl, which can be singly or doubly, similarly or differently, substituted with residues selected from the range fluorine, oxo, hydroxy, methoxy, ethoxy, trifluoromethyl, cyclopropyl and phenyl,
where phenyl can itself be up to doubly, similarly or differently, substituted with residues selected from the range fluorine, chlorine, cyano, methyl, hydroxymethyl, methoxy, hydroxycarbonyl, aminocarbonyl and dimethylaminocarbonyl,
or
R 1 stands for vinyl, allyl or cyclopropyl,
R 2 stands for phenyl or thienyl, which can be singly to doubly, similarly or differently, substituted with residues selected from the range fluorine, chlorine, methyl and methoxy
L 1 stands for —CH 2 —,
L 2 stands for a group of the formula *—CR 6A R 6B —(CR 7A R 7B ) q —, wherein
* means the binding site with the N atom of the amide group,
q means the number 0 or 1,
R 6A means hydrogen or methyl,
R 6B means hydrogen, methyl, trifluoromethyl or a residue of the formula —C(═O)—NR 17 R 18 , wherein
R 17 and R 18 mutually independently represent hydrogen, methyl, ethyl or cyclopropyl
or
R 17 and R 18 together with the nitrogen atom to which they are bound form an azetidine, pyrrolidine, piperidine or morpholine ring,
or
R 6A and R 6B are linked together and together with the carbon atom to which they are bound form a group of the formula
R 7A means hydrogen, fluorine or methyl,
R 7B means hydrogen, fluorine, methyl or a residue of the formula —C(═O)—OR 23 or —C(═O)—NR 24 R 25 , wherein
R 23 , R 24 and R 25 mutually independently represent hydrogen, methyl or ethyl
or
R 24 and R 25 together with the nitrogen atom to which they are bound form an azetidine, pyrrolidine, piperidine or morpholine ring,
or
R 7A and R 7B together form an oxo group
or
R 7A and R 7B are linked to one another and together form a —(CH 2 ) s bridge, wherein
s means the number 2, 3, 4 or 5
and one CH 2 group of the bridge can be exchanged for —O—,
or
L 2 stands for a group of the formula
and
R 3 stands for phenyl, which can be singly or doubly, similarly or differently, substituted with fluorine, chlorine, trifluoromethyl and/or trifluoromethoxy, or for 1-naphthyl,
and salts thereof.
8. The compound of the formula (I) according to claim 1 , in which
A stands for N or CH,
R 1 stands for (C 1 -C 4 ) alkyl, 2-methoxyethyl, cyclopropyl, cyclohexylmethyl, benzyl or 1-phenethyl,
where the phenyl ring in the said benzyl- and 1-phenethyl residues can be substituted with fluorine, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy,
R 2 stands for phenyl or thienyl, which are each singly or doubly, similarly or differently, substituted with fluorine, chlorine, bromine, methyl and/or methoxy,
L 1 stands for —CH 2 —, —CH 2 CH 2 — or —CH(CH 3 )—,
L 2 stands for —CH 2 —, —CH(CH 3 )— or —C(CH 3 ) 2 —
and
R 3 stands for phenyl, which is singly or doubly, similarly or differently, substituted with fluorine, chlorine, trifluoromethyl and/or trifluoromethoxy, or for 1-naphthyl,
and salts thereof.
9. A method of making compounds of the formula (I), as defined in claim 1 , characterized in that
[A] a compound of the formula (II)
in which A, L 1 , R 1 and R 2 each have the meanings stated in claims 1 to 8 ,
is coupled with a compound of the formula (III)
R 3 -L 2 -NH 2 (III),
in which L 2 and R 3 have the meanings stated in claims 1 to 8 , in an inert solvent with activation of the carboxylic acid function
or
[B] a compound of the formula (IV)
in which A, R 1 and R 2 each have the meanings stated in claims 1 to 8 ,
is reacted with a compound of the formula (V)
in which L 1 , L 2 and R 3 each have the meanings stated in claims 1 to 8
and
X stands for a leaving group, such as for example halogen, mesylate or tosylate,
in an inert solvent in the presence of a base
and the resulting compounds of the formula (I) are optionally converted into their solvates, salts and/or solvates of the salts with the appropriate (i) solvents and/or (ii) bases or acids.
10. A pharmaceutical composition comprising a compound of the formula (I) of claim 1 , in combination with an inert, non-toxic, pharmaceutically suitable additive.
11. The pharmaceutical composition of claim 10 , further comprising one or more further active substances selected from the group consisting of diuretics, angiotensin AII antagonists, ACE inhibitors, beta receptor blockers, mineralocorticoid receptor antagonists, organic nitrates, NO donors and substances with positive inotropic action.