FUSED IMIDAZOLE DERIVATIVES AND USE THEREOF AS ALDOSTERONE SYNTHASE INHIBITORS
The patent application relates to new heterocyclic compounds of the general formula (I) in which A, R, R 1 , R 2 , X, Y, Z, n and p have the definitions elucidated in more detail in the description, to a process for preparing them and to the use of these compounds as medicaments, particularly as aldosterone synthase inhibitors.
1 . Compound of the general formula
in which
A is aryl or heterocyclyl;
X is CR 3 R 4 or, if Y is CR 3 R 4 , is alternatively a bond;
Y is CR 3 R 4 , O, S(O) m or NR 5 ;
Z is CR 3 R 4 or
a) if Y is CR 3 R 4 , is alternatively O, S(O) m or NR 5 ; or
b) if Y is S(O) m , is alternatively NR 5 ; or
c) if Y is NR 5 , is alternatively S(O) m ;
R is C 1 -C 8 -alkoxy, C 1 -C 8 -alkyl, halogen, trifluoromethyl, tri-C 1 -C 4 -alkylsilyl, deuterium or hydrogen;
R 1 is C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxycarbonyl, C 1 -C 8 -alkyl, mono- and di-C 1 -C 8 -alkylamino, mono- and di-C 1 -C 8 -alkylaminocarbonyl, C 0 -C 8 -alkylcarbonyl, amino, carbamoyl, carboxy-C 1 -C 4 -alkyl, carboxyl, cyano, halogen, oxo, trifluoromethyl, trifluoromethoxy, heterocyclyl or aryl, which radicals may be substituted by 1-4 C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxycarbonyl, C 1 -C 8 -alkyl, C 0 -C 8 -alkylcarbonyl, tri-C 1 -C 4 -alkylsilyl, C 1 -C 8 -alkylsulphonyl, aryl, cyano, halogen, heterocyclyl, oxo, trifluoromethyl or trifluoromethoxy;
R 2 a) is, independently of one another, C 1 -C 8 -alkyl, mono- and di-C 1 -C 8 -alkylamino, mono- and di-C 1 -C 8 -alkylaminocarbonyl, C 0 -C 8 -alkylcarbonyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxycarbonyl, amino, carbamoyl, carboxy-C 1 -C 4 -alkyl, carboxyl, cyano, halogen, oxo, trifluoromethyl, trifluoromethoxy, hydrogen, heterocyclyl or aryl, which radicals may be substituted by 1-4 C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxycarbonyl, C 1 -C 8 -alkyl, C 0 -C 8 -alkylcarbonyl, tri-C 1 -C 4 -alkylsilyl, C 1 -C 8 -alkylsulphonyl, aryl, cyano, halogen, heterocyclyl, oxo, trifluoromethyl or trifluoromethoxy; or
b) together with R 1 is a fused-on 5-6-membered heterocyclic ring;
R 3 is hydrogen or C 1 -C 8 -alkyl;
R 4 a) is hydrogen or C 1 -C 8 -alkyl; or
b) together with R 3 is oxo;
R 5 is hydrogen, C 1 -C 8 -alkyl or C 0 -C 8 -alkylcarbonyl;
m is a number 0, 1 or 2;
n is a number 0, 1 or 2;
p is a number 1 or 2;
and its salts, preferably its pharmaceutically useful salts.
2 . Compound according to claim 1 , characterized in that it conforms to the general formula
the definitions of the substituents R, R 1 , R 2 , R 3 , R 4 , R 5 and p being as specified for compounds of the formula (I) according to claim 1 , and having a specific configuration at the asymmetric carbon atom labelled “*”.
3 . Compound according to claim 1 , wherein R is hydrogen or deuterium.
4 . Compound according to claim 1 , wherein R 1 is halogen, cyano, trifluoromethyl, heterocyclyl or C 0 -C 8 -alkylcarbonyl.
5 . Compound according to claim 1 , wherein R 2 is, independently of one another, hydrogen, C 1 -C 8 -alkyl, cyano or halogen or together with R 1 is a fused-on 5- or 6-membered heterocyclic ring.
6 . Compound according to claim 1 , wherein R 3 and R 4 are hydrogen or together are oxo.
7 . Compound according to claim 1 , wherein R 5 is hydrogen, methyl, formyl or acetyl.
8 . Compound according to claim 1 , wherein n is a number 0 or 1.
9 . Compound according to claim 2 , wherein
R is hydrogen or deuterium;
R 1 is halogen, cyano, trifluoromethyl, heterocyclyl or C 0 -C 8 -alkylcarbonyl;
R 2 is, independently of one another, hydrogen, C 1 -C 8 -alkyl or cyano or together with R 1 is a fused-on 5- or 6-membered heterocyclic ring;
R 3 and R 4 are hydrogen or together are oxo; and
R 5 is hydrogen, methyl, formyl or acetyl.
10 - 12 . (canceled)
13 . Method of preventing, delaying the progression of or treating pathological states which are wholly or partly caused by hyperaldosteronism, in a patient, which comprises administering a therapeutically effective amount of a compound of the general formula (I) according to claim 1 to the patient.
14 . Method of preventing, delaying the progression of or treating pathological states which are wholly or partly caused by excessive cortisol release, in a patient, which comprises administering a therapeutically effective amount of a compound of the general formula (I) according to claim 1 to the patient.
15 . Pharmaceutical composition comprising a compound of the general formula (I) according to claim 1 and conventional excipients.
16 . Pharmaceutical combination in the form of a product or kit composed of individual components consisting a) of a compound of the general formula (I) according to claim 1 and b) of at least one pharmaceutical form whose active ingredient has a blood pressure-lowering, an inotropic, a metabolic or a lipid-lowering effect.
17 . Compound according to claim 2 , wherein R is hydrogen or deuterium.
18 . Compound according to claim 2 , wherein R 1 is halogen, cyano, trifluoromethyl, heterocyclyl or C 0 -C 8 -alkylcarbonyl.
19 . Compound according to claim 2 , wherein R 2 is, independently of one another, hydrogen, C 1 -C 8 -alkyl, cyano or halogen or together with R 1 is a fused-on 5- or 6-membered heterocyclic ring.
20 . Compound according to claim 2 , wherein R 3 and R 4 are hydrogen or together are oxo.
21 . Compound according to claim 2 , wherein R 5 is hydrogen, methyl, formyl or acetyl.
22 . Method of preventing, delaying the progression of or treating pathological states which are wholly or partly caused by hyperaldosteronism, in a patient, which comprises administering a therapeutically effective amount of a compound of the general formula (I) according to claim 2 to the patient.
23 . Method of preventing, delaying the progression of or treating pathological states which are wholly or partly caused by excessive cortisol release, in a patient, which comprises administering a therapeutically effective amount of a compound of the general formula (I) according to claim 2 to the patient.
24 . Pharmaceutical composition comprising a compound of the general formula (I) according to claim 2 and conventional excipients.
25 . Pharmaceutical combination in the form of a product or kit composed of individual components consisting a) of a compound of the general formula (I) according to claim 2 and b) of at least one pharmaceutical form whose active ingredient has a blood pressure-lowering, an inotropic, a metabolic or a lipid-lowering effect.