Heterocyclic-Substituted Alkanamides Useful as Renin Inhibitors
Compounds of the general formula (I) in which the meanings of the substituents R 1 and R 2 are as stated in claim 1 , have renin-inhibiting properties and can be used as medicines.
1 - 13 . (canceled)
14 . A compound of the formula
in which
R 1 is a) saturated heterocyclyl which is bonded via a C atom and where the heterocyclyl radical contains oxygen as heteroatom and which is optionally substituted one or more times by C 1-8 alkanoyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxycarbonylamino, C 1-6 alkyl, C 0-6 alkylcarbonylamino, C 1-6 alkylcarbonyloxy, C 1-6 alkylenedioxy, optionally N-mono or N,N-di-C 1-6 -alkylated amino, aryl, optionally N-mono or N,N-di-C 1-6 -alkylated carbamoyl, optionally esterified carboxy, cyano, C 3-8 cycloalkoxy, C 3-8 cycloalkyl-C 0-6 alkyl, halogen, halo-C 1-6 alkoxy, halo-C 1-6 alkyl, heteroaryl, unsaturated, partially saturated or saturated heterocyclyl, hydroxy, nitro or oxo; or
b) dioxanyl-, dioxepanyl-, dioxolanyl-, oxepanyl-, tetrahydropyranyl-, tetrahydrofuranyl-, or bicyclic saturated heterocyclyl-C 1-4 alkyl and where the heterocyclyl radical contains oxygen as heteroatom, each of which is optionally substituted one or more times by C 1-8 alkanoyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxycarbonylamino, C 1-6 alkyl, C 0-6 alkylcarbonylamino, C 1-6 alkylcarbonyloxy, C 1-6 alkylenedioxy, optionally N-mono or N,N-di-C 1-6 -alkylated amino, aryl, optionally N-mono or N,N-di-C 1-6 -alkylated carbamoyl, optionally esterified carboxy, cyano, C 3-8 cycloalkoxy, C 3-8 cycloalkyl-C 0-6 alkyl, halogen, halo-C 1-6 alkoxy, halo-C 1-6 alkyl, heteroaryl, unsaturated, partially saturated or saturated heterocyclyl, hydroxy, nitro or oxo; or
c) C 2-8 alkynyl which is optionally substituted one or more times by C 1-8 alkanoyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxycarbonylamino, C 1-6 alkyl, C 0-6 alkylcarbonylamino, C 1-6 alkylcarbonyloxy, C 1-6 alkylenedioxy, optionally N-mono or N,N-di-C 1-6 -alkylated amino, aryl, optionally N-mono or N,N-di-C 1-6 -alkylated carbamoyl, optionally esterified carboxy, cyano, C 3-8 cycloalkoxy, C 3-8 cycloalkyl-C 0-6 alkyl, halogen, halo-C 1-6 -alkoxy, halo-C 1-6 alkyl, heteroaryl, unsaturated, partially saturated or saturated heterocyclyl, hydroxy, nitro or oxo; or
R 2 is, independently of one another, 1-4 radicals selected from:
C 1-8 alkanoyl, C 1-8 alkanoyl-C 2-4 alkoxy bearing the alkanoyl group in a position higher than α, C 1-8 alkanoylamino-C 1-4 alkoxy, N—C 1-4 alkanoylamino-C 1-4 alkyl, C 1-8 alkanoyloxy-C 1-4 alkyl, N′—C 2-8 alkanoyIpiperazino-C 1-4 alkoxy, N′—C 2-8 alkanoyIpiperazino-C 4 alkyl, C 1-8 alkanesulphonyl-C 1-4 alkoxy, C 1-8 alkanesulphonyl-C 1-4 alkyl, C 1-8 alkanesulphonylamino-C 1-4 alkoxy, C 1-4 alkanesulphonylamino-C 1-4 alkyl, C 1-8 alkanesulphonyl-C 1-4 (hydroxy)alkoxy, C 2-8 alkenyloxy, C 2-8 alkenyloxy-C 1-4 alkoxy, C 2-8 alkenyloxy-C 1-4 alkyl, C 1-8 alkoxy, C 1-6 alkoxy-C 1-6 alkanoyl, C 1-4 alkoxy-C 2-4 alkenyl, C 1-4 alkoxy-C 2-4 alkenyloxy, C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxycarbonyl-C 1-4 alkoxy, C 1-4 alkoxycarbonyl-C 1-4 alkyl, C 1-8 alkoxycarbonylamino-C 1-4 alkoxy, C 1-8 alkoxycarbonylamino-C 1-4 alkyl, C 1-8 alkyl, C 1-4 alkylamino, N,N-di-C 1-4 alkylamino, C 1-4 alkylamino-C 1-4 alkoxy, N,N-di-C 1-4 alkylamino-C 1-4 alkoxy, C 1-4 alkylamino-C 1-4 alkyl, N,N-di-C 1-4 alkylamino-C 1-4 alkyl, N-mono- or N,N-di-C 1-4 alkylcarbamoyl-C 1-4 alkoxy, N-mono- or N,N-di-C 1-4 alkylcarbamoyl-C 1-4 alkyl, N′—C 1-4 alkylpiperazino-C 1-4 alkoxy,N′—C 1-4 alkylpiperazino-C 1-4 alkyl, C 1-4 alkylthio-C 1-4 alkoxy, C 1-4 alkylthio-C 1-4 (hydroxy)alkoxy, C 1-4 alkylthio-C 1-4 alkyl, amino-C 2-4 alkoxy, amino-C 1-4 alkyl, carbamoyl-C 1-4 alkoxy, carbamoyl-C 1-8 alkyl, carboxy-C 1-4 alkoxy, carboxy-C 1-4 alkyl, cyano-C 1-4 alkoxy, cyano-C 1-4 alkyl, C 3-8 -cycloalkoxy, C 3-8 cycloalkoxy-C 1-4 alkoxy, C 3-8 cycloalkoxy-C 1-4 alkyl, C 3-8 cycloalkyl, S,S-dioxothiomorpholino-C 1-4 alkoxy, S,S-dioxothiomorpholino-C 1-4 alkyl, halogen, halo-C 1-4 alkoxy, halo-C 1-4 alkyl, halo-C 2-8 (hydroxy)alkoxy, hydroxy, hydroxy-C 2-8 alkoxy, hydroxy-C 2-8 alkyl, imidazolylthio-C 1-4 alkoxy, imidazolylthio-C 1-4 alkyl, optionally N-oxidized morpholino-C 1-4 alkoxy, morpholino-C 1-4 alkyl, S-oxothiomorpholino-C 1-4 alkoxy, S-oxothiomorpholino-C 1-4 alkyl, piperazino-C 1-4 alkoxy, piperazino-C 1-4 alkyl, piperidino-C 1-4 alkoxy, piperidino-C 1-4 alkyl, optionally partially hydrogenated pyridyl- or N-oxidopyridyl-C 1-4 alkoxy, optionally partially hydrogenated pyridyl- or N-oxidopyridyl-C 1-4 alkyl, optionally N-oxidized pyridylthio-C 1-4 alkoxy, optionally N-oxidized pyridylthio-C 1-4 alkyl, pyrimidinylthio-C 1-4 alkoxy, pyrimidinylthio-C 1-4 alkyl, pyrrolidino-C 1-4 alkoxy, pyrrolidino-C 1-4 alkyl, thiazolinylthio-C 1-4 alkoxy, thiazolinylthio-C 1-4 alkyl, thiazolyl-C 1-4 alkoxy, thiazolylthio-C 1-4 alkoxy, thiazolylthio-C 1-4 alkyl, thiomorpholino-C 1-4 alkoxy, thiomorpholino-C 1-4 alkyl, trifluoro-C 1-8 alkanesulphonyl-C 1-4 alkoxy, trifluoro-C 1-8 alkanesulphonylamino-C 1-4 alkyl, phenyl or naphthyl which is unsubstituted or mono-, di- or trisubstituted by C 1-4 alkoxy, C 1-4 alkyl, C 1-4 alkylamino, di-C 1-4 alkylamino, halogen, hydroxy and/or trifluoromethyl, and phenyl- or naphthyl-C 1-4 alkoxy which is unsubstituted or mono-, di- or trisubstituted by C 1-4 alkoxy, C 1-4 alkyl, C 1-4 alkylamino, di-C 1-4 alkylamino, halogen, hydroxy and/or trifluoromethyl, and its salt or compound in which one or more atoms are replaced by their stable, non-radioactive isotopes, especially pharmaceutically acceptable salt.
15 . A compound according to claim 14 of the formula
in which R 1 and R 2 has the meanings according to claim 14 .
16 . A compound according to claim 14 , of the formula
in which
R 1 has the meaning indicated for the compound of the formula (I) and
R′ and R″, independently of one another, have the meanings indicated for R 2 for the compound of the formula (I).
17 . A compound according to claim 14 , in which
R 1 is dioxanyl-, [1,4]dioxepanyl-, dioxolanyl-, oxepanyl-, tetrahydropyranyl-, tetrahydrofuranyl-, 2,5-dioxabicyclo[4.1.0]heptanyl-, 2-oxabicyclo[2.2.1]heptanyl-, 2-oxabicyclo[4.1.0]heptanyl-, 3-oxabicyclo[4.1.0]heptanyl-, 7-oxabicyclo[2.2.1]heptanyl-, 2-oxabicyclo[3.1.0]hexanyl-, 3-oxabicyclo[3.1.0]hexanyl-, 1-oxaspiro[2.5]octanyl-, 6-oxaspiro[2.5]octanyl- or 3-oxabicyclo[3.3.1]nonanyl-C 0-4 alkyl, each of which is optionally substituted one or more times by C 1-8 alkanoyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxycarbonylamino, C 1-6 alkyl, C 0-6 alkylcarbonylamino, C 1-6 alkylcarbonyloxy, C 1-6 alkylenedioxy, optionally N-mono or N,N-di-C 1-6 -alkylated amino, aryl, optionally N-mono or N,N-di-C 1-6 -alkylated carbamoyl, optionally esterified carboxy, cyano, C 3-8 cycloalkoxy, C 3-8 cycloalkyl-C 0-6 alkyl, halogen, halo-C 1-6 alkoxy, halo-C 1-6 alkyl, heteroaryl, unsaturated, partially saturated or saturated heterocyclyl, hydroxy, nitro or oxo.
18 . A compound according to claim 14 , in which
R 2 is, independently of one another, 1-4 radicals selected from: C 1-8 alkanoylamino-C 1-4 alkoxy, N—C 1-4 alkanoylamino-C 1-4 alkyl, C 1-8 alkoxy, C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-8 alkoxycarbonylamino-C 1-4 alkoxy, C 1-8 alkoxycarbonylamino-C 1-4 alkyl, C 1-8 alkyl, halogen, trifluoromethoxy and trifluoromethyl.
19 . A compound according to claim 14 , in which
R 1 is optionally substituted C 2-6 alkynyl, optionally substituted saturated bicyclic heterocyclyl-C 0-4 alkyl, optionally substituted pyrrolidinyl, C 1-6 -alkylated or C 3-8 cycloalkyl-C 0-6 -alkylated piperidine, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydrofuranylmethyl, optionally substituted tetrahydropyranyl or optionally substituted tetrahydropyranylmethyl.
20 . A compound according to claim 14 , in which
R 1 is optionally substituted tetrahydrofuranylmethyl or optionally substituted tetrahydropyranylmethyl.
21 . A compound according to claim 15 , in which
R′ is C 1-4 alkoxy-C 1-4 alkoxy;
R″ is fluorine; and
R 1 is optionally substituted tetrahydrofuranylmethyl, optionally substituted tetrahydropyranylmethyl, optionally substituted saturated heterocyclyl which is bonded via a C atom or optionally substituted saturated bicyclic heterocyclyl-C 0-4 alkyl, where the heterocyclyl radical in each case comprises an oxygen atom as heteroatom.
22 . The use of a compound of the general formula (I) according to claim 14 for producing a medicine.
23 . The use of a compound of the general formula (I) according to claim 14 for producing a human medicine for preventing, for delaying the progression or for treating high blood pressure, heart failure, glaucoma, myocardial infarction, renal failure, restenoses or stroke.
24 . A method for preventing, for delaying the progression or for treating high blood pressure, heart failure, glaucoma, myocardial infarction, renal failure, restenoses or stroke, where a therapeutically effective amount of a compound of the general formula (I) according to claim 14 is used.
25 . A pharmaceutical product comprising a compound of the general formula (I) according to claim 14 , and usual excipients.
26 . A pharmaceutical combination in the form of a product or of a kit composed of individual components consisting a) of a compound of the general formula (I) according to claim 14 , and b) at least one pharmaceutical form whose active ingredient has a cardiovascular effect.