US 6,211,196 B1Granted

Benzyloxy-substituted, fused N-heterocycles, processes for their preparation, and their use as bradykinin receptor antagonists

AssigneeAventis Pharma Deutschland GmbH

InventorsHolger Heitsch, Adalbert Wagner, Klaus Wirth, Bernward Schölkens

Life of this patent

Estimating the term…

Abstract

Benzyloxy-substituted, fused N-heterocycles, because of their ability to act as bradykinin receptor antagonists, have been found to be useful as therapeutics for the treatment and prevention of liver cirrhosis or Alzheimer's disease. This application describes such compounds, as well as processes for their preparation and use. The compounds according to this invention include compounds of formula (I) in which B, D, R1, and R2 have the meanings indicated herein.

Claims22

Dependent claims

A compound of formula (I):

wherein:
D is a radical of formula (II) or (III):
wherein:
X1 is —C—R6;
X2 is —C—R7;
X3 is —C—R8;
B is a radical of formula (VIII)
R1 and R2, which may be identical or different, are
(a) hydrogen,
(b) halogen, or
(c) (C1-C3)-alkyl;
R3 and R4, which may be identical or different, are
(a) hydrogen,
(b) halogen,
(c) cyano,
(d) (C1-C3)-alkyl,
(e) —O—(C1-C3)-alkyl,
(f) —S—(C1-C3)-alkyl,
wherein, in the radicals mentioned under (d), (e), or (f), 1 to 5 of the hydrogen atoms present in the alkyl groups can be replaced by halogen atoms,
(g) —OH,
(h) tetrazolyl,
(i) —CONHR9, or
(j) —COOR9;
R5 is
(a) nitro,
(b) amino,
(c) a radical of formula (IV)
(d) a radical of formula (V)
R6, R8, and R′″, which may be identical or different, are
(a) hydrogen,
(b) halogen,
(c) (C1-C4)-alkyl,
(d) (C1-C4)-alkoxy,
(e) amino,
(f) (C1-C4)-alkylamino,
(g) hydroxyl,
(h) (C6-C12)-aryl,
(i) (C6-C12)-aryl-(C1-C4)-alkandiyl, or
(j) —COOR9;
R7, R′, and R″, which may be identical or different, are
(a) hydrogen, or
(b) (C1-C4)-alkyl,
wherein each R″ in formula (III) may be identical or different;
R9 is
(a) hydrogen,
(b) (C1-C4)-alkyl,
(c) (C2-C5)-alkenyl, or
(d) (C6-C12)-aryl-(C1-C3)-alkandiyl;
A is a bivalent radical of an aminocarboxylic acid;
Y is
E is
(a) (C2-C5)-alkenediyl,
(b) (C1-C7)-alkanediyl,
(c) (C3-C10)-cycloalkanediyl, or
(d) —(CH2)m—To—(CH2)n—, wherein m, n, and o are defined such that —(CH2)m—To—(CH2)n— is not a (C1-C7)-alkanediyl or a single bond,
wherein the radicals mentioned under (a) through (d) optionally can be substituted;
T is
(a) O,
(b) S, or
(c) —NR15;
m and n, which may be identical or different, are each an integer from 0-6;
o is 0 or 1;
R10 is
(a) hydrogen,
(b) (C1-C5)-alkyl,
(c) (C6-C10)-aryl,
(d) (C1-C3)-alkandiyl-(C6-C10)-aryl, or
(e) a heteroaryl group,
wherein (c), (d), and (e) can optionally be substituted by one or more groups;
R15 is
(a) hydrogen,
(b) —C(O)—(C1-C3)-alkyl, or
(c) (C1-C3)-alkyl;
or a physiologically tolerable salt thereof;
with a first proviso that formula (I) does not include a compound wherein D is a radical of formula (II), R3 and R4 are simultaneously halogen, (C1-C3)-alkyl, —O—(C1-C3)-alkyl, or a combination thereof, and R3 and R4 are hydrogen in combination with halogen, (C1-C3)-alkyl, —O—(C1-C3)-alkyl, or a combination thereof,
(α) with a first exception to the first proviso being that formula (I) does include a compound
wherein D is a radical of formula (II) and R5 is a radical of formula (IV),
wherein R10 is a heteroaryl group or a radical of formula (VI)
wherein p is an integer from 1 to 3, and
R11 is (a) (C1-C5)-alkyl, wherein the hydrogen atoms are partially or completely replaced by fluorine or chlorine, or (b) (C1-C5)-alkoxy, wherein the hydrogen atoms are partially or completely replaced by fluorine or chlorine, and
(β) with a second exception to the first proviso being that formula (I) does include a compound wherein D is a radical of formula (II) and R5 is a radical of formula (V);
said first and second exceptions to the first proviso do not include a compound of formula (I) wherein R10 has the formula (VI), R3 and R4 are identically or differently hydrogen and halogen, and wherein D is a radical of formula (II) and R5 is a radical of formula (V), R3 and R4 are halogen;
said first and second exceptions to the first proviso do not include a compound of formula (I) wherein D is a radical of formula (II), R5 is a radical of formula (IV), R9 is hydrogen or (C1-C4)-alkyl, Y is —CO—, E is (C2-C5)-alkenediyl, (C1-C6)-alkanediyl, (CH2)m—NH— where m is 0 or 1, or —CH2—S—, and R10 is a heteroaryl group;
said first and second exceptions to the first proviso do not include a compound of formula (I) wherein D is a radical of formula (II), R5 is a radical of formula (IV), R9 is hydrogen or (C1-C4)-alkyl, Y is —CO—, E is (C2-C5)-alkenediyl or —NH—, and R10 is pyridyl monosubstituted with —COOH or —CONR13R14 wherein R13 is hydrogen, (C1-C5)-alkyl, (C2-C5)-alkenyl, or (C6-C12)-aryl, and R14 is hydrogen;
said first and second exceptions to the first proviso do not include a compound of formula (I) wherein D is a radical of formula (II), R5 is a radical of formula (IV), R9 is methyl, Y is —CO—, E is —NH—CH2—, and R10 is unsubstituted pyridyl;
and
with a second proviso that when D is a radical of formula (II) and R5 is nitro or amino, R3 and R4 cannot simultaneously be hydrogen.

84 more elements

Dependencies are inferred from the claim text.

patentgrep

Loading patent…

Abstract

A compound of formula (I):

wherein:
D is a radical of formula (II) or (III):
wherein:
X1 is —C—R6;
X2 is —C—R7;
X3 is —C—R8;
B is a radical of formula (VIII)
R1 and R2, which may be identical or different, are
(a) hydrogen,
(b) halogen, or
(c) (C1-C3)-alkyl;
R3 and R4, which may be identical or different, are
(a) hydrogen,
(b) halogen,
(c) cyano,
(d) (C1-C3)-alkyl,
(e) —O—(C1-C3)-alkyl,
(f) —S—(C1-C3)-alkyl,
wherein, in the radicals mentioned under (d), (e), or (f), 1 to 5 of the hydrogen atoms present in the alkyl groups can be replaced by halogen atoms,
(g) —OH,
(h) tetrazolyl,
(i) —CONHR9, or
(j) —COOR9;
R5 is
(a) nitro,
(b) amino,
(c) a radical of formula (IV)
(d) a radical of formula (V)
R6, R8, and R′″, which may be identical or different, are
(a) hydrogen,
(b) halogen,
(c) (C1-C4)-alkyl,
(d) (C1-C4)-alkoxy,
(e) amino,
(f) (C1-C4)-alkylamino,
(g) hydroxyl,
(h) (C6-C12)-aryl,
(i) (C6-C12)-aryl-(C1-C4)-alkandiyl, or
(j) —COOR9;
R7, R′, and R″, which may be identical or different, are
(a) hydrogen, or
(b) (C1-C4)-alkyl,
wherein each R″ in formula (III) may be identical or different;
R9 is
(a) hydrogen,
(b) (C1-C4)-alkyl,
(c) (C2-C5)-alkenyl, or
(d) (C6-C12)-aryl-(C1-C3)-alkandiyl;
A is a bivalent radical of an aminocarboxylic acid;
Y is
E is
(a) (C2-C5)-alkenediyl,
(b) (C1-C7)-alkanediyl,
(c) (C3-C10)-cycloalkanediyl, or
(d) —(CH2)m—To—(CH2)n—, wherein m, n, and o are defined such that —(CH2)m—To—(CH2)n— is not a (C1-C7)-alkanediyl or a single bond,
wherein the radicals mentioned under (a) through (d) optionally can be substituted;
T is
(a) O,
(b) S, or
(c) —NR15;
m and n, which may be identical or different, are each an integer from 0-6;
o is 0 or 1;
R10 is
(a) hydrogen,
(b) (C1-C5)-alkyl,
(c) (C6-C10)-aryl,
(d) (C1-C3)-alkandiyl-(C6-C10)-aryl, or
(e) a heteroaryl group,
wherein (c), (d), and (e) can optionally be substituted by one or more groups;
R15 is
(a) hydrogen,
(b) —C(O)—(C1-C3)-alkyl, or
(c) (C1-C3)-alkyl;
or a physiologically tolerable salt thereof;
with a first proviso that formula (I) does not include a compound wherein D is a radical of formula (II), R3 and R4 are simultaneously halogen, (C1-C3)-alkyl, —O—(C1-C3)-alkyl, or a combination thereof, and R3 and R4 are hydrogen in combination with halogen, (C1-C3)-alkyl, —O—(C1-C3)-alkyl, or a combination thereof,
(α) with a first exception to the first proviso being that formula (I) does include a compound
wherein D is a radical of formula (II) and R5 is a radical of formula (IV),
wherein R10 is a heteroaryl group or a radical of formula (VI)
wherein p is an integer from 1 to 3, and
R11 is (a) (C1-C5)-alkyl, wherein the hydrogen atoms are partially or completely replaced by fluorine or chlorine, or (b) (C1-C5)-alkoxy, wherein the hydrogen atoms are partially or completely replaced by fluorine or chlorine, and
(β) with a second exception to the first proviso being that formula (I) does include a compound wherein D is a radical of formula (II) and R5 is a radical of formula (V);
said first and second exceptions to the first proviso do not include a compound of formula (I) wherein R10 has the formula (VI), R3 and R4 are identically or differently hydrogen and halogen, and wherein D is a radical of formula (II) and R5 is a radical of formula (V), R3 and R4 are halogen;
said first and second exceptions to the first proviso do not include a compound of formula (I) wherein D is a radical of formula (II), R5 is a radical of formula (IV), R9 is hydrogen or (C1-C4)-alkyl, Y is —CO—, E is (C2-C5)-alkenediyl, (C1-C6)-alkanediyl, (CH2)m—NH— where m is 0 or 1, or —CH2—S—, and R10 is a heteroaryl group;
said first and second exceptions to the first proviso do not include a compound of formula (I) wherein D is a radical of formula (II), R5 is a radical of formula (IV), R9 is hydrogen or (C1-C4)-alkyl, Y is —CO—, E is (C2-C5)-alkenediyl or —NH—, and R10 is pyridyl monosubstituted with —COOH or —CONR13R14 wherein R13 is hydrogen, (C1-C5)-alkyl, (C2-C5)-alkenyl, or (C6-C12)-aryl, and R14 is hydrogen;
said first and second exceptions to the first proviso do not include a compound of formula (I) wherein D is a radical of formula (II), R5 is a radical of formula (IV), R9 is methyl, Y is —CO—, E is —NH—CH2—, and R10 is unsubstituted pyridyl;
and
with a second proviso that when D is a radical of formula (II) and R5 is nitro or amino, R3 and R4 cannot simultaneously be hydrogen.

84 more elements