Benzyloxy-substituted, fused N-heterocycles, processes for...

Details Benzyloxy-substituted, fused N-heterocycles, processes for... Benzyloxy-substituted, fused N-heterocycles, processes for...

1998-03-26

2001-04-03

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S174000, C546S175000, C546S177000, C546S178000, C546S146000, C546S148000, C546S149000, C546S153000, C546S155000, C546S156000, C546S157000, C546S158000, C546S159000, C546S165000, C546S166000, C546S170000, C546S172000, C514S248000, C514S249000, C514S252040, C514S255050, C514S256000, C514S259500, C514S307000, C514S312000, C514S313000, C514S314000, C544S235000, C544S237000, C544S238000, C544S283000, C544S284000, C544S333000, C544S335000, C544S336000, C544S353000, C544S363000, C544S405000

Reexamination Certificate

active

06211196

ABSTRACT:

BACKGROUND AND DESCRIPTION OF THE INVENTION
EP-A-622 361, WO 96-13485, and WO 96-40639, and the earlier priority, non-laid-open patent applications P 19610784.9 and P 19609827.0, disclose benzyloxy-substituted, fused N-heterocycles and their use as bradykinin antagonists.
The present invention relates to novel benzyloxy-substituted, fused N-heterocycles having high affinity for the bradykinin B
2
receptor and improved pharmacokinetics.
The compounds according to the invention are described by formula (I)
in which the symbols have the following meanings:
D is a radical of formula (II) or (III):
 wherein:
X
1
is N or —C—R
6
;
X
2
is N or —C—R
7
; and
X
3
is N or —C—R
8
;
B is a radical of formula (VIII):
R
1
and R
2
, which may be identical or different, are
1. hydrogen,
2. halogen, or
3. (C
1
-C
3
)-alkyl;
R
3
and R
4
, which may be identical or different, are
1. hydrogen,
2. halogen,
3. cyano,
4. (C
1
-C
3
)-alkyl,
5. —O—(C
1
-C
3
)-alkyl,
6. —S—(C
1
-C
3
)-alkyl,
wherein, in the radicals identified under 4, 5, and 6 above, 1 to 5 of the hydrogen atoms in the alkyl groups can be replaced by halogen atoms,
7. —OH,
8. tetrazolyl,
9. —CONHR
9
, or
10. —COOR
9
;
R
5
is
1. nitro,
2. amino,
3. a radical of formula (IV)
4. a radical of formula (V)
R
6
, R
8
, and R′″, which may be identical or different, are
1. hydrogen,
2. halogen,
3. (C
1
-C
4
)-alkyl,
4. (C
1
-C
4
)-alkoxy,
5. amino,
6. (C
1
-C
4
)-alkylamino,
7. hydroxyl,
8. (C
6
-C
12
)-aryl,
9. (C
6
-C
12
)-aryl-(C
1
-C
4
)-alkandiyl, or
10. —CO
2
R
9
;
R
7
,R′, and R″, which may be identical or different, are
1. hydrogen, or
2. (C
1
-C
4
)-alkyl,
wherein each R″ in formula (III) may be identical or different;
R
9
is
1. hydrogen,
2. (C
1
-C
4
)-alkyl,
3. (C
2
-C
5
)-alkenyl, or
4. (C
6
-C
12
)-aryl-(C
1
-C
3
)-alkandiyl;
A is a bivalent radical of an aminocarboxylic acid, such as methionine, alanine, phenylalanine, tyrosine, o-methylthyrosine, &bgr;-(2-thienyl)alanine, glycine, cyclohexylalanine, leucine, isoleucine, valine, norleucine, phenylglycine, serine, cysteine, aminopropionic acid, or aminobutyric acid;
Y is
E is
1. (C
2
-C
5
)-alkenediyl,
2. (C
1
-C
7
)-alkanediyl,
3. (C
3
-C
10
)-cycloalkanediyl, or
4. —(CH
2
)
m
—T
o
—(CH
2
)
n
—, wherein m, n, and o are defined such that —(CH
2
)
m
—T
o
—(CH
2
)
n
— is not a (C
1
-C
7
)-alkanediyl,
wherein the radicals, identified under 1-4 above, optionally, can be substituted by one or more groups, such as —O—R
12
, —NO
2
, —CN, —CO
2
R
9
, —NR
13
R
14
, —SO
3
R
12
, —SO
2
NR
13
R
14
or —CONR
13
R
14
;
T is
1. O,
2. S, or
3. NR
15
;
m and n, which may be identical or different, are each an integer from 0-6;
o is an integer 0 or 1;
R
10
is
1. hydrogen,
2. (C
1
-C
5
)-alkyl,
3. (C
6
-C
10
)-aryl,
4. (C
1
-C
3
)-alkandiyl-(C
6
-C
10
)-aryl-, or
5. a heteroaryl group,
wherein radicals 3, 4, and 5 above can optionally be substituted by one or more groups, such as halogen, —CN, —NO
2
, (C
1
-C
5
)-alkylthio, —NR
13
R
14
, —NR
13
CO—R
16
, —CO
2
R
9
, —SO
3
R
12
, —SO
2
NR
13
R
14
, —OR
12
, (C
1
-C
6
)-alkyl, (C
6
-C
10
)-aryl, (C
2
-C
5
)-alkenyl, and (C
1
-C
5
)-alkoxy, and wherein the last four
radicals (i.e., the (C
1
-C
6
)-alkyl, (C
6
-C
10
)-aryl, (C
2
-C
5
)-alkenyl, and
(C
1
-C
5
)-alkoxy radicals) can optionally be partially or completely substituted by halogen;
R
12
and R
13
, which may be identical or different, are
1. hydrogen,
2. (C
1
-C
5
)-alkyl,
3. (C
2
-C
5
)-alkenyl,
4. (C
6
-C
12
)-aryl,
5. (C
6
-C
12
)-aryl-(C
1
-C
5
)-alkandiyl,
6. (C
3
-C
10
)-cycloalkyl,
7. (C
3
-C
10
)-cycloalkyl-(C
1
-C
2
)-alkandiyl,
8. —C(O)—O—(C
1
-C
5
)-alkyl, or
9. —C(O)NH—(C
1
-C
5
)-alkyl;
R
14
is
1. hydrogen,
2. —C(O)—O—(C
1
-C
4
)-alkyl, or
3. —C(O)—O—(C
1
-C
3
)-alkyl-(C
6
-C
10
)-aryl;
R
15
is
1. hydrogen,
2. —C(O)—(C
1
-C
3
)-alkyl, or
3. (C
1
-C
3
)-alkyl; and
R
16
is
1. (C
1
-C
3
)-alkyl,
2. (C
6
-C
12
)-aryl, or
3. a heteroaryl group,
wherein these radicals can optionally be substituted by one or more groups, such as halogen, —CN, —NO
2
, —NR
13
R
14
, and —CO
2
R
9;
and their physiologically tolerable salts;
with the proviso that in the case of compounds of formula (I) in which D is a radical of formula (II), R
3
and R
4
are not simultaneously halogen, (C
1
-C
3
)-alkyl, and/or —O—(C
1
-C
3
)-alkyl, or R
3
and R
4
are not hydrogen in combination with halogen, (C
1
-C
3
)-alkyl, or —O—(C
1
-C
3
)-alkyl; excluded from these are
&agr;. compounds of formula (I) in which D is a radical of formula (II) and R
5
is a radical of formula (IV), wherein R
10
is a heteroaryl group or a radical of formula (VI)
 wherein p is an integer from 1 to 3; and
R
11
is
1. (C
1
-C
5
)-alkyl, wherein the hydrogen atoms are partially or completely replaced by fluorine or chlorine, or
2. (C
1
-C
5
)-alkoxy, wherein the hydrogen atoms are partially or completely replaced by fluorine or chlorine;
for which, for its part, the proviso applies that when R
10
has the formula (VI), R
3
and R
4
are not identically or differently hydrogen and halogen; and
&bgr;. compounds of formula (I) in which D is a radical of formula (II) and R
5
is a radical of formula (V), for which, for its part, the proviso applies that R
3
and R
4
are not halogen.
To summarize, this invention relates to compounds according to formula (I) (and their physiologically tolerable salts), as defined above. Specifically, the invention includes the compounds and salts according to formula (I), except, the compounds and salts according to provisos (A) and (B) below are not included within the scope of the invention:
(A) compounds and salts of formula (I) in which D is a radical of formula (II), and R
3
and R
4
are simultaneously halogen, (C
1
-C
3
)-alkyl, and/or —O—(C
1
-C
3
)-alkyl; and
(B) compounds and salts of formula (I) in which D is a radical of formula (II), and R
3
and R
4
are hydrogen in combination with halogen, (C
1
-C
3
)-alkyl, or —O—(C
1
-C
3
)-alkyl.
There are exceptions to the provisos (A) and (B) above. In particular, of the compounds and salts according to (A) and (B) which would be excluded from the scope of this invention by the terms of provisos (A) and (B), the following compounds and salts defined in (&agr;) and (&bgr;) are included within the scope of this invention:
(&agr;) compounds and salts of formula (I) in which D is a radical of formula (II) and R
5
is a radical of formula (IV), where R
10
is a heteroaryl group or a radical of formula (VI)
 wherein p is an integer from 1 to 3, and R
11
is: (a) a (C
1
-C
5
) -alkyl, wherein the hydrogen atoms are partially or completely replaced by fluorine or chlorine, or (b) a (C
1
-C
5
)-alkoxy, wherein the hydrogen atoms are partially or completely replaced by fluorine or chlorine; and
(&bgr;) compounds and salts of formula (I) in which D is a radical of formula (II) and R
5
is a radical of formula (V). Of the compounds and salts included within the scope of the invention by proviso &agr; above, however, the following compounds and salts are excluded from the scope of the invention: (i) compounds and salts where R
10
has the formula (VI) and R
3
and R
4
are, identically or differently, hydrogen or halogen. Additionally, of the compounds and salts included within the scope of the invention by proviso &bgr; above, the following compounds and salts are excluded from the scope of the invention: (ii) compounds and salts where R
3
and R
4
are halogen.
Alkyl and alkenyl groups included in the compounds according to formula (I) can be straight-chain or branched. The same applies to radicals derived therefrom, such as, for example, alkoxy groups.
“Alkenyl” represents mono- or polyunsaturated radicals, such as 1,4-butadienyl and butenyl.
“Cycloalkyl” represents mono- or bicyclic radicals, such as cyclopropyl, cyclopentyl, cyclohexyl, and bicyclononyl. Likewise, “cycloalkenyl” represents mono- or bicyclic radicals, at least one of which includes a mono- or polyunsaturation.
A “(C
6
-C
12
)-aryl” is, for example, phenyl, naphthyl, or biphenylyl, and preferably phenyl. The same also applies to radica

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