U.S. patent application number 10/469817 was filed with the patent office on 2004-04-29 for novel amino dicarboxylic acid derivatives with pharmaceutical properties.
Invention is credited to Alonso-Alija, Cristina, Hahn, Michael, Harter, Michael, Pernerstorfer, Josef, Stasch, Johannes-Peter, Weigand, Stefan, Wunder, Frank.
Application Number | 20040082798 10/469817 |
Document ID | / |
Family ID | 7676478 |
Filed Date | 2004-04-29 |
United States Patent
Application |
20040082798 |
Kind Code |
A1 |
Alonso-Alija, Cristina ; et
al. |
April 29, 2004 |
Novel amino dicarboxylic acid derivatives with pharmaceutical
properties
Abstract
The invention relates to the use of compounds of formula (I) and
of their salts and stereoisomers for producing medicaments used in
the treatment of cardiovascular diseases. 1
Inventors: |
Alonso-Alija, Cristina;
(Haan, DE) ; Harter, Michael; (Leverkusen, DE)
; Hahn, Michael; (Langenfeld, DE) ; Pernerstorfer,
Josef; (Wuppertal, DE) ; Weigand, Stefan;
(Wuppertal, DE) ; Stasch, Johannes-Peter;
(Wuppertal, DE) ; Wunder, Frank; (Wuppertal,
DE) |
Correspondence
Address: |
Jeffrey M Greenman
Bayer Corporation
400 Morgan Lane
West Haven
CT
06516
US
|
Family ID: |
7676478 |
Appl. No.: |
10/469817 |
Filed: |
December 22, 2003 |
PCT Filed: |
February 22, 2002 |
PCT NO: |
PCT/EP02/01891 |
Current U.S.
Class: |
549/23 |
Current CPC
Class: |
A61P 21/00 20180101;
C07C 2602/10 20170501; A61P 7/02 20180101; A61P 9/12 20180101; C07D
333/20 20130101; C07C 229/38 20130101; C07D 213/65 20130101; A61P
9/04 20180101; A61P 9/10 20180101; A61P 9/00 20180101; A61P 1/16
20180101 |
Class at
Publication: |
549/023 |
International
Class: |
C07D 335/06 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 7, 2001 |
DE |
10110750.1 |
Claims
1. A compound of the formula (I) 82where Z represents a phenyl ring
which is fused with a saturated, partially unsaturated or aromatic
carba- or heterocycle having up to 3 heteroatoms from the group
consisting of S, N and/or O or with a partially unsaturated or
aromatic heterocycle having 1 to 9 carbon atoms and up to 3
heteroatoms from the group consisting of S, N and/or O, V is
missing or represents O, NR.sup.4, NR.sup.4CONR.sup.4, NR.sup.4CO,
NR.sup.4SO.sub.2, COO, CONR.sup.4 or S(O).sub.o, where R.sup.4
independently of any other radical R.sup.4 optionally present
represents hydrogen, straight-chain or branched alkyl having up to
8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having
6 to 10 carbon atoms or arylalkyl having 7 to 18 carbon atoms,
where the aryl radical for its part may be mono- or polysubstituted
by halogen, alkyl, alkoxy having up to 6 carbon atoms, o represents
0, 1 or 2, Q is missing or represents straight-chain or branched
alkylene, straight-chain or branched alkenediyl or straight-chain
or branched alkynediyl having in each case up to 12 carbon atoms,
which radicals may in each case comprise one or more groups
selected from the group consisting of O, S(O).sub.p, NR.sup.5, CO,
NR.sup.5SO.sub.2 or CONR.sup.5 and which may be mono- or
polysubstituted by halogen, hydroxyl or alkoxy having up to 4
carbon atoms, where optionally any two atoms of the above chain may
be attached to one another forming a three- to eight-membered ring,
where R.sub.5 represents hydrogen, straight-chain or branched alkyl
having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon
atoms which may be substituted by halogen or alkoxy having up to 4
carbon atoms, p represents 0, 1 or 2, Y represents hydrogen,
NR.sup.8R.sup.9, aryl having 6 to 10 carbon atoms, an aromatic or
saturated heterocycle having 1 to 9 carbon atoms and up to 3
heteroatoms from the group consisting of S, N and O or
straight-chain or branched cycloalkyl having 3 to 8 carbon atoms,
which may also be attached via N, where the cyclic radicals may in
each case be mono- to trisubstituted by straight-chain or branched
alkyl, straight-chain or branched alkenyl, straight-chain or
branched alkynyl, straight-chain or branched alkoxy, straight-chain
or branched haloalkyl, straight-chain or branched haloalkoxy having
in each case up to 8 carbon atoms, straight-chain or branched
cycloalkyl having 3 to 8 carbon atoms, halogen, hydroxyl, CN,
SR.sup.6, NO.sub.2, NR.sup.1R.sup.9, NR.sup.7COR.sup.10,
NR.sup.7CONR.sup.7R.sup.10 or CONR.sup.11R.sup.12, where R.sup.6
represents hydrogen, straight-chain or branched alkyl having up to
8 carbon atoms, straight-chain or branched haloalkyl having up to 8
carbon atoms or cycloalkyl having 3 to 8 carbon atoms, R.sup.7
independently of any other radical R.sup.7 optionally present
represents hydrogen, straight-chain or branched alkyl having up to
8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, R.sup.8,
R.sup.9, R.sup.11 and R.sup.2 independently of one another
represent hydrogen, straight-chain or branched alkyl,
straight-chain or branched alkenyl having up to 8 carbon atoms,
aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1
to 9 carbon atoms and up to 3 heteroatoms from the group consisting
of S, N and O, arylalkyl having 8 to 18 carbon atoms, cycloalkyl
having 3 to 8 carbon atoms or a radical of the formula
SO.sub.2R.sup.13, where the aryl radical for its part may be mono-
or polysubstituted by halogen, hydroxyl, CN, NO.sub.2, NH.sub.2,
NHCOR.sup.7, alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6
carbon atoms, or two substituents selected from R.sup.8 and R.sup.9
or R.sup.11 and R.sup.12 may be attached to one another forming a
five- or six-membered ring which may contain O or N, where R.sup.13
represents straight-chain or branched alkyl having up to 4 carbon
atoms or aryl having 6 to 10 carbon atoms, where the aryl radical
for its part may be mono- or polysubstituted by halogen, CN,
NO.sub.2, alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6
carbon atoms, R.sup.10 represents hydrogen, straight-chain or
branched alkyl having up to 12 carbon atoms, straight-chain or
branched alkenyl having up to 12 carbon atoms, aryl having 6 to 10
carbon atoms, an aromatic heterocycle having 1 to 9 carbon atoms
and up to 3 heteroatoms from the group consisting of S, N and O or
cycloalkyl having 3 to 8 carbon atoms, which may optionally
furthermore be substituted by halogen, hydroxyl, CN, NO.sub.2,
NH.sub.2, NHCOR.sup.7, alkyl, alkoxy, haloalkyl or haloalkoxy
having up to 6 carbon atoms; and/or the cyclic radicals may in each
case be mono- to trisubstituted by aryl having 6 to 10 carbon
atoms, a saturated carbocycle having 6 to 10 carbon atoms, an
aromatic or saturated heterocycle having 1 to 9 carbon atoms and up
to 3 heteroatoms from the group consisting of S, N and O, which may
also be attached via N, which may be attached directly or via a
group selected from the group consisting of O, S, SO, SO.sub.2,
NR.sup.7, SO.sub.2NR.sup.7, CONR.sup.7, straight-chain or branched
alkylene, straight-chain or branched alkenediyl, straight-chain or
branched alkyloxy, straight-chain or branched oxyalkyloxy,
straight-chain or branched sulfonylalkyl, straight-chain or
branched thioalkyl having in each case up to 8 carbon atoms and
which may be mono- to trisubstituted by straight-chain or branched
alkyl, straight-chain or branched alkoxy, straight-chain or
branched alkoxyalkoxy, straight-chain or branched haloalkyl,
straight-chain or branched haloalkoxy, carbonylalkyl or
straight-chain or branched alkenyl having in each case up to 6
carbon atoms, halogen, SR.sup.6, CN, NO.sub.2, NR.sup.8R.sup.9,
CONR.sup.15R.sup.16 or NR.sup.14COR.sup.17, where R.sup.14
represents hydrogen, straight-chain or branched alkyl having up to
8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, R.sup.15,
R.sup.16 independently of one another represent hydrogen,
straight-chain or branched alkyl having up to 8 carbon atoms,
cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon
atoms or a radical of the formula SO.sub.2R.sup.18, where the aryl
radical for its part may be mono- or polysubstituted by halogen,
hydroxyl, CN, NO.sub.2, NH.sub.2, NHCOR.sup.7, alkyl, alkoxy,
haloalkyl or haloalkoxy having up to 6 carbon atoms, where R.sup.18
represents straight-chain or branched alkyl having up to 4 carbon
atoms or aryl having 6 to 10 carbon atoms, where the aryl radical
for its part may be mono- or polysubstituted by halogen, hydroxyl,
CN, NO.sub.2, NH.sub.2, NHCOR.sup.7, alkyl, alkoxy, haloalkyl or
haloalkoxy having up to 6 carbon atoms, and R.sup.17 represents
hydrogen, straight-chain or branched alkyl having up to 12 carbon
atoms, straight-chain or branched alkenyl having up to 12 carbon
atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocycle
having 1 to 9 carbon atoms and up to 3 heteroatoms from the group
consisting of S, N and O or cycloalkyl having 3 to 8 carbon atoms,
which may optionally furthermore be substituted by halogen,
hydroxyl, CN, NO.sub.2, NH.sub.2, NHCOR.sup.7, alkyl, alkoxy,
haloalkyl or haloalkoxy having up to 6 carbon atoms; and/or the
cyclic radicals may be fused with an aromatic or saturated
carbocycle having 1 to 10 carbon atoms or an aromatic or saturated
heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from
the group consisting of S, N and O, R.sup.3 represents hydrogen,
halogen, straight-chain or branched alkyl which may optionally
carry one or more substituents from the group consisting of
C.sub.1-6-alkoxy, NR.sup.19R.sup.20 and cycloalkyl having 3 to 8
carbon atoms, straight-chain or branched haloalkyl, straight-chain
or branched alkoxy, or alkoxycarbonyl having in each case up to 4
carbon atoms, CN, NO.sub.2, NR.sup.19R.sup.20, SR.sup.17,
SO.sub.2R.sup.17, cycloalkyl having 3 to 8 carbon atoms,
haloalkoxy, haloalkoxy having up to 6 carbon atoms, cycloalkoxy
having up to 14 carbon atoms, CONH.sub.2, CONR.sup.17R.sup.17,
SO.sub.2NH.sub.2, SO.sub.2NR.sup.17R.sup.17, alkoxyalkoxy having up
to 12 carbon atoms, NHCOOR.sup.17, NHCOR.sup.17,
NHSO.sub.2R.sup.17, NHCONH.sub.2, OCONR.sup.17R.sup.17,
OSO.sub.2R.sup.17, C.sub.2-12-alkenyl or C.sub.2-12-alkynyl, where
R.sup.19 and R.sup.20 independently of one another represent
hydrogen, straight-chain or branched alkyl having up to 4 carbon
atoms or cycloalkyl having 3 to 8 carbon atoms, m represents an
integer from 1 to 4, W represents straight-chain or branched
alkylene having up to 6 carbon atoms or straight-chain or branched
alkenediyl having up to 6 carbon atoms which may in each case
contain a group selected from the group consisting of O,
S(O).sub.q, NR.sup.21, CO or CONR.sup.21, or represents CO, NHCO or
OCO, where q represents 0, 1 or 2, R.sup.21 represents hydrogen,
straight-chain or branched alkyl having up to 8 carbon atoms or
cycloalkyl having 3 to 8 carbon atoms, U represents straight-chain
or branched alkyl having up to 4 carbon atoms, A represents aryl
having 6 to 10 carbon atoms or an aromatic heterocycle having 1 to
9 carbon atoms and up to 3 heteroatoms from the group consisting of
S, N and O, which may optionally be mono- to trisubstituted by
halogen, straight-chain or branched alkyl, straight-chain or
branched haloalkyl, straight-chain or branched alkoxy, haloalkoxy
or alkoxycarbonyl having up to 4 carbon atoms, CN, NO.sub.2 or
NR.sup.22R.sup.23, where R.sup.22 and R.sup.23 in each case
independently of one another represent hydrogen, straight-chain or
branched alkyl having up to 8 carbon atoms or cycloalkyl having 3
to 8 carbon atoms, carbonylalkyl or sulfonylalkyl, R.sup.2
represents tetrazolyl, COOR.sup.24 or CONR.sup.25R.sup.26, where
R.sup.24 [lacuna] hydrogen, alkyl having 1 to 8 carbon atoms or
cycloalkyl having 3 to 8 carbon atoms R.sup.25 and R.sup.26 in each
case independently of one another represent hydrogen,
straight-chain or branched alkyl having up to 8 carbon atoms,
cycloalkyl having 3 to 8 carbon atoms or a radical of the formula
SO.sub.2R.sup.27, or R.sup.25 and R.sup.26 together form a five- or
six-membered ring which may contain N or O, where R.sup.27
represents straight-chain or branched alkyl having up to 4 carbon
atoms or aryl having 6 to 10 carbon atoms, where the aryl radical
for its part may be mono- or polysubstituted by halogen, CN,
NO.sub.2, alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6
carbon atoms, X represents straight-chain or branched alkylene
having up to 12 carbon atoms or straight-chain or branched
alkenediyl having up to 12 carbon atoms, which may in each case
contain one to three groups selected from the group consisting of
O, S(O).sub.r, NR.sup.28, CO or CONR.sup.29, aryl and aryloxy
having 6 to 10 carbon atoms, where the aryl radical for its part
may be mono- or polysubstituted by halogen, CN, NO.sub.2, alkyl,
alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms, where
optionally any two atoms of the abovementioned chains are attached
to one another via an alkyl chain forming a three- to
eight-membered ring, where r represents 0, 1 or 2, R.sup.28
represents hydrogen, alkyl having 1 to 8 carbon atoms or cycloalkyl
having 3 to 8 carbon atoms, R.sup.29 represents hydrogen,
straight-chain or branched alkyl having up to 8 carbon atoms or
cycloalkyl having 3 to 8 carbon atoms, n represents 1 or 2; R.sup.1
represents tetrazolyl, COOR.sup.30 or CONR.sup.31R.sup.32, where
R.sup.30 [lacuna] hydrogen, alkyl having 1 to 8 carbon atoms or
cycloalkyl having 3 to 8 carbon atoms R.sup.31 and R.sup.32 in each
case independently of one another represent hydrogen,
straight-chain or branched alkyl having up to 8 carbon atoms,
cycloalkyl having 3 to 8 carbon atoms or a radical of the formula
SO.sub.2R.sup.33, where R.sup.33 represents straight-chain or
branched alkyl having up to 4 carbon atoms or aryl having 6 to 10
carbon atoms, where the aryl radical for its part may be mono- or
polysubstituted by halogen, CN, NO.sub.2, alkyl, alkoxy, haloalkyl
or haloalkoxy having up to 6 carbon atoms, and its stereoisomers
and salts.
2. A compound as claimed in claim 1, where Z represents a cyclic
radical from the group consisting of 83 where the radicals V and W
may be attached to any carbon ring atom or any nitrogen ring atom
optionally present, selected; V is missing or represents O,
NR.sup.4, NR.sup.4CONR.sup.4, NR.sup.4CO, NR.sup.4SO.sub.2, COO,
CONR.sup.4 or S(O).sub.o, where R.sup.4 independently of any other
radical R.sup.4 optionally present represents hydrogen,
straight-chain or branched alkyl having up to 8 carbon atoms,
cycloalkyl having 3 to 8 carbon atoms, 5 aryl having 6 to 10 carbon
atoms or arylalkyl having 7 to 18 carbon atoms, where the aryl
radical for its part may be mono- or polysubstituted by halogen,
alkyl, alkoxy having up to 6 carbon atoms, o represents 0, 1 or 2,
Q is missing or represents straight-chain or branched alkylene,
straight-chain or branched alkenediyl or straight-chain or branched
alkynediyl having in each case up to 12 carbon atoms, which
radicals may in each case comprise one or more groups selected from
the group consisting of O, S(O).sub.p, NR.sup.5, CO,
NR.sup.5SO.sub.2 or CONR.sup.5 and which may be mono- or
polysubstituted by halogen, hydroxyl or alkoxy having up to 4
carbon atoms, where optionally any two atoms of the above chain may
be attached to one another forming a three- to eight-membered ring,
where R.sub.5 represents hydrogen, straight-chain or branched alkyl
having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon
atoms which may be substituted by halogen or alkoxy having up to 4
carbon atoms, p represents 0, 1 or 2, Y represents hydrogen,
NR.sup.8R.sup.9, aryl having 6 to 10 carbon atoms, an aromatic or
saturated heterocycle having 1 to 9 carbon atoms and up to 3
heteroatoms from the group consisting of S, N and O or
straight-chain or branched cycloalkyl having 3 to 8 carbon atoms,
which may also be attached via N, where the cyclic radicals may in
each case be mono- to trisubstituted by straight-chain or branched
alkyl, straight-chain or branched alkenyl, straight-chain or
branched alkynyl, straight-chain or branched alkoxy, straight-chain
or branched alkoxyalkoxy, straight-chain or branched haloalkyl,
straight-chain or branched haloalkoxy having in each case up to 8
carbon atoms, straight-chain or branched cycloalkyl having 3 to 8
carbon atoms, halogen, hydroxyl, CN, SR.sup.6, NO.sub.2,
NR.sup.8R.sup.9, NR.sup.7COR.sup.10, NR.sup.7CONR.sup.7R.sup.10 or
CONR.sup.11R.sup.12, where R.sup.6 represents hydrogen,
straight-chain or branched alkyl having up to 8 carbon atoms,
straight-chain or branched haloalkyl having up to 8 carbon atoms or
cycloalkyl having 3 to 8 carbon atoms, R.sup.7 independently of any
other radical R.sup.7 optionally present represents hydrogen,
straight-chain or branched alkyl having up to 8 carbon atoms or
cycloalkyl having 3 to 8 carbon atoms, R.sup.8, R.sup.9, R.sup.11
and R.sup.12 independently of one another represent hydrogen,
straight-chain or branched alkyl, straight-chain or branched
alkenyl having up to 8 carbon atoms, aryl having 6 to 10 carbon
atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to
3 heteroatoms from the group consisting of S, N and O, arylalkyl
having 8 to 18 carbon atoms, cycloalkyl having 3 to 8 carbon atoms
or a radical of the formula SO.sub.2R.sup.13, where the aryl
radical for its part may be mono- or polysubstituted by halogen,
hydroxyl, CN, NO.sub.2, NH.sub.2, NHCOR.sup.7, alkyl, alkoxy,
haloalkyl or haloalkoxy having up to 6 carbon atoms, or two
substituents selected from R.sup.8 and R.sup.9 or R.sup.11 and
R.sup.12 may be attached to one another forming a five- or
six-membered ring which may contain O or N, where R.sup.13
represents straight-chain or branched alkyl having up to 4 carbon
atoms or aryl having 6 to 10 carbon atoms, where the aryl radical
for its part may be mono- or polysubstituted by halogen, CN,
NO.sub.2, alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6
carbon atoms, R.sup.10 represents hydrogen, straight-chain or
branched alkyl having up to 12 carbon atoms, straight-chain or
branched alkenyl having up to 12 carbon atoms, aryl having 6 to 10
carbon atoms, an aromatic heterocycle having 1 to 9 carbon atoms
and up to 3 heteroatoms from the group consisting of S, N and O or
cycloalkyl having 3 to 8 carbon atoms, which may optionally
furthermore be substituted by halogen, hydroxyl, CN, NO.sub.2,
NH.sub.2, NHCOR.sup.7, alkyl, alkoxy, haloalkyl or haloalkoxy
having up to 6 carbon atoms; and/or the cyclic radicals may in each
case be mono- to trisubstituted by aryl having 6 to 10 carbon
atoms, an aromatic or saturated heterocycle having 1 to 9 carbon
atoms and up to 3 heteroatoms from the group consisting of S, N and
O, which may also be attached via N, which may be attached directly
or via a group selected from the group consisting of O, S, SO,
SO.sub.2, NR.sup.7, SO.sub.2NR.sup.7, CONR.sup.7, straight-chain or
branched alkylene, straight-chain or branched alkenediyl,
straight-chain or branched alkyloxy, straight-chain or branched
oxyalkyloxy, straight-chain or branched sulfonylalkyl,
straight-chain or branched thioalkyl having in each case up to 8
carbon atoms and which may be mono- to trisubstituted by
straight-chain or branched alkyl, straight-chain or branched
alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or
branched haloalkyl, straight-chain or branched haloalkoxy,
carbonylalkyl or straight-chain or branched alkenyl having in each
case up to 6 carbon atoms, halogen, SR.sup.6, CN, NO.sub.2,
NR.sup.8R.sup.9, CONR.sup.15R.sup.16 or NR.sup.14COR.sup.17, where
R.sup.14 represents hydrogen, straight-chain or branched alkyl
having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon
atoms, R.sup.15, R.sup.16 independently of one another represent
hydrogen, straight-chain or branched alkyl having up to 8 carbon
atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of the
formula SO.sub.2R.sup.18, where R.sup.18 represents straight-chain
or branched alkyl having up to 4 carbon atoms or aryl having 6 to
10 carbon atoms, where the aryl radical for its part may be mono-
or polysubstituted by halogen, CN, NO.sub.2, alkyl, alkoxy,
haloalkyl or haloalkoxy having up to 6 carbon atoms, and R.sup.17
represents hydrogen, straight-chain or branched alkyl having up to
12 carbon atoms, straight-chain or branched alkenyl having up to 12
carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic
heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from
the group consisting of S, N and O or cycloalkyl having 3 to 8
carbon atoms, which may optionally furthermore be substituted by
halogen, CN, NO.sub.2, alkyl, alkoxy, haloalkyl or haloalkoxy
having up to 6 carbon atoms; and/or the cyclic radicals may be
fused with an aromatic or saturated carbocycle having 1 to 10
carbon atoms or an aromatic or saturated heterocycle having 1 to 9
carbon atoms and up to 3 heteroatoms from the group consisting of
S, N and O, R.sup.3 represents hydrogen, halogen, straight-chain or
branched alkyl which may optionally carry one or more substituents
from the group consisting of C.sub.1-6-alkoxy, NR.sup.19R.sup.20
and cycloalkyl having 3 to 8 carbon atoms, straight-chain or
branched haloalkyl, straight-chain or branched alkoxy, or
alkoxycarbonyl having in each case up to 4 carbon atoms, CN,
NO.sub.2, NR.sup.19R.sup.20, SR.sup.17, SO.sub.2R.sup.17,
cycloalkyl having 3 to 8 carbon atoms, haloalkoxy, haloalkoxy
having up to 6 carbon atoms, cycloalkoxy having up to 14 carbon
atoms, CONH.sub.2, CONR.sup.17R.sup.17, SO.sub.2NH.sub.2,
SO.sub.2NR.sup.17R.sup.17, alkoxyalkoxy having up to 12 carbon
atoms, NHCOOR.sup.17, NHCOR.sup.17, NHSO.sub.2R.sup.17,
NHCONH.sub.2, OCONR.sup.17R.sup.17, C.sub.2-12-alkenyl or
C.sub.2-12-alkynyl, m represents an integer from 1 to 4, W
represents straight-chain or branched alkylene or straight-chain or
branched alkenediyl having in each case up to 4 carbon atoms, U
represents --CH.sub.2--, A represents phenyl or an aromatic
heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from
the group consisting of S, N and O, which may optionally be mono-
to trisubstituted by halogen, straight-chain or branched alkyl,
straight-chain or branched haloalkyl or straight-chain or branched
alkoxy having up to 4 carbon atoms, R.sup.2 represents COOR.sup.24,
where R.sup.24 represents hydrogen or straight-chain or branched
alkyl having up to 6 carbon atoms, X represents straight-chain or
branched alkylene having up to 8 carbon atoms or straight-chain or
branched alkenediyl having up to 8 carbon atoms which may in each
case contain one to three groups selected from the group consisting
of phenyl, phenyloxy, O, CO and CONR.sup.29, where R.sup.29
represents hydrogen, straight-chain or branched alkyl having up to
6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, n
represents 1 or 2; R.sup.1 represents COOR.sup.30, where R.sup.30
represents hydrogen or straight-chain or branched alkyl having up
to 6 carbon atoms.
3. A compound as claimed in claim 1, where Z represents a cyclic
radical from the group consisting of 84 where the radicals V and W
may be attached to any carbon ring atom or any nitrogen ring atom
optionally present, selected; V is missing or represents O, S or
NR.sup.4, where R.sup.4 represents hydrogen or methyl, Q is missing
or represents straight-chain or branched alkylene having up to 9
carbon atoms or straight-chain or branched alkenediyl or
straight-chain or branched alkynediyl having up to 4 carbon atoms
which may be monosubstituted by halogen, Y represents H,
NR.sup.8R.sup.9, cyclohexyl, phenyl, naphtyl or a heterocycle
selected from the group consisting of 85 which may also be attached
via N, where the cyclic radicals may in each case be mono- to
trisubstituted by straight-chain or branched alkyl, straight-chain
or branched alkenyl, straight-chain or branched alkynyl,
straight-chain or branched alkoxy, straight-chain or branched
alkoxyalkoxy, straight-chain or branched haloalkyl, straight-chain
or branched haloalkoxy having in each case up to 4 carbon atoms,
straight-chain or branched cycloalkyl having 3 to 6 carbon atoms,
F, Cl, Br, I, NO.sub.2, SR.sup.6, NR.sup.8R.sup.9,
NR.sup.7COR.sup.10 or CONR.sup.11R.sup.12, where R.sup.6 represents
hydrogen, straight-chain or branched alkyl having up to 8 carbon
atoms, or straight-chain or branched haloalkyl having up to 4
carbon atoms, R.sup.7 represents hydrogen, or straight-chain or
branched alkyl having up to 4 carbon atoms, R.sup.8, R.sup.9,
R.sup.11 and R.sup.12 independently of one another represent
hydrogen, straight-chain or branched alkyl having up to 4 carbon
atoms, or phenyl, where the phenyl radical may be mono- to
trisubstituted by F, Cl Br, hydroxyl, methyl, ethyl, n-propyl,
i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy, ethoxy,
amino, acetylamino, NO.sub.2, CF.sub.3, OCF.sub.3 or CN, or two
substituents selected from R.sup.8 and R.sup.9 or R.sup.11 and
R.sup.12 may be attached to one another forming a five- or
six-membered ring which may be interrupted by O or N, R.sup.10
represents hydrogen, straight-chain or branched alkyl having up to
4 carbon atoms, or phenyl, where the phenyl radical may be mono- to
trisubstituted by F, Cl Br, hydroxyl, methyl, ethyl, n-propyl,
i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy, ethoxy,
amino, acetylamino, NO.sub.2, CF.sub.3, OCF.sub.3 or CN; and/or the
cyclic radicals may in each case be mono- to trisubstituted by
phenyl or a heterocycle from the group consisting of 86 which may
be attached directly or via a group selected from the group
consisting of O, S, SO, SO.sub.2, NR.sup.4, SO.sub.2NR.sup.7,
CONR.sup.7, straight-chain or branched alkylene, straight-chain or
branched alkenediyl, straight-chain or branched alkyloxy,
straight-chain or branched oxyalkyloxy, straight-chain or branched
sulfonylalkyl, straight-chain or branched thioalkyl having in each
case up to 4 carbon atoms and which may be mono- to trisubstituted
by straight-chain or branched alkyl, straight-chain or branched
alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or
branched haloalkyl or straight-chain or branched alkenyl having in
each case up to 4 carbon atoms, F, Cl, Br, I, CN, SCH.sub.3,
OCF.sub.3, NO.sub.2, NR.sup.8R.sup.9 or NR.sup.14COR.sup.17, where
R.sup.14 represents hydrogen, straight-chain or branched alkyl
having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon
atoms, and R.sup.17 represents hydrogen, straight-chain or branched
alkyl having up to 12 carbon atoms, straight-chain or branched
alkenyl having up to 12 carbon atoms, aryl having 6 to 10 carbon
atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to
3 heteroatoms from the group consisting of S, N and O or cycloalkyl
having 3 to 8 carbon atoms, which may optionally furthermore be
substituted by F, Cl Br, hydroxyl, methyl, ethyl, n-propyl,
i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy, ethoxy,
amino, acetylamino, NO.sub.2, CF.sub.3, OCF.sub.3 or CN; and/or the
cyclic radicals may be fused with an aromatic or saturated
carbocycle having 1 to 10 carbon atoms or an aromatic or saturated
heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms
selected from the group consisting of S, N and O, R.sup.3
represents hydrogen, methyl or fluorine, m represents an integer
from 1 to 2, W represents CH.sub.2, --CH.sub.2CH.sub.2--,
CH.sub.2CH.sub.2CH.sub.2, CH.dbd.CHCH.sub.2, U represents
--CH.sub.2--, A represents phenyl, pyridyl, thienyl or thiazolyl
which may optionally be mono- to trisubstituted by methyl, ethyl,
n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, CF.sub.3,
methoxy, ethoxy, F, Cl, Br, R.sup.2 represents COOR.sup.24, where
R.sup.24 represents hydrogen or straight-chain or branched alkyl
having up to 4 carbon atoms, X represents straight-chain or
branched alkylene having up to 8 carbon atoms or straight-chain or
branched alkenediyl having up to 8 carbon atoms which may in each
case contain one to three groups from the group consisting of
phenyl, phenyloxy, O, CO and CONR.sup.30, where R.sup.30 represents
hydrogen, straight-chain or branched alkyl having up to 6 carbon
atoms or cycloalkyl having 3 to 6 carbon atoms, n represents 1 or
2; R.sup.1 represents COOR.sup.35, where R.sup.35 represents
hydrogen or straight-chain or branched alkyl having up to 6 carbon
atoms.
4. A compound as claimed in claim 1, where Z represents a cyclic
radical from the group consisting of 87 where the radicals V and W
may be attached to any carbon ring atom or any nitrogen ring atom
optionally present, selected; V represents O, Q represents
straight-chain or branched alkylene having up to 9 carbon atoms or
straight-chain or branched alkenediyl or straight-chain or branched
alkynediyl having up to 4 carbon atoms which may be monosubstituted
by halogen, Y represents H, cyclohexyl, phenyl or a heterocycle
from the group consisting of 88 where the cyclic radicals may in
each case be mono- to trisubstituted by straight-chain or branched
alkyl, straight-chain or branched alkenyl, straight-chain or
branched alkynyl, straight-chain or branched alkoxy, straight-chain
or branched alkoxyalkoxy, straight-chain or branched haloalkyl,
straight-chain or branched haloalkoxy having in each case up to 4
carbon atoms, straight-chain or branched cycloalkyl having 3 to 6
carbon atoms, F, Cl, Br, I, NO.sub.2, SR.sup.6, NR.sup.8R.sup.9,
NR.sup.7COR.sup.10 or CONR.sup.11R.sup.12, where R.sup.6 represents
hydrogen, straight-chain or branched alkyl having up to 4 carbon
atoms, or straight-chain or branched haloalkyl having up to 4
carbon atoms, R.sup.7 represents hydrogen, or straight-chain or
branched alkyl having up to 4 carbon atoms, R.sup.8, R.sup.9,
R.sup.11 and R.sup.12 independently of one another represent
hydrogen, straight-chain or branched alkyl having up to 4 carbon
atoms, or phenyl, where the phenyl radical may be mono- to
trisubstituted by F, Cl Br, hydroxyl, methyl, ethyl, n-propyl,
i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy, ethoxy,
amino, acetylamino, NO.sub.2, CF.sub.3, OCF.sub.3 or CN, or two
substituents selected from R.sup.8 and R.sup.9 or R.sup.11 and
R.sup.12 may be attached to one another forming a five- or
six-membered ring which may be interrupted by O or N, R.sup.10
represents hydrogen, straight-chain or branched alkyl having up to
4 carbon atoms, or phenyl, where the phenyl radical may be mono- to
trisubstituted by F, Cl Br, hydroxyl, methyl, ethyl, n-propyl,
i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy, ethoxy,
amino, acetylamino, NO.sub.2, CF.sub.3, OCF.sub.3 or CN; and/or the
cyclic radicals may in each case be mono- to trisubstituted by
phenyl or a heterocycle from the group consisting of 89 which may
be attached directly or via a group selected from the group
consisting of O, S, SO, SO.sub.2, straight-chain or branched
alkylene, straight-chain or branched alkenediyl, straight-chain or
branched alkyloxy, straight-chain or branched oxyalkyloxy,
straight-chain or branched sulfonylalkyl, straight-chain or
branched thioalkyl having in each case up to 4 carbon atoms and
which may be mono- to trisubstituted by straight-chain or branched
alkyl, straight-chain or branched alkoxy, straight-chain or
branched alkoxyalkoxy, straight-chain or branched haloalkyl or
straight-chain or branched alkenyl having in each case up to 4
carbon atoms, F, Cl, Br, I, CN, SCH.sub.3, OCF.sub.3, NO.sub.2,
NR.sup.8R.sup.9 or NR.sup.14COR.sup.17, where R.sup.14 represents
hydrogen, straight-chain or branched alkyl having up to 6 carbon
atoms or cycloalkyl having 3 to 6 carbon atoms, and R.sup.17
represents hydrogen, straight-chain or branched alkyl having up to
6 carbon atoms, straight-chain or branched alkenyl having up to 6
carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic
heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from
the group consisting of S, N and O or cycloalkyl having 3 to 6
carbon atoms, which may optionally furthermore be substituted by F,
Cl Br, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl,
s-butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino,
NO.sub.2, CF.sub.3, OCF.sub.3 or CN; and/or the cyclic radicals may
be fused with an aromatic or saturated carbocycle having 1 to 10
carbon atoms or an aromatic or saturated heterocycle having 1 to 9
carbon atoms and up to 3 heteroatoms from the group consisting of
S, N and O, R.sup.3 represents hydrogen, methyl or fluorine, m
represents an integer from 1 to 2, W represents --CH.sub.2-- or
--CH.sub.2CH.sub.2--, U represents --CH.sub.2--, A represents
phenyl which may optionally be mono- to trisubstituted by methyl,
ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,
CF.sub.3, methoxy, ethoxy, F, Cl, Br, R.sup.2 represents
COOR.sup.24, where R.sup.24 represents hydrogen or straight-chain
or branched alkyl having up to 4 carbon atoms, X represents
straight-chain or branched alkylene having up to 6 carbon atoms or
straight-chain or branched alkenediyl having up to 6 carbon atoms
which may in each case contain one to three groups selected from
the group consisting of phenyloxy, O, CO and CONR.sup.30, where
R.sup.30 represents hydrogen, straight-chain or branched alkyl
having up to 6 carbon atoms or cycloalkyl having 3 to 6 carbon
atoms, n represents 1 or 2; R.sup.1 represents COOR.sup.35, where
R.sup.35 represents hydrogen or straight-chain or branched alkyl
having up to 4 carbon atoms.
5. A compound as claimed in claim 1, where Z represents a cyclic
radical from the group consisting of 90 where the radicals V and W
may be attached to any carbon ring atom or any nitrogen ring atom
optionally present, selected; V represents O, Q represents
straight-chain or branched alkylene having up to 9 carbon atoms or
straight-chain or branched alkenediyl or straight-chain or branched
alkynediyl having up to 4 carbon atoms which may be monosubstituted
by halogen, Y represents H, cyclohexyl, phenyl or a heterocycle
from the group consisting of 91 where the cyclic radicals may in
each case be mono- to trisubstituted by straight-chain or branched
alkyl, straight-chain or branched alkenyl, straight-chain or
branched alkynyl, straight-chain or branched alkoxy, straight-chain
or branched alkoxyalkoxy, straight-chain or branched haloalkyl,
straight-chain or branched haloalkoxy having in each case up to 4
carbon atoms, straight-chain or branched cycloalkyl having 3 to 6
carbon atoms, F, Cl, Br, I, NO.sub.2, SR.sup.6, NR.sup.8R.sup.9,
NR.sup.7COR.sup.10 or CONR.sup.11R.sup.12, where R.sup.6 represents
hydrogen, straight-chain or branched alkyl having up to 4 carbon
atoms, or straight-chain or branched haloalkyl having up to 4
carbon atoms, R.sup.7 represents hydrogen, or straight-chain or
branched alkyl having up to 4 carbon atoms, R.sup.8, R.sup.9,
R.sup.11 and R.sup.12 independently of one another represent
hydrogen, straight-chain or branched alkyl having up to 4 carbon
atoms, or phenyl, where the phenyl radical may be mono- to
trisubstituted by F, Cl Br, hydroxyl, methyl, ethyl, n-propyl,
i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy, ethoxy,
amino, acetylamino, NO.sub.2, CF.sub.3, OCF.sub.3 or CN, or two
substituents selected from R.sup.8 and R.sup.9 or R.sup.11 and
R.sup.12 may be attached to one another forming a five- or
six-membered ring which may be interrupted by O or N, R.sup.10
represents hydrogen, straight-chain or branched alkyl having up to
4 carbon atoms, or phenyl, where the phenyl radical may be mono- to
trisubstituted by F, Cl Br, hydroxyl, methyl, ethyl, n-propyl,
i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy, ethoxy,
amino, acetylamino, NO.sub.2, CF.sub.3, OCF.sub.3 or CN; and/or the
cyclic radicals may in each case be mono- to trisubstituted by
phenyl or a heterocycle from the group consisting of 92 which may
be attached directly or via a group selected from the group
consisting of O, S, SO, SO.sub.2, straight-chain or branched
alkylene, straight-chain or branched alkenediyl, straight-chain or
branched alkyloxy, straight-chain or branched oxyalkyloxy,
straight-chain or branched sulfonylalkyl, straight-chain or
branched thioalkyl having in each case up to 4 carbon atoms and
which may be mono- to trisubstituted by straight-chain or branched
alkyl, straight-chain or branched alkoxy, straight-chain or
branched alkoxyalkoxy, straight-chain or branched haloalkyl or
straight-chain or branched alkenyl having in each case up to 4
carbon atoms, F, Cl, Br, I, CN, SCH.sub.3, OCF.sub.3, NO.sub.2,
NR.sup.8R.sup.9 or NR.sup.14COR.sup.17, where R.sup.14 represents
hydrogen, straight-chain or branched alkyl having up to 6 carbon
atoms or cycloalkyl having 3 to 6 carbon atoms, and R.sup.17
represents hydrogen, straight-chain or branched alkyl having up to
6 carbon atoms, straight-chain or branched alkenyl having up to 6
carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic
heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from
the group consisting of S, N and O or cycloalkyl having 3 to 6
carbon atoms, which may optionally furthermore be substituted by F,
Cl Br, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl,
s-butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino,
NO.sub.2, CF.sub.3, OCF.sub.3 or CN; and/or the cyclic radicals may
be fused with an aromatic or saturated carbocycle having 1 to 10
carbon atoms or an aromatic or saturated heterocycle having 1 to 9
carbon atoms and up to 3 heteroatoms from the group consisting of
S, N and O, R.sup.3 represents hydrogen, methyl or fluorine, m
represents an integer from 1 to 2, W represents --CH.sub.2-- or
--CH.sub.2CH.sub.2--, U represents --CH.sub.2--, A represents
phenyl which may optionally be mono- to trisubstituted by methyl,
ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,
CF.sub.3, methoxy, ethoxy, F, Cl, Br, R.sup.2 represents COOH, X
represents straight-chain or branched alkylene having up to 6
carbon atoms or straight-chain or branched alkenediyl having up to
6 carbon atoms which may in each case contain one to three groups
selected from the group consisting of phenyloxy, O, CO and
CONR.sup.30, where R.sup.30 represents hydrogen, straight-chain or
branched alkyl having up to 6 carbon atoms or cycloalkyl having 3
to 6 carbon atoms, n represents 1 or 2; R.sup.1 represents
COOH.
6. A compound as claimed in claim 1, where Z represents a cyclic
radical from the group consisting of 93 where the radicals V and W
may be attached to any carbon ring atom or any nitrogen ring atom
optionally present, selected; V represents O, Q represents
CH.sub.2, Y represents phenyl which is substituted by a radical
selected from the group consisting of 2-phenylethyl, cyclohexyl,
4-chlorophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl,
4-cyanophenyl, 4-chlorophenoxy, 4-methoxyphenoxy,
4-trifluoromethylphenoxy, 4-cyanophenoxy, 4-methylphenyl, R.sup.3
represents hydrogen, methyl or fluorine, m represents an integer
from 1 to 2, W represents --CH.sub.2CH.sub.2--, U represents
--CH.sub.2--, A represents phenyl, R.sup.2 represents COOH, where
R.sub.2 is located in the 4-position to the radical U, X represents
(CH.sub.2).sub.4, R.sup.1 represents COOH.
7. A compound as claimed in claim 1, where Z represents a cyclic
radical from the group consisting of 94 where the radicals V and W
may be attached to any carbon ring atom or any nitrogen ring atom
optionally present, selected; V is missing, Q represents CH.sub.2O
which is attached via its carbon atom to Z, Y represents phenyl
which is substituted by a radical selected from the group
consisting of 2-phenylethyl, cyclohexyl, 4-chlorophenyl,
4-methoxyphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl,
4-chlorophenoxy, 4-methoxyphenoxy, 4-trifluoromethylphenoxy,
4-cyanophenoxy, 4-methylphenyl, 4-tert-butylphenyl,
4-carboxyphenyl, 4-fluorophenyl, 3-methoxyphenyl,
2,4-dichlorophenyl, R.sup.3 represents hydrogen, methyl or
fluorine, m represents an integer from 1 to 2, W represents
--CH.sub.2CH.sub.2--, U represents --CH.sub.2--, A represents
phenyl, R.sup.2 represents COOH where R.sub.2 is located in the
4-position to the radical U, X represents (CH.sub.2).sub.4, R.sup.1
represents COOH.
8. A process for preparing compounds of the general formula (I),
characterized in that [A] compounds of the formula (II) 95 are
reacted with compounds of the formula (III) E-X--R.sup.1 (III)
where Z, R.sup.1, R.sup.2, R.sup.3, V, Q, Y, W, X, U, A and m are
as defined above, E represents either a leaving group which is
substituted in the presence of a base or an optionally activated
hydroxyl function; or [B] compounds of the formula (IV) 96 are
reacted with compounds of the formula (V) 97 where Z, R.sup.1,
R.sup.2, R.sup.3, V, Q, Y, W, X, U, A and m are as defined above, E
represents either a leaving group which is substituted in the
presence of a base or an optionally activated hydroxyl function; or
[C] compounds of the formula (VI) 98 are reacted with compounds of
the formula (VII) E-U-A-R.sup.2 (VII) where Z, R.sup.1, R.sup.2,
R.sup.3, V, Q, Y, W, X, U, A and m are as defined above, E
represents either a leaving group which is substituted in the
presence of a base or an optionally activated hydroxyl function; or
[D] compounds of the formula (VIII) 99 where Va represents O or S
and Z, R.sup.1, R.sup.2, R.sup.3, Y, Q, W, U, A, X and m are as
defined above, are reacted with compounds of the formula (IX) 100
where Q, Y are as defined above, E represents either a leaving
group which is substituted in the presence of a base or an
optionally activated hydroxyl function; or [E] compounds of the
formula (X) 101 where Z, R.sup.3, V, Q, Y, W, X, U, A and m are as
defined above, R.sup.1.sub.b and R.sup.2.sub.b each independently
of one another represent CN or COOAlk, where Alk represents a
straight-chain or branched alkyl radical having up to 6 carbon
atoms, are converted with aqueous solutions of strong acids or
strong bases into the corresponding free carboxylic acids. or [F]
compounds of the formula (XI) 102 where Z, R.sup.1, R.sup.2,
R.sup.3, V, Q, X, W, U, A and m are as defined above, L represents
Br, I or the group CF.sub.3SO.sub.2--O, are reacted with compounds
of the formula (XII) M-Z' (XII) where M represents an aryl or
heteroaryl radical, a straight-chain or branched alkyl, alkenyl or
alkynyl radical or cycloalkyl radical or represents an arylalkyl,
an arylalkenyl or an arylalkynyl radical, Z' represents the
groupings --B(OH).sub.2, --CH.ident.CH, --CH.dbd.CH.sub.2 or
--Sn(nBu).sub.3 in the presence of a palladium compound, if
appropriate additionally in the presence of a reducing agent and
further additives and in the presence of a base; or [G] compounds
of the formula (XIII) 103 where Ar represents an aryl or heteroaryl
radical, E represents a leaving group which is substituted in the
presence of a base. are reacted according to process D with
compounds of the formula (VIII) and the resulting compounds of the
formula (XIV) 104 are hydrogenated with hydrogen in the presence of
a catalyst.
9. A medicament, comprising at least one compound of the general
formula (I) as claimed in any of the preceding claims.
10. The use of compounds of the formula (I) as claimed in any of
the preceding claims for preparing a medicament for treating
cardiovascular disorders.
11. The use of compounds of the general formula (I) as claimed in
any of the preceding claims for preparing medicaments for treating
angina pectoris, ischemias and heart failure.
12. The use of compounds of the general formula (I) as claimed in
any of the preceding claims for preparing medicaments for treating
hypertension, thromboembolic disorders, arteriosclerosis and venous
diseases.
13. The use of compounds of the general formula (I) as claimed in
any of the preceding claims for preparing medicaments for treating
fibrotic disorders.
14. The use as claimed in claim 16, characterized in that the
fibrotic disorder is fibrosis of the liver.
Description
[0001] The present invention relates to novel chemical compounds
which stimulate soluble guanylate cyclase also via a novel
mechanism of action which takes place without involvement of the
heme group of the enzyme, to their preparation and to their use as
medicaments, in particular as medicaments for treating
cardiovascular disorders.
[0002] One of the most important cellular transmission systems in
mammalian cells is cyclic guanosine monophosphate (cGMP). Together
with nitric oxide (NO), which is released from the endothelium and
transmits hormonal and mechanical signals, it forms the NO/cGMP
system. Guanylate cyclases catalyze the biosynthesis of cGMP from
guanosine triphosphate (GTP). The representatives of this family
disclosed to date can be divided both according to structural
features and according to the type of ligands into two groups: the
particulate guanylate cyclases which can be stimulated by
natriuretic peptides, and the soluble guanylate cyclases which can
be stimulated by NO. The soluble guanylate cyclases consist of two
subunits and very probably contain one heme per heterodimer, which
is part of the regulatory center. The latter is of central
importance for the mechanism of activation. NO is able to bind to
the iron atom of heme and thus markedly increase the activity of
the enzyme. Heme-free preparations cannot, by contrast, be
stimulated by NO. CO is also able to attach to the central iron
atom of heme, but the stimulation by CO is distinctly less than
that by NO.
[0003] Through the production of cGMP and the regulation, resulting
therefrom, of phosphodiesterases, ion channels and protein kinases,
guanylate cyclase plays a crucial part in various physiological
processes, in particular in the relaxation and proliferation of
smooth muscle cells, in platelet aggregation and adhesion and in
the neuronal signal transmission, and in disorders caused by an
impairment of the aforementioned processes. Under
pathophysiological conditions, the NO/cGMP system may be
suppressed, which may lead for example to high blood pressure,
platelet activation, increased cell proliferation, endothelial
dysfunction, atherosclerosis, angina pectoris, heart failure,
thromboses, stroke and myocardial infarction.
[0004] A possible way of treating such disorders which is
independent of NO and aims at influencing the cGMP signal pathway
in organisms is a promising approach because of the high efficiency
and few side effects which are to be expected.
[0005] Compounds, such as organic nitrates, whose effect is based
on NO have to date been exclusively used for the therapeutic
stimulation of soluble guanylate cyclase. NO is produced by
bioconversion and activates soluble guanylate cyclase by attaching
to the central iron atom of heme. Besides the side effects, the
development of tolerance is one of the crucial disadvantages of
this mode of treatment.
[0006] Some substances which directly stimulate soluble guanylate
cyclase, i.e. without previous release of NO, have been described
in recent years, such as, for example,
3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1, Wu et al.,
Blood 84 (1994), 4226; Muilsch et al., Br. J. Pharmacol. 120
(1997), 681), fatty acids (Goldberg et al, J. Biol. Chem. 252
(1977), 1279), diphenyliodonium hexafluorophosphate (Pettibone et
al., Eur. J. Pharmcol. 116 (1985), 307), isoliquiritigenin (Yu et
al., Brit. J. Pharmacol. 114 (1995), 1587) and various substituted
pyrazole derivatives (WO 98/16223, WO 98/16507 and WO
98/23619).
[0007] The stimulators of soluble guanylate cyclase known to date
stimulate the enzyme either directly via the heme group (carbon
monoxide, nitrogen monoxide or diphenyliodonium
hexafluorophosphate) by interaction with the central iron of the
heme group and a resulting change in conformation which leads to an
increase in enzyme activity (Gerzer et al., FEBS Lett. 132(1981),
71), or via a heme-dependent mechanism which is independent of NO
but leads to a potentiation of the stimulating action of NO or CO
(for example YC-1, Hoenicka et al., J. Mol. Med. (1999) 14; or the
pyrazole derivatives described in WO 98/16223, WO 98/16507 and WO
98/23619).
[0008] The stimulating action of isoliquiritigenin and of fatty
acids, such as, for example, arachidonic acid, prostaglandin
endoperoxides and fatty acid hydroperoxides on soluble guanylate
cyclase claimed in the literature could not be confirmed (cf., for
example, Hoenicka et al., J. Mol. Med. 77 (1999), 14).
[0009] If the heme group is removed from soluble guanylate cyclase,
the enzyme still has detectable catalytic basal activity, i.e. cGMP
is still being formed. The residual catalytic basal activity of the
heme-free enzyme cannot be stimulated by any of the known
stimulators mentioned above.
[0010] Stimulation of heme-free soluble guanylate cyclase by
protoporphyrin IX has been described (Ignarro et al., Adv.
Pharmacol. 26 (1994), 35). However, protoporphyrin IX can be
considered to be a mimic of the NO-heme adduct, as a consequence of
which the addition of protoporphyrin IX to soluble guanylate
cyclase would be expected to result in the formation of a structure
of the enzyme corresponding to heme-containing soluble guanylate
cyclase stimulated by NO. This is also confirmed by the fact that
the stimulating action of protoporphyrin IX is increased by the
above-described NO-independent but heme-dependent stimulator YC-1
(Muilsch et al., Naunyn Schmiedebergs Arch. Pharmacol. 355,
R47).
[0011] Thus, hitherto compounds capable of stimulating soluble
guanylate cyclase independently of the heme group present in the
enzyme have not been described.
[0012] It was an object of the present invention to provide
medicaments for treating cardiovascular disorders or other
disorders accessible to therapy by influencing the cGMP signal
pathway in organisms.
[0013] The above object is achieved by using compounds for
preparing medicaments capable of stimulating soluble guanylate
cyclase even independently of NO and the heme group present in the
enzyme.
[0014] Surprisingly, it has been found that there are compounds
capable of stimulating soluble guanylate cyclase even independently
of the heme group present in the enzyme. The biological activity of
these stimulators is based on an entirely novel mechanism for
stimulating soluble guanylate cyclase. In contrast to the
above-described compounds, known from the prior art as stimulators
of soluble guanylate cyclase, the compounds according to the
invention are capable of stimulating both the heme-containing and
the heme-free form of soluble guanylate cyclase. Thus, in the case
of these novel stimulators, stimulation of the enzyme is effected
via a heme-independent path, and this is also confirmed by the fact
that firstly the novel stimulators do not have any synergistic
action with NO at the heme-containing enzyme and that secondly the
action of these novel stimulators cannot be blocked by the
heme-dependent inhibitor of soluble guanylate cyclase, i.e.
1H-1,2,4-oxadiazole-(4,3a)-q- uinoxalin-1-one (ODQ).
[0015] This is a novel therapeutic approach for treating
cardiovascular disorders and other disorders accessible to therapy
by influencing the cGMP signal pathway in organisms.
[0016] EP-A-0 345 068 describes, inter alia, the
aminoalkanecarboxylic acid (1) as an intermediate in the synthesis
of GABA antagonists: 2
[0017] WO 93/00359 describes the aminoalkanecarboxylic acid (2) as
an intermediate in peptide synthesis and its use as active compound
for treating disorders of the central nervous system: 3
[0018] However, neither of these two publications describes that
such aminoalkanecarboxylic acids may have a stimulating effect,
independent of the heme group present in the enzyme, on soluble
guanylate cyclase.
[0019] Substances having a structure similar to that of the
compounds according to the invention are furthermore known from WO
01/19776, WO 01/19355, WO 01/19780 and WO 01/19778.
[0020] According to the present invention, the compounds used for
stimulating, independently of the heme group present in the enzyme,
soluble guanylate cyclase are aminoalkanecarboxylic acids of the
formula (I): 4
[0021] where
[0022] Z represents a phenyl ring which is fused with a saturated,
partially unsaturated or aromatic carba- or heterocycle having up
to 3 heteroatoms from the group consisting of S, N and/or O or with
a partially unsaturated or aromatic heterocycle having 1 to 9
carbon atoms and up to 3 heteroatoms from the group consisting of
S, N and/or O,
[0023] V is missing or represents O, NR.sup.4, NR.sup.4CONR.sup.4,
NR.sup.4CO, NR.sup.4SO.sub.2, COO, CONR.sup.4 or S(O).sub.o,
[0024] where
[0025] R.sup.4 independently of any other radical R.sup.4
optionally present represents hydrogen, straight-chain or branched
alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon
atoms, aryl having 6 to 10 carbon atoms or arylalkyl having 7 to 18
carbon atoms, where the aryl radical for its part may be mono- or
polysubstituted by halogen, alkyl, alkoxy having up to 6 carbon
atoms,
[0026] o represents 0, 1 or 2,
[0027] Q is missing or represents straight-chain or branched
alkylene, straight-chain or branched alkenediyl or straight-chain
or branched alkynediyl having in each case up to 12 carbon atoms,
which radicals may in each case comprise one or more groups
selected from the group consisting of O, S(O).sub.p, NR.sup.5, Co,
NR.sup.5SO.sub.2 or CONR.sup.5 and which may be mono- or
polysubstituted by halogen, hydroxyl or alkoxy having up to 4
carbon atoms, where optionally any two atoms of the above chain may
be attached to one another forming a three- to eight-membered
ring,
[0028] where
[0029] R.sub.5 represents hydrogen, straight-chain or branched
alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8
carbon atoms which may be substituted by halogen or alkoxy having
up to 4 carbon atoms,
[0030] p represents 0, 1 or 2,
[0031] Y represents hydrogen, NR.sup.8R.sup.9, aryl having 6 to 10
carbon atoms, an aromatic or saturated heterocycle having 1 to 9
carbon atoms and up to 3 heteroatoms from the group consisting of
S, N and O or straight-chain or branched cycloalkyl having 3 to 8
carbon atoms, which may also be attached via N, where the cyclic
radicals may in each case be mono- to trisubstituted by
straight-chain or branched alkyl, straight-chain or branched
alkenyl, straight-chain or branched alkynyl, straight-chain or
branched alkoxy, straight-chain or branched alkoxyalkoxy,
straight-chain or branched haloalkyl, straight-chain or branched
haloalkoxy having in each case up to 8 carbon atoms, straight-chain
or branched cycloalkyl having 3 to 8 carbon atoms, halogen,
hydroxyl, CN, SR.sup.6, NO.sub.2, NR.sup.8R.sup.9,
NR.sup.8COR.sup.10, NR.sup.7CONR.sup.7R.sup.10 or
CONR.sup.11R.sup.12,
[0032] where
[0033] R.sup.6 represents hydrogen, straight-chain or branched
alkyl having up to 8 carbon atoms, straight-chain or branched
haloalkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8
carbon atoms,
[0034] R.sup.7 independently of any other radical R.sup.7
optionally present represents hydrogen, straight-chain or branched
alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8
carbon atoms,
[0035] R.sup.8, R.sup.9, R.sup.11 and R.sup.12 independently of one
another represent hydrogen, straight-chain or branched alkyl,
straight-chain or branched alkenyl having up to 8 carbon atoms,
aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1
to 9 carbon atoms and up to 3 heteroatoms from the group consisting
of S, N and O, arylalkyl having 8 to 18 carbon atoms, cycloalkyl
having 3 to 8 carbon atoms or a radical of the formula
SO.sub.2R.sup.13,
[0036] where the aryl radical for its part may be mono- or
polysubstituted by halogen, hydroxyl, CN, NO.sub.2, NH.sub.2,
NHCOR.sup.7, alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6
carbon atoms,
[0037] or two substitutents selected from R.sup.8 and R.sup.9 or
R.sup.11 and R.sup.12 may be attached to one another forming a
five- or six-membered ring which may contain O or N,
[0038] where
[0039] R.sup.13 represents straight-chain or branched alkyl having
up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, where the
aryl radical for its part may be mono- or polysubstituted by
halogen, CN, NO.sub.2, alkyl, alkoxy, haloalkyl or haloalkoxy
having up to 6 carbon atoms,
[0040] R.sup.10 represents hydrogen, straight-chain or branched
alkyl having up to 12 carbon atoms, straight-chain or branched
alkenyl having up to 12 carbon atoms, aryl having 6 to 10 carbon
atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to
3 heteroatoms from the group consisting of S, N and O or cycloalkyl
having 3 to 8 carbon atoms, which may optionally furthermore be
substituted by halogen, hydroxyl, CN, NO.sub.2, NH.sub.2,
NHCOR.sup.7, alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6
carbon atoms;
[0041] and/or the cyclic radicals may in each case be mono- to
trisubstituted by aryl having 6 to 10 carbon atoms, a saturated
carbocycle having 6 to 10 carbon atoms, an aromatic or saturated
heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from
the group consisting of S, N and O, which may also be attached via
N,
[0042] which may be attached directly or via a group selected from
the group consisting of O, S, SO, SO.sub.2, NR.sup.7,
SO.sub.2NR.sup.7, CONR.sup.7, straight-chain or branched alkylene,
straight-chain or branched alkenediyl, straight-chain or branched
alkyloxy, straight-chain or branched oxyalkyloxy, straight-chain or
branched sulfonylalkyl, straight-chain or branched thioalkyl having
in each case up to 8 carbon atoms and which may be mono- to
trisubstituted by straight-chain or branched alkyl, straight-chain
or branched alkoxy, straight-chain or branched alkoxyalkoxy,
straight-chain or branched haloalkyl, straight-chain or branched
haloalkoxy, carbonylalkyl or straight-chain or branched alkenyl
having in each case up to 6 carbon atoms, halogen, SR.sup.6, CN,
NO.sub.2, NR.sup.8R.sup.9, CONR.sup.15R.sup.16 or
NR.sup.14COR.sup.7,
[0043] where
[0044] R.sup.14 represents hydrogen, straight-chain or branched
alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8
carbon atoms,
[0045] R.sup.15, R.sup.16 independently of one another represent
hydrogen, straight-chain or branched alkyl having up to 8 carbon
atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10
carbon atoms or a radical of the formula SO.sub.2R.sup.18, where
the aryl radical for its part may be mono- or polysubstituted by
halogen, hydroxyl, CN, NO.sub.2, NH.sub.2, NHCOR.sup.7, alkyl,
alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms,
[0046] where
[0047] R.sup.18 represents straight-chain or branched alkyl having
up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, where the
aryl radical for its part may be mono- or polysubstituted by
halogen, hydroxyl, CN, NO.sub.2, NH.sub.2, NHCOR.sup.7, alkyl,
alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms,
and
[0048] R.sup.17 independently of one another represents hydrogen,
straight-chain or branched alkyl having up to 12 carbon atoms,
straight-chain or branched alkenyl having up to 12 carbon atoms,
aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1
to 9 carbon atoms and up to 3 heteroatoms from the group consisting
of S, N and O or cycloalkyl having 3 to 8 carbon atoms, which may
optionally furthermore be substituted by halogen, hydroxyl, CN,
NO.sub.2, NH.sub.2, NHCOR.sup.7, alkyl, alkoxy, haloalkyl or
haloalkoxy having up to 6 carbon atoms;
[0049] and/or the cyclic radicals may be fused with an aromatic or
saturated carbocycle having 1 to 10 carbon atoms or an aromatic or
saturated heterocycle having 1 to 9 carbon atoms and up to 3
heteroatoms from the group consisting of S, N and O,
[0050] R.sup.3 represents hydrogen, halogen, straight-chain or
branched alkyl which may optionally carry one or more substituents
from the group consisting of C.sub.1-6-alkoxy, NR.sup.19R.sup.20
and cycloalkyl having 3 to 8 carbon atoms, straight-chain or
branched haloalkyl, straight-chain or branched alkoxy, or
alkoxycarbonyl having in each case up to 4 carbon atoms, CN,
NO.sub.2, NR.sup.9R.sup.20, SR.sup.17, SO.sub.2R.sup.17, cycloalkyl
having 3 to 8 carbon atoms, haloalkoxy, haloalkoxy having up to 6
carbon atoms, cycloalkoxy having up to 14 carbon atoms, CONH.sub.2,
CONR.sup.17R.sup.17, SO.sub.2NH.sub.2, SO.sub.2NR.sup.17R.sup.17,
alkoxyalkoxy having up to 12 carbon atoms, NHCOOR.sup.17,
NHCOR.sup.17, NHSO.sub.2R.sup.17, NHCONH.sub.2,
OCONR.sup.17R.sup.17, OSO.sub.2R.sup.17, C.sub.2-12-alkenyl or
C.sub.2-12-alkynyl,
[0051] where
[0052] R.sup.19 and R.sup.20 independently of one another represent
hydrogen, straight-chain or branched alkyl having up to 4 carbon
atoms or cycloalkyl having 3 to 8 carbon atoms,
[0053] m represents an integer from 1 to 4,
[0054] W represents straight-chain or branched alkylene having up
to 6 carbon atoms or straight-chain or branched alkenediyl having
up to 6 carbon atoms which may in each case contain a group
selected from the group consisting of O, S(O).sub.q, NR.sup.21, CO
or CONR.sup.21, or represents CO, NHCO or OCO,
[0055] where
[0056] q represents 0, 1 or 2,
[0057] R.sup.21 represents hydrogen, straight-chain or branched
alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8
carbon atoms,
[0058] U represents straight-chain or branched alkyl having up to 4
carbon atoms,
[0059] A represents aryl having 6 to 10 carbon atoms or an aromatic
heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from
the group consisting of S, N and O,
[0060] which may optionally be mono- to trisubstituted by halogen,
straight-chain or branched alkyl, straight-chain or branched
haloalkyl, straight-chain or branched alkoxy, haloalkoxy or
alkoxycarbonyl having up to 4 carbon atoms, CN, NO.sub.2 or
NR.sup.22R.sup.23,
[0061] where
[0062] R.sup.22 and R.sup.23 in each case independently of one
another represent hydrogen, straight-chain or branched alkyl having
up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
carbonylalkyl or sulfonylalkyl,
[0063] R.sup.2 represents tetrazolyl, COOR.sup.24 or
CONR.sup.25R.sup.26,
[0064] where
[0065] R.sup.24 [lacuna] hydrogen, alkyl having 1 to 8 carbon atoms
or cycloalkyl having 3 to 8 carbon atoms
[0066] R.sup.25 and R.sup.26 in each case independently of one
another represent hydrogen, straight-chain or branched alkyl having
up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a
radical of the formula 15 SO.sub.2R.sup.27,
[0067] or R.sup.25 and R.sup.26 together form a five- or
six-membered ring which may contain N or O,
[0068] where
[0069] R.sup.27 represents straight-chain or branched alkyl having
up to 4 carbon atoms or aryl having 6 to 10 carbon atoms,
[0070] where the aryl radical for its part may be mono- or
polysubstituted by halogen, CN, NO.sub.2, alkyl, alkoxy, haloalkyl
or haloalkoxy having up to 6 carbon atoms,
[0071] X represents straight-chain or branched alkylene having up
to 12 carbon atoms or straight-chain or branched alkenediyl having
up to 12 carbon atoms, which may in each case contain one to three
groups selected from the group 30 consisting of O, S(O).sub.r,
NR.sup.28, CO or CONR.sup.29, aryl and aryloxy having 6 to 10
carbon atoms, where the aryl radical for its part may be mono- or
polysubstituted by halogen, CN, NO.sub.2, alkyl, alkoxy, haloalkyl
or haloalkoxy having up to 6 carbon atoms, where optionally any two
atoms of the abovementioned chains are attached to one another via
an alkyl chain forming a three- to eight-membered ring,
[0072] where
[0073] r represents 0, 1 or 2,
[0074] R.sup.28 represents hydrogen, alkyl having 1 to 8 carbon
atoms or cycloalkyl having 3 to 8 carbon atoms,
[0075] R.sup.29 represents hydrogen, straight-chain or branched
alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8
carbon atoms,
[0076] n represents 1 or 2;
[0077] R.sup.1 represents tetrazolyl, COOR.sup.30 or
CONR.sup.31R.sup.32,
[0078] where
[0079] R.sup.30 [lacuna] hydrogen, alkyl having 1 to 8 carbon atoms
or cycloalkyl having 3 to 8 carbon atoms
[0080] R.sup.31 and R.sup.32 in each case independently of one
another represent hydrogen, straight-chain or branched alkyl having
up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a
radical of the formula SO.sub.2R.sup.33,
[0081] where
[0082] R.sup.33 represents straight-chain or branched alkyl having
up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, where the
aryl radical for its part may be mono- or polysubstituted by
halogen, CN, NO.sub.2, alkyl, alkoxy, haloalkyl or haloalkoxy
having up to 6 carbon atoms,
[0083] and their stereoisomers and salts.
[0084] Here, preference is given to compounds of the formula
(I)
[0085] where
[0086] Z represents a cyclic radical from the group consisting of
5
[0087] where the radicals V and W may be attached to any carbon
ring atom or any nitrogen ring atom optionally present,
selected;
[0088] V is missing or represents O, NR.sup.4, NR.sup.4CONR.sup.4,
NR.sup.4CO, NR.sup.4SO.sub.2, COO, CONR.sup.4 or S(O).sub.o,
[0089] where
[0090] R.sup.4 independently of any other radical R.sup.4
optionally present represents hydrogen, straight-chain or branched
alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon
atoms, aryl having 6 to 10 carbon atoms or arylalkyl having 7 to 18
carbon atoms, where the aryl radical for its part may be mono- or
polysubstituted by halogen, alkyl, alkoxy having up to 6 carbon
atoms,
[0091] o represents 0, 1 or 2,
[0092] Q is missing or represents straight-chain or branched
alkylene, straight-chain or branched alkenediyl or straight-chain
or branched alkynediyl having in each case up to 12 carbon atoms,
which radicals may in each case comprise one or more groups
selected from the group consisting of O, S(O).sub.p, NR.sup.5, CO,
NR.sup.5SO.sub.2 or CONR.sup.5 and which may be mono- or
polysubstituted by halogen, hydroxyl or alkoxy having up to 4
carbon atoms, where optionally any two atoms of the above chain may
be attached to one another forming a three- to eight-membered
ring,
[0093] where
[0094] R.sub.5 represents hydrogen, straight-chain or branched
alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8
carbon atoms which may be substituted by halogen or alkoxy having
up to 4 carbon atoms,
[0095] p represents 0, 1 or 2,
[0096] Y represents hydrogen, NR.sup.8R.sup.9, aryl having 6 to 10
carbon atoms, an aromatic or saturated heterocycle having 1 to 9
carbon atoms and up to 3 heteroatoms from the group consisting of
S, N and O or straight-chain or branched cycloalkyl having 3 to 8
carbon atoms, which may also be attached via N, where the cyclic
radicals may in each case be mono- to trisubstituted by
straight-chain or branched alkyl, straight-chain or branched
alkenyl, straight-chain or branched alkynyl, straight-chain or
branched alkoxy, straight-chain or branched alkoxyalkoxy,
straight-chain or branched haloalkyl, straight-chain or branched
haloalkoxy having in each case up to 8 carbon atoms, straight-chain
or branched cycloalkyl having 3 to 8 carbon atoms, halogen,
hydroxyl, CN, SR.sup.6, NO.sub.2, NR.sup.8R.sup.9,
NR.sup.7COR.sup.10, NR.sup.7CONR.sup.7R.sup.10 or
CONR.sup.11R.sup.12,
[0097] where
[0098] R.sup.6 represents hydrogen, straight-chain or branched
alkyl having up to 8 carbon atoms, straight-chain or branched
haloalkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8
carbon atoms,
[0099] R.sup.7 independently of any other radical R.sup.7
optionally present represents hydrogen, straight-chain or branched
alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8
carbon atoms,
[0100] R.sup.8, R.sup.9, R.sup.11 and R.sup.2 independently of one
another represent hydrogen, straight-chain or branched alkyl,
straight-chain or branched alkenyl having up to 8 carbon atoms,
aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1
to 9 carbon atoms and up to 3 heteroatoms from the group consisting
of S, N and O, arylalkyl having 8 to 18 carbon atoms, cycloalkyl
having 3 to 8 carbon atoms or a radical of the formula
SO.sub.2R.sup.13, where the aryl radical for its part may be mono-
or polysubstituted by halogen, hydroxyl, CN, NO.sub.2, NH.sub.2,
NHCOR.sup.7, alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6
carbon atoms, or two substituents selected from R.sup.8 and R.sup.9
or R.sup.11 and R.sup.12 may be attached to one another forming a
five- or six-membered ring which may contain O or N,
[0101] where
[0102] R.sup.13 represents straight-chain or branched alkyl having
up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, where the
aryl radical for its part may be mono- or polysubstituted by
halogen, CN, NO.sub.2, alkyl, alkoxy, haloalkyl or haloalkoxy
having up to 6 carbon atoms,
[0103] R.sup.10 represents hydrogen, straight-chain or branched
alkyl having up to 12 carbon atoms, straight-chain or branched
alkenyl having up to 12 carbon atoms, aryl having 6 to 10 carbon
atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to
3 heteroatoms from the group consisting of S, N and O or cycloalkyl
having 3 to 8 carbon atoms, which may optionally furthermore be
substituted by halogen, hydroxyl, CN, NO.sub.2, NH.sub.2,
NHCOR.sup.7, alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6
carbon atoms;
[0104] and/or the cyclic radicals may in each case be mono- to
trisubstituted by aryl having 6 to 10 carbon atoms, an aromatic or
saturated heterocycle having 1 to 9 carbon atoms and up to 3
heteroatoms from the group consisting of S, N and O, which may also
be attached via N,
[0105] which may be attached directly or via a group selected from
the group consisting of O, S, SO, SO.sub.2, NR.sup.7,
SO.sub.2NR.sup.7, CONR.sup.7, straight-chain or branched alkylene,
straight-chain or branched alkenediyl, straight-chain or branched
alkyloxy, straight-chain or branched oxyalkyloxy, straight-chain or
branched sulfonylalkyl, straight-chain or branched thioalkyl having
in each case up to 8 carbon atoms and which may be mono- to
trisubstituted by straight-chain or branched alkyl, straight-chain
or branched alkoxy, straight-chain or branched alkoxyalkoxy,
straight-chain or branched haloalkyl, straight-chain or branched
haloalkoxy, carbonylalkyl or straight-chain or branched alkenyl
having in each case up to 6 carbon atoms, halogen, SR.sup.6, CN,
NO.sub.2, NR.sup.8R.sup.9, CONR.sup.15R.sup.16 or
NR.sup.14COR.sup.17,
[0106] where
[0107] R.sup.14 represents hydrogen, straight-chain or branched
alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8
carbon atoms,
[0108] R.sup.15, R.sup.16 independently of one another represent
hydrogen, straight-chain or branched alkyl having up to 8 carbon
atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of the
formula SO.sub.2R.sup.18,
[0109] where
[0110] R.sup.18 represents straight-chain or branched alkyl having
up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, where the
aryl radical for its part may be mono- or polysubstituted by
halogen, CN, NO.sub.2, alkyl, alkoxy, haloalkyl or haloalkoxy
having up to 6 carbon atoms, and
[0111] R.sup.17 represents hydrogen, straight-chain or branched
alkyl having up to 12 carbon atoms, straight-chain or branched
alkenyl having up to 12 carbon atoms, aryl having 6 to 10 carbon
atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to
3 heteroatoms from the group consisting of S, N and O or cycloalkyl
having 3 to 8 carbon atoms, which may optionally furthermore be
substituted by halogen, CN, NO.sub.2, alkyl, alkoxy, haloalkyl or
haloalkoxy having up to 6 carbon atoms;
[0112] and/or the cyclic radicals may be fused with an aromatic or
saturated carbocycle having 1 to 10 carbon atoms or an aromatic or
saturated heterocycle having 1 to 9 carbon atoms and up to 3
heteroatoms from the group consisting of S, N and O,
[0113] R.sup.3 represents hydrogen, halogen, straight-chain or
branched alkyl, straight-chain or branched haloalkyl or
straight-chain or branched alkoxy having in each case up to 4
carbon atoms,
[0114] m represents an integer from 1 to 4,
[0115] W represents straight-chain or branched alkylene or
straight-chain or branched alkenediyl having in each case up to 4
carbon atoms,
[0116] U represents --CH.sub.2--,
[0117] A represents phenyl or an aromatic heterocycle having 1 to 9
carbon atoms and up to 3 heteroatoms from the group consisting of
S, N and O,
[0118] which may optionally be mono- to trisubstituted by halogen,
straight-chain or branched alkyl, straight-chain or branched
haloalkyl or straight-chain or branched alkoxy having up to 4
carbon atoms,
[0119] R.sup.2 represents COOR.sup.24,
[0120] where
[0121] R.sup.24 represents hydrogen or straight-chain or branched
alkyl having up to 6 carbon atoms,
[0122] X represents straight-chain or branched alkylene having up
to 8 carbon atoms or straight-chain or branched alkenediyl having
up to 8 carbon atoms which may in each case contain one to three
groups selected from the group consisting of phenyl, phenyloxy, O,
CO and CONR.sup.29,
[0123] where
[0124] R.sup.29 represents hydrogen, straight-chain or branched
alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 6
carbon atoms,
[0125] n represents 1 or 2;
[0126] R.sup.1 represents COOR.sup.30,
[0127] where
[0128] R.sup.30 represents hydrogen or straight-chain or branched
alkyl having up to 6 carbon atoms.
[0129] Particular preference is given to compounds of the formula
(I)
[0130] where
[0131] Z represents a cyclic radical from the group consisting of
6
[0132] where the radicals V and W may be attached to any carbon
ring atom or any nitrogen ring atom optionally present,
selected;
[0133] V is missing or represents O, S or NR.sup.4,
[0134] where
[0135] R.sup.4 represents hydrogen or methyl,
[0136] Q is missing or represents straight-chain or branched
alkylene having up to 9 carbon atoms or straight-chain or branched
alkenediyl or straight-chain or branched alkynediyl having up to 4
carbon atoms which may be monosubstituted by halogen,
[0137] Y represents H, NR.sup.8R.sup.9, cyclohexyl, phenyl, naphtyl
or a heterocycle selected from the group consisting of 7
[0138] which may also be attached via N,
[0139] where the cyclic radicals may in each case be mono- to
trisubstituted by straight-chain or branched alkyl, straight-chain
or branched alkenyl, straight-chain or branched alkynyl,
straight-chain or branched alkoxy, straight-chain or branched
alkoxyalkoxy, straight-chain or branched haloalkyl, straight-chain
or branched haloalkoxy having in each case up to 4 carbon atoms,
straight-chain or branched cycloalkyl having 3 to 6 carbon atoms,
F, Cl, Br, I, NO.sub.2, SR.sup.6, NR.sup.8R.sup.9,
NR.sup.7COR.sup.10 or CONR.sup.11R.sup.12,
[0140] where
[0141] R.sup.6 represents hydrogen, straight-chain or branched
alkyl having up to 8 carbon atoms, or straight-chain or branched
haloalkyl having up to 4 carbon atoms,
[0142] R.sup.7 represents hydrogen, or straight-chain or branched
alkyl having up to 4 carbon atoms,
[0143] R.sup.8, R.sup.9, R.sup.11 and R.sup.12 independently of one
another represent hydrogen, straight-chain or branched alkyl having
up to 4 carbon atoms, or phenyl,
[0144] where the phenyl radical may be mono- to trisubstituted by
F, Cl Br, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl,
s-butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino,
NO.sub.2, CF.sub.3, OCF.sub.3 or CN,
[0145] or two substituents selected from R.sup.8 and R.sup.9 or
R.sup.11 and R.sup.12 may be attached to one another forming a
five- or six-membered ring which may be interrupted by O or N,
[0146] R.sup.10 represents hydrogen, straight-chain or branched
alkyl having up to 4 carbon atoms, or phenyl,
[0147] where the phenyl radical may be mono- to trisubstituted by
F, Cl Br, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl,
s-butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino,
NO.sub.2, CF.sub.3, OCF.sub.3 or CN;
[0148] and/or the cyclic radicals may in each case be mono- to
trisubstituted by phenyl or a heterocycle from the group consisting
of 8
[0149] which may be attached directly or via a group selected from
the group consisting of O, S, SO, SO.sub.2, NR.sup.4,
SO.sub.2NR.sup.7, CONR.sup.7, straight-chain or branched alkylene,
straight-chain or branched alkenediyl, straight-chain or branched
alkyloxy, straight-chain or branched oxyalkyloxy, straight-chain or
branched sulfonylalkyl, straight-chain or branched thioalkyl having
in each case up to 4 carbon atoms and which may be mono- to
trisubstituted by straight-chain or branched alkyl, straight-chain
or branched alkoxy, straight-chain or branched alkoxyalkoxy,
straight-chain or branched haloalkyl or straight-chain or branched
alkenyl having in each case up to 4 carbon atoms, F, Cl, Br, I, CN,
SCH.sub.3, OCF.sub.3, NO.sub.2, NR.sup.8R.sup.9 or
NR.sup.14COR.sup.17,
[0150] where
[0151] R.sup.14 represents hydrogen, straight-chain or branched
alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8
carbon atoms, and
[0152] R.sup.17 represents hydrogen, straight-chain or branched
alkyl having up to 12 carbon atoms, straight-chain or branched
alkenyl having up to 12 carbon atoms, aryl having 6 to 10 carbon
atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to
3 heteroatoms from the group consisting of S, N and O or cycloalkyl
having 3 to 8 carbon atoms, which may optionally furthermore be
substituted by F, Cl Br, hydroxyl, methyl, ethyl, n-propyl,
i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy, ethoxy,
amino, acetylamino, NO.sub.2, CF.sub.3, OCF.sub.3 or CN;
[0153] and/or the cyclic radicals may be fused with an aromatic or
saturated carbocycle having 1 to 10 carbon atoms or an aromatic or
saturated heterocycle having 1 to 9 carbon atoms and up to 3
heteroatoms selected from the group consisting of S, N and O,
[0154] R.sup.3 represents hydrogen, methyl or fluorine,
[0155] m represents an integer from 1 to 4,
[0156] W represents CH.sub.2, --CH.sub.2CH.sub.2--,
CH.sub.2CH.sub.2CH.sub.2, CH.dbd.CHCH.sub.2,
[0157] U represents --CH.sub.2--,
[0158] A represents phenyl, pyridyl, thienyl or thiazolyl which may
optionally be mono- to trisubstituted by methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, CF.sub.3, methoxy,
ethoxy, F, Cl, Br,
[0159] R.sup.2 represents COOR.sup.24,
[0160] where
[0161] R.sup.24 represents hydrogen or straight-chain or branched
alkyl having up to 4 carbon atoms,
[0162] X represents straight-chain or branched alkylene having up
to 8 carbon atoms or straight-chain or branched alkenediyl having
up to 8 carbon atoms which may in each case contain one to three
groups from the group consisting of phenyl, phenyloxy, O, CO and
CONR.sup.30,
[0163] where
[0164] R.sup.30 represents hydrogen, straight-chain or branched
alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 6
carbon atoms,
[0165] n represents 1 or 2;
[0166] R.sup.1 represents COOR.sup.35,
[0167] where
[0168] R.sup.35 represents hydrogen or straight-chain or branched
alkyl having up to 6 carbon atoms.
[0169] Here, very particular preference is given to compounds of
the formula (I)
[0170] where
[0171] Z represents a cyclic radical from the group consisting of
9
[0172] where the radicals V and W may be attached to any carbon
ring atom or any nitrogen ring atom optionally present,
selected;
[0173] V represents O,
[0174] Q represents straight-chain or branched alkylene having up
to 9 carbon atoms or straight-chain or branched alkenediyl or
straight-chain or branched alkynediyl having up to 4 carbon atoms
which may be monosubstituted by halogen,
[0175] Y represents H, cyclohexyl, phenyl or a heterocycle from the
group consisting of 10
[0176] where the cyclic radicals may in each case be mono- to
trisubstituted by straight-chain or branched alkyl, straight-chain
or branched alkenyl, straight-chain or branched alkynyl,
straight-chain or branched alkoxy, straight-chain or branched
alkoxyalkoxy, straight-chain or branched haloalkyl, straight-chain
or branched haloalkoxy having in each case up to 4 carbon atoms,
straight-chain or branched cycloalkyl having 3 to 6 carbon atoms,
F, Cl, Br, I, NO.sub.2, SR.sup.6, NR.sup.8R.sup.9,
NR.sup.7COR.sup.10 or CONR.sup.11R.sup.12,
[0177] where
[0178] R.sup.6 represents hydrogen, straight-chain or branched
alkyl having up to 4 carbon atoms, or straight-chain or branched
haloalkyl having up to 4 carbon atoms,
[0179] R.sup.7 represents hydrogen, or straight-chain or branched
alkyl having up to 4 carbon atoms,
[0180] R.sup.8, R.sup.9, R.sup.11 and R.sup.12 independently of one
another represent hydrogen, straight-chain or branched alkyl having
up to 4 carbon atoms, or phenyl,
[0181] where the phenyl radical may be mono- to trisubstituted by
F, Cl Br, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl,
s-butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino,
NO.sub.2, CF.sub.3, OCF.sub.3 or CN,
[0182] or two substituents selected from R.sup.8 and R.sup.9 or
R.sup.11 and R.sup.12 may be attached to one another forming a
five- or six-membered ring which may be interrupted by O or N,
[0183] R.sup.10 represents hydrogen, straight-chain or branched
alkyl having up to 4 carbon atoms, or phenyl,
[0184] where the phenyl radical may be mono- to trisubstituted by
F, Cl Br, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl,
s-butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino,
NO.sub.2, CF.sub.3, OCF.sub.3 or CN;
[0185] and/or the cyclic radicals may in each case be mono- to
trisubstituted by phenyl or a heterocycle from the group consisting
of 11
[0186] which may be attached directly or via a group selected from
the group consisting of O, S, SO, SO.sub.2, straight-chain or
branched alkylene, straight-chain or branched alkenediyl,
straight-chain or branched alkyloxy, straight-chain or branched
oxyalkyloxy, straight-chain or branched sulfonylalkyl,
straight-chain or branched thioalkyl having in each case up to 4
carbon atoms and which may be mono- to trisubstituted by
straight-chain or branched alkyl, straight-chain or branched
alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or
branched haloalkyl or straight-chain or branched alkenyl having in
each case up to 4 carbon atoms, F, Cl, Br, I, CN, SCH.sub.3,
OCF.sub.3, NO.sub.2, NR.sup.8R.sup.9 or NR.sup.14COR.sup.17,
[0187] where
[0188] R.sup.14 represents hydrogen, straight-chain or branched
alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 6
carbon atoms, and
[0189] R.sup.17 represents hydrogen, straight-chain or branched
alkyl having up to 6 carbon atoms, straight-chain or branched
alkenyl having up to 6 carbon atoms, aryl having 6 to 10 carbon
atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to
3 heteroatoms from the group consisting of S, N and O or cycloalkyl
having 3 to 6 carbon atoms, which may optionally furthermore be
substituted by F, Cl Br, hydroxyl, methyl, ethyl, n-propyl,
i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy, ethoxy,
amino, acetylamino, NO.sub.2, CF.sub.3, OCF.sub.3 or CN;
[0190] and/or the cyclic radicals may be fused with an aromatic or
saturated carbocycle having 1 to 10 carbon atoms or an aromatic or
saturated heterocycle having 1 to 9 carbon atoms and up to 3
heteroatoms selected from the group consisting of S, N and O,
[0191] R.sup.3 represents hydrogen, methyl or fluorine,
[0192] m represents an integer from 1 to 2,
[0193] W represents CH.sub.2, or --CH.sub.2CH.sub.2--,
[0194] U represents --CH.sub.2--,
[0195] A represents phenyl, which may optionally be mono- to
trisubstituted by methyl, ethyl, n-propyl, i-propyl, n-butyl,
i-butyl, s-butyl, t-butyl, CF.sub.3, methoxy, ethoxy, F, Cl,
Br,
[0196] R.sup.2 represents COOR.sup.24,
[0197] where
[0198] R.sup.24 represents hydrogen or straight-chain or branched
alkyl having up to 4 carbon atoms,
[0199] X represents straight-chain or branched alkylene having up
to 6 carbon atoms or straight-chain or branched alkenediyl having
up to 6 carbon atoms which may in each case contain one to three
groups from the group consisting of phenyloxy, O, CO and
CONR.sup.30,
[0200] where
[0201] R.sup.30 represents hydrogen, straight-chain or branched
alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 6
carbon atoms,
[0202] n represents 1 or 2;
[0203] R.sup.1 represents COOR.sup.35,
[0204] where
[0205] R.sup.35 represents hydrogen or straight-chain or branched
alkyl having up to 4 carbon atoms.
[0206] Particular preference according to the invention is given to
compounds of the formula (I) in which R.sup.1 and R.sup.2 are each
COOH.
[0207] Very particular preference according to the present
invention is given to compounds in which
[0208] Z represents a cyclic radical from the group consisting of
12
[0209] where the radicals V and W may be attached to any carbon
ring atom or any nitrogen ring atom optionally present,
selected;
[0210] V represents O,
[0211] Q represents CH.sub.2,
[0212] Y represents phenyl which is substituted by a radical
selected from the group consisting of 2-phenylethyl, cyclohexyl,
4-chlorophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl,
4-cyanophenyl, 4-chlorophenoxy, 4-methoxyphenoxy,
4-trifluoromethylphenoxy, 4-cyanophenoxy, 4-methylphenyl,
[0213] R.sup.3 represents hydrogen, methyl or fluorine,
[0214] m represents an integer from 1 to 2,
[0215] W represents --CH.sub.2CH.sub.2--,
[0216] U represents --CH.sub.2--,
[0217] A represents phenyl,
[0218] R.sup.2 represents COOH, where R.sup.2 is located in the
4-position to the radical U,
[0219] X represents (CH.sub.2).sub.4,
[0220] R.sup.1 represents COOH.
[0221] Very particular preference according to the present
invention is also given to compounds in which
[0222] Z represents a cyclic radical from the group consisting of
13
[0223] where the radicals V and W may be attached to any carbon
ring atom or any nitrogen ring atom optionally present,
selected;
[0224] V is missing,
[0225] Q represents CH.sub.2O which is attached via its carbon atom
to Z,
[0226] Y represents phenyl which is substituted by a radical
selected from the group consisting of 2-phenylethyl, cyclohexyl,
4-chlorophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl,
4-cyanophenyl, 4-chlorophenoxy, 4-methoxyphenoxy,
4-trifluoromethylphenoxy, 4-cyanophenoxy, 4-methylphenyl,
4-tert-butylphenyl, 4-carboxyphenyl, 4-fluorophenyl,
3-methoxyphenyl, 2,4-dichlorophenyl,
[0227] R.sup.3 represents hydrogen, methyl or fluorine,
[0228] m represents an integer from 1 to 2,
[0229] W represents --CH.sub.2CH.sub.2--,
[0230] U represents --CH.sub.2--,
[0231] A represents phenyl,
[0232] R.sup.2 represents COOH where R.sub.2 is located in the
4-position to the radical U,
[0233] X represents (CH.sub.2).sub.4,
[0234] R.sup.1 represents COOH.
[0235] The compounds according to the invention of the general
formula (I) may also be in the form of their salts. Mention may
generally be made here of salts with organic or inorganic bases or
acids.
[0236] Physiologically acceptable salts are preferred for the
purposes of the present invention. Physiologically acceptable salts
of the compounds according to the invention may be salts of the
substances according to the invention with mineral acids,
carboxylic acids or sulfonic acids. Particularly preferred examples
are salts with hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphoric acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic
acid, acetic acid, propionic acid, lactic acid, tartaric acid,
citric acid, fumaric acid, maleic acid or benzoic acid.
[0237] Physiologically acceptable salts may likewise be metal or
ammonium salts of the compounds according to the invention having a
free carboxyl group. Particularly preferred examples are sodium,
potassium, magnesium or calcium salts, and ammonium salts derived
from ammonia, or organic amines, such as, for example, ethylamine,
di- or triethylamine, di- or triethanolamine, dicyclohexylamine,
dimethylaminoethanol, arginine, lysine or ethylenediamine.
[0238] The compounds according to the invention may exist in
stereoisomeric forms which are either like image and mirror image
(enantiomers), or not like image and mirror image (diastereomers).
The invention relates both to the enantiomers or diastereomers and
to their respective mixtures. The racemic forms, like the
diastereomers, can be separated into the stereoisomerically uniform
components in a known manner, for example by optical resolution or
chromatographic separation. The double bonds present in the
compounds according to the invention can be in the cis or trans
configuration (Z or E form).
[0239] For the purposes of the present invention, the substituents
are, unless defined otherwise, generally as defined below:
[0240] Alkyl generally represents a straight-chain or branched
hydrocarbon radical having 1 to 20 carbon atoms. Examples which may
be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and
isooctyl, nonyl, decyl, dodeyl, eicosyl.
[0241] Alkylene generally represents a straight-chain or branched
hydrocarbon bridge having 1 to 20 carbon atoms. Examples which may
be mentioned are methylene, ethylene, propylene,
.alpha.-methylethylene, .beta.-methylethylene,
.alpha.-ethylethylene, .beta.-ethylethylene, butylene,
.alpha.-methylpropylene, .beta.-methylpropylene,
.gamma.-methylpropylene, .alpha.-ethylpropylene,
.beta.-ethylpropylene, .gamma.-ethylpropylene, pentylene, hexylene,
heptylene, octylene, nonylene, decylene, dodeylene and
eicosylene.
[0242] Alkenyl generally represents a straight-chain or branched
hydrocarbon radical having 2 to 20 carbon atoms and one or more,
preferably one or two, double bonds. Examples which may be
mentioned are allyl, propenyl, isopropenyl, butenyl, isobutenyl,
pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl,
octenyl, isooctenyl.
[0243] Alkynyl generally represents a straight-chain or branched
hydrocarbon radical having 2 to 20 carbon atoms and one or more,
preferably one or two, triple bonds. Examples which may be
mentioned are ethynyl, 2-butynyl, 2-pentynyl and 2-hexynyl.
[0244] Alkenediyl generally represents a straight-chain or branched
hydrocarbon bridge having 2 to 20 carbon atoms and one or more,
preferably one or two, double bonds. Examples which may be
mentioned are ethene-1,2-diyl, propene-1,3-diyl, propene-1,2-diyl,
1-butene-1,4-diyl, 1-butene-1,3-diyl, 1-butene-1,2-diyl,
2-butene-1,4-diyl, 2-butene-1,3-diyl, 2-butene-2,3-diyl.
[0245] Alkynediyl generally represents a straight-chain or branched
hydrocarbon bridge having 2 to 20 carbon atoms and one or more,
preferably one or two, triple bonds. Examples which may be
mentioned are ethyne-1,2-diyl, propyne-1,3-diyl, 1-butyne-1,4-diyl,
1-butyne-1,3-diyl, 2-butene-1,4-diyl.
[0246] Acyl generally represents straight-chain or branched lower
alkyl having 1 to 9 carbon atoms which is attached via a carbonyl
group. Examples which may be mentioned are: acetyl, ethylcarbonyl,
propylcarbonyl, isopropylcarbonyl, butylcarbonyl and
isobutylcarbonyl.
[0247] Alkoxy generally represents a straight-chain or branched
hydrocarbon radical having 1 to 14 carbon atoms which is attached
via an oxygen atom. Examples which may be mentioned are methoxy,
ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy isopentoxy,
hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy. The
terms "alkoxy" and "alkyloxy" are used synonymously.
[0248] Alkoxyalkyl generally represents an alkyl radical having up
to 8 carbon atoms which is substituted by an alkoxy radical having
up to 8 carbon atoms.
[0249] Alkoxycarbonyl may be represented, for example, by the
formula 14
[0250] Here, alkyl generally represents a straight-chain or
branched hydrocarbon radical having 1 to 13 carbon atoms. The
following alkoxycarbonyl radicals may be mentioned by way of
example: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.
[0251] Cycloalkyl generally represents a cyclic hydrocarbon radical
having 3 to 8 carbon atoms. Preference is given to cyclopropyl,
cyclopentyl and cyclohexyl. Cyclopentyl, cyclohexyl, cycloheptyl
and cyclooctyl may be mentioned by way of example.
[0252] Cycloalkoxy, for the purposes of the invention, represents
an alkoxy radical whose hydrocarbon radical is a cycloalkyl
radical. The cycloalkyl radical generally has up to 8 carbon atoms.
Examples which may be mentioned are: cyclopropyloxy and
cyclohexyloxy. The terms "cycloalkoxy" and "cycloalkyloxy" are used
synonymously.
[0253] Aryl generally represents an aromatic radical having 6 to 10
carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
[0254] Halogen, for the purposes of the invention, represents
fluorine, chlorine, bromine and iodine.
[0255] Heterocycle, for the purposes of the invention, generally
represents a saturated, unsaturated or aromatic 3- to 10-membered,
for example 5- or 6-membered, heterocycle which may contain up to 3
heteroatoms from the group consisting of S, N and O and which may,
if a nitrogen atom is present, also be attached via this nitrogen
atom. Examples which may be mentioned are: oxadiazolyl,
thiadiazolyl, pyrazolyl, pyridyl, pyrimdinyl, pyridazinyl,
pyrazinyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, piperazinyl,
tetrahydropyranyl, tetrahydrofuranyl, 1,2,3 triazolyl, thiazolyl,
oxazolyl, imidazolyl, morpholinyl or piperidyl. Preference is given
to thiazolyl, furyl, oxazolyl, pyrazolyl, triazolyl, pyridyl,
pyrimidinyl, pyridazinyl and tetrahydropyranyl. The term
"heteroaryl" (or "hetaryl") denotes an aromatic heterocyclic
radical.
[0256] In the structures of heterocycles shown in the present
application, in each case only one bond to the adjacent group is
indicated, for example in the case of the heterocycle structures
possible for Y the bond to the unit Q. However, independently
thereof, these heterocycle structures may carry further
substituents as indicated.
[0257] The present invention furthermore relates to a process for
preparing the compounds of the formula (I), characterized in
that
[0258] [A] compounds of the formula (II) 15
[0259] are reacted with compounds of the formula (III)
E-X--R.sup.1 (III)
[0260] where
[0261] Z, R.sup.1, R.sup.2, R.sup.3, V, Q, Y, W, X, U, A and m are
as defined above,
[0262] E represents either a leaving group which is substituted in
the presence of a base or an optionally activated hydroxyl
function; or
[0263] [B] compounds of the formula (IV) 16
[0264] are reacted with compounds of the formula (V) 17
[0265] where
[0266] Z, R.sup.1, R.sup.2, R.sup.3, V, Q, Y, W, X, U, A and m are
as defined above,
[0267] E represents either a leaving group which is substituted in
the presence of a base or an optionally activated hydroxyl
function; or
[0268] [C] compounds of the formula (VI) 18
[0269] are reacted with compounds of the formula (VII)
E-U-A-R.sup.2 (VII)
[0270] where
[0271] Z, R.sup.1, R.sup.2, R.sup.3, V, Q, Y, W, X, U, A and m are
as defined above,
[0272] E represents either a leaving group which is substituted in
the presence of a base or an optionally activated hydroxyl
function; or
[0273] [D] compounds of the formula (VIII) 19
[0274] where
[0275] Va represents O or S and
[0276] Z, R.sup.1, R.sup.2, R.sup.3, Y, Q, W, U, A, X and m are as
defined above,
[0277] are reacted with compounds of the formula (IX) 20
[0278] where
[0279] Q, Y are as defined above,
[0280] E represents either a leaving group which is substituted in
the presence of a base or an optionally activated hydroxyl
function; or
[0281] [E] compounds of the formula (X) 21
[0282] where
[0283] Z, R.sup.3, V, Q, Y, W, X, U, A and m are as defined
above,
[0284] R.sup.1.sub.b and R.sup.2.sub.b each independently of one
another represent CN or COOAlk, where Alk represents a
straight-chain or branched alkyl radical having up to 6 carbon
atoms,
[0285] are converted with aqueous solutions of strong acids or
strong bases into the corresponding free carboxylic acids. or
[0286] [F] compounds of the formula (XI) 22
[0287] where
[0288] Z, R.sup.1, R.sup.2, R.sup.3, V, Q, X, W, U, A and m are as
defined above,
[0289] L represents Br, I or the group CF.sub.3SO.sub.2--O,
[0290] are reacted with compounds of the formula (XII)
M-Z' (XII)
[0291] where
[0292] M represents an aryl or heteroaryl radical, a straight-chain
or branched alkyl, alkenyl or alkynyl radical or cycloalkyl radical
or represents an arylalkyl, an arylalkenyl or an arylalkynyl
radical,
[0293] Z' represents the groupings --B(OH).sub.2, --CH.ident.CH,
--CH.dbd.CH.sub.2 or --Sn(nBu).sub.3
[0294] in the presence of a palladium compound, if appropriate
additionally in the presence of a reducing agent and further
additives and in the presence of a base; or
[0295] [G] compounds of the formula (XIII) 23
[0296] where
[0297] Ar represents an aryl or heteroaryl radical,
[0298] E represents a leaving group which is substituted in the
presence of a base.
[0299] are reacted according to process D with compounds of the
formula (VIII) and the resulting compounds of the formula (XIV)
24
[0300] are hydrogenated with hydrogen in the presence of a
catalyst.
[0301] The processes according to the invention for preparing
compounds of the formula (I) are illustrated below using exemplary,
non-limiting embodiments:
[0302] Example for the Reaction Sequence According to Process A/E:
25
[0303] Example for the Reaction Sequence According to Process D/E:
26
[0304] Example for the Reaction Sequence According to Process B/E:
27
[0305] Example for the Reaction Sequence According to Process C/E:
28 Preferably R=t-Bu
[0306] Example for the Reaction Sequence According to Process
D/F/E: 29
[0307] Example for the Reaction Sequence According to Process
D/G/E: 30
[0308] Alternatively, the compounds of the formula (I) can also be
prepared on a solid phase, such as a polystyrene resin,
particularly preferably a commercially available Wang polystyrene
resin. Here, the resin is initially swollen in a solvent such as
dimethylformamide (DMF). The appropriate carboxylic acid which
serves as starting material is then attached to the resin using
standard processes. For example, the carboxylic acid can be
attached to the resin in the presence of a base, such as pyridine
or 4-dimethylaminopyridine (DMAP), and a reagent which activates
the carboxyl unit, such as an acid halide, for example
dichlorobenzoyl chloride, in a solvent such as dimethylformamide
(DMF). However, it is also possible to use other reagents
customarily used for this purpose. The reaction mixture is stirred
for at least 2 hours, preferably 12 hours, particularly preferably
about 24 hours, at room temperature and atmospheric pressure, an
excess of carboxylic acid, preferably a two- to three-fold excess,
based on the loading of the solid phase, being used.
[0309] After removal of any unreacted reagents, the carboxylic acid
attached to the resin can be derivatized without it being necessary
to remove the carboxylic acid from the resin beforehand. Thus, for
example, an appropriate 4-aminobenzoic acid or 4-formylbenzoic acid
derivative can be attached to the resin and then be converted by
successive reductive aminations, as described below for the
preparation of the compounds of the formula (II), (IV) and (VI),
into a compound of the formula (VIII) which can then be converted
analogously to process [D] on the solid phase into the target
compounds.
[0310] Removal from the resin is carried out in a customary manner
in acidic medium after the desired synthesis of the target compound
on the solid phase. The product which has been cleaved from the
resin can, after removal of any solvents present, be purified by
known purification processes, such as, for example, chromatographic
processes.
[0311] The schemes below illustrate possible solid-phase syntheses
of compounds of the formula (I); however, other synthesis routes
familiar to the person skilled in the art or known from the
literature are also possible:
[0312] Example A of Solid-Phase Synthesis: 3132
[0313] Here, Wang denotes a Wang polystyrene resin.
[0314] Example B of Solid-Phase Synthesis: 3334
[0315] Here, Wang denotes a Wang polystyrene resin.
[0316] Preferred solvents for the processes according to the
invention are customary organic solvents which do not change under
the reaction conditions, or water. For the process according to the
invention, preference is given to using ethers, such as diethyl
ether, butyl methyl ether, dioxane, tetrahydrofuran, glycol
dimethyl ether, or diethylene glycol dimethyl ether, or
hydrocarbons, such as benzene, toluene, xylene or petroleum ether,
or amides, such as dimethylformamide or hexamethylphosphoric
triamide, or 1,3-dimethylimidazolidin-2-one,
1,3-dimethyltetrahydropyrimidin-2-one, acetonitrile, ethyl acetate
or dimethyl sulfoxide. It is, of course, also possible to use
mixtures of the solvents mentioned above.
[0317] Bases which are preferred for the processes according to the
invention include basic compounds which are customarily used for
basic reactions. Preference is given to using alkali metal
hydrides, such as, for example, sodium hydride or potassium
hydride, or alkali metal alkoxides, such as sodium methoxide,
sodium ethoxide, potassium methoxide, potassium ethoxide or
potassium t-butoxide, or carbonates, such as sodium carbonate,
cesium carbonate or potassium carbonate, or amides, such as sodium
amide or lithium diisopropylamide, or organolithium compounds, such
as phenyllithium, butyllithium or methyllithium, or sodium
hexamethyldisilazane.
[0318] The processes A to C according to the invention can
preferably be carried out in acetonitrile, in each case by reacting
the compounds (II) and (III), (IV) and (V) and (VI) and (VII),
respectively, in the presence of a base such as sodium carbonate,
Et.sub.3N, DABCO, K.sub.2CO.sub.3, KOH, NaOH or NaH. The reaction
can generally be carried out in a temperature range of from
-20.degree. C. to +90.degree. C., preferably of from 0.degree. C.
to +70.degree. C. The reaction can be carried out under atmospheric
pressure, elevated pressure or reduced pressure (for example in a
range of from 0.5 to 5 bar). In general, the reaction is carried
out under atmospheric pressure.
[0319] In the processes A to C according to the invention, a
compound of the formula (I) is prepared by nucleophilic
substitution of a leaving group E in one of the compounds of the
formula (III), (V) or (VII) by the amine function of one of the
compounds of the formula (II), (IV) or (VI). Suitable leaving
groups E are, for example: halogen, tosylate, mesylate, or a
hydroxyl function which is activated by reagents such as
diisopropyl azodicarboxylate/PPh.sub.3 (Mitsonobu reaction).
[0320] The process D according to the invention can preferably be
carried out in acetonitrile by reacting the compounds (VIII) and
(IX) in the presence of a base such as sodium carbonate, potassium
carbonate, Et.sub.3N, DABCO, K.sub.2CO.sub.3, KOH, NaOH or NaH. The
reaction can generally be carried out in a temperature range of
from -20.degree. C. to +90.degree. C., preferably of from 0.degree.
C. to +90.degree. C. The reaction can be carried out under
atmospheric pressure, elevated pressure or reduced pressure (for
example in a range of from 0.5 to 5 bar). In general, the reaction
is carried out under atmospheric pressure.
[0321] In the process D according to the invention, a compound of
the formula (I) is prepared by nucleophilic substitution of a
leaving group E in the compound of the formula (IX) by the hydroxyl
or thiol function of the compound of the formula (VIII). Suitable
leaving groups E are, for example: halogen, tosylate, mesylate, or
a hydroxyl function which is activated by reagents such as
diisopropyl azodicarboxylate/PPh.sub.3 (Mitsonobu reaction).
[0322] In the process E according to the invention, a compound of
the formula (I) in which R.sup.1 and R.sup.2 each represent a free
carboxyl function is obtained by converting ester and/or nitrile
functions of the compound (X) into the corresponding free carboxyl
functions. This reaction can be carried out, for example, by adding
aqueous solutions of strong acids, such as, for example, HCl or
H.sub.2SO.sub.4, or strong bases, such as, for example, NaOH, KOH
or LiOH. The reaction can be carried out in one of the organic
solvents mentioned above, in water or in mixtures of organic
solvents or in mixtures of organic solvents with water. Preference
according to the invention is given, for example, to carrying out
the reaction in a mixture of water and methanol or dioxane. In
general, the reaction can be carried out in a temperature range of
from -20.degree. C. to +90.degree. C., preferably of from 0.degree.
C. to +90.degree. C. The reaction can be carried out under
atmospheric pressure, elevated pressure or reduced pressure (for
example in a range of from 0.5 to 5 bar). In general, the reaction
is carried out at atmospheric pressure.
[0323] In the process F according to the invention, a compound of
the formula (I) is prepared by reacting a compound of the formula
(XI) which contains a substitutable group L with a compound of the
group (XII) in the presence of a palladium compound and, if
appropriate, a reducing agent and further additives in basic
medium. Formally, the reaction is a reductive coupling of the
compounds of the formulae (XI) and (XII), as described, for
example, in L. S. Hegedus, Organometallics in Synthesis, M.
Schlosser, Ed., Wiley & Sons, 1994.
[0324] Suitable substitutable groups L in the compounds of the
formula (XI) are, for example, a halogen radical, such as Br or I,
or a customary leaving group, such as, for example, a triflate
radical.
[0325] The compounds of the formula (XII) contain a reactive group
Z which can be selected from the group consisting of --B(OH).sub.2,
--CH.ident.CH, --CH.dbd.CH.sub.2 or --Sn(nBu).sub.3.
[0326] Suitable for use as palladium compound are palladium(II)
compounds, such as, for example, Cl.sub.2Pd(PPh.sub.3).sub.2 or
Pd(OAc).sub.2 or palladium(0) compounds, such as, for example,
Pd(PPh.sub.3).sub.4 or Pd.sub.2(dba).sub.3. If required, a reducing
agent, such as, for example, triphenylphosphine, or other
additives, such as, for example, Cu(I)Br, NBu.sub.4NCl, LiCl or
Ag.sub.3PO.sub.4, may additionally be added to the reaction mixture
(cf. T Jeffery, Tetrahedron lett. 1985, 26, 2667-2670; T. Jeffery,
J. Chem. Soc., Chem. Commun. 1984, 1287-1289; S. Brse, A. deMejiere
in "Metal-catalyzed cross-coupling reactions", Ed. F. Diederich, P.
J. Stang, Wiley-VCH, Weinheim 1998, 99-166).
[0327] The reaction is carried out in the presence of a customary
base, such as, for example, Na.sub.2CO.sub.3, NaOH or
triethylamine. Suitable solvents are the organic solvents mentioned
above, ethers, such as, for example, dimethoxyethane, being
particularly preferred. In general, the reaction can be carried out
in a temperature range of from -20.degree. C. to +90.degree. C.,
preferably of from 0.degree. C. to +90.degree. C. The reaction can
be carried out under atmospheric pressure, elevated or reduced
pressure (for example in a range of from 0.5 to 5 bar). In general,
the reaction is carried out under atmospheric pressure.
[0328] In the process G according to the invention, compounds of
the formula (I) are obtained by reacting compounds of the formula
(XIII), which contain a leaving group E, with compounds of the
formula (VIII) according to process D according to the invention,
followed by hydrogenation of the resulting compounds of the formula
(XIV).
[0329] Thus, the first step of process G is analogous to process D,
but, instead of the compounds of the formula (IX), compounds of the
formula (XIII) are reacted here with the alcohols or thiols of the
formula (XIII). This gives the unsaturated compounds of the formula
(XIV) which can be converted by customary hydrogenation processes
into the compounds of the formula (I).
[0330] Preference according to the invention is given to
hydrogenation of the compounds of the formula (XIV) with hydrogen
in the presence of a catalyst, such as, for example, Pd/carbon or
PtO.sub.2.
[0331] The process G can be carried out in one of the organic
solvents mentioned above. Preference is given here to ethyl
acetate. In general, the reaction can be carried out in a
temperature range of from -20.degree. C. to +90.degree. C.,
preferably of from 0.degree. C. to +90.degree. C. The reaction can
be carried out under atmospheric pressure, elevated or reduced
pressure (for example in a range of from 0.5 to 5 bar). In general,
the reaction is carried out under atmospheric pressure.
[0332] The novel compounds of the formula II, IV and VI can be
obtained in a generally known manner by the following methods:
[0333] a) by reacting amines of the formulae (XV), (XVI) and (XVII)
35
[0334] where the radicals R.sup.1, R.sup.2, R.sup.3, m, V, Q, U, W,
X, Y and A are as defined above;
[0335] with carbonyl compounds of the formulae (XVIII), (XIX), (XX)
36
[0336] where
[0337] Ua, Wa and Xa have the meanings of U, W and X, respectively,
but are one carbon unit shorter, and
[0338] T represents hydrogen or a C.sub.1-C.sub.4-alkyl function,
which may also be attached to Ua or Xa forming a cycle,
[0339] and the other radicals are as defined above,
[0340] are reacted initially giving a Schiff base which is then
reduced with customary reducing agents, such as, for example,
NaBH.sub.4, H.sub.2/Pd/C, etc., or reacted directly under the
conditions of a reductive alkylation in the presence of a reducing
agent, such as, for example, H.sub.2/Pd/C, NaCNBH.sub.3,
NaH(OAc).sub.3 (cf. Patai, Ed., The Chemistry of the
Carbon-Nitrogen Double Bond, pp. 276-293 and the literature cited
therein);
[0341] b) by reacting amines of the formulae (XV), (XVI) and (XVII)
with compounds of the formulae (III), (V), (VII) (cf., for example,
J. March, Advanced Organic Chemistry, fourth edition, Wiley, 1992,
page 411 and the literature cited therein).
[0342] Amines of the formula (IIa) or compounds of the formula
(VIII) 37
[0343] where Va represents O or S,
[0344] can be obtained in a generally known manner by the following
reaction scheme: 38
[0345] In the scheme above, PGo denotes a customary phenol or
thiophenol protective group, such as, for example, CH.sub.3,
CH.sub.2Ph, CH.sub.2CH.dbd.CH.sub.2, CH.sub.2OCH.sub.3,
CH.sub.2OCH.sub.2SiMe.sub.3, SiMe.sub.3, PGn denotes an amine
protective group, such as, for example, tBuOCO, T represents
hydrogen or a C.sub.1-C.sub.4-alkyl function, which may also be
attached to Ua forming a cycle, and Ua has the meaning of U, but is
one CH.sub.2 group shorter. The other radicals are as defined
above.
[0346] (IIb) is obtained, for example, when initially (XVa) is
reacted with (XVIII) to give a Schiff base which is then reduced
with customary reducing agents, such as, for example, NaBH.sub.4,
H.sub.2/Pd/C, etc., or reacted directly under the conditions of a
reductive alkylation in the presence of a reducing agent, such as,
for example, H.sub.2/Pd/C, NaCNBH.sub.3 or NaH(OAc).sub.3. By
reaction with a compound of the formula (III) in the presence of a
base, the compound (IIb) can be converted into a compound of the
formula (XXI) (cf. process A).
[0347] An O or S protective group in (IIb) or (XXI) can be removed
with a suitable reagent (cf., T. W. Greene, P. G. M. Wuts,
Protective Groups in Organic Synthesis, second edition, New York,
1991). If, in formula (IIb) or (XXI), -Va-PGo denotes, for example,
--O--CH.sub.3, the methyl group can be removed with formation of
the phenol using boron tribromide in methylene chloride at from
-70.degree. C. to 20.degree. C., using trimethylsilyl iodide in
chloroform at 25-50.degree. C. or using sodium ethylthiolate in DMF
at 150.degree. C.
[0348] From the resulting compound of the formula (IIc), it is
possible to obtain a compound of the formula (XXIII) by protecting
the amino function (cf. T. W. Greene, P. G. M. Wuts, Protective
Groups in Organic Synthesis, second edition, New York, 1991) and
subsequently reacting the resulting amino-protected compound of the
formula (XXII) with a compound of the formula (IX) (cf. process
D).
[0349] An N protective group such as in (XXII) can be introduced
and removed again by customary methods (cf. T. W. Greene, P. G. M.
Wuts, Protective Groups in Organic Synthesis, second edition, New
York, 1991). If, in formula (XXII), PGn denotes, for example,
tBuOCO, the protective group can be introduced by reacting the
amine with tert-butyl pyrrocarbonate in polar or unpolar solvents
at from 0.degree. C. to 25.degree. C. The removal of the protective
group to give (IIa) can be carried out with a large number of
acids, such as, for example, HCl, H.sub.2SO.sub.4 or CF.sub.3COOH,
at from 0.degree. C. to 25.degree. C. (cf. the literature cited
above).
[0350] Substances of the formulae (III) are commercially available,
known from the literature or can be synthesized according to
processes known from the literature (cf., for example, J. Chem.
Soc. 1958, 3065).
[0351] Substances of the formulae (V) are known from the literature
or can be synthesized analogously to processes known from the
literature (cf., for example, J. Med. Chem. 1989, 32, 1757; Indian
J. Chem. Sect. B 1985, 24, 1015; Recl. Trav. Chim. Pays-Bas 1973,
92, 1281; Tetrahedron Lett. 1986, 37, 4327).
[0352] Substances of the formula (VII) are commercially available,
known from the literature, or can be prepared analogously to
processes known from the literature (cf. for example, J. Org. Chem.
1959, 24, 1952; Collect Czech. Chem. Commun 1974, 39, 3527, Helv.
Chim. Acta 1975, 58, 682; Liebigs Ann. Chem. 1981, 623).
[0353] Substances of the formula (IX) are commercially available,
known from the literature, or can be prepared analogously to
processes known from the literature (cf., for example, J. prakt.
Chem. 1960, 341; Farmaco Ed. Sci. 1956, 378; Eur. J. Med. Chem.
Chim. Ther. 1984, 19, 205; Bull, Soc. Chim. Fr. 1951, 97. Liebigs
Ann. Chem. 1954, 586, 52; EP-A-0 334 137). In particular,
4-chloromethylbiphenyl compounds which carry a further substituent
in the 4'-position can be prepared by coupling
4-(B(OH).sub.2-Ph-CHO with the corresponding 4-substituted
bromophenyl compounds in the presence of palladium catalysts, such
as, for example, Pd(PPh.sub.3).sub.4 or
PdCl.sub.2(PPh.sub.3).sub.2, and sodium carbonate, giving the
corresponding biphenyl compounds, and subsequent reduction to the
alcohol with NaBH.sub.4 and conversion into the corresponding
chloride using, for example, SOCl.sub.2.
[0354] If, in the formulae (III), (V), (VII) and (IX), E represents
halogen, the compounds can also be prepared by generally known
processes, for example by reacting an alcohol with a chlorinating
agent, such as, for example, thionyl chloride or sulfuryl chloride
(cf., for example, J. March, Advanced Organic Chemistry, fourth
edition, Wiley, 1992, page 1274 and the literature cited
therein).
[0355] Amines of the formula (XV) are commercially available, known
from the literature, or can be synthesized analogously to processes
known from the literature (cf., for example, Tetrahedron 1997, 53,
2075; J. Med. Chem. 1984, 27, 1321; WO 97/29079; J. Org. Chem.
1982, 47, 5396). These compounds can be obtained, for example, from
the corresponding halide compounds and in particular chloride
compounds in which, instead of the radicals W--NH.sub.2 of the
compounds of the formula (XV), there is a group W'-Hal, where W' is
a radical W which is shorter by one C atom, by substitution of the
halide radical by a cyano group, giving the corresponding nitrile
compounds, and reduction of the nitrile group, or by reacting
corresponding aldehyde compounds, in which, instead of the radicals
W--NH.sub.2 of the compounds of the formula (XV), there is a group
W'--CHO, where W' is a radical W which is shorter by one C atom,
using nitromethane and subsequent reduction. Some exemplary
synthesis routes for the amines of the formula (XV) are shown
below, where the given reagents are generally only one of a number
of possibilities. Thus, for example, reductions of aldehyde groups
to alcohol groups, substitutions of alcohol groups by halogen
groups, substitutions of halogen functions by nitrile groups or
reductions of nitrile groups to corresponding amino groups can be
carried out using all reagents which are customarily employed for
such reactions (cf., for example, the appropriate chapters in
March, Advanced Organic Chemistry, Wiley, 3th ed., 1985).
[0356] In the synthesis routes shown in an exemplary manner below,
the given radicals have the same meaning as defined above.
[0357] Synthesis Route a): 39
[0358] Synthesis Route b): 40
[0359] This synthesis route can be used, for example, starting with
hydroxycarboxylic acids, which are commercially available or are
known from the literature: 41
[0360] Synthesis Route c): 42
[0361] For synthesis routes a) to d), it is also possible to use,
instead of the hydroxyaldehydes, the corresponding
hydroxycarboxylic acids or hydroxycarboxylic acid esters. In these
synthesis routes, it is also possible to convert the primary
hydroxyl group into the nitrile group via the corresponding
bromide, mesylate, tosylate or acetate instead of via the
corresponding halide.
[0362] Synthesis Route d): 43
[0363] This process can be carried out, for example, starting with
2-hydroxynaphth-1-aldehyde, 1-hydroxymethyl-2-methoxynaphthalene or
one of the hydroxyaldehydes below, which are commercially available
or known from the literature: 44
[0364] Synthesis Route e): 45
[0365] Synthesis Route f): 46
[0366] Synthesis Route g): 47
[0367] 2-Cyanomethyl-3-hydroxypyridine can also be obtained by the
method of Desideri et al, J. Heterocycl. Chem. 1988, 333-335.
[0368] Synthesis Route h): 48
[0369] Amines of the formula (XVI) are commercially available,
known from the literature, or can be synthesized analogously to
processes known from the literature (cf., for example, J. Am. Chem.
Soc. 1982, 104, 6801; Chem. Lett. 1984, 1733; J. Med. Chem. 1998,
41, 5219; DE-2059922).
[0370] Amines of the formula (XVII) are commercially available,
known from the literature, or can be synthesized analogously to
processes known from the literature (cf., for example, J. Org.
Chem. 1968, 33, 1581; Bull. Chem. Soc. Jpn. 1973, 46, 968; J. Am.
Chem. Soc. 1958, 80, 1510; J. Org. Chem. 1961, 26, 2507; Synth.
Commun. 1989, 19, 1787).
[0371] Amines of the formulae (XV), (XVI) and (XVII) can also be
prepared by generally known processes, for example by reducing a
corresponding nitrile, by reacting a corresponding halide with
phtalimide and subsequent reaction with hydrazine or by rearranging
acyl azides in the presence of water (cf., for example, J. March,
Advanced Organic Chemistry, fourth edition, Wiley, 1992, page 1276
and the literature cited therein).
[0372] Carbonyl compounds of the formula (XVIII) are commercially
available, known from the literature, or can be synthesized
analogously to processes known from the literature (cf., for
example, J. Med. Chem. 1989, 32, 1277; Chem. Ber. 1938, 71, 335;
Bull. Soc. Chim. Fr. 1996, 123, 679).
[0373] Carbonyl compounds of the formula (XIX) are commercially
available, known from the literature, or can be synthesized
analogously to processes known from the literature, (cf., for
example, WO 96/11902; DE-2209128; Synthesis 1995, 1135; Bull. Chem.
Soc. Jpn. 1985, 58, 2192).
[0374] Carbonyl compounds of the formula (XX) are commercially
available, known from the literature, or can be synthesized
analogously to processes known from the literature (cf., for
example, Synthesis 1983, 942; J. Am. Chem. Soc. 1992, 114,
8158).
[0375] Carbonyl compounds of the formulae (XVIII), (XIX) and (XX)
can also be prepared according to generally known processes, for
example by oxidizing alcohols, by reducing acid chlorides or by
reducing nitrites (cf., for example, J. March, Advanced Organic
Chemistry, fourth edition, Wiley, 1992, page 1270 and the
literature cited therein).
[0376] Compounds of the formula (XII) are commercially available,
known from the literature, or can be synthesized analogously to
processes known from the literature (cf., for example, for aromatic
boronic acids: J. Chem. Soc. C 1966, 566. J. Org. Chem., 38, 1973,
4016; or for tributyltin compounds: Tetrahedron Lett. 31, 1990,
1347).
[0377] Compounds of the formula (XIII) are commercially available,
known from the literature, or can be synthesized analogously to
processes known from the literature (cf., for example, J. Chem.
Soc. Chem. Commun., 17, 1994, 1919).
[0378] The compounds according to the invention, in particular the
compounds of the general formula (I), show a valuable range of
pharmacological effects which could not have been predicted.
[0379] The compounds according to the invention, in particular the
compounds of the general formula (I), bring about vasorelaxation
and an inhibition of platelet aggregation and lead to a reduction
in blood pressure and an increase in the coronary blood flow. These
effects are mediated by direct stimulation of soluble guanylate
cyclase and an intracellular increase in cGMP.
[0380] They can therefore be employed in medicaments for the
treatment of cardiovascular disorders such as, for example, for the
treatment of high blood pressure and heart failure, stable and
unstable angina pectoris, peripheral and cardiac vascular
disorders, of arrhythmias, for the treatment of thromboembolic
disorders and ischemias such as myocardial infarction, stroke,
transitory and ischemic attacks, disturbances of peripheral blood
flow, prevention of restenosis such as after thrombolysis
therapies, percutaneous transluminal angioplasties (PTAs),
percutaneous transluminal coronary angioplasties (PTCAs), bypass
and for the treatment of arteriosclerosis, fibrotic disorders, such
as fibrosis of the liver or pulmonary fibrosis, asthmatic disorders
and diseases of the urogenital system such as, for example,
prostate hypertrophy, erectile dysfunction, female sexual
dysfunction and incontinence and also for the treatment of
glaucoma.
[0381] The compounds described in the present invention, in
particular the compounds of the general formula (I), are also
active compounds suitable for controlling central nervous system
diseases characterized by disturbances of the NO/cGMP system. They
are suitable in particular for removing cognitive deficits, for
improving learning and memory performances and for treating
Alzheimer's disease. They are also suitable for treating disorders
of the central nervous system such as states of anxiety, tension
and depression, CNS-related sexual dysfunctions and sleep
disturbances, and for controlling pathological disturbances of the
intake of food, stimulants and addictive substances.
[0382] The active compounds are furthermore also suitable for
regulating cerebral blood flow and thus represent effective agents
for controlling migraine.
[0383] They are also suitable for the prophylaxis and control of
the sequelae of cerebral infarction (apoplexia cerebri) such as
stroke, cerebral ischemias and craniocerebral trauma. The compounds
according to the invention, in particular the compounds of the
general formula (I), can likewise be employed for controlling
states of pain.
[0384] In addition, the compounds according to the invention have
an anti-inflammatory effect and can therefore be employed as
anti-inflammatory agents.
[0385] Vasorelaxant Effect In Vitro
[0386] Rabbits are anesthetized or killed by intravenous injection
of thiopental sodium (about 50 mg/kg) and exsanguinated. The
arteria saphena is removed and divided into rings 3 mm wide. The
individual rings are in each case mounted on a pair of hooks of
triangular shape, open at the ends and made of special wire
(Remanium.RTM.) having a diameter of 0.3 mm. Under tension, each
ring is introduced into a 5 ml organ bath containing
carbogen-gassed Krebs-Henseleit solution at 37.degree. C. with the
following composition (mM): NaCl: 119; KCl: 4.8;
CaCl.sub.2.times.2H.sub.2O: 1; MgSO.sub.4.times.7H.sub.2O: 1.4;
KH.sub.2PO.sub.4: 1.2; NaHCO.sub.3: 25; glucose: 10; bovine serum
albumin: 0.001%. The force of contraction is detected with Statham
UC2 cells, amplified and digitized via A/D converters (DAS-1802 HC,
Keithley Instruments, Munich) and recorded in parallel on chart
recorders. Contractions are generated by adding phenylephrine.
[0387] After several (generally 4) control cycles, the substance to
be investigated is added in each further run in increasing dosage
in each case, and the height of the contraction reached under the
influence of the test substance is compared with the height of the
contraction reached in the last preceding run. The concentration
necessary to reduce the height of the control value by 50%
(IC.sub.50) is calculated from this. The standard application
volume is 5 .mu.l. The DMSO content in the bath solution
corresponds to 0.1%.
[0388] The results are shown in Table 1:
1TABLE 1 Vasorelaxant effect in vitro Example IC.sub.50 [nM] 3 2 4
22 5 7 9 61 10 51 13 94 16 125
[0389] Stimulation of Recombinant Soluble Guanylate Cyclase (sGC)
In Vitro
[0390] The investigations of the stimulation of recombinant soluble
guanylate cyclase (sGC) and the compounds according to the
invention with and without sodium nitroprusside and with and
without the heme-dependent sGC inhibitor
1H-1,2,4-oxadiazole-(4,3a)-quinoxalin-1-one (ODQ) were carried out
according to the method described in detail in the following
literature reference: M. Hoenika, E. M. Becker, H. Apeler, T.
Sirichoke, H. Schroeder, R. Gerzer and J-P. Stasch: Purified
soluble guanylyl cyclase expressed in a baculovirus/Sf9 system:
stimulation by YC-1, nitric oxide, and carbon oxide. J. Mol. Med.
77 (1999): 14-23.
[0391] The heme-free guanylate cyclase was obtained by adding Tween
20 to the sample buffer (final concentration 0.5%).
[0392] Activation of sGC by a test substance is stated as n-fold
stimulation of basal activity.
[0393] The present invention includes pharmaceutical preparations
which, in addition to non-toxic, inert, pharmaceutically acceptable
carriers, comprises the compounds according to the invention, in
particular the compounds of the general formula (I), and processes
for preparing these preparations.
[0394] The active compound, if appropriate in one or more of the
carriers listed above, can also be present in microencapsulated
form.
[0395] The therapeutically effective compounds, in particular the
compounds of the general formula (I), should be present in the
pharmaceutical preparations detailed above in a concentration of
about 0.1 to 99.5, preferably of about 0.5 to 95, % by weight of
the complete mixture.
[0396] The pharmaceutical preparations detailed above may, apart
from the compounds according to the invention, in particular the
compounds of the general formula (I), also contain other active
pharmaceutical ingredients.
[0397] It has generally proved to be advantageous both in human and
in veterinary medicine to administer the active compound(s)
according to the invention in total amounts of about 0.5 to about
500, preferably 5 to 100, mg/kg of body weight every 24 hours,
where appropriate in the form of a plurality of single doses, to
achieve the desired results. A single dose contains the active
compound(s) according to the invention preferably in amounts of
about 1 to about 80, in particular 3 to 30, mg/kg of body
weight.
[0398] Below, the present invention is illustrated in more detail
using non-limiting preferred examples. Unless indicated otherwise,
all quantities are stated in percent by weight.
EXAMPLES
[0399] Abbreviations
2 RT: room temperature EA: ethyl acetate BABA: n-butyl
acetate/n-butanol/glacial acetic acid/phosphate buffer pH 6
(50:9:25.15; org. phase)
[0400] Mobile Phases for Thin-Layer Chromatography:
3 T1 E1: toluene - ethyl acetate (1:1) T1 EtOH1: toluene - methanol
(1:1) C1 E1: cyclohexane - ethyl acetate (1:1) C1 E2: cyclohexane -
ethyl acetate (1:2)
[0401] Starting Materials
Example I
[0402] [4-(Chloromethyl)-2,5-dimethyl-3-thienyl]acetonitrile 49
[0403] A solution of 2.98 g (14.24 mmol) of
3,4-bis(chloromethyl)-2,5-dime- thylthiophene (Grtner et al., J.
Amer. Chem. Soc., 73, 1951, 5872) in 30 ml of dry acetonitrile is,
with 1.9 ml (14.24 mmol) of trimethylsilyl cyanide and 12.96 ml
(14.42 mmol) of a 1-N-tetra-n-butylammonium fluoride solution in
THF, slowly added dropwise and stirred at room temperature
overnight. The mixture is then evaporated to dryness using a rotary
evaporator and the resulting crude product is purified by column
chromatography (cyclohexane/ethyl acetate 10:1). This gives 0.82 g
(4.1 mmol, 28% yield) of a colorless oil.
[0404] R.sub.f(cyclohexane/ethyl acetate 2:1): 0.39.
[0405] .sup.1H-NMR (200 MHz, CDCl.sub.3 .delta./ppm): 4.58 (2H, s),
3.64 (2H, s), 2.42 (3H, s), 2.39 (3H, s).
[0406] MS (DCI, NH.sub.3): 234 (M+N.sub.2H.sub.7.sup.+), 217
(M+NH.sub.4.sup.+).
Example II
[0407]
{4[(4-Bromophenoxy)methyl]-2,5-dimethyl-3-thienyl}acetonitrile
50
[0408] 830 mg (6.04 mmol) of anhydrous potassium carbonate are
added to a solution of 800 mg (4.33 mmol) of
[4-(chloromethyl)-2,5-dimethyl-3-thieny- l]acetonitrile from Ex. I
and 840 mg (4.83 mmol) of 4-bromophenol in 20 ml of acetonitrile,
and the mixture is, under argon, heated at reflux for 12 h. After
cooling and removal of the solvent, the resulting crude product is
purified by preparative HPLC, giving 1.149 g (3.42 mmol, 85% yield)
of a colorless solid.
[0409] R.sub.f(cyclohexane/ethyl acetate 2:1): 0.45.
[0410] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta./ppm): 7.48 (2H,
d), 7.01 (2H, d), 4.98 (2H, s), 3.81 (2H, s), 2.38 (3H, s), 2.36
(3H, s).
[0411] MS (DCI, NH.sub.3: 353.1 (M+NH.sub.4.sup.+).
Example III
[0412]
2-{4-[(4-Bromophenoxy)methyl]-2,5-dimethyl-3-thienyl}ethylamine
51
[0413] 557 mg (4.18 mmol) of aluminum trichloride are dissolved in
10 ml of THF and, under argon, cooled to 0.degree. C., and 2.81 ml
of a lithium aluminum hydride solution (1M in THF) are added
slowly. A solution of 937 mg (2.79 mmol) of
{4[(4-bromophenoxy)methyl]-2,5-dimeethyl-3-thienyl}acet- onitrile
from Ex. II in 10 ml of THF is then slowly added dropwise to the
reaction solution. After 2 h of stirring at room temperature, the
reaction solution is cooled to 0.degree. C. and quenched with
ice-water, made alkaline using aqueous sodium hydroxide solution,
extracted with ethyl acetate and dried over magnesium sulfate.
After removal of the solvent, the resulting crude product is
purified by preparative HPLC, giving 693 mg (2.04 mmol, 73% yield)
of a colorless oil.
[0414] R.sub.f(dichloromethane/methanol 10:1): 0.26.
[0415] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta./ppm): 7.48 (2H,
d), 7.0 (2H, d), 4.86 (2H, s), 3.3 (2H, s broad), 2.65-2.52 (4H,
m), 2.32 (3H, s), 2.29 (3H, s).
[0416] MS (DCI, NH.sub.3): 680.9 [2M+H.sup.+], 340.1
(M+H.sup.+).
Example IV
[0417] Methyl
4-{[(2-{4-[(4-bromophenoxy)methyl]-2,5-dimethyl-3-thienyl}et-
hyl)-amino]methyl}benzoate 52
[0418] A solution of 640 mg (1.88 mmol) of
2-{4-[(4-bromophenoxy)methyl]-2- ,5-dimethyl-3-thienyl}ethylamine
from Example III and 308 g (1.88 mmol) of methyl 4-formylbenzoate
in 5 ml of ethanol is heated at reflux for 2 hours. The solvent is
then removed under reduced pressure and the resulting residue is
dissolved in 5 ml of methanol. A total of 142 mg (3.76 mmol) of
solid NaBH.sub.4 are added a little at a time. After two hours of
stirring at room temperature, the mixture is poured into water and
extracted with ethyl acetate. The organic extract is washed with
saturated sodium chloride solution and dried over Na.sub.2SO.sub.4.
After filtration, the solvent is removed under reduced pressure and
the resulting crude product is purified by preparative HPLC. This
gives 897 mg (1.84 mmol, 97% yield) of a colorless oil.
[0419] R.sub.f(cyclohexane/ethyl acetate, 1:1): 0.57.
[0420] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta./ppm): 8.01 (2H,
d), 7.59 (2H, d), 7.42 (2H, d), 6.88 (2H, d), 4.81 (2H, s), 4.23
(2H, pt, including 1H, broad), 3.89 (3H, s), 3.05-2.90 (2H, m),
2.89-2.77 (2H, m), 2.34 (3H, s), 2.31 (3H, s).
[0421] MS (DCI, NH.sub.3): 488.1 (M+H.sup.+).
Example V
[0422] Methyl
3-[(4-bromobenzyl)oxy]-5,6,7,8-tetrahydro-2-naphthalenecarbo-
xylate 53
[0423] 16.1 g (116.4 mmol) of potassium carbonate are added to a
solution of 20 g (96.97 mmol) of methyl
3-hydroxy-5,6,7,8-tetrahydro-2-naphthalene- carboxylate (CAS
52888-73-0) and 25.45 g (101.8 mmol) of 4-bromobenzyl bromide in
600 ml of anhydrous acetonitrile, and the mixture is heated at
reflux. After 20 hours, most of the solvent is removed using a
rotary evaporator and the residue is partitioned between diethyl
ether and phosphate buffer (pH 5.5). The organic phase is separated
off and dried over anhydrous sodium sulfate. Filtration and
concentration using a rotary evaporator give a crude product which
is purified by crystallization from ether. This gives 20.2 g (56%
yield) of a colorless solid.
[0424] R.sub.f(cyclohexane/ethyl acetate 5:1): 0.49.
[0425] .sup.1H-NMR (200 MHz, DMSO-d.sub.6, .delta./ppm): 12.71 (dd,
4H), 2.63-2.77 (m, 4H), 3.78 (s, 3H), 5.12 (s, 2H), 6.91 (s, 1H),
7.43 (s, 1H), 7.46 (d, 2H), 7.60 (d, 2H).
[0426] MS (ESI): 375 and 377 (M+H.sup.+), 397 and 399
(M+Na.sup.+).
Example VI
[0427]
{3-[(4-Bromobenzyl)oxy]-5,6,7,8-tetrahydro-2-naphthyl}methanol
54
[0428] Under argon and at -78.degree. C., a solution of 20.0 g
(53.3 mmol) of methyl
3-[(4-bromobenzyl)oxy]-5,6,7,8-tetrahydro-2-naphthalenecarboxyl-
ate in 250 ml of anhydrous diethyl ester is admixed with 40 ml (40
mmol) of a one-molar solution of LiAlH.sub.4 in ether. Overnight,
the mixture is allowed to warm to room temperature. The mixture is
then carefully adjusted to pH 1-2 using 2-molar hydrochloric acid
and extracted with ether. The organic phase is separated off and
dried over anhydrous sodium sulfate. Filtration and concentration
using a rotary evaporator gives 16.4 g (89% yield) of a colorless
solid.
[0429] R.sub.f(cyclohexane/ethyl acetate 5:1): 0.20.
[0430] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta./ppm): 1.69 (dd,
4H), 2.60-2.68 (m, 4H), 4.47 (d, 2H), 4.90 (t, 1H), 5.03 (s, 2H),
6.67 (s, 1H), 7.03 (s, 1H), 7.40 (d, 2H), 7.59 (d, 2H).
[0431] MS (DCI, NH.sub.3): 364 and 366 (M+NH.sub.4.sup.+).
Example VII
[0432]
6-[(4-Bromobenzyl)oxy]-7-(chloromethyl)-1,2,3,4-tetrahydronaphthale-
ne 55
[0433] 35 ml (473 mmol) of freshly distilled thionyl chloride are
added to a solution of 16.4 g (47.23 mmol) of
{3-[(4-bromobenzyl)oxy]-5,6,7,8-tetr- ahydro-2-naphthyl}-methanol
in 35 ml of dichloromethane. A drop of DMF is added, and the
mixture is then heated at reflux for one hour. The solvent and
excess thionyl chloride are then distilled off. The residue is
recrystallized from ether which contains a little cyclohexane. This
gives 17.2 g (99% yield) of a yellow solid.
[0434] R.sub.f(cyclohexane/ethyl acetate 1:1): 0.78.
[0435] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta./ppm): 1.69 (dd,
4H), 2.60-2.70 (m, 4H), 4.67 (s, 2H), 5.10 (s, 2H), 6.77 (s, 1H),
7.07 (s, 1H), 7.43 (d, 2H), 7.60 (d, 2H).
[0436] MS (DCI, NH.sub.3): 382 (M+NH.sub.4.sup.+).
Example VIII
[0437]
{3-[(4-Bromobenzyl)oxy]-5,6,7,8-tetrahydro-2-naphthyl}acetonitrile
56
[0438] 2.78 g (56.77 mmol) of sodium cyanide are added to a
solution of 17.3 g (47.31 mmol) of
6-[(4-bromobenzyl)oxy]-7-(chloromethyl)-1,2,3,4-te-
trahydronaphthalene in 850 ml of dimethylformamide, and the mixture
is stirred at room temperature overnight. Water is then added, and
the mixture is extracted with ether. The organic phase is dried
over anhydrous sodium sulfate. Filtration and concentration using a
rotary evaporator give 13.89 g (82% yield) of product.
[0439] R.sub.f(cyclohexane/ethyl acetate 3:1): 0.51.
[0440] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta./ppm): 1.69 (dd,
4H), 2.61-2.70 (m, 4H), 3.80 (s, 2H), 5.10 (s, 2H), 6.80 (s, 1H),
7.01 (s, 1H), 7.46 (d, 2H), 7.59 (d, 2H).
[0441] MS (DCI, NH.sub.3): 373 and 375 (M+NH.sub.4.sup.+).
Example IX
[0442]
2-{3-[(4-Bromobenzyl)oxy]-5,6,7,8-tetrahydro-2-naphthyl}ethylamine
57
[0443] 38 ml of a 2-molar solution of borane/dimethyl sulfide
complex in tetrahydrofuran (THF) are added to a solution of 13.5 g
(37.89 mmol) of
{3-[(4-bromobenzyl)oxy]-5,6,7,8-tetrahydro-2-naphthyl}acetonitrile
in 300 ml of anhydrous THF. The mixture is heated at reflux for 5
hours. After cooling, the mixture is acidified with dilute
hydrochloric acid and once more heated briefly (5 minutes). The
mixture is then made alkaline using aqueous sodium hydroxide
solution and extracted with ether. The organic extract is dried
over anhydrous sodium sulfate. Filtration and concentration using a
rotary evaporator give 14.2 g of a yellow wax-like solid which is
only about 92% pure but, in spite of this, is used without
purification for the next step.
[0444] R.sub.f(cyclohexane/ethyl acetate 3:1) 0.81.
[0445] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta./ppm): 1.68 (dd,
4H), 2.03 (s broad, 2H), 2.57-2.70 (m, 8H), 5.01 (s, 2H), 6.67 (s,
1H), 6.80 (s, 1H), 7.40 (d, 2H), 7.59 (d, 2H).
[0446] MS (DCI, NH.sub.3): 360 and 362 (M+H.sup.+).
Example X
[0447] Methyl
4-{[(2-{3-[(4-bromobenzyl)oxy]-5,6,7,8-tetrahydro-2-naphthyl-
}-ethyl)amino]methyl}benzoate 58
[0448] A solution of 14.84 g (41.18 mmol) of
2-{3-[(4-bromobenzyl)oxy]-5,6-
,7,8-tetrahydro-2-naphthyl}ethylamine and 6.08 g (37.06 mmol) of
methyl 4-formylbenzoate in 300 ml of toluene is heated at reflux in
a water separator for 30 minutes. The toluene is then removed using
a rotary evaporator and the residue is taken up in methanol. 2.34 g
(61.77 mmol) of solid sodium borohydride are added with ice-cooling
to the methanolic solution. The mixture is stirred at room
temperature for 30 minutes and then neutralized with 5% strength
sodium dihydrogen phosphate solution, diluted with water and
extracted with ether. The organic phase is dried over sodium
sulfate. The crude product obtained after filtration and
concentration using a rotary evaporator is purified by silica gel
flash chromatography using the mobile phase cyclohexane/ethyl
acetate 2:1. This gives 5.62 g (27% yield).
[0449] R.sub.f(cyclohexane/ethyl acetate 1:1): 0.26.
[0450] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta./ppm): 1.68 (dd,
4H), 2.56-2.68 (m, 8H), 3.74 (s, 2H), 3.83 (s, 3H), 4.99 (s, 2H),
6.66 (s, 1H), 6.79 (s, 1H), 7.33 (d, 2H), 7.41 (d, 2H), 7.53 (d,
2H), 7.87 (d, 2H).
[0451] MS (ESI): 508 and 510 (M+H.sup.+).
Example XI
[0452] Methyl
4-{[(2-{3-[(4-bromobenzyl)oxy]-5,6,7,8-tetrahydro-2-naphthyl-
}ethyl)(5-methoxy-5-oxopentyl)amino]methyl}benzoate 59
[0453] 2.3 g (4.52 mmol) of methyl
4-{[(2-{3-[(4-bromobenzyl)oxy]-5,6,7,8--
tetrahydro-2-naphthyl}ethyl)amino]methyl}benzoate, 1.06 g (5.43
mmol) of methyl bromovalerate and 0.75 g (5.43 mmol) of potassium
carbonate in 150 ml of butyronitrile are heated at reflux. After 48
hours, the reaction has ended. The mixture is evaporated to
dryness. The residue is then taken up in ethyl acetate and washed
with water. The organic phase is dried over sodium sulfate. After
filtration and concentration using a rotary evaporator, the crude
product is purified by silica gel flash chromatography using the
mobile phase cyclohexane/ethyl acetate 6:1. This gives 622 mg (60%
yield) of a colorless oil.
[0454] R.sub.f(cyclohexane/ethyl acetate 1:1): 0.53
[0455] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta./ppm): 1.32-1.47
(m, 4H), 1.67 (dd, 4H), 2.17 (t, 2H), 2.39 (t, 2H), 2.50-2.69 (m,
8H), 3.54 (s, 3H), 3.58 (s, 2H), 3.82 (s, 3H), 4.92 (s, 2H), 6.63
(s, 1H), 6.75 (s, 1H), 7.31 (d, 2H), 7.36 (d, 2H), 7.52 (d, 2H),
7.82 (d, 2H).
[0456] MS (ESI): 622 and 624 (M+H.sup.+).
Example XII
[0457] {3-[(4-Bromobenzyl)oxy]-6-methyl-2-pyridinyl}methanol 60
[0458] 9.58 g (69.31 mmol) of anhydrous potassium carbonate are
added to a solution of 3.86 g (37.73 mmol) of
2-(hydroxymethyl)-6-methyl-3-pyridinol and 8.32 g (33.27 mmol) of
4-bromobenzyl bromide in 50 ml of acetonitrile, and the mixture is,
under argon, heated at reflux for 12 h. After cooling and removal
of the solvent, the resulting crude product is purified by column
chromatography (cyclohexane/ethyl acetate 2/1), giving 7.205 g
(23.38 mmol, 82% yield) of a colorless solid.
[0459] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta./ppm): 7.59 (2H,
d), 7.42 (2H, d), 7.35 (1H, d), 7.1 (1H, d), 5.14 (2H, s), 4.79
(1H, t), 4.55 (2H, d), 2.4 (3H, s).
[0460] MS (DCI, NH.sub.3): 308/310 (M+H.sup.+).
Example XIII
[0461] 3-[(4-Bromobenzyl)oxy]-2-(bromomethyl)-6-methylpyridine
61
[0462] A solution of 7.205 g (23.38 mmol) of
{3-[(4-bromobenzyl)oxy]-6-met- hyl-2-pyridinyl}methanol in 160 ml
of THF is added to a solution of 9.2 g (35.07 mmol) of
triphenylphosphine and 11.63 g (35.07 mmol) of carbon tetrabromide
in 320 ml of THF. After 5 hours of stirring at room temperature, a
further 3.066 g of triphenylphosphine and 3.877 g of carbon
tetrabromide (in each case 0.5 equivalents) are added in solid
form. After 12 hours, the mixture is evaporated to dryness, taken
up in ether and filtered through kieselguhr, the organic phase is
concentrated by evaporation and the resulting product is isolated
by flash chromatography (silica gel, dichloromethane). This gives
2.028 g (5.46 mmol, 23% yield) of a colorless solid.
[0463] R.sub.f(cyclohexane/ethyl acetate 1:1): 0.35.
[0464] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 7.61 (2H,
d), 7.46 (2H, d), 7.43 (1H, d), 7.19 (1H, d), 5.21 (2H, s), 4.64
(2H, s), 2.38 (3H, s).
[0465] MS (DCI, NH.sub.3): 370/372 (M+H.sup.+).
Example XIV
[0466] {3-[(4-Bromobenzyl)oxy]-6-methyl-2-pyridinyl}acetonitrile
62
[0467] 2.99 ml (22.45 mmol) of trimethylsilyl cyanide and 22.45 ml
(22.45 mmol) of a 1-N-tetra-n-butylammonium fluoride solution in
THF are slowly added dropwise to a solution of 5.55 g (14.97 mmol)
of 3-[(4-bromobenzyl)oxy]-2-(bromomethyl)-6-methylpyridine in 350
ml of dry acetonitrile, and the mixture is stirred at room
temperature overnight. The mixture is then evaporated to dryness
using a rotary evaporator and the resulting crude product is
purified by column chromatography (cyclohexane/ethyl acetate
1.5:1). This gives 4.29 g (13.53 mmol, 90% yield) of a colorless
oil.
[0468] R.sub.f(cyclohexane/ethyl acetate 2:1): 0.21.
[0469] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta./ppm): 7.59 (2H,
d), 7.45 (2H, d), 7.42 (1H, d), 7.29 (1H, d), 5.19 (2H, s), 4.09
(2H, s), 2.4 (3H, s).
[0470] MS (DCI, NH.sub.3): 632.7/634.8 (2M+H.sup.+), 317
(M+H.sup.+).
Example XV
[0471] 2-{3-[(4-Bromobenzyl)oxy]-6-methyl-2-pyridinyl}ethylamine
63
[0472] At 0.degree. C., 525 .mu.l (30.76 mmol) of a borane-dimethyl
sulfide complex solution are slowly added dropwise to a solution of
3.25 g (10.25 mmol) of
{3-[(4-bromobenzyl)-oxy]-6-methyl-2-pyridinyl}acetonitr- ile in 50
ml of THF. After thawing and two hours of stirring at room
temperature, the reaction solution is cooled to 0.degree. C. and
quenched with a 1-N--HCl solution. The mixture is then evaporated
to dryness using a rotary evaporator, taken up in ethyl acetate and
made alkaline using aqueous sodium hydroxide solution. The organic
phase is dried over magnesium sulfate, and, after removal of the
solvent, the resulting crude product is purified by column
chromatography (dichloromethane/methanol/ac- etic acid 100:10:1.5),
giving 325 mg (1.01 mmol, 10% yield) of a colorless oil.
[0473] R.sub.f(dichloromethane/methanol 10:1): 0.05.
[0474] LC-MS: Rt=1.524 min, MS (ESI): 321 (M+H.sup.+).
[0475] LC-MS Method:
[0476] Column: Symmetry C 18; 21 mm.times.150 mm; 5 .mu.m
[0477] Ionization: ESI positive/negative
[0478] Oven temperature: 70.degree. C.
[0479] Solvent A: acetonitrile
[0480] Solvent B: 0.3 g of HCl (30%)/1 l of water
[0481] Gradient: A/B 2/98 to 95/5 over a period of 2.5 min
[0482] Flow rate: 0.9 ml/min to 1.2 ml/min over a period of 2
min
[0483] MS (DCI, NH.sub.3): 321.1/323.1 (M+H.sup.+).
Example XVI
[0484] Methyl
4-{[(2-{3-[(4-bromobenzyl)oxy]-6-methyl-2-pyridinyl}ethyl)am-
ino]methyl}-benzoate 64
[0485] A solution of 675 mg (2.10 mmol) of
2-{3-[(4-bromobenzyl)oxy]-6-met- hyl-2-pyridinyl}ethylamine and 345
mg (2.10 mmol) of methyl 4-formylbenzoate in 5 ml of ethanol is
heated at reflux for two hours. The solvent is then removed under
reduced pressure and the resulting residue is dissolved in 5 ml of
methanol. A total of 159 mg (4.21 mmol) of solid NaBH.sub.4 are
added a little at a time. After two hours of stirring at room
temperature, the mixture is poured into water and extracted with
ethyl acetate. The organic extract is washed with saturated sodium
chloride solution and dried over Na.sub.2SO.sub.4. After
filtration, the solvent is removed under reduced pressure and the
resulting crude product is purified by preparative HPLC. This gives
351 mg (0.75 mmol, 35% yield) of a colorless oil.
[0486] .sup.1H-NMR (200 MHz, DMSO-d.sub.6, .delta./ppm): 7.90 (2H,
d), 7.56 (2H, d), 7.46 (2H, d), 7.37 (2H, d), 7.29 (1H, d), 7.02
(1H, d), 5.08 (2H, s), 3.80 (3H, s), 3.41-3.12 (2H, s broad),
2.99-2.71 (4H m), 2.36 (3H, s).
[0487] MS (ESI): 469 (M+H.sup.+).
Example XVII
[0488] Methyl
4-{[(2-{3-[(4-bromobenzyl)oxy]-6-methyl-2-pyridinyl}ethyl)(5-
-ethoxy-5-oxopentyl)amino]methyl}benzoate 65
[0489] 134 mg (1.27 mmol) of anhydrous sodium carbonate are added
to a solution of 298 mg (0.63 mmol) of methyl
4-{[(2-{3-[(4-bromobenzyl)oxy]-6-
-methyl-2-pyridinyl}ethyl)amino]methyl}benzoate and 150 .mu.l (0.95
mmol) of methyl 5-bromovalerate in 3 ml of acetonitrile, and the
mixture is heated at reflux for 12 hours. The mixture is then
concentrated by evaporation, taken up in ethyl acetate and washed
with water. After drying over Na.sub.2SO.sub.4, filtration and
concentration, the product is purified by preparative HPLC. This
gives 293 mg (0.49 mmol, 77% yield) of a colorless oil.
[0490] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta./ppm): 7.83 (2H,
d), 7.54 (2H, d), 7.39-7.22 (5H, m), 7.0 (1H, d), 5.02 (2H, s),
3.99 (2H, q), 3.61 (2H, s), 3.29 (3H, s), 2.92-2.81 (2H, m),
2.76-2.64 (2H, m), 2.39 (2H, t), 2.32 (3H, s), 2.12 (2H, t),
1.42-1.26 (4H, m), 1.18 (3H, t).
[0491] LC-MS: Rt=3.45 min; MS (ESIpos): 597/599 (M.sup.+).
[0492] LC-MS Method:
[0493] HPLC unit: HP 1100
[0494] UV detector DAD: 208-400 nm
[0495] Column: Symmetry C18; 50 mm.times.2.1 mm; 3.5 .mu.m
[0496] Ionization: ESI positive/negative
[0497] Oven temperature: 40.degree. C.
[0498] Solvent A: CH.sub.3CN+0.1% formic acid
[0499] Solvent B: H.sub.2O+0.1% formic acid
[0500] Gradient:
4 Time A % B % Flow rate 0.00 10.0 90.0 0.50 4.00 90.0 10.0 0.50
6.00 90.0 10.0 0.50 6.10 10.0 90.0 1.00 7.50 10.0 90.0 0.50
SYNTHESIS EXAMPLES
Example 1
[0501] Methyl
4-{[(2-{4-[(4-bromophenoxy)methyl]-2,5-dimethyl-3-thienyl}et-
hyl)(5-ethoxy-5-oxopentyl)amino]methyl}benzoate 66
[0502] 365 mg (3.45 mmol) of anhydrous sodium carbonate are added
to a solution of 842 mg (1.72 mmol) of methyl
4-{[2-{4-[(4-bromophenoxy)methyl-
]-2,5-dimethyl-3-thienyl}ethyl)amino]methyl}benzoate from Ex. IV
and 409 .mu.l (2.59 mmol) of methyl 5-bromovalerate in 10 ml of
acetonitrile, and the mixture is heated at reflux for 12 hours. The
mixture is then concentrated by evaporation, taken up in ethyl
acetate and washed with water. After drying over Na.sub.2SO.sub.4,
filtration and concentration, the product is purified by
preparative HPLC. This gives 1.058 g (1.71 mmol, 93% yield) of a
colorless oil.
[0503] R.sub.f(cyclohexane/ethyl acetate 2:1): 0.44.
[0504] .sup.1H-NMR (200 MHz, DMSO-d.sub.6, .delta./ppm): 7.99 (2H,
d), 7.67 (2H, d), 7.43 (2H, d), 6.91 (2H, d), 4.83 (2H, s), 4.46
(2H, s), 4.03 (2H, q), 3.89 (3H, s), 3.18-2.78 (6H, m), 2.34 (3H,
s), 2.27 (3H, s), 2.16 (2H, t), 1.72-1.51 (2H, m), 1.49-1.29 (2H,
m), 1.19 (3H, t).
[0505] MS (ESI): 616 (M+H.sup.+).
Example 2
[0506] Methyl
4-{[[2-(4-{(2',4'-dichloro-1,1'-biphenyl-4-yl)oxy]methyl}-2,-
5-dimethyl-3-thienyl)ethyl](5-ethoxy-5-oxopentyl)amino]methyl}benzoate
67
[0507] 120 mg (0.19 mmol) of methyl
4-{[(2-{4-[(4-bromophenoxy)methyl]-2,5-
-dimethyl-3-thienyl}ethyl)(5-ethoxy-5-oxopentyl)amino]methyl}benzoate
from Ex. 1 are dissolved in 2 ml of 1,2-dimethoxyethane, and 44 mg
(0.23 mmol) of 2,4-dichlorophenylboronic acid, 7 mg (0.01 mmol) of
bis(triphenylphoshine)-palladium(II) chloride and 215 .mu.l of a
2-molar solution of Na.sub.2CO.sub.3 in water are added under
argon. The reaction mixture is then stirred under reflux for 12 h.
The mixture is then cooled and filtered through 1 g of Extrelute,
the filter cake is washed with dichloromethane and the filtrate is
concentrated using a rotary evaporator. The resulting product is
purified by preparative HPLC. This gives 73 mg (0.11 mmol, 53%
yield) of a colorless oil.
[0508] R.sub.f(cyclohexane/ethyl acetate 2:1): 0.51. .sup.1H-NMR
(300 MHz, DMSO-d.sub.6, .delta./ppm): 8.01 (2H, d), 7.71 (1H, d),
7.64 (2H, d), 7.49 (1H, dd), 7.41 (1H, s), 7.36 (2H, d), 7.00 (2H,
d), 4.89 (2H, s), 4.47 (2H, s), 4.00 (2H, q), 3.84 (3H, s),
3.21-2.71 (6H, m), 2.37 (3H, s), 2.28 (3H, s), 2.14 (2H, t),
1.691.51 (2H, m), 1.48-1.31 (2H, m), 1.13 (3H, t).
[0509] MS (ESI): 681.9 (M+H.sup.+).
Example 3
[0510]
4-({(4-Carboxybutyl)[2-(4-{[(2',4'-dichloro-1,1'-biphenyl-4-yl)oxy]-
methyl}-2,5-dimethyl-3-thienyl)ethyl]amino}methyl)benzoic Acid
68
[0511] 500 .mu.l of a 45% strength solution of NaOH in water are
added to a solution of 68 mg (0.1 mmol) of methyl
4-{[[2-(4-{(2',4'-dichloro-1,1'--
biphenyl-4-yl)oxy]methyl}-2,5-dimethyl-3-thienyl)ethyl](5-ethoxy-5-oxopent-
yl)amino]methyl}benzoate from Ex. 2 in 4.0 ml of dioxane and 2 ml
of water, and the mixture is stirred at 90.degree. C. for 2 hours.
After cooling, the dioxane is removed under reduced pressure and
the aqueous phase is adjusted to pH 4 to 5 using 1-molar
hydrochloric acid. This results in the precipitation of the
product, which is filtered off, washed with water and dried. This
gives 47 mg (0.07 mmol, 72% yield) of a white solid.
[0512] R.sub.f(ethyl acetate/methanol, 7:3): 0.22.
[0513] .sup.1H-NMR (200 MHz, DMSO-d.sub.6, .delta./ppm): 12.4 (2H,
broad), 7.84 (2H, d), 7.70 (1H, d), 7.53-7.29 (6H, m), 7.03 (2H,
d), 4.82 (2H, s), 3.61 (2H, s), 2.71-2.38 (6H, m, partially
obscured by DMSO), 2.35 (3H, s), 2.18 (3H, s), 2.08 (2H, t)),
1.48-1.28 (4H, m).
[0514] MS (ESI): 639.9 (M+H.sup.+).
[0515] The following compounds were prepared in an analogous
manner:
5 Ex. Formula Analytical data 4 (from 1 and 4-trifluoro-
methylphenyl- boronic acid and then analogously to Ex. 2 and 3) 69
.sup.1H-NMR: .delta.[ppm] (DMSO- d.sub.6): 12.31(1H, broad), 9.99
(1H, broad), 8.08-7.91 (2H, m), 7.89-7.72(6H, m), 7.67 (2H, d),
7.08(2H, d), 4.89 (2H, s), 3.45(2H, s), 3.22-2.88(4H, m), 2.60-2.00
(10H, m, including 2.39 (3H, s), 2.27(3H, s), 2.08 (2H, t)), #
1.76-1.49(2H, m), 1.48-1.29(2H, m). (200 MHz) 5 (from 1 and
4-methoxy- phenylboronic acid and then analogously to Ex. 2 and 3)
70 .sup.1H-NMR: .delta.[ppm] (DMSO- d.sub.6): 12.4(2H, broad), 7.53
(6H, dd), 6.98(6H, d), 4.81 (2H, s), 3.79(3H, s), 3.60 (2H, s),
2.71-2.02(16H, m, partially obscured by DMSO, including 2.37(3H,
s), 2.21(3H, s), 2.09(2H, t)), 1.48-1.28(4H, m). (200 MHz) 6 (from
1 and 4- chlorophenyl- boronic acid and then analogously to Ex. 2
and 3) 71 .sup.1H-NMR: .delta.[ppm] (DMSO- d.sub.6): 12.2(2H,
broad), 7.82 (2H, d), 7.61(4H, t), 7.49 (2H, d), 7.35(2H, d), 7.03
(2H, d), 4.71(2H, s), 3.60 (2H, s), 2.71-2.37(6H, m, partially
obscured by DMSO), 2.35(3H, s), 2.19 (3H, s), 2.08(2H, t)),
1.46-1.31(4H, m). (200 MHz) 7 (from 1 and 4-fluoro- phenylboronic
acid and then analogously to Ex. 2 and 3) 72 .sup.1H-NMR:
.delta.[ppm] (DMSO- d.sub.6): 12.5(1H, broad), 10.05 (1H, broad),
8.08-7.77(2H, m), 7.71-7.51(6H, m), 7.38 (2H, t), 7.02(2H, d), 4.86
(2H, s), 4.48(2H, s), 3.20-2.69(4H, m), 2.60-2.02 (10H, m,
partially obscured by DMSO, including 2.36 (3H, s), # 2.27(3H, s),
2.09 (2H, t)), 1.48-1.29(4H, m). (200 MHz) 8 (from 1 and 4-carboxy-
phenylboronic acid and then analogously to Ex. 2 and 3) 73 MS:
616.1 (M + H.sup.+) 9 (from land 4- t-butylphenyl- boronic acid and
then analogously to Ex. 2 and 3) 74 MS: 628.1 (M + H.sup.+) 10
(from 1 and 3-methoxy- phenylboronic acid and then analogously to
Ex. 2 and 3) 75 .sup.1H-NMR: .delta.[ppm] (DMSO- d.sub.6): 12.2(1H,
broad), 10.05 (1H, broad), 8.09-7.78(2H, m), 7.59(2H, d), 7.41-7.29
(2H, m), 7.22-7.09(2H, m), 7.01(2H, d), 6.91(2H, d), 4.87(2H, s),
4.46(2H, s), 3.82(3H, s), 3.21-2.89(4H, m), 2.59-2.02(10H, m,
partially obscured # by DMSO, mcludmg 2.38(3H, s), 2.28(3H, s),
2.09(2H, t)), 1.48-1.28(4H, m). (200 MHz)
Example 11
[0516] Methyl
4-{[(2-{3-[(4'-methoxy-1,1'-biphenyl-4-yl)methoxy]-5,6,7,8-t-
etrahydro-2-naphthyl}-ethyl)(5-methoxy-5-oxopentyl)amino]methyl}benzoate
76
[0517] 56.5 mg (0.35 mmol) of 4-methoxyphenylboronic acid and 0.48
ml of a 2-molar solution of sodium carbonate in water are added to
a solution of 200 mg (0.32 mmol) of methyl
4-{[(2-{3-[(4-bromobenzyl)oxy]-5,6,7,8-tetra-
hydro-2-naphthyl}ethyl)(5-methoxy-5-oxopentyl)amino]methyl}benzoate
and 11.1 mg (3 mol %) of tetrakis-(triphenylphosphine)palladium-(0)
in 10 ml of dimethoxyethane (DME). Under argon, the mixture is
heated at reflux for three hours. pH5 phosphate buffer and ether
are then added. The phases are separated. The aqueous phase is
extracted with ether. The combined ether phases are dried over
sodium sulfate, filtered and concentrated using a rotary
evaporator. The product is isolated by silica gel flash
chromatography using the mobile phase cyclohexane/ethyl acetate
8:1. This gives 160 mg (77% yield) of a pale yellow oil.
[0518] R.sub.f(cyclohexane/ethyl acetate 5:1): 0.10.
[0519] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 1.58-1.72
(m, 8H), 2.16 (t, 2H), 2.41 (t, 2H), 2.55-2.59 (m, 4H), 2.63-2.69
(m, 4H), 3.52 (s, 3H), 3.60 (s, 2H), 3.81 (s, 6H), 5.00 (s, 2H),
6.69 (s, 1H), 6.77 (s, 1H), 7.02 (d, 2H), 7.37 (d, 2H), 7.41 (d,
2H), 7.58 (2d, 4H), 7.83 (d, 2H).
[0520] MS (ESI): 650 (M+H.sup.+).
Example 12
[0521] Methyl
4-({(5-methoxy-5-oxopentyl)[2-(3-{[4'-(trifluoromethyl)-1,1'-
-biphenyl-4-yl]-methoxy}-5,6,7,8-tetrahydro-2-naphthyl)ethyl]amino}methyl)-
benzoate 77
[0522] In a manner analogous to that described for Synthesis
Example 11, 200 mg (0.32 mmol) of methyl
4-{[(2-{3-[(4-bromobenzyl)oxy]-5,6,7,8-tetra-
hydro-2-naphthyl}ethyl)(5-methoxy-5-oxopentyl)amino]methyl}benzoate,
11.1 mg (3 mol %) of tetrakis(triphenylphosphine)palladium-(0),
70.6 mg (0.35 mmol) of 4-(trifluoromethyl)phenylboronic acid and
and 0.48 ml of a 2-molar solution of sodium carbonate in 10 ml of
DME give, after silica gel flash chromatography (cyclohexane/ethyl
acetate 10:1), 170 mg (67% yield) of a light-yellow oil.
[0523] R.sub.f(cyclohexane/ethyl acetate 5:1): 0.16.
[0524] .sup.1H-NMR (200 MHz, DMSO-d.sub.6, .delta./ppm): 1.61-1.72
(m, 8H), 2.13 (t, 2H), 2.40 (t, 2H), 2.50-2.70 (m, 4H, partially
obscured by DMSO signal), 3.50 (s, 3H), 3.60 (s, 2H), 3.79 (s, 3H),
5.03 (s, 2H), 6.69 (s, 1H), 6.78 (s, 1H), 7.36 (d, 2H), 7.49 (d,
2H), 7.71 (d, 2H), 7.79-7.86 (m, 6H).
[0525] MS (ESI): 688 (M+H.sup.+).
Example 13
[0526]
4-{[(4-Carboxybutyl)(2-{3-[(4'-methoxy-1,1'-biphenyl-4-yl)methoxy]--
5,6,7,8-tetrahydro-2-naphthyl}ethyl)amino]methyl]benzoic Acid
78
[0527] 8 ml of a 2-molar aqueous sodium hydroxide solution are
added to a solution of 140 mg (0.22 mmol) of methyl
4-{[(2-{3-[(4'-methoxy-1,1'-biph-
enyl-4-yl)-methoxy]-5,6,7,8-tetrahydro-2-naphthyl}
ethyl)(5-methoxy-5-oxop- entyl)amino]-methyl}benzoate in 4 ml of
tetrahydrofuran and 4 ml of methanol, and the mixture is heated at
reflux. After the reaction has ended, the mixture is diluted with a
little water and extracted with ether. The aqueous phase is
adjusted to pH 5 using 2-molar hydrochloric acid and extracted with
ethyl acetate. The ethyl acetate extract is evaporated to dryness.
The residue is boiled with ether and, after cooling, filtered. This
gives 85 mg (63% yield) of a light-beige solid.
[0528] Melting point: >240.degree. C.
[0529] R.sub.f(ethyl acetate): <0.05.
[0530] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 1.39-1.47
(m, 4H), 1.67-1.70 (m, 4H), 2.11 (t, 2H), 2.44 (m, 2H), 2.57 (m,
4H), 2.65 (m, 4H), 3.62 (s broad, 2H), 3.80 (s, 3H), 5.00 (s, 2H),
6.69 (s, 1H), 6.78 (s, 1H), 7.01 (d, 2H), 7.37 (d, 2H), 7.41 (d,
2H), 7.58 (2 d, 4H), 7.83 (d, 2H), 12.38 (broad, 2H).
[0531] MS (ESI): 622 (M+H.sup.+).
Example 14
[0532]
4-({(4-Carboxybutyl)[2-(3-{[4'-trifluoromethyl)-1,1'-biphenyl-4-yl]-
methoxy}-5,6,7,8-tetrahydro-2-naphthyl)ethyl]amino}methyl)benzoic
Acid 79
[0533] Analogously to the procedure described in Synthesis Example
13, 140 mg of methyl
4-({(5-methoxy-5-oxopentyl)[2-(3-{[4'-(trifluoromethyl)-1,1'-
-biphenyl-4-yl]-methoxy}-5,6,7,8-tetrahydro-2-naphthyl)ethyl]amino}methyl)-
benzoate give 79 mg (56% yield) of a white solid.
[0534] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta./ppm): 1.42 (m,
4H), 1.68 (m, 4H), 2.10 (dd, 2H), 2.42 (dd, 2H), 2.59 (m, 4H) 2.68
(m, 4H), 3.61 (s, 2H), 5.02 (s, 2H), 6.69 (s, 1H), 6.78 (s, 1H),
7.33 (d, 2H), 7.49 (d, 2H), 7.71 (d, 2H), 7.78-7.88 (m, 6H), 12.27
(broad, 2H).
[0535] MS (ESI): 660 (M+H.sup.+).
Example 15
[0536] Methyl
4-({(5-ethoxy-5-oxopentyl)[2-(6-methyl-3-{[4'-(trifluorometh-
yl)-1,1'-biphenyl-4-yl]methoxy}-2-pyridinyl)ethyl]amino}methyl)benzoate
80
[0537] 134 mg (0.22 mmol) of methyl
4-{[(2-{3-[(4-bromobenzyl)oxy]-6-methy-
l-2-pyridinyl}ethyl)(5-ethoxy-5-oxopentyl)amino]methyl}benzoate are
dissolved in 2 ml of 1,2-dimethoxyethane, and 51 mg (0.27 mmol) of
4-trifluoromethylphenylboronic acid, 8 mg (0.01 mmol) of
bis(triphenylphoshine)palladium(II) chloride and 250 .mu.l of a
2-molar solution of Na.sub.2CO.sub.3 in water are added under
argon. The reaction mixture is then stirred under reflux for 12 h.
The mixture is then cooled and filtered through 3 g of Extrelute,
the filter cake is washed with dichloromethane and the filtrate is
concentrated using a rotary evaporator. The resulting product is
purified by column chromatography (dichloromethane/methanol,
100:5). This gives 135 mg (0.20 mmol, 91% yield) of a colorless
oil.
[0538] R.sub.f(cyclohexane/ethyl acetate 2:1): 0.28.
[0539] .sup.1H-NMR (200 MHz, DMSO-d.sub.6, .delta./ppm): 7.92-7.42
(10H, m), 7.39-7.23 (3H, m), 7.01 (1H, d), 5.11 (2H, s), 3.98 (2H,
q), 3.59 (2 h, s), 3.32 (3H, s), 2.99-2.81 (2H, m), 2.79-2.62 (2H,
m), 2.39 (2H, t), 2.33 (3H, s), 2.09 (2H, t), 1.48-1.21 (4H, m),
1.1 (3H, t).
[0540] MS (ESI): 663 (M+H.sup.+).
Example 16
[0541]
4-({(4-Carboxybutyl)[2-(6-methyl-3-{[4'-trifluoromethyl)-1,1'-biphe-
nyl-4-yl]-methoxy}-2-pyridinyl)ethyl]amino}methyl)benzoic Acid
81
[0542] 51 .mu.l of a 45% strength solution of NaOH in water are
added to a solution of 125 mg (0.19 mmol) of methyl
4-({(5-ethoxy-5-oxopentyl)[2-(6--
methyl-3-{[4'-(trifluoromethyl)-1,1'-biphenyl-4-yl]methoxy}-2-pyridinyl)et-
hyl]amino}methyl)-benzoate in 1.0 ml of dioxane and 1 ml of water,
and the mixture is stirred at 60.degree. C. for 4 hours. After
cooling, the dioxane is removed under reduced pressure and the
aqueous phase is adjusted to pH 4-5 using 1-molar hydrochloric
acid. This causes the precipitation of the product, which is
filtered off, washed with water and dried. This gives 83 mg (0.13
mmol, 89% yield) of a white solid.
[0543] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta./ppm): 12.4 (2H,
broad), 7.93-7.78 (4H, m), 7.72 (2H, d), 7.68-7.46 (6H, m), 7.33
(1H, d), 7.03 (1H, d), 5.13 (2H, s), 3.75-3.52 (2H, s, broad),
3.04-2.88 (2H, m), 2.87-2.66 (2H, m), 2.57-2.49 (2H, m, partially
obscured by DMSO), 2.32 (3H, s), 2.11 (2H, t), 1.51-1.29 (4H,
m).
[0544] MS (ESI): 621 (M+H.sup.+).
* * * * *